levoleucovorin and Pancreatic-Neoplasms

Limited data exist on the management of patients with locally advanced (aPC) or metastatic pancreatic (mPC) cancer who achieve stable disease/response after first-line chemotherapy. In this setting, maintenance therapy is important to minimize toxicity while preserving survival benefits. The aim of this study is to conduct a narrative review of the evidence available on the topic and present the results of a retrospective case series of patients with aPC or mPC who received maintenance therapy following a good response to induction chemotherapy. Olaparib is the only drug approved for maintenance therapy in patients with metastatic pancreatic cancer and germline Breast Cancer gene mutation. Data from several trials, including the phase II PANOPTIMOX-PRODIGE35 trial, showed clinical benefit from the use of 5-fluorouracil (5-FU) as maintenance. We also conducted a case series including 12 patients who received FOLFIRINOX as induction chemotherapy for aPC or mPC followed by fluorouracil (5-FU) or FOLFIRI maintenance therapy. Median progression-free survival is 22.13 months which is higher than that reported in the literature, which ranges between 5 and 10.6 months. Although further conclusions cannot be drawn because of the small sample size, the results are promising and encourage further exploration of this topic in larger prospective trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Maintenance Chemotherapy; Pancreatic Neoplasms; Prospective Studies; Retrospective Studies

The aim of this review was to characterize the second- and later-line (≥2L) treatment landscape for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).. This systematic literature review (PROSPERO: CRD42021279753) involved searches of MEDLINE® and Embase to identify results from prospective studies of ≥2L treatment options for metastatic pancreatic cancer published from 2016 to 2021. Publications were screened according to predetermined eligibility criteria; population-level data were extracted using standardized data fields. Publication quality was assessed according to Grading of Recommendations Assessment, Development and Evaluation (GRADE). The data were analyzed descriptively, grouped by drug class.. Sixty publications were identified, including 23 relating to comparative trials. GRADE assessment found that, of these 23 trials, 83% reported high or moderate-quality evidence. Of the publications relating to comparative trials, nine (three trials) reported favorable results: the pivotal phase 3 NAPOLI-1 trial for liposomal irinotecan; a phase 3 trial of non-liposomal irinotecan within the FOLFIRINOX regimen; and a phase 2 trial of eryaspase plus chemotherapy.. The level of unmet need for ≥2L treatment options for mPDAC remains high. Irinotecan-based regimens currently offer the greatest promise. Investigations into paradigm-changing agents and combination approaches continue.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Fluorouracil; Humans; Irinotecan; Leucovorin; Pancreatic Neoplasms; Prospective Studies

Over the past decade, neoadjuvant therapy has become the standard of care for patients with borderline resectable and locally advanced pancreatic cancer. The surgical community remains divided regarding the value of neoadjuvant therapy for patients who present with clearly resectable disease. Thus far, randomized controlled trials comparing neoadjuvant therapy with conventional upfront surgical strategies for patients with clearly resectable pancreatic cancer have been plagued by poor accrual, and are often underpowered. Nonetheless, meta-analyses of the results of these trials suggest that neoadjuvant therapy can be offered as an acceptable standard of care for patients with clearly resectable pancreatic cancer. Previous trials used neoadjuvant gemcitabine, but more recent studies have demonstrated superior survival for patients who were able to tolerate neoadjuvant FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan hydrochloride, and oxaliplatin). The increased utilization of FOLFIRINOX may be shifting the treatment paradigm in favor of neoadjuvant therapy among patients with clearly resectable disease. Randomized controlled trials assessing the value of neoadjuvant FOLFIRINOX in clearly resectable pancreatic cancer, which are expected to provide more conclusive recommendations, are still ongoing. This review outlines the rationale, considerations, and current level of evidence for the use of neoadjuvant therapy in patients with clearly resectable pancreatic cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Gemcitabine; Humans; Leucovorin; Neoadjuvant Therapy; Pancreatic Neoplasms

Pancreatic cancer often presents as locally advanced (LAPC) or borderline resectable (BRPC). Neoadjuvant systemic therapy is recommended as initial treatment. It is currently unclear what chemotherapy should be preferred for patients with BRPC or LAPC.. We performed a systematic review and multi-institutional meta-analysis of patient-level data regarding the use of initial systemic therapy for BRPC and LAPC. Outcomes were reported separately for tumor entity and by chemotherapy regimen including FOLFIRINOX (FIO) or gemcitabine-based.. A total of 23 studies comprising 2930 patients were analyzed for overall survival (OS) calculated from the beginning of systemic treatment. OS for patients with BRPC was 22.0 months with FIO, 16.9 months with gemcitabine/nab-paclitaxel (Gem/nab), 21.6 months with gemcitabine/cisplatin or oxaliplatin or docetaxel or capecitabine (GemX), and 10 months with gemcitabine monotherapy (Gem-mono) (p < 0.0001). In patients with LAPC, OS also was higher with FIO (17.1 months) compared with Gem/nab (12.5 months), GemX (12.3 months), and Gem-mono (9.4 months; p < 0.0001). This difference was driven by the patients who did not undergo surgery, where FIO was superior to other regimens. The resection rates for patients with BRPC were 0.55 for gemcitabine-based chemotherapy and 0.53 with FIO. In patients with LAPC, resection rates were 0.19 with Gemcitabine and 0.28 with FIO. In resected patients, OS for patients with BRPC was 32.9 months with FIO and not different compared to Gem/nab, (28.6 months, p = 0.285), GemX (38.8 months, p = 0.1), or Gem-mono (23.1 months, p = 0.083). A similar trend was observed in resected patients converted from LAPC.. In patients with BRPC or LAPC, primary treatment with FOLFIRINOX compared with Gemcitabine-based chemotherapy appears to provide a survival benefit for patients that are ultimately unresectable. For patients that undergo surgical resection, outcomes are similar between GEM+ and FOLFIRINOX when delivered in the neoadjuvant setting.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Gemcitabine; Humans; Leucovorin; Multicenter Studies as Topic; Neoadjuvant Therapy; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

In metastatic pancreatic ductal adenocarcinoma (mPDAC), first line treatment options usually include combination regimens of folinic acid, 5-fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX or mFOLFIRINOX) or gemcitabine based regimens such as in combination with albumin-bound paclitaxel (GEM + nab-PTX). After progression, multiple regimens including NALIRI + 5-FU and folinic acid, FOLFIRINOX, 5-FU-based oxaliplatin doublets (OFF, FOLFOX, or XELOX), or 5-FU-based monotherapy (FL, capecitabine, or S-1) are considered appropriate by major guidelines. This network meta-analysis (NMA) aimed to compare the efficacy of different treatment strategies tested as second-line regimens for patients with mPDAC after first-line gemcitabine-based systemic treatment.. Randomized phase II and III clinical trials (RCTs) were included if they were published or presented in English. Trials of interest compared two active systemic treatments as second-line regimens until disease progression or unacceptable toxicity. We performed a Bayesian NMA with published hazard ratios (HRs) and 95%confidence intervals (CIs) to evaluate the comparative effectiveness of different second-line therapies for mPDAC. The main outcomes of interest were overall survival (OS) and progression free survival (PFS), secondary endpoints were grade 3-4 toxicities. We calculated the relative ranking of agents for each outcome as their surface under the cumulative ranking (SUCRA). A higher SUCRA score meant a higher ranking for efficacy outcomes.. A NMA of 9 treatments was performed for OS (n = 2521 patients enrolled). Compared with 5-FU + folinic acid both irinotecan or NALIRI + fluoropyrimidines had a trend to better OS (HR = 0.76, 95%CI 0.21-2.75 and HR = 0.74, 95%CI 0.31-1.85). Fluoropyrimidines + folinic acid + oxaliplatin were no better than the combination without oxaliplatin. The analysis of treatment ranking showed that the combination of NALIRI + 5-FU + folinic acid was most likely to yield the highest OS results (SUCRA = 0.7). Furthermore, the NMA results indicated that with the highest SUCRA score (SUCRA = 0.91), NALIRI + 5-FU + folinic acid may be the optimal choice for improved PFS amongst all regimens studied.. According to the NMA results, NALIRI + 5-FU, and folinic acid may represent the best second-line treatment for improved survival outcomes in mPDAC. Further evidence from prospective trials is needed to determine the best treatment option for this group of patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Clinical Trials, Phase II as Topic; Fluorouracil; Humans; Irinotecan; Leucovorin; Network Meta-Analysis; Oxaliplatin; Pancreatic Neoplasms; Prospective Studies; Randomized Controlled Trials as Topic

For patients with localized pancreatic cancer with minimal vascular involvement, optimal survivability requires a multidisciplinary approach of surgical resection and systemic chemotherapy. FOLFIRINOX is a combination chemotherapy regimen that offers promising results in the perioperative and metastatic settings; however, it can cause significant adverse effects. Such toxicity can negatively impact some patients, resulting in chemotherapy discontinuation or surgical unsuitability. In an effort to reduce toxicities and optimize outcomes, this investigation explores the safety and feasibility of substituting liposomal irinotecan (nal-IRI) for nonliposomal irinotecan to improve tumor drug delivery and potentially reduce toxicity. This regimen, NALIRIFOX, has the potential to be both safer and more effective when administered in the preoperative setting.. For patients with pancreatic cancer with little to no cancer near the blood vessels, the best life expectancy usually requires surgery and chemotherapy. FOLFIRINOX is a chemotherapy medicine that offers promising results for both patients getting surgery and for patients with widespread disease. However, it can cause harmful side effects. The side effects can be so bad that the chemotherapy has to be stopped or that surgery is no longer possible. In order to reduce the harmful side effects and improve outcomes, this investigation looks into the safety and practicality of using a different version of one of the medicines. The different version hopes to improve drug delivery and reduce harmful side effects. This regimen, NALIRIFOX, can be safer and more effective in patients awaiting surgery.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Radiation-Sensitizing Agents

Pancreatic ductal adenocarcinoma (PDAC) is a devastating tumor type where a very high proportion of people diagnosed end up dying from cancer. Surgical resection is an option for only about 20% of patients, where the 5-year survival increase ranges from 10 to 25%. In addition to surgical resection, there are adjuvant chemotherapy schemes, such as FOLFIRINOX (a mix of Irinotecan, oxaliplatin, 5-Fluorouraci and leucovorin) or gemcitabine-based treatment. These last two drugs have been compared in the NAPOLI-3 clinical trial, and the NALIRIFOX arm was found to have a higher overall survival (OS) (11.1 months vs. 9.2 months). Despite these exciting improvements, PDAC still has no effective treatment. An interesting approach would be to drive ferroptosis in PDAC cells. A non-apoptotic reactive oxygen species (ROS)-dependent cell death, ferroptosis was first described by Dixon et al. in 2012. ROS are constantly produced in the tumor cell due to high cell metabolism, which is even higher when exposed to chemotherapy. Tumor cells have detoxifying mechanisms, such as Mn-SOD or the GSH-GPX system. However, when a threshold of ROS is exceeded in the tumor cell, the cell's antioxidant systems are overwhelmed, resulting in lipid peroxidation and, ultimately, ferroptosis. In this review, we point out ferroptosis as an approach to consider in PDAC and propose that altering the cellular ROS balance by combining oxidizing agents or with inhibitors of the main cellular detoxifiers triggers ferroptosis in PDAC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Death; Fluorouracil; Humans; Leucovorin; Pancreatic Neoplasms; Reactive Oxygen Species

Various first-line chemotherapy treatment regimens for patients with metastatic pancreatic cancer have been approved in Japan, including gemcitabine (GEM); fluorouracil, leucovorin, irinotecan, and oxaliplatin combination (FOLFIRINOX); GEM plus albumin-bound paclitaxel (GEM+NPTX), and S-1 (tegafur + gimeracil + oteracil). However, direct comparisons of these chemotherapy regimens are limited.. To assess the short-term and long-term outcomes associated with first-line chemotherapy regimens for metastatic pancreatic cancer compared with chemotherapy regimens recommended in Japanese guidelines.. In this systematic review and network meta-analysis, the bibliographic databases PubMed, Cochrane Library, and Web of Science, as well as medical journals published between January 1, 2002, and December 31, 2018, were searched for clinical trials comparing chemotherapy regimens.. Randomized 2-arm clinical trials evaluating first-line chemotherapy for advanced or metastatic pancreatic cancer were included.. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions was followed for data abstractions. Data were pooled using a random-effects model. The SIGN 50 Quality Assessment Instrument was used to assess the risk of bias and overall study quality of the selected trials.. The primary end point was overall survival (OS), and the secondary end point was progression-free survival (PFS) compared with GEM for first-line chemotherapy for metastatic pancreatic cancer. The Kaplan-Meier curve of GEM from the literature and the estimated hazard ratios (HRs) were used to model the long-term associations to calculate the area under the curve (AUC) (person-months) for OS and PFS of each chemotherapy. Sensitivity analyses with multiple functional models were conducted to confirm the long-term estimations.. A total of 22 regimens (25 studies) for OS and a total of 18 regimens (21 studies) for PFS were identified from literature. The total number of participants was 10 186, with 5856 male (57.5%) and 4330 female (42.5%). The FOLFIRINOX and GEM+NPTX regimens were associated with reduction in the risk of death, with an HR of 0.57 (95% CI, 0.41-0.79) and 0.72 (95% CI, 0.55-0.95) compared with GEM, respectively. The curve estimation also showed that FOLFIRINOX had the largest AUC for survival at 15.49 person-months (range, 13.84-15.51 person-months), followed by GEM+NPTX with 12.36 person-months (range, 10.98-12.59 person-months), GEM+ERLO with 10.84 person-months (range, 9.66-11.23 person-months), S-1 with 8.44 person-months (range, 8.26-9.74 person-months), and GEM with 8.10 person-months (range, 7.93-9.38 person-months).. The results of this network meta-analysis support the relative short-term and long-term outcomes associated with first-line chemotherapy for metastatic pancreatic cancer used clinically in Japan.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Comparative Effectiveness Research; Deoxycytidine; Drug Combinations; Fluorouracil; Gemcitabine; Humans; Irinotecan; Japan; Kaplan-Meier Estimate; Leucovorin; Neoplasm Metastasis; Network Meta-Analysis; Oxaliplatin; Oxonic Acid; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival; Proportional Hazards Models; Pyridines; Survival Rate; Tegafur; Treatment Outcome

In pancreatic ductal adenocarcinoma cytoreduction can be curative, or palliative. FOLFIRINOX and GEM-NAB are the two FDA/EMA approved regimens for advanced disease. We aim to identified the most cytoreductive regimen on the basis of current literature.. PUBMED was searched for studies published to April 2021. Abstracts of annual meetings ASCO 2009-2021, and ESMO 2015-2020, were searched as well. Phase II, phase III clinical trials, prospective, observational and retrospective studies, reporting overall response rate (complete + partial response) (ORR) in patients treated either with FOLFIRINOX or GEM-NAB were included. The meta-analysis was performed using a randomized-effects model. Main outcome was cytoreduction with each regimen reported as ORR according to RECIST.. Among 2183 studies identified, 40 fulfilled the selection criteria (22 FOLFIRINOX, 18 GEM-NAB), totaling 2883 patients. Pooling of data found similar ORR between regimens: FOLFIRINOX [30% (95 CI 26-34%)] and GEM-NAB [30% (95 CI 26-35%),] P = 0.928. Disease control rate (DCR) was significantly higher with FOLFIRINOX [85% (95CI 82-88%)] compared to GEM-NAB [80% (95CI 77-84%)], P = 0.012. A significantly higher ORR irrespective of the regimen was observed in stage IV [36% (95CI 32-40%)] versus stage II-III [25% (95CI 20-31%)], P = 0.002.. Our meta-analysis did not find significant superiority of one regimen over the other in terms of RECIST-based cytoreduction both in palliative and curative setting of patients with pancreatic adenocarcinoma. The significantly better DCR with FOLFIRINOX compared with GEM-NAB deserves further investigation including waterfall plot and correlations with potential predictive factors.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Cytoreduction Surgical Procedures; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Paclitaxel; Pancreatic Neoplasms; Prospective Studies; Retrospective Studies

Irinotecan is a topoisomerase inhibitor, widely used in treatment of malignancies including pancreatic ductal adenocarcinoma (PDAC) as part of the FOLFIRINOX regimen prescribed as a first-line treatment in several countries. However, irinotecan has not been successfully introduced as a second-line treatment for pancreatic cancer and few randomized clinical studies have evaluated its added value. Efficacy of liposomal irinotecan (nal-IRI) combined with 5-fluorouracil and leucovorin (5-FU/LV) was reported in the phase III NAPOLI-1 trial in metastatic PDAC following failure of gemcitabine-based therapy. Several features of nal-IRI pharmacokinetics (PK) could result in better outcomes versus nonliposomal irinotecan. Irinotecan is a prodrug that is converted to active SN-38 by carboxylesterase enzymes and inactivated by cytochrome P450 3A4/3A5. SN-38 is inactivated by UGT1A1 enzymes. Individual variations in their expression and activity could influence enhanced localized irinotecan activity and toxicity. Liposomal irinotecan exploits the enhanced permeability and retention effect in cancer, accumulating in tumor tissues. Liposomal irinotecan also has a longer half-life and higher area under the concentration-time curve (0-∞) than nonliposomal irinotecan, as the liposomal formulation protects cargo from premature metabolism in the plasma. This results in irinotecan activation in tumor tissue, leading to enhanced cytotoxicity. Importantly, despite the longer exposure, overall toxicity for nal-IRI is no worse than nonliposomal irinotecan. Liposomal irinotecan exemplifies how liposomal encapsulation of a chemotherapeutic agent can alter its PK properties, improving clinical outcomes for patients. Liposomal irinotecan is currently under investigation in other malignancies including biliary tract cancer (amongst other gastrointestinal cancers), brain tumors, and small-cell lung cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Pancreatic Neoplasms; Randomized Controlled Trials as Topic

To undertake a meta-analysis of the treatment effects of different second-line chemotherapy regimens compared with FOLFIRINOX (FOL [folinic acid], F [fluorouracil], IRIN [irinotecan], OX [oxaliplatin]) after failure of gemcitabine-based first-line therapy in patients with pancreatic cancer.. This meta-analysis searched electronic databases, including Embase®, Medline, PubMed® and the Cochrane library, for eligible studies that reported the use of FOLFIRINOX and other drug regimens as second-line chemotherapy after failure of gemcitabine-based chemotherapy. Pooled analyses for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR) and grade 3/4 treatment-emergent adverse events (TRAEs) were undertaken.. The analysis included six studies with a total of 858 patients. Compared with the three other second-line regimens, FOLFIRINOX had a significantly longer PFS (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.52, 0.89) and OS (HR 0.71, 95% CI 0.59, 0.86); and a significantly better ORR (HR 0.43, 95% CI 0.23, 0.80) and DCR (HR 0.71, 95% CI 0.58, 0.88). However, grade 3/4 adverse events were more frequently reported in patients administered FOLFIRINOX compared with the other three regimens.. FOLFIRINOX is recommended as a second-line chemotherapy regimen for patients with pancreatic cancer that have failed on gemcitabine-based first-line therapy.Research Registry number: reviewregistry1300.

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms

Multi-agent regimens such as Folfirinox and gemcitabine plus nab-paclitaxel have shown significant improvements compared with single-agent gemcitabine as neoadjuvant chemotherapy for patients with borderline resectable or locally advanced pancreatic cancer. However, the efficacy and safety of Folfirinox and GNP as NAC for BRPC and LAPC is still controversial.. The eligible studies including prospective, retrospective, and randomized controlled trial related to Folfirinox and GNP as NAC for patients with BRPC or LAPC up to March 2022 were searched and assessed. Pooled analysis for chemotherapy response rate, resection rate, R0 resection rate, progress free survival, overall survival, and grade 3/4 events of toxicity were performed in the study.. Eight studies were included in this meta-analysis. Compared with GNP, Folfirinox had higher resection rate (HR=0.82; 95% CI 0.59-1.14) and R0 resection rate (HR=0.77; 95% CI 0.60-0.97), better PFS (HR=0.78; 95% CI 0.55-1.12) and OS (HR=0.68; 95% CI 0.46-0.99), and without increasing severe toxicity rate (HR=0.95; 95% CI 0.71-1.28). There are no differences in rate of stable disease (HR=1.06; 95% CI 0.92-1.22) and partial/complete regression (HR=0.85; 95% CI 0.59-1.23) between two groups.. Higher resection and R0 resection rate and better PFS and OS results were obtained in Folfirinox group compared with GNP group for patients with BRPC and LAPC. There was no increased severe toxicity rate for Folfirinox compared with GNP.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Prospective Studies; Retrospective Studies

Pancreatic cancer is highly aggressive and lethal. Due to the lack of effective methods for detecting the disease at an early stage, pancreatic cancer is frequently diagnosed late. Gemcitabine has been the standard chemotherapy drug for patients with pancreatic cancer for over 20 years, but its anti-tumor effect is limited. Therefore, FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin) as well as combination therapies using gemcitabine and conventional agents, such as cisplatin and capecitabine, has also been administered; however, these have not resulted in complete remission. Therefore, there is a need to develop novel and effective therapies for pancreatic cancer. Recently, some studies have reported that combinations of gemcitabine and targeted drugs have had significant anti-tumor effects on pancreatic cancer cells. As gemcitabine induced DNA damage response, the proteins related to DNA damage response can be suitable additional targets for novel gemcitabine-based combination therapy. Furthermore, KRAS/ RAF/MEK/ERK signaling triggered by oncogenic mutated

Topics: Antineoplastic Combined Chemotherapy Protocols; Biological Products; Capecitabine; Cisplatin; Fluorouracil; Humans; Irinotecan; Leucovorin; Mitogen-Activated Protein Kinase Kinases; Oxaliplatin; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras)

Treatment outcomes between FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) and GNP (gemcitabine with albumin-bound paclitaxel) as first-line chemotherapy regimens for metastatic pancreatic cancer (PC) were assessed according to ethnic groups categorized as Western or Asian subgroups. PubMed, EMBASE, and Cochrane library were searched. Thirteen studies were eligible in this meta-analysis. Overall survival was not significantly different between FOLFIRINOX and GNP (HR 1.00, 95% CI 0.83-1.20, P = 0.990). However, the Western subgroup showed a higher survival benefit for FOLFIRINOX over GNP (HR 0.84, 95% CI 0.74-0.95, P = 0.006) whereas the Asian subgroup showed the survival benefit for GNP over FOLFIRINOX (HR 1.29, 95% CI 1.03-1.60, P = 0.030). Progression free survival was not significantly different between the two regimens in the Western subgroup (HR 1.01, 95% CI 0.84-1.20, P = 0.950) and the Asian subgroup (HR 1.13, 95% CI 0.97-1.33, P = 0.110). Occurrence of febrile neutropenia was significantly higher in FOLFIRINOX at both ethnic subgroups; however, that of peripheral neuropathy was significantly higher only in GNP of the Asian subgroup. Therefore, pharmacoethnicity might be a factor worth considering when deciding on a frontline chemotherapeutic regimen although the overall survival was not significantly different between FOLFIRINOX and GNP for metastatic PCs.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Ethnicity; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Treatment Outcome

FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; DNA Damage; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; MicroRNAs; Neoadjuvant Therapy; Outcome Assessment, Health Care; Oxaliplatin; Pancreatic Neoplasms

As the population of western countries is aging, the number of patients diagnosed with cancer is growing. Therefore older people, more susceptible to develop pancreatic malignancy, will likely represent the prototype of a pancreatic cancer patient in the near future. Diagnostic modalities utilised for younger patients are also applicable for older individuals. There is accumulative evidence that biological age is not an independent factor predicting poor outcome in elderly patients with resectable disease undergoing surgery, however increased postoperative morbidity and mortality within the elderly group has also been reported. Adjuvant chemotherapy should be offered in all patients with good performance status regardless of their age. Palliative measures for unresectable tumours including relief from biliary and duodenal obstruction as well as chemotherapy should be considered in non-frail patients with reasonable life expectancy. Palliative chemotherapy options are FOLFIRINOX or gemcitabine/nab-paclitaxel for patients with good performance status (0-1) and gemcitabine alone for patients with performance status 2-3. The cornerstone for improving the outcomes of the elderly age group is careful patient selection and perioperative optimization of those who have indication for surgery. Patients and their carers should be involved in the decision making process with emphasis on the expected functional recovery after the proposed treatment modality. The presence of geriatricians in the multidisciplinary team meetings is crucial in order to identify the optimal treatment pathway for elderly patients. Geriatric input regarding peri-habilitation pathways to improve surgical outcomes, to decrease mortality and to expedite patients' functional recovery is highly recommended.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Enhanced Recovery After Surgery; Fluorouracil; Gemcitabine; Geriatric Assessment; Humans; Irinotecan; Leucovorin; Oxaliplatin; Paclitaxel; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy

Currently, the combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is the standard therapy for metastatic pancreatic cancer. In recent years, FOLFIRINOX-based neoadjuvant therapy for locally advanced pancreatic cancer (LAPC) has been gaining an increasing amount of attention, owing to its ability to reduce disease stage and transform LAPC to borderline resectable or even resectable pancreatic cancer. Accordingly, we aimed to evaluate the efficacy of first-line FOLFIRINOX chemotherapy in patients with LAPC.We searched PubMed, Embase, and Cochrane Library from the time of establishment till January 1, 2020 and included studies focusing on LAPC patients who received FOLFIRINOX as first-line neoadjuvant treatment. The primary outcomes were: resection rate and radical (R0) resection rate while the secondary outcomes were: objective response rate, overall survival, progression-free survival, and rate of grade 3 to 4 adverse events. The meta package for R 3.6.2 was used for heterogeneity and publication bias testing.Twenty-one studies, including 653 patients with LAPC, were selected. After treatment with FOLFIRINOX, the resection rate was 26% (95% confidence interval [CI] = 20%-32%, I2 = 61%) and R0 resection rate was 88% (95% CI = 78%-95%, I2 = 62%). The response rate was 34% (95% CI = 25%-43%, I2 = 56%). The median overall survival and progression-free survival durations ranged from 10.0 to 32.7 months and 3.0 to 25.3 months, respectively. The observed grade 3 to 4 adverse events were neutropenia (20.0 per 100 patients, 95% CI = 14%-27%, I2 = 75%), febrile neutropenia (7.0 per 100 patients, 95% CI = 5%-9%, I2 = 42%), thrombocytopenia (6.0 per 100 patients, 95% CI = 5%-8%, I2 = 27%), nausea/vomiting (7.0 per 100 patients, 95% CI = 7%-12%, I2 = 76%), diarrhea (10.0 per 100 patients, 95% CI = 8%-12%, I2 = 38%), and fatigue (9.0 per 100 patients, 95% CI = 7%-11%, I2 = 43%).FOLFIRINOX-based neoadjuvant chemotherapy has the potential to improve the rates of resection, R0 resection, and median OS in LAPC. Our results require further validation in large, high-quality randomized controlled trials.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms

Ductal pancreatic carcinoma is expected to become one of the most common malignant diseases worldwide in the coming decades. However, the prognosis of the disease remains very poor and has improved only slightly over the last decade. The 5-year survival rate of all patients with ductal adenocarcinoma has been increased to approximately 10 percent. The reasons for the very poor prognosis are the advanced stage of the disease at diagnosis with metastases already present in many cases, the anatomical location of the pancreas and the tumor biology. Therapeutically, chemotherapy remains the basis of systemic therapy. Intensive combinations with FOLFIRINOX (oxaliplatin, irinotecan, leucovorin/5-FU) and nanoparticel albumin bound (nab)paclitaxel/gemcitabine lead to an improvement in overall survival in the palliative situation; used preoperatively, they can increase the rate of secondary resections. Targeted therapies and immune checkpoint inhibitors could not be established. In patients with a proven germline mutation in the BRCA gene, a therapy with the PARP inhibitor olaparib is in the approval process.This article provides an overview of differential diagnoses, meaningful diagnostics, therapeutic concepts to improve surgical treatment, possibilities of palliative chemotherapy and targeted therapy in the presence of a BRCA mutation.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms

Adjuvant chemotherapy is the standard of care for resected pancreatic ductal adenocarcinoma (PDAC) based on level 1 evidence, but some studies suggest that a neoadjuvant approach (which is standard for borderline resectable PDAC) may be preferable for upfront resectable PDAC. An in-depth review was conducted of all randomized clinical trials that investigated neoadjuvant and adjuvant treatment of patients with resectable or resected PDAC, focusing on trial design, characteristics of enrolled population, and long-term outcomes.. The existing resectable PDAC trials have good internal validity but variable applicability because of their restrictive eligibility criteria. In these trials, overall survival is the criterion standard end point, but disease-free survival is more feasible, proximate, and specific to the assigned intervention (at the cost of subjective outcome assessment) and thus an acceptable end point in certain contexts. The prolonged survival in the PRODIGE 24 trial highlights both the success of mFOLFIRINOX (modified fluorouracil, leucovorin, irinotecan, and oxaliplatin) and the importance of patient selection. Neoadjuvant and perioperative trials have shown promising preliminary results; however, the number of patients who are not subsequently eligible for surgery reflects the limitations of this approach. Head-to-head comparisons of neoadjuvant and adjuvant treatments are limited to date in Western countries. Precision oncology with genomic and somatic testing for actionable mutations has promising preliminary results and may refine the management of PDAC, although the implications for early-stage disease and neoadjuvant therapy are unknown.. This review found that adjuvant chemotherapy with mFOLFIRINOX is currently the standard of care in fit patients with resected PDAC; however, the role of neoadjuvant treatment is expanding. Precision oncology may help individualize the treatment regimen and sequence and improve outcomes. Enrollment of patients with resectable PDAC in clinical trials is strongly encouraged.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with a dismal prognosis. The lack of symptoms in the early phase of the disease makes early diagnosis challenging, and about 80-85% of the patients are diagnosed only after the disease is locally advanced or metastatic. The current front-line treatment landscape in local stages comprises surgical resection and adjuvant chemotherapy. In Switzerland, although both FOLFIRINOX and gemcitabine plus nab-paclitaxel regimens are feasible and comparable in the first-line setting, FOLFIRINOX is preferred in the treatment of fit (Eastern Cooperative Oncology Group [ECOG] performance status [PS]: 0-1), young (<65 years old) patients with few comorbidities and normal liver function, while gemcitabine plus nab-paclitaxel is used to treat less fit (ECOG PS: 1-2) and more vulnerable patients. In the second-line setting of advanced PDAC, there is currently only one approved regimen, based on the phase III NAPOLI-1 trial. Furthermore, the use of liposomal-irinotecan in the second line is supported by real-world data. Beyond the standard of care, various alternative treatment modalities are being explored in clinical studies. Immunotherapy has demonstrated only limited benefits until now, and only in cases of high microsatellite instability (MSI-H). However, data on the benefit of poly (ADP-ribose) polymerase (PARP) inhibition as maintenance therapy in patients with germline BRCA-mutated tumors might signal of an advance in targeted therapy. Currently, there is a lack of molecular and genetic biomarkers for optimal stratification of patients and in guiding treatment decisions. Thus, identification of predictive and prognostic biomarkers and evaluating novel treatment strategies are equally relevant for improving the prognosis of metastatic pancreatic cancer patients.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Clinical Trials, Phase III as Topic; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Liposomes; Neoplasm Metastasis; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Randomized Controlled Trials as Topic

The annual incidence of pancreatic cancer is nearly 50,000 patients. The 5-year overall survival is only 9%, and there remains a great need for better therapy. A subset of these patients presents with locally advanced disease. Multidisciplinary therapy has evolved to include some combination of systemic chemotherapy, locoregional radiation, and surgery in select patients with excellent biology. This review will address the thoughtful evidence-based and individualized approach to these patients.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Chemoradiotherapy; Deoxycytidine; Disease Management; Evidence-Based Medicine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Precision Medicine

Despite overall advances in cancer therapy, patients with pancreatic ductal adenocarcinoma continue to have a poor prognosis. While adjuvant therapy is still considered standard, there is mounting evidence that neoadjuvant therapy confers similar benefits in patients with locally advanced disease. The primary measures of response are radiographic, biochemical, margin status, and pathologic. Given overall low response rates and the need for new treatment strategies, standard metrics remain important to the investigation of new systemic agents.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms

Surgery remains the only curative intent treatment modality for localized pancreatic adenocarcinoma. Even in those who can undergo successful margin negative resection, the ability to deliver adjuvant chemotherapy is suboptimal for various reasons, resulting in poor outcomes. The delivery of "standard of care" intensive modern neoadjuvant therapies can be challenging in low to-middle-income countries (LMICs) with limited resource. This article reviews the constraints in delivering neoadjuvant therapies in LMICs and strategies to improve its implementation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Tertiary Care Centers

Treatment of localized pancreatic cancer has also evolved to prioritize preoperative (neoadjuvant) multimodality therapy over a surgery-first approach. Given the complexities of pancreatic cancer staging and the challenge of delivering multiple treatment modalities (chemotherapy, radiation therapy, and surgery), an experienced and highly integrated multidisciplinary team is necessary to achieve the best outcomes. In this review, we will discuss our institutional experience with neoadjuvant therapy, guiding principles for treatment, and outline the landscape for future investigations.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Randomized Controlled Trials as Topic

For patients with localized pancreatic cancer, neoadjuvant therapy (NT) is increasingly delivered before surgery to maximize the receipt of multimodality therapy and the odds of a margin-negative resection. Three decades of refining the use of NT have led to its acceptance as a valid treatment approach for pancreatic adenocarcinoma. In this review, we discuss the rationale for and recent global trends in the utilization of NT for patients with pancreatic cancer.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Clinical Trials, Phase II as Topic; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Randomized Controlled Trials as Topic

Acinar cell carcinoma of the pancreas (pACC) forms a rare subgroup of pancreatic tumors. We report on our institutional experience with systemic first- and further-line therapy in patients with metastatic pACC and embed our findings in a review of the literature.. Patients with stage IV pACC who started systemic treatment between 2008 and 2019 at our institution were identified via our institutional database. Clinical data were extracted from the patients' electronic data records. Survival times were calculated by the Kaplan-Meier method.. Six patients received a fluoropyrimidine- and oxaliplatin-containing first-line treatment, and 4 patients were started on gemcitabine-based protocols. Median progression-free survival was 4.8 months [95% confidence interval (CI), 3.3 to not available (n.a.)], and median overall survival was 15.3 months (95% CI, 10.1 to n.a.). Residual survival for second-line treatment was 2.1 months (95% CI, 1.3 to n.a.), although 1 patient experienced almost complete remission under targeted therapy.. The most encouraging and deep responses result from poly-chemotherapy with leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), which seems to be the appropriate choice in fit patients. Gemcitabine monotherapy seems without substantial activity in pACC. Whenever possible, patients with pACC should be screened for targetable mutations.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Acinar Cell; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Retrospective Studies

The added value of radiotherapy following neoadjuvant FOLFIRINOX chemotherapy in patients with resectable or borderline resectable pancreatic cancer ((B)RPC) is unclear. The objective of this meta-analysis was to compare outcomes of patients who received neoadjuvant FOLFIRINOX alone or combined with radiotherapy.. A systematic literature search was performed in Embase, Medline (ovidSP), Web of Science, Scopus, Cochrane, and Google Scholar. The primary endpoint was pooled median overall survival (OS). Secondary endpoints included resection rate, R0 resection rate, and other pathologic outcomes.. We included 512 patients with (B)RPC from 15 studies, of which 7 were prospective nonrandomized studies. In total, 351 patients (68.6%) were treated with FOLFIRINOX alone (8 studies) and 161 patients (31.4%) were treated with FOLFIRINOX and radiotherapy (7 studies). The pooled estimated median OS was 21.6 months (range 18.4-34.0 months) for FOLFIRINOX alone and 22.4 months (range 11.0-37.7 months) for FOLFIRINOX with radiotherapy. The pooled resection rate was similar (71.9% vs. 63.1%, p = 0.43) and the pooled R0 resection rate was higher for FOLFIRINOX with radiotherapy (88.0% vs. 97.6%, p = 0.045). Other pathological outcomes (ypN0, pathologic complete response, perineural invasion) were comparable.. In this meta-analysis, radiotherapy following neoadjuvant FOLFIRINOX was associated with an improved R0 resection rate as compared with neoadjuvant FOLFIRINOX alone, but a difference in survival could not be demonstrated. Randomized trials are needed to determine the added value of radiotherapy following neoadjuvant FOLFIRINOX in patients with (B)PRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Prospective Studies

The prognosis of pancreatic cancer (PC) is extremely poor, and most patients with metastatic PC still receive palliative care. Here, we report the efficacy and safety of FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, 5-fluorouracil) in the treatment of metastatic PC.. We searched PubMed, Web of Science, EBSCO, and Cochrane library databases for articles that described efficacy and safety of FOLFIRINOX in patients with metastatic PC, from January 1996 to July 2020. The primary outcomes targeted included overall survival (OS) and progression-free survival (PFS).. We found that FOLFIRINOX could directly improve OS rate of patients with metastatic PC (HR 0.76, 95% Cl 0.67-0.86, p<0.001) but had no benefit on PFS. Results from subgroup analyses showed that FOLFIRINOX had superior benefits than monochemotherapy (HR 0.59, 95% Cl 0.52-0.67, p<0.001), followed by FOLFIRINOX versus combination chemotherapy (HR 0.76, 95% Cl 0.61-0.95, p<0.001). The result of FOLFIRINOX versus nab-paclitaxel + gemcitabine had no benefit (HR 0.91, 95% Cl 0.82-1.02, p>0.05). The main adverse events (AEs) targeted hematological toxicity and the gastrointestinal system, and included febrile neutropenia, a reduction in white blood cells and appetite, as well as diarrhea.. These findings indicated that FOLFIRINOX has potential benefits for the prognosis of patients with metastatic PC. Furthermore, there is no difference between the regimen of FOLFIRINOX and nab-paclitaxel + gemcitabine in this study. The application of FOLFIRINOX should be according to the actual situation of the patients and the experience of the doctors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Prognosis

Modified FOLFIRINOX and gemcitabine plus nab-paclitaxel (GEM-NAB) have been recommended as first-line therapies for advanced pancreatic cancer (PC). Due to the lack of evidence to directly compare them, we conducted this network meta-analysis to indirectly compare the effectiveness and toxicity of modified FOLFIRINOX and GEM-NAB.. The eligible retrospective studies on treatments related to modified FOLFIRINOX and GEM-NAB up to 4 April 2020 were searched and assessed. We used the frequentist model to analyze the survival and toxicity data between different treatments. Pooled analysis for overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and events of toxicity were analyzed in this study.. Twenty-two studies were involved in this network meta-analysis. The comparisons on OS and PFS showed that modified FOLFIRINOX and GEM-NAB had similar treatment efficacy (OS: 1.13; 95% CI: 0.78-1.63; PFS: HR: 1.19; 95% CI: 0.85-1.67). GEM-NAB was more effective than modified FOLFIRINOX based on the result of ORR (RR: 1.43; 95% CI: 1.04-1.96). Moreover, our analysis showed a similar toxicity profile between modified FOLFIRINOX and GEM-NAB.. The current evidence showed that modified FOLFIRINOX and GEM-NAB were similar in survival and toxicity. Many factors should be considered for in the formulation of optimal treatment, and our meta-analysis could provide some guidance to treatment selection in the first-line setting for advanced PC.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Prognosis; Publication Bias; Treatment Outcome

The modalities of management of resectable pancreatic ductal adenocarcinoma (PDAC) have evolved in recent years with new practice guidelines on adjuvant chemotherapy and results of randomized phase III trials. The aim of this review is to describe the state of the art in this setting and to highlight future possible perspectives.. Resectable PDAC is the tumor without vascular contact or a limited venous contact without vein irregularity. Several pathologic and biologic robust prognostic factors such as an R0 resection defined by a margin at least 1 mm have been validated. In phase III trials, the doublet gemcitabine-capecitabine provided a statistically significant, albeit modest overall survival benefit, but failed to show an improvement in relapse-free survival. Similarly, gemcitabine plus nab-paclitaxel did not increase disease-free survival. Modified FOLFIRINOX led to improved disease-free survival, overall survival, and metastasis-free survival, with acceptable toxicity. In the future, prognostic and/or predictive biomarkers could lead the optimization of therapeutic strategies and neoadjuvant treatment could become a standard of care in PDAC.. After curative intent resection, modified FOLFIRINOX is the standard of care in adjuvant in fit patients with PDAC. Others regimens (monotherapy or gemcitabine-based) are an option in unfit patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Carcinoma, Pancreatic Ductal; Chemoradiotherapy, Adjuvant; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Randomized Controlled Trials as Topic

Topics: Adenocarcinoma; Antineoplastic Agents; DNA Topoisomerases, Type I; Fluorouracil; Humans; Irinotecan; Leucovorin; Pancreatic Neoplasms; Topoisomerase I Inhibitors

Late detection, compromised immune system, and chemotherapy resistance underlie the poor patient prognosis for pancreatic ductal adenocarcinoma (PDAC) patients, making it the 3

Topics: Adaptive Immunity; Animals; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cancer Vaccines; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Clinical Trials as Topic; Combined Modality Therapy; Disease Models, Animal; Disease-Free Survival; Fluorouracil; Humans; Immunity, Innate; Immunotherapy; Irinotecan; Leucovorin; Lymph Node Excision; Lymph Nodes; Mice; Mice, Transgenic; Neoadjuvant Therapy; Oxaliplatin; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Spleen; Splenectomy; T-Lymphocytes; Transplantation, Autologous; Tumor Escape; Tumor Microenvironment; United States

Pancreatic cancer has a poor prognosis and few choices of therapy. For patients with adequate performance status, FOLFIRINOX or gemcitabine plus nab-paclitaxel are preferred first-line treatment. 5-Fluorouracil (5-FU)-based therapy (e.g. FOLFIRI, OFF, or FOLFOX) are often used in patients who previously received gemcitabine-based regimens. A systematic review was conducted of the safety and efficacy of FOLFOX for metastatic pancreatic cancer following prior gemcitabine-based therapy. A Bayesian fixed-effect meta-analysis with adjustment of patient performance status (PS) was conducted to evaluate overall survival (OS) and compare outcomes with nanoliposomal irinotecan combination therapy.. PubMed.gov , FDA.gov , ClinicalTrials.gov , congress abstracts, Cochrane.org library, and EMBASE database searches were conducted to identify randomized controlled trials of advanced/metastatic disease, prior gemcitabine-based therapy, and second-line treatment with 5-FU and oxaliplatin. The database search dates were January 1, 1990-June 30, 2019. Endpoints were OS and severe treatment-related adverse events (TRAEs). Trial-level PS scores were standardized by converting Karnofsky grade scores to Eastern Cooperative Oncology Group (ECOG) Grade, and overall study-weighted PS was calculated based on weighted average of all patients.. Of 282 studies identified, 11 randomized controlled trials (N = 454) were included in the meta-analysis. Baseline weighted PS scores predicted OS in 10 of the 11 studies, and calculated PS scores of 1.0 were associated with a median OS of 6.3 months (95% posterior interval, 5.4-7.4). After adjusting for baseline PS, FOLFOX had a similar treatment effect profile (median OS, range 2.6-6.7 months) as 5-FU/leucovorin plus nanoliposomal irinotecan therapy (median OS, 6.1 months; 95% confidence interval 4.8-8.9). Neutropenia and fatigue were the most commonly reported Grade 3-4 TRAEs associated with FOLFOX.. Baseline PS is a strong prognostic factor when interpreting the efficacy of 5-FU and oxaliplatin-based therapy of pancreatic cancer after progression on first-line gemcitabine-based regimens. When baseline PS is considered, FOLFOX has a similar treatment effect as 5-FU and nanoliposomal irinotecan therapy and a comparable safety profile. These findings suggest that 5-FU and oxaliplatin-based therapies remain an acceptable and alternative second-line treatment option for patients with pancreatic cancer and adequate PS (e.g. ECOG 0-1) following gemcitabine treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Fluorouracil; Gemcitabine; Humans; Karnofsky Performance Status; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Randomized Controlled Trials as Topic; Risk Factors; Survival Analysis; Treatment Outcome

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, and the mortality of patients with PDAC has not significantly decreased over the last few decades. Novel strategies exhibiting promising effects in preclinical or phase I/II clinical trials are often situated in an embarrassing condition owing to the disappointing results in phase III trials. The efficacy of the current therapeutic regimens is consistently compromised by the mechanisms of drug resistance at different levels, distinctly more intractable than several other solid tumours. In this review, the main mechanisms of drug resistance clinicians and investigators are dealing with during the exploitation and exploration of the anti-tumour effects of drugs in PDAC treatment are summarized. Corresponding measures to overcome these limitations are also discussed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Hypoxia; Clinical Trials as Topic; Deoxycytidine; Drug Resistance, Neoplasm; Fluorouracil; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Leucovorin; Molecular Targeted Therapy; Mutation; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Progression-Free Survival; Survival Rate; Treatment Outcome; Tumor Microenvironment

Pancreatic ductal adenocarcinoma, an exocrine tumor, is the most common type of cancer of the pancreas and one of the top five most prominent causes of cancer-associated mortality worldwide. The survival rate for pancreatic cancer is sadly less than 8%. The high fatality rate is partly related to late diagnosis and partly to the aggressive nature of malignant cells that disseminate to nearby tissues at an early stage of the disease, making treatment difficult. Available treatment choices consist of both medical and surgical: removal of the tumor, use of various medications like chemotherapeutic drugs and immunotherapeutic agents, radiation therapy, and targeted drug therapy. Since most patients suffer from advanced cancer at the time of diagnosis, chemotherapy becomes the primary therapeutic option in such cases. Drugs like Gemcitabine, Abraxane, FOLFIRINOX, and newer combination therapies are all effective in management, either curatively or palliatively. However, chemoresistance poses a significant challenge. Several factors, both intrinsic and acquired, are involved in drug resistance. Here, we review the mechanism of action of the first-line chemotherapy drugs in pancreatic cancer and various factors associated with cancer chemoresistance.

Topics: Albumin-Bound Paclitaxel; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Drug Resistance, Neoplasm; Fluorouracil; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Signal Transduction; Treatment Outcome

Locally advanced pancreatic cancer (LAPC) has several definitions, but it is essentially a non-metastatic tumor, in which the initial surgical resection is not considered beneficial due to the extensive vascular involvement and consequent high chance of a nonradical resection. The introduction of chemotherapy with calcium leucovorin, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) and gemcitabine-nab (nanoparticle albumin-bound)-paclitaxel (gem-nab) had very important implications for the management of patients with LAPC. After 4 to 6 months of induction chemotherapy, a large proportion of them have stable disease or even tumor regression, allowing to rescue those who initially were not candidates for surgery, with 30-35 months overall survival after surgery.. El cáncer de páncreas localmente avanzado (CPLA) tiene varias definiciones, pero esencialmente es un tumor no metastásico, en el que la resección quirúrgica inicial no se considera beneficiosa debido a la extensa afectación vascular y la alta probabilidad de tener márgenes quirúrgicos con compromiso tumoral. La introducción de la quimioterapia con leucovorina cálcica, fluorouracilo, clorhidrato de irinotecán y oxaliplatino (FOLFIRINOX) y gemcitabina-nab-paclitaxel (paclitaxel acoplado a albúmina, lo que aumenta su solubilidad) ha tenido alcances muy importantes en el tratamiento de pacientes con CPLA. Después de 4 a 6 meses de quimioterapia de inducción, una gran proporción tiene enfermedad estable o incluso regresión tumoral, permitiendo rescatarlos quirúrgicamente, que de inicio no eran candidatos a una cirugía resectiva, con una supervivencia global de 30 a 35 meses.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Induction Chemotherapy; Irinotecan; Leucovorin; Neoadjuvant Therapy; Neoplasm Staging; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Survival Analysis

Pancreatic cancer is the twelfth most common cancer in the United States, representing 3.2% of all new cancer cases. While composing a small percentage of cancer diagnoses, pancreatic cancer is amongst the most lethal carcinomas, with an overall 5-year survival of 8.2% and incidence rates almost equivocal to death rates. By the time of diagnosis, a majority of patients will present with advanced stage disease. For patients with resectable disease, the estimated overall survival (OS) remains low at 20% as most will develop metastatic disease within 5 years. The lethality of this cancer is attributed to several factors including delayed presentation, lack of effective screening, and complex tumor biology and genetics. Data also suggest that even upon early presentation, pancreatic cancer is a systemic disease with micrometastasis present in the early stages. Traditional cytotoxic therapies have not been clinically impactful in pancreatic cancer, especially in advanced stages, and very little headway has been made in the development of new targeted therapies. As such, this review will discuss current advances in standard of care treatments and novel drug targets being researched.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Combinations; Drug Delivery Systems; Fluorouracil; Humans; Immunotherapy; Irinotecan; Leucovorin; Neoplastic Stem Cells; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms

Data regarding management of frail patients with pancreatic ductal adenocarcinoma practice is currently very scarce. Randomized clinical trials usually exclude these subgroup of patients and the majority of the publications only consider chronological age and ECOG performance status for their classification. Therefore, the current available data do not reflect daily clinical practice. Only data from a phase two study (FRAGANCE study), designed to select a tolerable dose-schedule of nab-placitaxel + gemcitabine (Phase one) and to evaluate the efficacy of the selected regimen (Phase two) in patients with ECOG-2 and previously untreated advanced PDAC, are currently available. Management of these particular patients is exceedingly complex and requires collaboration of multidisciplinary teams and intensive support treatment. This article reviews the literature available regarding the management of the so-called frail patients and provide guidance for chemotherapy as well as supportive care treatments.

Topics: Aged; Aged, 80 and over; Albumins; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Fluorouracil; Frail Elderly; Frailty; Gemcitabine; Humans; Leucovorin; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms; Randomized Controlled Trials as Topic

One of the main reasons for the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is its late diagnosis. At the time of presentation, only approximately 15-20% of all patients with PDAC are considered resectable and around 30% are considered borderline resectable. A surgical approach, which is the only curative option, is limited in borderline resectable patients by local involvement of surrounding structures. In borderline resectable pancreatic cancer (BRPC), neoadjuvant treatment regimens have been introduced with the rationale to downstage and downsize the tumor in order to enable resection and eliminate -microscopic distant metastases. However, there are no official guidelines for the preoperative treatment of BRPC. In the majority of cases, patients are administered -Gemcitabine-based or FOLFIRINOX-based chemotherapy regimens with or without radiation. Radiologic restaging after neoadjuvant therapy has to be judged with caution when it comes to predict tumor response and resectability, since inflammation induced by neoadjuvant therapy may mimic solid tumor. Patients who do not show any disease progression during neoadjuvant therapy should be offered surgical exploration, since a high percentage is likely to undergo resection with negative margins (R0) and, thus, achieve improved overall survival although imaging judged it unlikely. Despite the promising new approaches of neoadjuvant treatment regimens during the last 2 decades, surgery remains the first choice if the tumor appears to be primary resectable at the time of diagnosis. At present, there are no international guidelines regarding the preoperative treatment of BRPC. Therefore, in order to standardize and adjust neoadjuvant treatment in the future, new guidelines have to be determined on the basis of upcoming prospective randomized studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Neoplasm Staging; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Tumor Burden

The study aimed to evaluate the effectiveness of the first-line chemotherapy FOLFIRINOX in treating pancreatic cancer. Pertinent studies were derived from the PubMed, Cochrane Library and EMBASE. The outcomes were analyzed according to resection rate and radical (R0) resection rate. Data were expressed as weighted commix proportions with 95% confidence intervals (CIs). Twenty-three studies, involving 968 patients with locally advanced pancreatic cancer (LAPC) and borderline resectable pancreatic cancer (BRPC), were examined. After treatment, 55% (95% CI 52-58%) of the patients underwent resection and 40% (95% CI 37-43%) underwent R0 resection, and the median overall survival ranged from 15.5 to 35.4 months, with a 10.0-27.1 months' median progression-free survival. The meta-analysis shows that FOLFIRINOX, as the first-line therapy, has significant down-staging effects in patients with LAPC or BRPC, with a 40% R0 resection rate and the adverse events under control.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

Pancreatic cancer is a lethal disease with a very poor prognosis. In contrast to treatments for many other tumor types, cytotoxic agents are still the first-line drugs for pancreatic cancer in both the palliative and adjuvant settings. Some progress has been made in recent years, but most large phase 3 studies have not shown significant improvements in survival. Because the available drugs and regimens are limited in both type and effect, the selection of chemotherapy based on clinicopathologic characteristics may be consequential for pancreatic cancer. In the present report, we focused on 7 landmark clinical trials for pancreatic cancer. We observed that FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) and NG (nab-paclitaxel and gemcitabine), 2 first-line regimens, exerted opposite effects on metastatic pancreatic cancer patients with different baseline carbohydrate antigen 19-9 (CA19-9) levels. This suggested that not only the performance status but possibly also CA19-9 levels should be considered when making a therapeutic choice for patients with advanced pancreatic cancer. Moreover, we found that patients with a diagnosis of pancreatic cancer who have undergone a surgical resection with a negative margin (R0) may benefit more from fluorouracil and/or oral prodrugs of fluorouracil-based adjuvant therapy than from gemcitabine. Conversely, gemcitabine or gemcitabine-based regimens may be more effective for patients with a positive resection margin (R1). Based on these findings, we propose flowcharts for selecting chemotherapy for both advanced and resected pancreatic cancer. Furthermore, we present possible mechanisms and interpretations underlying the selection of chemotherapy for pancreatic cancer and propose the tumor burden as a key variable in this process. Regardless of the possible bias and exact treatment selection process, this study offers an opportunity to improve patient outcomes by using agents currently used in the therapy of pancreatic cancer. Although these conclusions are based on indirect evidence, we provide insights and possibilities to drive the selection of chemotherapy for pancreatic cancer.

Topics: Albumins; Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Deoxycytidine; Drug Combinations; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Margins of Excision; Organometallic Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Prognosis; Treatment Outcome

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited effective therapeutic options and exceedingly high mortality rates. Currently, cure can only be achieved through resection, however the vast majority of patients present with advanced disease for which upfront surgery is not an option. In an effort to improve surgical candidacy, neoadjuvant chemotherapy, with or without radiation therapy, is often used in an effort to downstage borderline resectable and locally advanced tumors, and some argue for its use even in patients with resectable tumors. Underlying this thinking is the recognition that pancreatic cancer is simultaneously both a locally invasive and systemic disease, even in patients without evidence of metastasis on imaging. Current evidence to date is largely retrospective, but suggests that neoadjuvant therapy can increase R0 (pathologically negative margin) resection rates and improve overall survival. The standard approach to neoadjuvant treatment involves choosing between the two most active combination regimens for metastatic disease, namely modified FOLFIRNOX and gemcitabine/nab-paclitaxel. Nonrandomized data indicate that these regimens can yield resection rates up to 68% and 36%, in borderline resectable and locally advanced PDAC, respectively. Furthermore, randomized data in patients with resectable PDAC treated with gemcitabine-based neoadjuvant therapy suggests that despite an approximate 10% drop in resection rates, there is a significant improvement in median overall survival. Herein, we will discuss the rationale for neoadjuvant therapy, current and former treatment regimens, common issues faced by clinicians when using these combinations, and several ongoing clinical trials.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Neoadjuvant Therapy; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms

Pancreatic cancer is considered to be one of the most aggressive cancers. For unknown reasons, the incidence of pancreatic cancer is slowly rising and so too are mortality rates. Over 75% of patients are diagnosed with locally advanced disease or with metastases; and more than 95% of patients have metastases at diagnosis or will develop metastases during their follow-up. Despite recent improvements in the therapy of pancreatic cancer, initially with demonstration of the activity of the FOLFIRINOX regimen and subsequently the approval of nab-paclitaxel in combination with gemcitabine, prognosis remains poor and the 5-year survival rate is less than 5%. To date, neither personalized medicine nor immunotherapy, the 2 recent revolutions of cancer treatment, have delivered major positive results in the treatment of pancreatic cancer; and it is especially clear that immune checkpoint inhibitors will not become a major tool in the treatment of pancreatic cancer. There are many ongoing studies, including those exploring combinations of chemotherapy with immunotherapy. Vaccines or T cells modified with a chimeric antigen receptor (CAR-T cells) could also play a role in the treatment of cancer in the future. The aim of this review is to discuss recent improvements in standard of care, major obstacles to overcome, recent results of new treatment combinations, and the most interesting innovative approaches.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Immunotherapy; Irinotecan; Leucovorin; Pancreatic Neoplasms; Prognosis; Survival Analysis

Pancreatic cancer is typically diagnosed in the late stage of the disease, making it the fourth leading cause of cancer-related death in the United States. It is also one of the few cancers with an increasing incidence, particularly in the younger population. By 2030, it is expected to become the second leading cause of cancer-related death. Patients with pancreatic cancer encounter monthly medical costs 15 times higher than those without, with costs highest in the later stages of the disease. Treatments for pancreatic cancer include surgery (available to fewer than 20% of newly diagnosed patients) and, for advanced disease, chemotherapy with gemcitabine with nab-paclitaxel or FOLFIRINOX, which can increase overall survival (OS) by a few months. Economic and outcome analyses of clinical data find no significant difference in OS between the 2 regimens, although FOLFIRINOX carries a much higher rate of serious adverse effects, limiting its use to patients with good performance status. In 2017, the FDA approved immunotherapy for patients with microsatellite instability-high or mismatch repair-deficient solid tumors, which occurs in approximately 1% of pancreatic cancer diagnoses. Several immunotherapies and targeted therapies are currently in clinical trials and may significantly alter the trajectory of the disease. However, they typically cost more than $100,000 per year, putting significant strain on payers. Thus, it is important that payers plan now for the potential arsenal of new treatments and identify opportunities to manage their utilization as well as patients with the disease to contain costs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cost Control; Cost-Benefit Analysis; Deoxycytidine; Early Detection of Cancer; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Microsatellite Instability; Oxaliplatin; Pancreatic Neoplasms; Terminal Care

Topics: Aged; Aged, 80 and over; Albumin-Bound Paclitaxel; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Comorbidity; Deoxycytidine; Diabetes Mellitus; Diet; Drug Resistance, Neoplasm; Early Detection of Cancer; Fluorouracil; Gemcitabine; Genetic Predisposition to Disease; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Neoplasm Metastasis; Oxaliplatin; Palliative Care; Pancreatectomy; Pancreatic Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Prognosis; Radiosurgery; Risk Factors; Spain

Pancreatic cancer is one of the most lethal of all malignancies. One of the reasons for the dismal prognosis is that most diagnoses are made when the disease is either locally advanced or metastatic. Recent advances in chemotherapy and chemoradiotherapy (CRT) enable "conversion surgery" to be performed for selected patients with initially unresectable pancreatic cancer following favorable responses to preoperative treatment. Using FOLFIRINOX as preoperative treatment, the resection rate was reported as 6-44% of patients with locally advanced cancer and the prognosis of these patients was favorable. Even for metastasized cancer, recent reports show the effectiveness of conversion surgery, which has achieved 27-56 months of median overall survival. However, there are many unanswered questions about conversion surgery. The optimal regimen and duration of preoperative treatment remain unclear and there is still debate regarding the safety and effectiveness of vascular resection, which is often required for curative resection of locally advanced cancer. Accumulation of more data on conversion surgery is required to establish the safety and effectiveness of this treatment. In this review, we summarize the current status and unresolved issues about conversion surgery for initially unresectable pancreatic cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy, Adjuvant; Chemotherapy, Adjuvant; Combined Modality Therapy; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Preoperative Care; Prognosis; Survival Rate

Pancreatic cancer will soon become one of the most common causes of cancer death. Early detection of pancreatic cancer remains impossible and only 20% of patients are suitable for surgery once diagnosed. Even in this specific subgroup of patients, and despite improvements in surgery, overall survival remains poor, with an 80% recurrence rate. Consequently, many attempts have been made to prevent recurrence by adding chemotherapy, radiotherapy, or both.. Here, we will focus on results of randomized trials evaluating the role of different postoperative treatments. Over 15 years ago, a trial demonstrated that chemoradiotherapy has a deleterious effect on survival. The same trial recommended adjuvant chemotherapy with fluorouracil as standard of care. Subsequent trials sought to identify better chemotherapy regimens. Two recently published trials evaluated the role of combination therapies for resected pancreatic cancer and demonstrated better outcomes with a gemcitabine and capecitabine combination and a fluorouracil, oxaliplatin, and irinotecan combination (FOLFIRINOX) versus gemcitabine alone.. Results from recent trials suggest that FOLFIRINOX should be considered standard of care for fit patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Randomized Controlled Trials as Topic

FOLFIRINOX is a standard treatment for metastatic pancreatic cancer patients. The effectiveness of neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer (BRPC) remains debated.. We performed a systematic review and patient-level meta-analysis on neoadjuvant FOLFIRINOX in patients with BRPC. Studies with BRPC patients who received FOLFIRINOX as first-line neoadjuvant treatment were included. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival, resection rate, R0 resection rate, and grade III-IV adverse events. Patient-level survival outcomes were obtained from authors of the included studies and analyzed using the Kaplan-Meier method.. We included 24 studies (8 prospective, 16 retrospective), comprising 313 (38.1%) BRPC patients treated with FOLFIRINOX. Most studies (n = 20) presented intention-to-treat results. The median number of administered neoadjuvant FOLFIRINOX cycles ranged from 4 to 9. The resection rate was 67.8% (95% confidence interval [CI] = 60.1% to 74.6%), and the R0-resection rate was 83.9% (95% CI = 76.8% to 89.1%). The median OS varied from 11.0 to 34.2 months across studies. Patient-level survival data were obtained for 20 studies representing 283 BRPC patients. The patient-level median OS was 22.2 months (95% CI = 18.8 to 25.6 months), and patient-level median progression-free survival was 18.0 months (95% CI = 14.5 to 21.5 months). Pooled event rates for grade III-IV adverse events were highest for neutropenia (17.5 per 100 patients, 95% CI = 10.3% to 28.3%), diarrhea (11.1 per 100 patients, 95% CI = 8.6 to 14.3), and fatigue (10.8 per 100 patients, 95% CI = 8.1 to 14.2). No deaths were attributed to FOLFIRINOX.. This patient-level meta-analysis of BRPC patients treated with neoadjuvant FOLFIRINOX showed a favorable median OS, resection rate, and R0-resection rate. These results need to be assessed in a randomized trial.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Progression-Free Survival; Treatment Outcome

Pancreatic cancer is one of the leading causes of cancer death worldwide. Adjuvant chemotherapy has been developed based on the experiences made with palliative chemotherapy, and advocated to improve long-term survival of patients with this disease. However, the optimal chemotherapeutic regimen remains controversial. Recently, Conroy et al demonstrated the impressive benefits of modified FOLFIRINOX over gemcitabine alone in the multicenter Partenariat de Recherche en Oncologie Digestive 24 (PRODIGE-24) trial. The remarkable results mark a new milestone in treating resectable pancreatic cancer and have now changed the standard of care for this patient population. In this commentary, we discuss an issue of difference of tumor grade between the PRODIGE-24 trial and previous phase III trials. We also discuss potential biomarkers predicting therapeutic response to modified FOLFIRINOX. Finally, we summarize several ongoing clinical trials of replacing part of the FOLFIRINOX regimen with Xeloda/S-1/nanoliposomal irinotecan for pancreatic cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Germany; Humans; Irinotecan; Leucovorin; Pancreatic Neoplasms

This network meta-analysis is adopted in order to compare the toxicity of different chemotherapy regimens in the treatment of advanced/metastatic pancreatic cancer (PC). Randomized controlled trials (RCTs) about different chemotherapy regimens for advanced/metastatic PC were included in this network meta-analysis using Cochrane Library and PubMed electronic databases. The network meta-analysis was performed to combine direct and indirect evidence in order to calculate the odd ratios (OR) and draw a surface under the cumulative ranking (SUCRA) curve. A total of 19 RCTs were enrolled in this network meta-analysis including 12 chemotherapy regimens (Gemcitabine, Gemcitabine + S-1 [tegafur], Gemcitabine + nab-paclitaxel, Gemcitabine + Capecitabine, Gemcitabine + Cisplatin, FOLFIRINOX [oxaliplatin + irinotecan + fluorouracil + leucovorin], Gemcitabine + oxaliplatin, Gemcitabine + irinotecan, Gemcitabine + Exatecan, Gemcitabine + pemetrexed, Gemcitabine + 5-FU, S-1). The incidence of anemia of Gemcitabine + Capecitabine regimen was higher compared with Gemcitabine regimen, Gemcitabine + pemetrexed regimen exhibited the highest incidence rates of anemia and neutropenia; while Gemcitabine + S-1, Gemcitabine + Cisplatin and FOLFIRINOX regimens exhibited the highest incidence rates of neutropenia. However, S-1 regimen exhibited lower incidence rates of leukopenia and thrombocytopenia. Moreover, the incidence rates of nausea/vomiting and rash of Gemcitabine + S-1 regimen were higher compared with Gemcitabine regimen, while Gemcitabine + Cisplatin regimen had the highest incidence rate of nausea/vomiting. This study demonstrated that the hematologic toxicity of S-1 regimen was the lowest, while Gemcitabine regimen exhibited the lowest incidence rate of non-hematologic toxicity, providing guidance for the treatment of advanced/metastatic PC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Network Meta-Analysis; Oxaliplatin; Pancreatic Neoplasms

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Shire Pharmaceuticals) of pegylated liposomal irinotecan hydrochloride trihydrate (liposomal irinotecan) to submit clinical and cost-effectiveness evidence for its use in combination with 5-fluorouracil (5-FU) and folic acid/leucovorin (LV) for treating patients with pancreatic cancer following prior treatment with gemcitabine as part of the institute's Single Technology Appraisal process. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article presents a summary of the company's evidence, the ERG review and the resulting NICE guidance (TA440), issued on 26 April 2017. Clinical evidence for liposomal irinotecan + 5-FU/LV versus 5-FU/LV was derived from 236 patients with metastatic pancreatic cancer in the multinational, open-label, randomised controlled NAPOLI-1 trial. Results from analyses of progression-free survival and overall survival showed statistically significant improvements for patients treated with liposomal irinotecan + 5-FU/LV compared with those treated with 5-FU/LV. However, 5-FU/LV alone is rarely used in National Health Service clinical practice for patients with metastatic pancreatic cancer previously treated with gemcitabine. The company, ERG and Appraisal Committee (AC) all agreed that oxaliplatin + 5-FU/LV is the most commonly used treatment. Oxaliplatin + 5-FU/LV was compared with 5-FU/LV in two trials identified by the company. However, the company and the ERG both considered attempts to compare the efficacy of liposomal irinotecan + 5-FU/LV with oxaliplatin + 5-FU/LV to be methodologically flawed; not only was there heterogeneity between trials and their populations but also the proportional hazards assumption required to conduct a robust indirect treatment comparison (ITC) was violated. Nonetheless, data derived from an ITC were used to inform the company's economic model. Using the discounted patient access scheme price for liposomal irinotecan + 5-FU/LV, the company reported an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £54,412 for the comparison with oxaliplatin + 5-FU/LV. The ERG considered that the company's base-case cost-effectiveness results for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV were underestimates and should be interpreted with extreme caution. Follow

Topics: Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Fluorouracil; Folic Acid; Humans; Irinotecan; Leucovorin; Pancreatic Neoplasms; Technology Assessment, Biomedical; Topoisomerase I Inhibitors

As part of the single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited Celgene Ltd to submit clinical and cost-effectiveness evidence for paclitaxel as albumin-bound nanoparticles (Nab-Pac) in combination with gemcitabine (Nab-Pac + Gem) for patients with untreated metastatic pancreatic cancer. The STA was a review of NICE's 2015 guidance (TA360) in which Nab-Pac + Gem was not recommended for patients with untreated metastatic pancreatic cancer. The review was prompted by a proposed Patient Access Scheme (PAS) discount on the price of Nab-Pac and new evidence that might lead to a change in the guidance. The Liverpool Reviews and Implementation Group at the University of Liverpool was the Evidence Review Group (ERG). This article summarises the ERG's review of the company's evidence submission for Nab-Pac + Gem, and the Appraisal Committee (AC) decision. The final scope issued by NICE listed three comparators: gemcitabine monotherapy (Gem), gemcitabine in combination with capecitabine (Gem + Cap), and a combination of oxaliplatin, irinotecan, leucovorin and fluorouracil (FOLFIRINOX). Clinical evidence for the comparison of Nab-Pac + Gem versus Gem was from the phase III CA046 randomized controlled trial. Analysis of progression-free survival (PFS) and overall survival (OS) showed statistically significant improvement for patients treated with Nab-Pac + Gem versus Gem. Clinical evidence for the comparison of Nab-Pac + Gem versus FOLFIRINOX and versus Gem + Cap was derived from a network meta-analysis (NMA). Results of the NMA did not indicate a statistically significant difference in OS or PFS for the comparison of Nab-Pac + Gem versus either Gem + Cap or FOLFIRINOX. The ERG's main concerns with the clinical effectiveness evidence were difficulties in identifying the patient population for whom treatment with Nab-Pac + Gem is most appropriate, and violation of the proportional hazards (PH) assumption in the CA046 trial. The ERG highlighted methodological issues in the cost-effectiveness analysis pertaining to the modelling of survival outcomes, estimation of drug costs and double counting of adverse-event disutilities. The AC accepted all the ERG's amendments to the company's cost-effectiveness model; however, these did not make important differences to the incremental cost-effectiveness ratios (ICERs). The company's base-case ICER was £46,932 per quality-adjusted life-year (QALY) gained for the compar

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Cost-Benefit Analysis; Deoxycytidine; Disease-Free Survival; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Models, Economic; Nanoparticles; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Technology Assessment, Biomedical

We performed a meta-analysis of previous reports evaluating the effect of mFIO (modified FOLFIRINOX; leucovorin, 5-fluorouracil, irinotecan, oxaliplatin) regimens in advanced pancreatic cancer.. We performed a meta-analysis of reported studies in PubMed, Scopus, and Web of Science (1950-2016) in December 2016. The inclusion criteria were randomized trials, prospective or retrospective cohorts, patients with metastatic pancreatic adenocarcinoma, the use of mFIO or FOLFIRINOX (FIO) chemotherapy, and available information for ≥ 1 efficacy endpoint (response rate, progression-free survival, and/or overall survival). The outcomes were compared according to the chemotherapy regimen using a random effects model. We also performed a meta-regression analysis to evaluate the effect of dose reductions on outcomes.. Of 2525 abstracts, 32 were considered eligible. Modifications in the FIO regimen included omission of the 5-fluorouracil bolus and/or dose reductions in infusional 5-fluorouracil, irinotecan, and/or oxaliplatin. mFIO was not associated with inferior response rates (32% vs. 33%; P = .879), lower rates of survival at 11 months (47% vs. 50%; P = .38), or lower 6-month progression-free survival rates (47% vs. 53%; P = .38). The meta-regression of the percentage of dose reduction failed to show any association.. The results of the present meta-analysis with a combined sample size of 1461 patients suggest that it is reasonable to consider mFIO regimens for patients with metastatic pancreatic adenocarcinoma.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Fluorouracil; Humans; Irinotecan; Leucovorin; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Progression-Free Survival; Survival Rate

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers with very few available treatments. For many decades, gemcitabine was the only treatment for patients with PDAC. A recent attempt to improve patient survival by combining this chemotherapy with FOLFIRINOX and nab-paclitaxel failed and instead resulted in increased toxicity. Novel therapies are urgently required to improve PDAC patient survival. New treatments in other cancers such as melanoma, non-small-cell lung cancer, and renal cancer have emerged, based on immunotherapy targeting the immune checkpoints cytotoxic T-lymphocyte-associated antigen 4 or programmed death 1 ligand. However, the first clinical trials using such immune checkpoint inhibitors in PDAC have had limited success. Resistance to immunotherapy in PDAC remains unclear but could be due to tissue components (cancer-associated fibroblasts, desmoplasia, hypoxia) and to the imbalance between immunosuppressive and effector immune populations in the tumor microenvironment. In this review, we analyzed the presence of "good and bad immunological cops" in PDAC and discussed the significance of changes in their balance.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Cycle Checkpoints; Clinical Trials as Topic; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Hypoxia; Immunotherapy; Irinotecan; Leucovorin; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Tumor Microenvironment

FOLFIRINOX has been one of the first-line options for advanced pancreatic cancer, even though it induces significant adverse effects. Several institutions have begun using modified FOLFIRINOX to decrease its side effects and increase its tolerability. We systematically investigated the outcome from patients who initially received modified FOLFIRINOX as a chemotherapy regimen for advanced pancreatic cancer. We used the random-model generic inverse variance method to analyse the binary data with 95% confidence intervals (CIs). Eleven studies were included in the meta-analysis with 563 total patients. The 6-month and 1-year overall survival (OS) rates of locally advanced pancreatic cancer (LAPC) were 90.9% and 76.2%. The 6-month and 1-year progression-free survival (PFS) rates of LAPC were 81.5% and 48.5%. The 6-month and 1-year OS rates of metastatic pancreatic cancer (MPC) were 79.7% and 47.6%. The 6-month and 1-year PFS rates of MPC were 56.3% and 20.6%. The following rates were also calculated: complete response rate (CR): 2.9%; partial response rate (PR): 35.9%; stable disease rate (SD): 41.2%; overall response rate (OR): 34.6%; disease control rate (DCR): 76.7%; progressive disease: 23.1%; and grade III/IV adverse events (AEs): neutropenia 23.1%, febrile neutropenia 4.8%, thrombocytopenia 4.8%, anaemia 5.7%, fatigue 11.5%, nausea 9.1%, diarrhoea 10.1%, vomiting 5.7%, neuropathy 3.8%, and increased ALT 5.7%. In conclusion, modified FOLFIRINOX could provide comparative survival benefits with fewer adverse events compared to the conventional dosage.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Fatigue; Fluorouracil; Humans; Irinotecan; Leucovorin; Nausea; Neutropenia; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Survival Analysis; Thrombocytopenia; Treatment Outcome

Metastatic pancreatic ductal adenocarcinoma (mPDAC) is a lethal disease with a poor 5-year survival. Systemic treatments can be used to control symptoms and prolong life. Cytotoxic chemotherapies are commonly administered, with combination treatments, such as fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) or nab-paclitaxel and gemcitabine showing the largest clinical benefits. Newer genomic classifications of PDAC may provide a rationale for targeted therapies or immunotherapies, although at present these remain largely experimental. This review discusses the evidence behind the currently used regimens, while introducing the potential future of pancreatic cancer care.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Drug Combinations; Fluorouracil; Humans; Immunotherapy; Irinotecan; Leucovorin; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Practice Guidelines as Topic; Randomized Controlled Trials as Topic

Managing patients with metastatic pancreatic adenocarcinoma (mPDA) is a challenging proposition for any treating oncologist. Although the potency of first-line therapies has improved with the approvals of FOLFIRINOX and gemcitabine plus nab-paclitaxel, many patients are unable to derive significant benefit from later lines of therapy upon progression. Enrollment on clinical trials remains among the best options for patients with mPDA in all lines of therapy. At our institution, we routinely check for microsatellite instability (MSI-H) and perform next-generation sequencing (NGS) at the time of diagnosis in all good performance status mPDA patients. Although MSI-H status is only found in 1% of patients with mPDA, given pembrolizumab's tissue-agnostic approval for MSI-H tumors in later-line settings, it is a viable option when deciding on subsequent lines of therapy. Any use of immune therapy in mPDA is investigational outside the MSI-H setting. NGS can identify BRCA or other DNA damage response (DDR) defects in patients which can predict sensitivity to platinum-based therapies and influence choice of both initial and later lines of therapy. It can also identify rare actionable genomic alterations such as HER2 (2%) and TRK fusions (0.1%) and offer patients the option of enrollment on clinical trials with agents targeting these or other identified alterations. We believe enrolling mPDA patients on clinical trials with immune-modulating agents is critical to determine if there are other patient subsets, outside of the MSI-H setting, who would benefit from these approaches. Immunotherapy's general tolerability and potential to generate durable responses make it particularly appealing for mPDA patients. Although single-modality immunotherapy such as checkpoint inhibitors or vaccines have not demonstrated efficacy in this disease, combinatorial strategies targeting unique aspects of PDA including the tumor microenvironment and desmoplastic stroma have shown preclinical or early-phase success. Validating these treatments with later-phase prospective studies is essential to making immunotherapy a routine component of the treatment armamentarium for mPDA patients.

Topics: Albumins; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Immunotherapy; Irinotecan; Leucovorin; Microsatellite Instability; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

The incidence of pancreatic ductal adenocarcinoma (PDAC) is rapidly increasing. Up to 30% of patients present with locally advanced disease and therefore are not candidates for surgery. Locally advanced pancreatic cancer (LAPC) is an emerging entity lacking in level III evidence-based recommendations for its treatment. Currently, systemic chemotherapy is the main treatment for LAPC. However, due to lack of response or disease progression, downsizing of the tumour, making it resectable is successful in only a small proportion of patients. Radiotherapy is often advocated to improve local disease control if there is stability following chemotherapy. Recently, Irreversible Electroporation (IRE), a novel non-thermal ablation technique, has been proposed for the treatment of LAPC.. This narrative review aims to explore the potential role and timing for the use of IRE in patients with LAPC.. To date, there is limited and inconsistent level I and II evidence available in the literature regarding the use of IRE for the treatment of PDAC.. Although some of the preliminary experience of the use of IRE in patients with LAPC is encouraging, it should only be used after conventional evidence-based treatments and/or within the research context.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Electroporation; Fluorouracil; Humans; Irinotecan; Leucovorin; Organometallic Compounds; Oxaliplatin; Pancreatic Ducts; Pancreatic Neoplasms; Radiotherapy

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Liposomes; Pancreatic Neoplasms; Randomized Controlled Trials as Topic; Treatment Outcome

The vast majority of patients diagnosed with pancreatic adenocarcinoma have inoperable, most commonly metastatic, disease at the time of initial presentation, at which point systemic therapy becomes the mainstay of treatment. Although survival rates remain very poor in this clinical setting, patients currently have a greater number of therapeutic options available to them than ever before, and consequently individuals are more frequently able to be sequenced through multiple lines of treatment. In this review, we will provide an overview of the current treatment landscape for metastatic pancreatic cancer in 2017, focusing on best practices and the various factors that should be considered in selecting the most appropriate regimen for a given individual. Options for front-line therapy include both infusional 5-fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX) and the combination of gemcitabine plus nab-paclitaxel; however, how to choose between these two regimens can sometimes pose a challenging problem, and some patients may not be suitable candidates for either. For patients who are robust enough to receive second-line therapy (and beyond), the selection of treatment depends in part on their prior treatment exposure; newer drugs such as nanoliposomal irinotecan (nal-IRI) (in combination with infusional 5-fluorouracil and leucovorin) are now approved by the United States Food and Drug Administration (FDA) specifically for use following disease progression on first-line gemcitabine-based therapy. Despite these welcome advances in standard of care treatment, patients should still be encouraged to participate in clinical trials whenever possible.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Fluorouracil; Gentamicins; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Practice Guidelines as Topic; Treatment Outcome; United States

Pancreatic cancer is a highly lethal disease, for which mortality closely parallels incidence. Most patients with pancreatic cancer remain asymptomatic until the disease reaches an advanced stage. There is no standard programme for screening patients at high risk of pancreatic cancer (eg, those with a family history of pancreatic cancer and chronic pancreatitis). Most pancreatic cancers arise from microscopic non-invasive epithelial proliferations within the pancreatic ducts, referred to as pancreatic intraepithelial neoplasias. There are four major driver genes for pancreatic cancer: KRAS, CDKN2A, TP53, and SMAD4. KRAS mutation and alterations in CDKN2A are early events in pancreatic tumorigenesis. Endoscopic ultrasonography and endoscopic ultrasonography-guided fine-needle aspiration offer high diagnostic ability for pancreatic cancer. Surgical resection is regarded as the only potentially curative treatment, and adjuvant chemotherapy with gemcitabine or S-1, an oral fluoropyrimidine derivative, is given after surgery. FOLFIRINOX (fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) are the treatments of choice for patients who are not surgical candidates but have good performance status.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Camptothecin; Carcinoembryonic Antigen; Carcinoma, Pancreatic Ductal; Deoxycytidine; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Endosonography; Fluorouracil; Gemcitabine; Genes, p16; Humans; Irinotecan; Leucovorin; Neoplasms, Cystic, Mucinous, and Serous; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatectomy; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Smad4 Protein; Tumor Suppressor Protein p53

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with half of patients diagnosed in the metastatic setting. Until recently, patients after progression on front-line gemcitabine-based regimen had no standard second-line option, although flouropyrimidine-based regimens were frequently used in this setting. Encapsulation of chemotherapeutics in liposomal formulation is an effective way of prolonging drug deposition thereby enhancing cytotoxic efficacy. In a large phase III randomized trial on metastatic PDAC patients who progressed after gemcitabine-based chemotherapy, a novel nanoliposome-encapsulated irinotecan (PEP02, MM-398, nal-IRI, Onivyde, Merrimack, Boston, US) plus fluorouracil and folinic acid demonstrated a significant survival advantage compared to fluorouracil and folinic acid alone. This pivotal study led to the recent FDA approval of nanoliposomal irinotecan in patients with metastatic PDAC. In this article, we will review the literature regarding existing treatment options for metastatic PDAC, focusing specifically on nanoliposomal irinotecan in the clinical setting and its future implication.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Nanoparticles; Pancreatic Neoplasms; Randomized Controlled Trials as Topic

Systemic chemotherapy remains the standard of care for patients with advanced pancreatic ductal adenocarcinoma (PDAC). The introductions of FOLFIRINOX and nab-paclitaxel/gemcitabine combinations have improved the first-line treatment outcomes of patients with metastatic PDAC; while second-line therapy options are limited. Based on the results of pivotal NAPOLI-1 study, nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) became the first US Food and Drug Administration (FDA) approved regimen for patients with metastatic PDAC with previous gemcitabine-based chemotherapy in November 2015.. We reviewed and summarized the rationale, pharmacokinetics, therapeutic efficacy and adverse events of nal-IRI alone or combined with 5-FU/LV for metastatic PDAC with previous gemcitabine-based chemotherapy.. In the NAPOLI study, nal-IRI plus 5-FU/LV significantly improved the overall survival, progression-free survival and objective response rate compared to 5-FU/LV alone. The nal-IRI plus 5-FU/LV treatment was associated with a manageable toxicity profile and comparable outcomes in patients with negative demographic characteristics. The relatively sparse of neurotoxicity makes nal-IRI plus 5-FU/LV as a more favorable option than oxaliplatin-containing regimens and the current recommended standard treatment for patients with metastatic PDAC after frontline nab-paclitaxel/gemcitabine treatment. The front-line therapeutic role of nal-IRI is currently under investigation.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Disease-Free Survival; Drug Combinations; Fluorouracil; Humans; Leucovorin; Pancreatic Neoplasms; Sucrose; Treatment Outcome

35% of patients with pancreatic cancer have unresectable locally advanced disease at diagnosis. Several studies have examined systemic chemotherapy with FOLFIRINOX (leucovorin and fluorouracil plus irinotecan and oxaliplatin) in patients with locally advanced pancreatic cancer. We aimed to assess the effectiveness of FOLFIRINOX as first-line treatment in this patient population.. We systematically searched Embase, MEDLINE (OvidSP), Web of Science, Scopus, PubMed Publisher, Cochrane, and Google Scholar from July 1, 1994, to July 2, 2015, for studies of treatment-naive patients of any age who received FOLFIRINOX as first-line treatment of locally advanced pancreatic cancer. Our primary outcome was overall survival. Secondary outcomes were progression-free survival; rates of grade 3 or 4 adverse events; and the proportion of patients who underwent radiotherapy or chemoradiotherapy, surgical resection after FOLFIRINOX, and R0 resection. We evaluated survival outcomes with the Kaplan-Meier method with patient-level data. Grade 3 or 4 adverse events, and the proportion of patients who underwent subsequent radiotherapy or chemoradiotherapy or resection, were pooled in a random-effects model.. We included 13 studies comprising 689 patients, of whom 355 (52%) patients had locally advanced pancreatic cancer. 11 studies, comprising 315 patients with locally advanced disease, reported survival outcomes and were eligible for patient-level meta-analysis. Median overall survival from the start of FOLFIRINOX ranged from 10·0 months (95% CI 4·0-16·0) to 32·7 months (23·1-42·3) across studies with a pooled patient-level median overall survival of 24·2 months (95% CI 21·7-26·8). Median progression-free survival ranged from 3·0 months (95% CI not calculable) to 20·4 months (6·5-34·3) across studies with a patient-level median progression-free survival of 15·0 months (95% 13·8-16·2). In ten studies comprising 490 patients, 296 grade 3 or 4 adverse events were reported (60·4 events per 100 patients). No deaths were attributed to FOLFIRINOX toxicity. The proportion of patients who underwent radiotherapy or chemoradiotherapy ranged from 31% to 100% across studies. In eight studies, 154 (57%) of 271 patients received radiotherapy or chemoradiotherapy after FOLFIRINOX. The pooled proportion of patients who received any radiotherapy treatment was 63·5% (95% CI 43·3-81·6, I(2) 90%). The proportion of patients who underwent surgical resection for locally advanced pancreatic cancer ranged from 0% to 43%. The proportion of patients who had R0 resection of those who underwent resection ranged from 50% to 100% across studies. In 12 studies, 91 (28%) of 325 patients underwent resection after FOLFIRINOX. The pooled proportion of patients who had resection was 25·9% (95% CI 20·2-31·9, I(2) 24%). R0 resection was reported in 60 (74%) of 81 patients. The pooled proportion of patients who had R0 resection was 78·4% (95% CI 60·2-92·2, I(2) 64%).. Patients with locally advanced pancreatic cancer treated with FOLFIRINOX had a median overall survival of 24·2 months-longer than that reported with gemcitabine (6-13 months). Future research should assess these promising results in a randomised controlled trial, and should establish which patients might benefit from radiotherapy or chemoradiotherapy or resection after FOLFIRINOX.. None.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Survival Rate

Patients with advanced and metastatic pancreatic cancer refractory to gemcitabine based therapy have a dismal prognosis and limited therapeutic options. Recently, the FDA approved nanoliposomal irinotecan combined with fluorouracil/folinic acid for such patients based upon results of the NAPOLI-1 study which showed this regimen compared to fluorouracil/folinic acid significantly prolonged progression free survival (3.1 vs. 1.5 months) and overall survival (6.2 vs. 4.1 months).. The pharmacokinetic and pharmacogenetic characteristics of this novel formulation of irinotecan, its safety profile, and use in a clinical context for patients with pancreatic cancer are reviewed. Expert commentary: Nanoliposomal irinotecan, in combination with 5-FU/folinic acid, represents an important step forward in improving second line treatment options in patients with progression of metastatic pancreatic cancer. Furthermore, the novel drug formulation offers pharmacokinetic advantages which serve as a basis for further clinical testing in a various pancreatic cancer settings and other malignancies.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Disease-Free Survival; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Liposomes; Pancreatic Neoplasms; Prognosis

Pancreatic cancer is an aggressive cancer that continues to have single-digit 5-year mortality rates despite advancements in the field. Surgery remains the only curative treatment; however, most patients present with late-stage disease deemed unresectable, either due to extensive local vascular involvement or the presence of distant metastasis. Resection guidelines that include a borderline resectable group, as well as advancements in neoadjuvant chemotherapy and radiation that improve resectability of locally advanced disease, may improve outcomes for patients with more invasive disease. Multi-agent chemotherapy regimens fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and nab-paclitaxel with gemcitabine improved response rates and survival in metastatic pancreatic cancer and are now being used in earlier stages for patients with localized potentially resectable and unresectable disease, with goals of downstaging tumors to allow margin-negative resection and reducing systemic recurrence. Chemoradiotherapy, although still controversial for both resectable and unresectable pancreatic cancer, is being used in the context of contemporary chemotherapy backbone regimens, and novel radiation techniques such as stereotactic body frame radiation therapy (SBRT) are studied on the premise of maintaining or improving efficacy and reducing treatment duration. Patient selection for optimal treatment designation is currently provided by multidisciplinary tumor boards, but biomarker discovery, in blood, tumors, or through novel imaging, is an area of intense research. Results to date suggest that some patients with unresectable disease at the outset have survival rates as good as those with initially resectable disease if able to undergo surgical resection. Long-term follow-up and improved clinical trials options are needed to determine optimal treatment modalities for patients with localized pancreatic cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Pancreatectomy; Pancreatic Neoplasms; Radiosurgery

FOLFIRINOX prolongs survival in patients with metastatic pancreatic cancer and may also benefit patients with locally advanced pancreatic cancer (LAPC). Furthermore, it may downstage a proportion of LAPC into (borderline) resectable disease, however data are lacking. This review assessed outcomes after FOLFIRINOX-based therapy in LAPC.. The PubMed, EMBASE and Cochrane library databases were systematically searched for studies published to 31 August 2015. Primary outcome was the (R0) resection rate.. Fourteen studies involving 365 patients with LAPC were included; three studies administered a modified FOLFIRINOX regimen. Of all patients, 57 % (n = 208) received radiotherapy. The pooled resection rate was 28 % (n = 103, 77 % R0), with a perioperative mortality of 3 % (n = 2), and median overall survival ranged from 8.9 to 25.0 months. Survival data after resection were scarce, with only one study reporting a median overall survival of 24.9 months in 28 patients. A complete pathologic response was found in 6 of 85 (7 %) resected specimens. Dose reductions were described in up to 65 % of patients, grade 3-4 toxicity occurred in 23 % (n = 51) of patients, and 2 % (n = 5) had to discontinue treatment. Data of patients treated solely with FOLFIRINOX, without additional radiotherapy, were available from 292 patients: resection rate was 12 % (n = 29, 70 % R0), with 15.7 months median overall survival and 19 % (n = 34) grade 3-4 toxicity.. Outcomes after FOLFIRINOX-based therapy in patients with LAPC seem very promising but further prospective studies are needed, especially with regard to survival after resection.

Topics: Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Camptothecin; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Radiotherapy; Radiotherapy, Adjuvant; Survival Rate

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a median 5-year survival of <8%. At the time of diagnosis, a vast majority of pancreatic cancer patients were found to be with either metastatic spread of the disease or locally advanced tumors. Despite relatively low efficacy, gemcitabine administration was the first choice chemotherapeutic strategy in advanced PDAC for many years. In the last 5 years, however, our understanding of pancreatic carcinogenesis has improved dramatically and with this our therapeutic options have expanded significantly.. With the FOLFIRINOX protocol or the combination of gemcitabine and nab-paclitaxel, 2 novel and more effective chemotherapeutic regimens have been introduced in clinical routine, which increased the overall survival by 4-5 months in the palliative situation. Most recently, we learned that both regimens can be modified and dosages can be adapted in older patients without significant loss of efficacy. Additionally, novel application strategies such as nanoparticle fused liposomal irinotecan along with 5-FU/LV provided convincing results in patients previously treated with gemcitabine. Current preclinical and clinical trials investigate efficacy and tolerability of novel drugs aiming at the inhibition of key inflammatory pathways, for example, JAK-STAT signaling, or the tumor surrounding desmoplasia. Prospectively, immunovaccination approaches or immune checkpoint inhibition appears as promising strategies in the near future, particularly when combined with epigenetic drugs in advanced PDAC patients. In this 'to-the-point' article, we review the current standard and summarize the most recent and encouraging advances in cytostatic PDAC treatment.. (1) FOLFIRINOX and nab-paclitaxel/gemcitabine as first-line treatment regime significantly increase survival in patients with advanced PDAC; (2) Selection of appropriate treatment regime depends on patient performance, comorbidity, and toxicity; (3) PDAC patients will benefit from second-line chemotherapy and selection of appropriate regimes depends on first line therapy and patient criteria; (4) Future therapeutic strategies in advanced PDAC will respect molecular tumor profiling and other biomarkers.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Clinical Trials as Topic; Deoxycytidine; Disease-Free Survival; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Nanoparticles; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Palliative Care; Pancreatic Neoplasms

Pancreatic cancer is an extremely aggressive disease; although progress has been made in the last few years, the prognosis of these patients remains dismal. FOLFIRINOX is now considered a standard treatment in first-line setting, since it demonstrated an improved overall and progression-free survival vs gemcitabine alone. However, the enthusiasm over the benefit of this three-drug regimen is tempered by the associated increased toxicity profile, and many efforts have been made to improve the feasibility of this schedule. After a more recent phase III trial showing an improved outcome over gemcitabine, the combination of gemcitabine/nab-paclitaxel emerged as another standard first-line treatment. However, this treatment is also associated with more side effects. In addition, despite initial promising data on the predictive role of SPARC levels, recent studies showed that these levels are not associated with nab-paclitaxel efficacy. The choice to use this treatment over FOLFIRINOX is therefore a topic of debate, also because no validated biomarkers to guide FOLFIRINOX treatment are available. In the era of actionable mutations and target agents it would be desirable to identify molecular factors or biomarkers to predict response to therapy in order to maximize the efficacy of treatment and avoid useless toxic effects for non-responding patients. However, until today the milestone of treatment for pancreatic cancer remains chemotherapy combinations, without predictive or monitoring tools existing to optimize therapy. This review analyzes the state-of-the-art treatments, promises and limitations of targeted therapies, ongoing trials and future perspectives, including potential role of microRNAs as predictive biomarkers.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; ErbB Receptors; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Precision Medicine; Translational Research, Biomedical; Vascular Endothelial Growth Factor A

A systematic review and critical evaluation of randomized trial evidence for oxaliplatin- or irinotecan-containing regimens in patients with advanced pancreatic cancer previously treated with gemcitabine has not yet been published. We conducted a comparative systematic review of randomized trials evaluating oxaliplatin- or irinotecan-based therapies in patients with advanced pancreatic cancer previously treated with gemcitabine to assess trial similarity and the feasibility of performing an indirect treatment comparison (ITC). Studies were identified through PubMed and key oncology conference abstracts. The following trials met our criteria: NAPOLI-1 (nanoliposomal irinotecan [nal-IRI] or nal-IRI+5-fluorouracil [5-FU]/leucovorin [LV] vs 5-FU/LV), CONKO-003 (oxaliplatin+5-FU/LV [OFF] vs 5-FU/LV), PANCREOX (oxaliplatin+5-FU/LV [mFOLFOX6] vs 5-FU/LV), and Yoo et al. (2009) (irinotecan+5-FU/LV [mFOLFIRI3] vs mFOLFOX). Fundamental differences were identified in study design (i.e., number of study sites, number of countries), patient (i.e., locally advanced vs metastatic disease, stratification variables, prior and subsequent treatments) and treatment (i.e., regimens, dose intensity) characteristics, and primary and secondary outcomes (i.e., primary vs secondary outcomes, overall survival [OS], progression-free survival [PFS]) among the 4 included trials. Our comparative review demonstrated significant dissimilarity across trials, which precluded conducting an ITC. In the absence of head-to-head nal-IRI- and/or oxaliplatin-based therapy trials, clinicians are advised to interpret these studies separately within the context of their individual patient population.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Deoxycytidine; Disease-Free Survival; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Liposomes; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Randomized Controlled Trials as Topic

Pancreatic cancer is one of the deadliest cancers, ranking fourth among cancer-related deaths. Despite all the major molecular advances and treatment breakthroughs, mainly targeted therapies, the cornerstone treatment of metastatic pancreatic cancer (mPC) remains cytotoxic chemotherapy. In 2016, more than 40 years after the introduction of gemcitabine in the management of mPC, the best choice for first-line treatment has not yet been fully elucidated. Two main strategies have been adopted to enhance treatment efficacy. The first strategy is based on combining non-cross resistant drugs, while the second option includes the development of newer generations of chemotherapy. More recently, two new regimens, FOLFIRINOX and gemcitabine/nab-paclitaxel (GNP), have both been shown to improve overall survival in comparison with gemcitabine alone, at the cost of increased toxicity. Therefore, the best choice for first line therapy is a matter of debate. For some authors, FOLFIRINOX should be the first choice in patients with an Eastern Cooperative Oncology Group score (0-1) given its lower hazard ratio. However, others do not share this opinion. In this paper, we review the main comparison points between FOLFIRINOX and GNP. We analyze the two pivotal trials to determine the similarities and differences in study design. In addition, we compare the toxicity profile of the two regimens as well as the impact on quality of life. Finally, we present studies revealing real life experiences and review the advantages and disadvantages of possible second-line therapies including their cost effectiveness.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Drug-Related Side Effects and Adverse Reactions; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Quality of Life; Treatment Outcome

FOLFIRINOX (FFX) was introduced to clinical practice in 2010 following publication of the PRODIGE 4/ACCORD 11 study, which compared this novel regimen to gemcitabine in metastatic pancreatic cancer. Median overall survival, progression-free survival, and objective responses were all superior with FFX and there was improved time to definitive deterioration in quality of life. Despite initial concerns over toxicity, there has been rapid uptake of this regimen, both revolutionizing management and opening the door to innovative research. As experience with FFX has accrued, many questions have arisen including the management of toxicities, the impact of frequent modifications, the optimal number of cycles, integration with other regimens and modalities, interpretation of radiologic and serologic response, utility of molecular signatures, and potential benefit in unique clinical settings such as pre- and postsurgery. This review will closely examine these issues, not only to summarize current knowledge but also to fuel scientific debate.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemoradiotherapy; Clinical Trials, Phase III as Topic; Drug Administration Schedule; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Patient Care Planning; Postoperative Care; Preoperative Care; Randomized Controlled Trials as Topic; Treatment Outcome

The use of neoadjuvant chemotherapy can enable surgical resection of borderline resectable or unresectable pancreatic cancer (PC). The aim of this study was to evaluate the effectiveness of the multiagent 5-fluorouracil + oxaliplatin + irinotecan + leucovorin (FOLFIRINOX) regimen as a neoadjuvant treatment for PC.. Studies in which FOLFIRINOX with or without radiotherapy was given before surgery to patients with borderline resectable or unresectable PC were analyzed using a meta-analytical approach. The primary outcomes were resection rate and radical (R0) resection rate. Data were expressed as weighted pooled proportions with 95% confidence intervals (CIs).. Thirteen studies, with a total of 253 patients, were included in this meta-analysis. After undergoing the treatment, 43% (95% CI, 32.8-53.8) of patients were resected and 39.4% (95% CI, 32.4-46.9) underwent R0 resection (85% of surgical specimens). In particular, among borderline resectable PCs, R0 resection was possible in 63.5% (95% CI, 49%-76%) of the cases. The rate of R0 resection in unresectable PCs was 22.5% (95% CI, 13.3-35.4).. This meta-analysis shows that down-staging after neoadjuvant FOLFIRINOX-based therapy is noticeable in patients with borderline resectable/unresectable PC, with a total R0 resection rate of 40%.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Treatment Outcome

There have been many clinical trials conducted to evaluate novel systemic regimens for unresectable pancreatic cancer. However, most of the trial results were negative, and gemcitabine monotherapy has remained the standard systemic treatment for years. A number of molecular targeted agents, including those against epidermal growth factor receptor and vascular endothelial growth factor receptors, have also been tested. In recent years, there have been some breakthroughs in the deadlock: three regimens, namely gemcitabine-erlotinib, FOLFIRINOX, and gemcitabine-nab-paclitaxel, have been shown to prolong the overall survival of patients when compared with gemcitabine monotherapy. In addition, emerging data suggested that the membrane protein human equilibrative nucleotide transporter 1 is a potential biomarker with which to predict the efficacy of gemcitabine. Here we review the literature on the development of systemic agents for pancreatic cancer, discuss the current choices of treatment, and provide future directions on the development of novel agents.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Equilibrative Nucleoside Transporter 1; ErbB Receptors; Erlotinib Hydrochloride; Fluorouracil; Gemcitabine; Humans; Leucovorin; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms; Quinazolines; Receptors, Vascular Endothelial Growth Factor

Treatment of metastatic and locally advanced pancreatic cancer has made slow progress during the last decade. Single agent gemcitabine or in combination with capecitabine or erlotinib remained the preferred systemic treatment options until 2010 when the ACCORD study demonstrated significantly improved outcomes achieved with FOFIRINOX compared with gemcitabine monotherapy. Since 2010, use of FOLFIRINOX has increased both in metastatic and locally advanced cancer. Despite its gaining popularity among oncologists, unanswered questions remain. Do the often necessary dose modifications affect its efficacy? Are the toxicities manageable and how applicable are the results of the ACCORD study in the general population of patients with newly diagnosed pancreatic cancer? In the present manuscript, we review the published literature regarding the use of FOLFIRINOX, the challenges associated with its use and how it will be optimally incorporated into the management of patients with different stages of pancreatic cancer and ultimately, in a more biomarker-driven pathway algorithm.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

Treatment of locally advanced pancreatic cancer is palliative, based on chemotherapy and according to response, chemoradiotherapy can be applied. The authors summarize three abstracts (#LBA146, #256 and #303) presented on the 2013 ASCO Gastrointestinal Cancers Symposium, which were focused on treatment of locally advanced pancreatic cancer. A discussion is presented about the different chemotherapy or chemoradiotherapy regimens, that move away from gemcitabine-based treatment, and the effort to find less toxic, but efficient therapeutic combinations.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase II as Topic; Deoxycytidine; Disease Progression; Fluorouracil; Gemcitabine; Humans; Leucovorin; Neoplasm Invasiveness; Organoplatinum Compounds; Pancreatic Neoplasms; Randomized Controlled Trials as Topic

Metastatic pancreatic cancer is a rapidly fatal disease with few therapeutic options. The authors summarize four abstracts (#148, #233, #158, #291) presented at the 2013 ASCO Gastrointestinal Cancers Symposium which were focused on novel agents for metastatic pancreatic cancer.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Deoxycytidine; Erlotinib Hydrochloride; Fluorouracil; Gemcitabine; Humans; Leucovorin; Neoadjuvant Therapy; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms; Quinazolines; Randomized Controlled Trials as Topic

Topics: Albumins; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Deoxycytidine; Drug Combinations; Erlotinib Hydrochloride; Fluorouracil; Gemcitabine; Humans; Leucovorin; Organoplatinum Compounds; Oxonic Acid; Paclitaxel; Pancreatic Neoplasms; Quinazolines; Tegafur

Although FOLFIRINOX significantly increases survival in metastatic pancreatic cancer (MPC) compared to gemcitabine (Conroy et al. N Engl J Med 364:1817-1825, 2011), toxicities have tempered enthusiasm for its use in full doses. To assess the impact of dose attenuations on toxicity and efficacy, we reviewed our institution's experience with FOLFIRINOX in locally advanced pancreatic cancer (LAPC) and MPC. We performed a retrospective review of dose, toxicity, and efficacy of FOLFIRINOX in all patients with LAPC and MPC treated between June 2010 and July 2011 at Yale. Toxicities in all patients and response rate (RR) and survival in previously untreated MPC were compared to data reported by Conroy. Overall survival (OS) and progression-free survival were estimated by Kaplan-Meier method. Thirty-five patients were treated (16 LAPC; 19 MPC). Twenty-nine patients received dose attenuations with the first cycle. Median relative doses of irinotecan and bolus fluorouracil were less than those reported by Conroy (64 vs. 81 % and 66 vs. 82 %, respectively). RR was 50 % in LAPC and 47 % in MPC, and the latter did not differ significantly from the RR reported by Conroy (p = 0.19). OS at 6 and 12 months in MPC was comparable to OS reported by Conroy. Grade 3/4 toxicities were less than reported by Conroy, including fatigue (p = 0.009) and neutropenia (p < 0.0001). Nine patients experienced transient dysarthria during irinotecan administration. Our findings validate the efficacy and tolerability of FOLFIRINOX in LAPC and MPC and suggest that dose attenuations of irinotecan and bolus fluorouracil improve tolerability without compromising efficacy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Disease-Free Survival; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

In 2010, the FOLFIRINOX regimen (bolus and infusional 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) emerged as a new option in patients with metastatic pancreatic cancer and a good performance status. However, at that time, some doubts were raised regarding safety issues. Similarly, no data on FOLFIRINOX were published in patients with unresectable/locally advanced or borderline resectable pancreatic cancer. This article presents the available experience with FOLFIRINOX outside clinical trials in metastatic and locally advanced pancreatic cancer patients. The safety of the regimen in patients with biliary stents and in previously treated patients is also described. FOLFIRINOX usage in clinical practice, including modification of the regimen (omission of bolus 5-fluorouracil; FOLFOXIRI regimen), is also presented. These data suggest that a phase III randomized study is warranted to further explore the role of FOLFIRINOX in locally advanced pancreatic cancer.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials as Topic; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Acinar Cell; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Pancreatic Neoplasms; Prostatic Neoplasms; Review Literature as Topic; Tomography, X-Ray Computed; Treatment Outcome

Currently gemcitabine-based regimens and FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) are widely used standard for first-line treatment of patients with advanced pancreatic adenocarcinoma. Refractory patients may receive either FOLFOX (5-fluorouracil and oxaliplatin) or gemcitabine based on the first line regimen. This review is an update from the 2012 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium regarding recent developments in the treatment of refractory pancreatic cancer, as these were presented in Abstracts #248 and #373 of the meeting.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Drug Resistance, Neoplasm; Fluorouracil; Gemcitabine; Humans; Leucovorin; Organoplatinum Compounds; Pancreatic Neoplasms

Topics: Adenocarcinoma; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dexamethasone; Diabetes Mellitus, Type 2; Disease Management; Drug Resistance; Drug Therapy, Combination; Exenatide; Fluorouracil; Humans; Hyperglycemia; Hyperglycemic Hyperosmolar Nonketotic Coma; Hypoglycemic Agents; Insulin; Leucovorin; Male; Malnutrition; Metformin; Middle Aged; Nausea; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Pancreatectomy; Pancreatic Neoplasms; Peptides; Sulfonylurea Compounds; Venoms

Pancreatic cancer is usually detected at an advanced stage and responds poorly to treatment. In 2010 new insights were gained into understanding the complex biology of pancreatic cancer. Importantly, these insights offer novel opportunities for early diagnosis and treatment of this disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; DNA, Neoplasm; Fluorouracil; Genomic Instability; Humans; Leucovorin; Pancreatic Neoplasms; Vitamin B Complex

The outcome for patients with metastatic pancreatic ductal adenocarcinoma is dismal. In this article, we will review current first-line treatments for metastatic pancreatic adenocarcinoma focusing on phase III randomized studies. Single-agent gemcitabine, the reference treatment since 1995, offers only slight benefit. Numerous trials using gemcitabine in combination with different cytotoxic agents have resulted in no major improvement compared to gemcitabine alone. Only the gemcitabine-erlotinib combination has shown a small, but statistically improvement in survival. In selected patients with good performance status ECOG 0-1, no cardiac ischemia and almost normal bilirubin level, the Folfirinox regimen, when compared to gemcitabine as single agent, was associated with more toxicities, but also with significant increased survival and delay in the degradation of quality of life. So, Folfirinox is a new more toxic and more efficient regimen that may be considered in patients with good performance status.

Topics: Angiogenesis Inhibitors; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Clinical Trials, Phase III as Topic; Deoxycytidine; ErbB Receptors; Erlotinib Hydrochloride; Fluorouracil; Gemcitabine; Humans; Leucovorin; Organoplatinum Compounds; Pancreatic Neoplasms; Quinazolines; Randomized Controlled Trials as Topic

Advanced pancreatic cancer is usually treated with first-line gemcitabine (GEM) (alone or in combination). More recently, GEM has become an established part of an adjuvant therapy based on two recently-reported randomized trials. There remains unresolved the problem of second-line therapy in patients relapsed during or after adjuvant or first-line GEM-based treatment. As of today, platinum analogues in combination with fluoropyrimidine or with GEM represent the most common schedule in clinical practice with data from single-centre or multicentric phase II studies. In 2008, for the first time, a randomized phase III trial conducted on good performance status GEM-refractory patients (CONKO 003) confirmed their benefit in progression-free and overall survival by adding oxaliplatin to a bolus 5-FU/folinic acid schedule. Other agents (irinotecan, taxanes, antifolates, biological) have been tested, although only dismal results have been achieved, as they turned out to be too toxic in combination and to have too low activity when used as single agents. Which the optimal candidate is for second-line therapies, is debatable. Good performance status and discrete progression-free survival since the beginning of the GEM therapy (more than 6 months?) are likely to be the best indicators of subsequent line benefit. The benefit of biological agents is unknown, also given the poor results achieved in the first-line treatment. In summary, as of today, there is one randomized study that confirms the benefit of second-line chemotherapy for the treatment of GEM-relapsed pancreatic cancer. Current data indicate 5-FU plus a platinum agent (oxaliplatin) as the standard of care for PS 0-1 patients. Ongoing clinical trials will clarify whether there is obviously a place for improvement and for other agents. At present, even though no data on benefits in unfit patients (Karnofsky < 70) are available, a fluopyrimidine agent still remains a reasonable treatment option.

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease Progression; Fluorouracil; Gemcitabine; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Pyrimidines; Randomized Controlled Trials as Topic; Survival Rate

A woman in her fifties underwent a right hemicolectomy (D3) for cancer of the ascending colon in October 2007, definitively and pathologically diagnosed as papillary adenocarcinoma invading to the subserosa, and no metastasis was detected to lymph node. But 13 months after the surgery, she was found to have a mass near the anastomosis by an abdominal CT scan. Colonoscopy showed an evaluating lesion with ulcer in the anal side of the anastomosis. We tried to resect the metastasis, but it was not resectable because of the invasion to the pancreas. The mFOLFOX regimen was effective. After the chemotherapy (6 courses), we decided to perform a radical resection. We conducted pancreatoduodenectomy in May 2009. She is still alive 12 months after surgery.

Topics: Adenocarcinoma, Papillary; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Duodenum; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Pancreatectomy; Pancreatic Neoplasms

The ESPAC-1, ESPAC-1 plus, and early ESPAC-3(v1) results (458 randomized patients; 364 deaths) were used to estimate the effectiveness of adjuvant 5FU/FA vs resection alone for pancreatic cancer using meta-analysis. The pooled hazard ratio of 0.70 (95% CI=0.55-0.88) P=0.003, and the median survival of 23.2 (95% CI=20.1-26.5) months with 5FU/FA vs 16.8 (95% CI=14.3-19.2) months with resection alone supports the use of adjuvant 5FU/FA in pancreatic cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Prognosis; Randomized Controlled Trials as Topic; Survival Rate; Treatment Outcome

Despite attempted curative resection of localized pancreatic adenocarcinoma, most patients succumb a recurrence and die of their disease. The Gastrointestinal Tumor Study Group, European Organization for Research and Treatment of Cancer, and European Study Group for Pancreatic Cancer trials have suggested the benefit of adjuvant therapy. However, the relatively few randomized trials available have not established a definite standard of care due to study limitations. Although these trials, and the recently published Charité Onkologie (CONKO)-001 trial, have shown a definite advantage of adjuvant chemotherapy, the most effective chemotherapy and the role of radiation therapy remain unclear. This review will discuss the data available from reported trials of adjuvant therapy in pancreatic cancer, especially the results of the ESPAC-3 study presented at the annual meeting of ASCO 2009, and consider future directions for clinical trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Combined Modality Therapy; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Pancreatic Neoplasms; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic

Whereas first-line chemotherapy (CT) with single-agent gemcitabine or gemcitabine-based combinations provides a proven benefit in patients with locally advanced or metastatic pancreatic cancer (PC), the role of salvage CT after gemcitabine-failure is not well-established and to date no regimen has emerged as preferred in this setting. Several clinical trials have investigated the efficacy and toxicity-profile of second-line CT and indicated that selected patients may obtain significant benefit from it, also with regard to survival. However, definitive results from large randomized phase III studies are still lacking, and the evidence for clinical benefit of salvage CT is based on small phase II trials that evaluated different treatment schedules in heterogeneous populations. The main goal of this paper is reviewing this topic.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Deoxycytidine; Drug Resistance, Neoplasm; Fluorouracil; Gemcitabine; Humans; Leucovorin; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Platinum Compounds; Predictive Value of Tests; Prognosis; Research Design; Risk Assessment; Risk Factors; Salvage Therapy; Survival Analysis

Pancreatic cancer is one of the major causes of cancer death. The majority of patients present with advanced disease and only 10-15% of patients can undergo resection. Survival after curative surgery is poor, as recurrences occur either locally or in the liver. Adjuvant therapy aims to improve survival and control systemic disease. Based on the results from the ESPAC-1 and Oettle studies, there is a significant survival advantage with 5-fluorouracil/folinic acid and a survival advantage trend with gemcitabine compared to surgery alone. The survival advantage of adjuvant chemotherapy is still observed when incorporated into an individual patient data meta-analysis. Based on the EORTC and ESPAC-1 trial results there is no significant evidence for the use of adjuvant chemoradiation. The use of chemoradiation with follow on chemotherapy, has not been shown to be superior to chemotherapy alone based on the results of the underpowered 1987 GITSG study and a recent combination study from the USA. The standard of care for adjuvant therapy based on level I evidence (from the ESPAC-1 trial) is postoperative chemotherapy using 5-fluorouracil with folinic acid providing a best estimate of 29% 5-year survival.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Neoadjuvant Therapy; Pancreatic Neoplasms; Radiotherapy, Adjuvant; Survival Analysis

Pancreatic cancer is a devastating disease with a poor prognosis for most patients. Surgical resection remains the cornerstone of treatment, providing the only realistic hope of long-term survival. Even with optimal surgical management, 5-year survival averages 15% to 20% for resectable disease. Progress is being made, however. Currently, the benefits of postoperative therapy for resected pancreatic ductal adenocarcinoma appear clear, and recommendations for such therapy appear to us to be well justified. Additional benefit to patients awaits the development of new agents, molecular targeted drugs, and novel approaches such as immunotherapy.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Chemotherapy, Adjuvant; Clinical Trials as Topic; Combined Modality Therapy; Drug Administration Schedule; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leucovorin; Pancreatectomy; Pancreatic Neoplasms; Radiotherapy Dosage; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Survival Rate

Colorectal cancers have been the first cancers to benefit from an efficient anti-angiogenic treatment, represented by bevacizumab, which has been approved for first-line metastatic treatment in combination with reference chemotherapies and which is under study in the adjuvant setting. Other gastro-intestinal malignancies appear less responsive to anti-angiogenic therapy, but inhibitors of the VEGF receptors (sorafenib, sunitinib, axitinib) are in development with encouraging results. The safety profile of anti-angiogenic agents is quite different from that of classical chemotherapy and may require a modification of treatment strategies.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma, Hepatocellular; Colorectal Neoplasms; Esophageal Neoplasms; Fluorouracil; Gastrointestinal Neoplasms; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Neovascularization, Pathologic; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Stomach Neoplasms

Following the successful introduction of oxaliplatin into the management of advanced colorectal cancer, its clinical utility is currently being investigated in a variety of other malignancies, including cancers of the upper gastrointestinal tract. In advanced pancreatic cancer, oxaliplatin has been found to be clinically effective in phase II trials in which it was combined with either 5-fluorouracil (5-FU) or gemcitabine, the current standard chemotherapy for this disease. In a phase II trial involving 67 patients, the combination of oxaliplatin and 5-FU in a high dose infusional regimen (n = 31) achieved an objective response rate of 9.7%, stable disease for at least three cycles in 48.4% of patients, tumour growth control in 58% of patients, a median time to progression of 4.9 months and median overall survival reaching 9.2 months. In combination with gemcitabine in a phase II trial involving 64 patients with metastatic (n = 34) or locally advanced (n = 30) pancreatic cancer, there was an objective response rate of 30.6%, treatment benefit in 39.7%, a median progression-free survival of 5.3 months and again a median overall survival of 9.2 months. Response rates and survival times did not differ between locally advanced and metastatic disease. On the basis of these encouraging results, phase III studies of oxaliplatin in advanced pancreatic cancer are now in progress in Europe and the United States. In metastatic gastric cancer, a phase II study investigated the combined use of oxaliplatin and 5-FU using the FOLFOX6 regimen in 53 patients, of whom 49 were evaluable for efficacy. The objective response rate was 44.9% and the median duration of response was 7.9 months. Large phase III trials of oxaliplatin-based treatment for advanced gastric cancer are now in progress. Oxaliplatin is also being investigated in oesophageal cancer and several other gastrointestinal tumours. In summary, oxaliplatin is emerging as an effective and highly promising chemotherapeutic agent for the treatment of upper gastrointestinal malignancies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease Progression; Esophageal Neoplasms; Fluorouracil; Gemcitabine; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Stomach Neoplasms; Survival Rate

Recent advances have been made in the treatment of pancreas cancer. Specialized pancreas centres have reported an increasing rate of resections with reduced postoperative mortality. On account of the highly aggressive nature of pancreas cancer, there is a great challenge in identifying effective therapy concepts for advanced stages of the cancer as well as for the development of resection-associated measures. As large-scale, randomised, controlled studies are lacking, the additive therapy concepts after resection do not have a sufficiently scientific basis. The ESPAC-1 study, which included 600 patients, surpassed all previous studies on adjuvant therapy for pancreas cancer. This study has shown,for example, that the most promising adjuvant chemotherapy with 5-fluorouracil and folic acid leads to an equal if not better result than the multimodal regimen. This regimen can be superseded with the use of Gemcitabine, which will be evaluated in the ESPAC-3 study that includes 990 patients from various European countries including Germany, as well as from Canada and Australia. Participation in the large, phase-3 study therefore plays a key role in the continued development of the management of pancreas cancer.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Chemotherapy, Adjuvant; Clinical Trials as Topic; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Controlled Clinical Trials as Topic; Deoxycytidine; Doxorubicin; Female; Fluorouracil; Folic Acid; Gemcitabine; Hematinics; Humans; Leucovorin; Male; Mitoxantrone; Multicenter Studies as Topic; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Pancreatic Neoplasms; Quality of Life; Radiotherapy Dosage; Randomized Controlled Trials as Topic; Retrospective Studies; Surveys and Questionnaires; Time Factors

Neoadjuvant radiochemotherapy in patients suffering from pancreatic cancer is presently not well established. Neoadjuvant radiochemotherapy is recommended to be applied in 5-8 weeks. The full dose of radiotherapy is between 50 and 54 Gy with 5FU used as radiosensitator. In patients with resectable pancreatic cancer, particularly in UICC-stage II neoadjuvant radiochemotherapy, this results in an improvement in survival: the median survival is between 15 and 30 months. In about 15% of the patients with resectable pancreatic cancer (UICC I-III), neoadjuvant radiochemotherapy results in downstaging. In combination with a R0-resection,neoadjuvant radiochemotherapy effects a reduction of local recurrence. Results from controlled clinical trials are necessary to objectify the benefits of neoadjuvant radiochemotherapy.

Topics: Adult; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Case-Control Studies; Child; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Controlled Clinical Trials as Topic; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Neoadjuvant Therapy; Neoplasm Metastasis; Pancreatectomy; Pancreatic Neoplasms; Postoperative Complications; Prospective Studies; Radiation-Sensitizing Agents; Radiotherapy Dosage; Streptozocin; Time Factors

Pancreatic cancer is one of the most frequently reported gastrointestinal tumors and has been reported to have a 5-year survival rate of < 5%. It is most commonly diagnosed at an advanced stage and until recently, the most frequently administered treatment for patients with advanced disease has been palliative 5-fluorouracil (5-FU)-based chemotherapy. However, in clinical trials, the novel antinucleoside gemcitabine is currently considered the standard of care and has demonstrated both a survival benefit over 5-FU and an improvement in disease-related symptoms in those patients with advanced disease. The current review presents an overview of recently completed and ongoing clinical trials of gemcitabine/5-FU combination therapy for pancreatic cancer. In these trials, the administration of 5-FU varied widely from bolus injection to 24-hour infusion to protracted infusion over several weeks. These variations make a definitive judgment of this combination difficult, especially because the majority of the data represent only Phase I and Phase II study results. Although a recently completed randomized Phase III trial of gemcitabine plus bolus 5-FU versus gemcitabine failed to show a clinically meaningful survival benefit for the combination arm, current data indicate that other gemcitabine/5-FU combinations might provide a therapeutic advantage over gemcitabine alone. However, the results of ongoing Phase III studies must be reviewed before a definitive statement can be made regarding the value of this combination in the treatment of pancreatic cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

Phase II trials of combination chemotherapies have shown encouraging palliative benefit, objective response rates, and survival outcomes. Until ongoing phase III trials confirm these benefits, the current standard treatment for metastatic pancreatic adenocarcinoma remains single agent gemcitabine. The fixed rate infusion schedule of 10 mg/m2/min is gaining wide acceptance and is a promising investigational priority. A very reasonable alternative to single agent gemcitabine, and our bias, is enrollment into clinical trials evaluating novel gemcitabine-based combinations. Further investigation is needed to determine optimal incorporation of so-called targeted therapy with combination chemotherapy.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Camptothecin; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Deoxycytidine; Docetaxel; Enzyme Inhibitors; Epirubicin; Fluorouracil; Gemcitabine; Hemolytic-Uremic Syndrome; Humans; Interferon alpha-2; Interferon-alpha; Irinotecan; Leucovorin; Multicenter Studies as Topic; Organoplatinum Compounds; Paclitaxel; Palliative Care; Pancreatic Neoplasms; Recombinant Proteins; Respiratory Distress Syndrome; Taxoids; Treatment Outcome

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Biopsy; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Cholangiopancreatography, Endoscopic Retrograde; Clinical Trials as Topic; Fluorouracil; Genetic Therapy; Humans; Leucovorin; Lymph Node Excision; Magnetic Resonance Imaging; Palliative Care; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy; Postoperative Period; Prospective Studies; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Survival Analysis; Time Factors; Tomography, X-Ray Computed

Between July 1990 and September 1993, 32 patients with locally advanced irresectable adenocarcinoma of the pancreas, histologically proven by laparotomy, were involved in our study. Patients were treated with hyperfractionated, accelerated radiotherapy and simultaneous application of 5-fluorouracil and folinic acid. Chemotherapy was given on days 1,2 and 3. Determination of the target volume for radiotherapy was carried out by computerized axial tomography. The total tumour dose of 44.8 Gy was applied relative to the 90% isodose in two daily fractions of 1.6 Gy, resulting in ten fractions per week. On the first three days of radiotherapy, 600 mg m-3 of 5-fluorouracil and 300 mg m-3 of folinic acid were given i.v. According to response, chemotherapy was repeated in 4-week intervals. The median survival time for all patients was 12.7 months, compared with 3-7 months after palliative surgery (historical control). The median progression-free interval was 6.6 months. Toxicity and therapy-induced morbidity were recorded according to WHO criteria. Nausea and vomiting of WHO grade I and II occurred in 72.1% and of grade III and IV in 27.9% of the patients. WHO grade I and II diarrhoea was seen in 11 patients. The overall incidence of leucopenia and thrombocytopenia was 37.4%; severe side-effects (WHO III-IV) occurred in 9.3% of all patients. One patient experienced a severe mucositis (WHO III). This combined modality treatment consisting of accelerated hyperfractionated radiotherapy and chemotherapy turned out to be feasible for patients with locally advanced, irresectable pancreatic cancer. The therapy could be applied in a short period of time, approximately half the time used in conventional therapy schemes.

Topics: Adenocarcinoma; Aged; Antidotes; Antimetabolites, Antineoplastic; Combined Modality Therapy; Disease-Free Survival; Feasibility Studies; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Radiotherapy Dosage; Weight Loss

Pancreatic cancer is an aggressive disease and its patients typically have a short survival, usually marked by pain and rapid debilitation. The disease has been considered relatively chemoresistant, although many chemotherapy regimens have been described.. Clinical results with chemotherapy, since the first publication of response in 1960, were reviewed for efficacy and toxicity. Emphasis was given to prospective trials with adequate power and clear evaluation criteria and endpoints.. Published response rates vary enormously in this disease, with rates in earlier single-institution trials tending to be much higher than those in studies with stringent response criteria, particularly recent cooperative group trials. Using stringent criteria, the upper limit of the objective response rate is approximately 20%. No convincing improvements in median survival can yet be attributed to chemotherapy. Few trials have measured quality of life, but symptomatic palliation rates may exceed objective response rates. Some low-toxicity regimens (such as those based on infusional 5-FU) yield response rates as high as some more toxic combinations.. Many early trials significantly overstate the efficacy of chemotherapy for patients with pancreatic cancer, apparently due to flexibility of response criteria. However, useful symptomatic palliation may occur even without an objective partial response. It is possible that slow resolution of the desmoplastic component of these tumors may underestimate tumor killing. Thus, quality of life is an important parallel endpoint (with survival and response) in chemotherapy trials in this disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Pancreatic Neoplasms

Few antitumor agents are effective for advanced pancreatic cancer. 5-fluorouracil, doxorubicin, epirubicin, and mitomycin C were tested as single agents for their respective efficacy against pancreatic cancer. Their response rates were 15, 12, 24 and 24%, respectively. Several trials of combination chemotherapy using mitomycin C, doxorubicin and 5-FU (FAM) were performed, but their response rates did not go exceed those of single agents. Recently, the goal of chemotherapy for pancreatic cancer is thought to be quality of life. Combination of 5-FU and cisplatin or 5-FU, leucovorin and alpha interferon were effective for the prolongation of life with less toxicities. Their median survival times were 7.6 months, and 22 months in PR cases, respectively. CPT-11, gemcitabine, taxotere and BOF-A2 are promising new drugs for their effectiveness and benefits for patients with pancreatic cancer. Combination of mitomycin C, carboquone and 5-FU with angiotensin II was effective in terms of antitumor effect and prolongation of life. Generally, a large number of patients with advanced pancreatic cancer cannot receive chemotherapy because of deterioration in performance status. For them, combination of continuous venous infusion of low-dose 5-FU and low-dose cisplatin could be effective. The majority of patients with pancreatic cancer must await new agents and methodology in the future.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Deoxycytidine; Docetaxel; Fluorouracil; Gemcitabine; Humans; Interferon-alpha; Irinotecan; Leucovorin; Paclitaxel; Pancreatic Neoplasms; Quality of Life; Taxoids

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Humans; Leucovorin; Liver Neoplasms; Lymphoma, B-Cell; Male; Methotrexate; Neoplasm Invasiveness; Pancreatic Neoplasms; Prednisone; Remission Induction; Retroperitoneal Neoplasms; Stomach Neoplasms; Vincristine

Pancreatic, gastric, and colorectal carcinomas are diagnosed in 200,000 Americans each year. Therapeutic options for patients with advanced disease are limited; conventional chemotherapy is palliative and produces complete responses in only a few patients. Clinical research has focused on the evaluation of investigational new drugs, combination regimens, and biochemical modulation of fluorouracil. Unfortunately, the results of recent phase II studies of new agents have been disappointing. The exception is CPT-11, a topoisomerase I inhibitor, which showed promising activity in colorectal cancer (in including patients who had failed prior fluorouracil therapy). Modified regimens of fluorouracil and methotrexate with either doxorubicin alone or with epirubicin and cisplatin were associated with response rates approaching 50% in patients with gastric cancer, but appeared to be less toxic than previously published regimens. A randomized trial comparing fluororacil alone or with oral leucovorin allowed early dose escalation according to individual tolerance; the response rate to fluorouracil alone (23%) was higher than that reported in previous phase III trials, suggesting the importance of using adequate doses to produce toxicity in terms of clinical response. Hepatic arterial infusion of floxuridine was associated with a 39% response rate in colorectal cancer patients with disease confined to the liver for whom systemic fluorouracil therapy had failed, suggesting this approach is a reasonable therapeutic option in carefully selected patients.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials as Topic; Combined Modality Therapy; Digestive System Neoplasms; Double-Blind Method; Drugs, Investigational; Gastrointestinal Neoplasms; Humans; Immunologic Factors; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Neoplasm Metastasis; Pancreatic Neoplasms; Prospective Studies; Survival Rate; Treatment Outcome

5-Fluorouracil (5-FU) is one of the important antineoplastic agents for the treatment of gastrointestinal cancers. The biochemical modulation of 5-FU by various drugs has brought about the two combinations of 5-FU/folinic acid (FA) and 5-FU/alpha-interferon (IFN), which have shown clinical activity in phase II and III trials, especially in colorectal cancer. The experience with both combinations in upper gastrointestinal cancers, however, is limited. In esophageal cancer, two phase II studies with 5-FU/IFN reported seven (27%) objective remissions in 26 patients, indicating superiority of 5-FU/IFN over 5-FU monotherapy. Trials with 5-FU/FA alone are lacking in esophageal cancer. The modulation of 5-FU by IFN or FA failed to show clinically significant activity in pancreatic cancer. However, in gastric cancer, 5-FU/FA and 5-FU/IFN seem to induce higher complete and overall remission rates in advanced gastric cancer compared with 5-FU alone. With the daily times five schedule of 5-FU/FA, 27% objective remissions were achieved; in combination with other cytotoxic drugs, such as etoposide, anthracyclines, cisplatin, mitomycin, or methotrexate, objective response rates up to 50% and more were reported.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Administration Schedule; Esophageal Neoplasms; Fluorouracil; Humans; Interferon-alpha; Leucovorin; Pancreatic Neoplasms; Stomach Neoplasms

Combination chemotherapy for advanced gastrointestinal malignancies remains unsatisfactory. Studies show a definite therapeutic advantage for folinic acid/5-fluorouracil (5-FU) regimen compared with single agent 5-FU given intravenously in the management of advanced colorectal cancer. Data on survival benefits vary. A definitive conclusion regarding this question must outweigh the maturation of the present studies and possibly generate further extensive investigations. The currently available data are insufficient from which to draw any conclusion on the effect of the attempt to modulate 5-FU activity further by the addition of cisplatin to the combination. Nevertheless, the combination appears to elicit some therapeutic advantage in patients with pancreatic carcinoma and rectal carcinoma. The paucity of data in gastric carcinoma is disappointing in light of sensitivity to both cisplatin and 5-FU.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colorectal Neoplasms; Drug Evaluation; Fluorouracil; Gastrointestinal Neoplasms; Humans; Leucovorin; Meta-Analysis as Topic; Pancreatic Neoplasms; Stomach Neoplasms

Nanoliposomal irinotecan (nal-IRI) was recently authorized in Japan for unresectable pancreatic cancer after disease progression following chemotherapy. Physicians now consider certain aspects of nal-IRI safety profile as slightly different from conventional irinotecan. This report aims to explore additional aspects of the nal-IRI safety in Japanese phase 2 study.. We analyzed the incidence, time to first onset, and time to resolution for adverse events that require special attention and other selected toxicities in the nal-IRI combination group (n = 46).. Leukopenia/neutropenia (76.1%/71.7%), diarrhea (58.7%) and hepatic dysfunction (41.3%) were the most commonly reported treatment-emergent adverse events, with a median time to onset of 21.0 days (range: 8, 97), 9.0 days (1, 61) and 22.0 days (2, 325), respectively, and a median time to resolution of 8.0 days (95% confidence intervals: 8, 9), 4.0 days (4, 8) and 40.0 days (9, -), respectively. Eight patients experienced Grade ≥ 3 diarrhea and their symptoms were well controlled by dose modification except one patient who had drug withdrawal. The median time to resolution for Grade ≥ 3 and Grade ≤ 2 diarrhea was 17.5 days (95% confidence intervals: 1, 31) and 4 days (3, 7), respectively. Anorexia occurred in 28/46 patients (60.9%) with a median time to onset of 4.0 days (range: 2, 132) and a median time to resolution of 12.0 days (95% confidence intervals: 6, 26).. We explored safety profile of nal-IRI combination regimen recognized as effective and tolerable treatment for Japanese unresectable pancreatic cancer patients. Although the treatment-emergent adverse events occurred were controllable, patients with prolonged toxicities should be closely managed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Diarrhea; East Asian People; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Liposomes; Pancreatic Neoplasms

We compared the efficacy of modified 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) with that of gemcitabine plus nab-paclitaxel (GnP) for locally advanced pancreatic cancer (LAPC).. Patients with untreated LAPC were randomly assigned (1:1) to receive mFOLFIRINOX or GnP. One-year overall survival (OS) was the primary endpoint. The major secondary end-points included progression-free survival (PFS), response rate (RR), carbohydrate antigen 19-9 (CA19-9) response, and adverse events. The sample size was 124 patients to select a more effective regimen with a minimum probability of 0.85 and to examine the null hypothesis of the 1-year OS <53%.. Of the 126 patients enrolled from 29 institutions, 125 were deemed eligible. The 1-year OS was 77.4% (95% CI, 64.9-86.0) and 82.5% (95% CI, 70.7-89.9) in the mFOLFIRINOX and GnP arms, respectively. The median PFS was 11.2 (95% CI, 9.9-15.9) and 9.4 months (95% CI, 7.4-12.8) in the mFOLFIRINOX and GnP arms, respectively. The RR and CA19-9 response rate were 30.9% (95% CI, 19.1-44.8) and 57.1% (95% CI, 41.0-72.3) and 42.1% (95% CI 29.1-55.9) and 85.0% (95% CI, 70.2-94.3) in the mFOLFIRINOX and GnP arms, respectively. Grade 3-4 diarrhoea and anorexia were predominant in the mFOLFIRINOX arm.. GnP was considered the candidate for a subsequent phase III trial because of its better RR, CA19-9 response, and mild gastrointestinal toxicities. Both regimens displayed higher efficacy in the 1-year survival than in the historical data of gemcitabine monotherapy.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Paclitaxel; Pancreatic Neoplasms

Adding losartan (LOS) to FOLFIRINOX (FFX) chemotherapy followed by chemoradiation (CRT) resulted in 61% R0 surgical resection in our phase II trial in patients with locally advanced pancreatic cancer (LAPC). Here we identify potential mechanisms of benefit by assessing the effects of neoadjuvant LOS on the tumor microenvironment.. We performed a gene expression and immunofluorescence (IF) analysis using archived surgical samples from patients treated with LOS+FFX+CRT (NCT01821729), FFX+CRT (NCT01591733), or surgery upfront, without any neoadjuvant therapy. We also conducted a longitudinal analysis of multiple biomarkers in the plasma of treated patients.. In comparison with FFX+CRT, LOS+FFX+CRT downregulated immunosuppression and pro-invasion genes. Overall survival (OS) was associated with dendritic cell (DC) and antigen presentation genes for patients treated with FFX+CRT, and with immunosuppression and invasion genes or DC- and blood vessel-related genes for those treated with LOS+FFX+CRT. Furthermore, LOS induced specific changes in circulating levels of IL-8, sTie2, and TGF-β. IF revealed significantly less residual disease in lesions treated with LOS+FFX+CRT. Finally, patients with a complete/near complete pathologic response in the LOS+FFX+CRT-treated group had reduced CD4+FOXP3+ regulatory T cells (Tregs), fewer immunosuppressive FOXP3+ cancer cells (C-FOXP3), and increased CD8+ T cells in pancreatic ductal adenocarcinoma lesions.. Adding LOS to FFX+CRT reduced pro-invasion and immunosuppression-related genes, which were associated with improved OS in patients with LAPC. Lesions from responders in the LOS+FFX+CRT-treated group had reduced Tregs, decreased C-FOXP3 and increased CD8+ T cells. These findings suggest that LOS may potentiate the benefit of FFX+CRT by reducing immunosuppression.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Forkhead Transcription Factors; Humans; Immunosuppression Therapy; Leucovorin; Losartan; Neoadjuvant Therapy; Pancreatic Neoplasms; Tumor Microenvironment

The NIFTY trial demonstrated the benefit of treatment with second-line liposomal irinotecan (nal-IRI) plus fluorouracil (FU) and leucovorin (LV) for patients with advanced biliary tract cancer (BTC).. To report the updated efficacy outcomes from the NIFTY trial with extended follow-up of 1.3 years with reperformed masked independent central review (MICR) with 3 newly invited radiologists.. The NIFTY trial was a randomized, multicenter, open-label, phase 2b clinical trial conducted between September 5, 2018, and December 31, 2021, at 5 tertiary referral centers in South Korea. Patients with advanced BTC whose disease progressed while receiving first-line gemcitabine plus cisplatin with at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors, version 1.1, were eligible. Data analysis was completed on May 9, 2022.. Patients were randomized 1:1 to receive LV, 400 mg/m2, bolus and FU, 2400 mg/m2, for a 46-hour infusion intravenously every 2 weeks with or without nal-IRI, 70 mg/m2, before LV intravenously. Patients were treated until disease progression or unacceptable toxic effects.. Primary end point was progression-free survival (PFS) as assessed by MICR. Secondary end points were PFS as assessed by the investigator, overall survival, and objective response rate.. A total of 178 patients (75 women [42.1%]; median [IQR] age, 64 [38-84] years) were randomly assigned, and 174 patients were included in the full analysis set (88 patients [50.6%] in the nal-IRI plus FU/LV group vs 86 patients [49.4%] in the FU/LV alone group). In this updated analysis, the median MICR-assessed PFS was 4.2 months (95% CI, 2.8-5.3) for the nal-IRI plus FU/LV group and 1.7 months (95% CI, 1.4-2.6) for the FU/LV alone group (hazard ratio, 0.61; 95% CI, 0.44-0.86; P = .004), in contrast to the 7.1 and 1.4 months reported in the previous study, respectively. The discordance rate for tumor progression date between the MICR and investigators was 17.8% (vs 30% in the previous study).. The NIFTY randomized clinical trial demonstrated significant improvement in PFS with treatment with nal-IRI plus FU/LV compared with FU/LV alone for patients with advanced BTC after progression to gemcitabine plus cisplatin. The combination of nal-IRI plus FU/LV could be considered as a second-line treatment option for patients with previously treated advanced BTC.. clinicaltrials.gov Identifier: NCT03524508.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Cisplatin; Deoxycytidine; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Middle Aged; Pancreatic Neoplasms

Pancreatic cancer is the fourth leading cause of cancer-related death in the US with an increasing incidence in older adults (OA) over age 70. There are currently no treatment guidelines for OA with metastatic pancreatic cancer (mPCA) and selecting a chemotherapy regimen for these patients is subjective, based largely on chronologic age and performance status (PS). Geriatric screening tools provide a more objective and accurate evaluation of a patient's overall health but have not yet been validated in patient selection for mPCA treatment. This study aims to elucidate the optimal chemotherapy treatment of vulnerable OA with mPCA and understand the geriatric factors that affect outcomes in this population.. The GIANT (ECOG-ACRIN EA2186) study is multicenter, randomized phase II trial enrolling patients over age 70 with newly diagnosed mPCA. This study utilizes a screening geriatric assessment (GA) which characterizes patients as fit, vulnerable, or frail. Patients with mild abnormalities in functional status and/or cognition, moderate comorbidities, or over age 80 are considered vulnerable. Enrolled patients are randomized to one of two dose-reduced treatment regimens (gemcitabine/nab-paclitaxel every other week, or dose-reduced 5-fluoruracil (5FU)/ liposomal irinotecan (nal-IRI) every other week). GA and quality of life (QoL) evaluations are completed prior to treatment initiation and at each disease evaluation. Overall survival (OS) is the primary endpoint, with secondary endpoints including progression free survival (PFS) and objective response rate (ORR). Enrolled patients will be stratified by age (70-74 vs ≥75) and ECOG PS (0-1 vs 2). Additional endpoints of interest for OA include evaluation of risk factors identified through GA, QoL evaluation, and toxicities of interest for older adults. Correlative studies include assessment of pro-inflammatory biomarkers of aging in the blood (IL-6, CRP) and imaging evaluation of sarcopenia as predictors of treatment tolerance.. The GIANT study is the first randomized, prospective national trial evaluating vulnerable OA with mPCA aimed at developing a tailored treatment approach for this patient population. This trial has the potential to establish a new way of objectively selecting vulnerable OA with mPCA for modified treatment and to establish a new standard of care in this growing patient population.. This trial is registered with ClinicalTrial.gov Identifier NCT04233866.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Pancreatic Neoplasms; Prospective Studies; Quality of Life

Folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) or modified FOLFIRINOX (mFFX) is the first-line standard of care for metastatic pancreatic adenocarcinoma; effective and safe treatment strategies are needed as survival remains poor. Sintilimab, a human immunoglobulin G4 monoclonal antibody for programmed cell death-1, has shown efficacy in various cancers. We evaluated the efficacy and safety of sintilimab with mFFX for metastatic/recurrent pancreatic ductal adenocarcinoma in China.. This was a single-center, randomized, controlled, open-label phase II study. Patients were assigned 1:1 to sintilimab + mFFX or mFFX (n = 55, each).. In the intention-to-treat population, median overall survivals (primary endpoint) were similar in the sintilimab + mFFX and mFFX groups: 10.9 and 10.8 months, respectively [hazard ratio (HR) 1.07, 95% confidence interval (CI) 0.69-1.68]. The objective response rate was higher [50.0% (95% CI 34.6-65.4%) versus 23.9% (95% CI 11.1-36.7%)] in the sintilimab + mFFX group (P < 0.05). Median (HR, 95% CI) progression-free survival and disease control rates (95% CI) were also similar at 5.9 and 5.7 months (0.93, 0.62-1.40), and 84.1% (72.8-95.3%) and 71.7%, (58.2-85.3%), respectively. Incidences of grade ≥ 3 treatment-emergent adverse events were 84.9% (45/53) and 74.1% (40/54), and that of grade ≥ 3 immune-related adverse events were 5.7% (3/53) and 0 in each group, respectively.. The study did not meet its primary endpoint, no clear survival benefit was observed, and the benefit of sintilimab + mFFX for advanced pancreatic cancer was not supported; however, the findings suggest that using this regimen for pancreatic cancer is feasible, has an acceptable safety profile, and leads to an objective response rate of 50%. Trial registration ClinicalTrials.Gov; NCT03977272.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Chronic Disease; Fluorouracil; Humans; Leucovorin; Neoplasm Recurrence, Local; Pancreatic Neoplasms

Organ preservation is now considered an acceptable alternative option in distal rectal cancer patients with clinical complete response (cCR) after neoadjuvant chemoradiation (CRT). But the cCR rate is low and about one-third of tumour will regrow, which requires more effective local treatment. CRT combined with intra-arterial chemotherapy (IAC) might be a promising approach. Additionally, total neoadjuvant therapy using FOLFIRINOX induction chemotherapy improved survival while consolidation chemotherapy improved organ preservation. We assess whether IAC plus CRT and FOLFIRINOX consolidation chemotherapy can improve the chance of organ preservation and survival in distal rectal cancer.. This prospective, monocentric, open-label, single-arm phase II study will include 32 patients with cT3-4NanyM0 distal rectal adenocarcinoma. All patients will receive one cycle of IAC (irinotecan, raltitrexed and oxaliplatin), followed by CRT (50 Gy/25 fractions with concomitant capecitabine) and then with six cycles of FOLFIRINOX (leucovorin, 5-fluorouracil, oxaliplatin and irinotecan). After final evaluation, patients with cCR will receive non-operative management or surgery at their own discretion and others are mandatorily referred to surgery. Adjuvant chemotherapy with six cycles of mFOLFOX6 (leucovorin, 5-fluorouracil and oxaliplatin) will be used for patients with adverse pathological features. The primary endpoint is the rate of complete response (CR; pathological CR or sustained cCR≥2 years). The main secondary endpoints are toxicity, compliance, short-term and long-term oncological outcomes, surgical morbidity and quality of life. This protocol has been designed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials 2013 guidelines.. This study was approved by the Academic and Ethics Committee of The Affiliated Hospital of Youjiang Medical University for Nationalities in March 2023. Trial results will be published in peer-reviewed international journals and on the ChiCTR website.. Registered on 18 April 2023; version #1.. ChiCTR2300070620.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Clinical Trials, Phase II as Topic; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Neoplasm Staging; Oxaliplatin; Pancreatic Neoplasms; Prospective Studies; Quality of Life; Rectal Neoplasms

The objective of this study was to evaluate the efficacy and safety of induction chemotherapy (ICT), GOFL (gemcitabine, oxaliplatin plus fluorouracil (5-FU)/leucovorin) versus modified FOLFIRINOX (irinotecan, oxaliplatin plus 5-FU/leucovorin), followed by concurrent chemoradiotherapy (CCRT) in locally advanced pancreatic adenocarcinoma (LAPC).. Chemo-naive patients with measurable LAPC were eligible and randomly assigned to receive biweekly ICT with either mFOLFIRINOX or GOFL for 3 months. Patients without systemic progression would have 5-FU- or gemcitabine-based CCRT (5040 cGy/28 fractions) and were then subjected to surgery or continuation of chemotherapy until treatment failure. The primary endpoint was 9-month progression-free survival (PFS) rate.. Between July 2013 and January 2019, 55 patients were enrolled. After ICT, 21 (77.8%) of 27 patients who received mFOLFIRINOX and 17 (60.7%) of 28 patients who received GOFL completed CCRT. Of them, one and five had per-protocol R0/R1 resection. On intent-to-treat analysis, the 9-month PFS rate, median PFS and overall survival in mFOLFIRINOX and GOFL arms were 30.5% versus 35.9%, 6.6 (95% confidence interval: 5.9-12.5) versus 7.6 months (3.9-12.3) and 19.6 (13.4-22.9) versus 17.9 months (13.4-23.9), respectively. Grade 3-4 neutropenia and diarrhoea during induction mFOLFIRINOX and GOFL were 37.0% versus 21.4% and 14.8% versus 3.6%, respectively.. Induction GOFL and mFOLFIRINOX followed by CCRT provided similar clinical outcomes in LAPC patients.. NCT01867892.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Fluorouracil; Humans; Induction Chemotherapy; Leucovorin; Pancreatic Neoplasms; Taiwan

Colorectal cancer (CRC) patients have a better prognosis if metastases are resectable. Initially, unresectable liver-only metastases can be converted to resectable with chemotherapy plus a targeted therapy. We assessed which of chemotherapy doublet (2-CTx) or triplet (3-CTx), combined with targeted therapy by RAS status, would be better in this setting.. PRODIGE 14 was an open-label, multicenter, randomised Phase 2 trial. CRC patients with initially defined unresectable liver-only metastases received either, 2-CTx (FOLFOX or FOLFIRI) or 3-CTx (FOLFIRINOX), plus bevacizumab/cetuximab by RAS status. The primary endpoint was to increase the R0/R1 liver-resection rate from 50 to 70% with the 3-CTx.. Patients (n = 256) were mainly men with an ECOG PS of 0, and a median age of 60 years. In total, 109 patients (42.6%) had RAS-mutated tumours. After a median follow-up of 45.6 months, the R0/R1 liver-resection rate was 56.9% (95% CI: 48-66) with the 3-CTx versus 48.4% (95% CI: 39-57) with the 2-CTx (P = 0.17). Median overall survival was 43.4 months with 3-CTx versus 40 months with 2-CTx.. We failed to increase from 50 to 70% the R0/R1 liver-resection rate with the use of 3-CTx combined with bevacizumab or cetuximab by RAS status in CRC patients with initially unresectable liver metastases.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms

Given the frequent adverse events with multidrug chemotherapy, not only the survival benefit but also the feasibility of using neoadjuvant chemotherapy to treat pancreatic cancer need to be clarified.. Although the development of multidrug chemotherapy regimens has improved the survival outcomes of patients with unresectable pancreatic cancer, the benefits of these treatments in the neo-adjuvant setting remain controversial.. Patients with borderline-resectable pancreatic cancer were enrolled and randomly assigned to receive neoadjuvant chemotherapy with either FOLFIRINOX or gemcitabine with nab-paclitaxel (GEM/nab-PTX). After the completion of chemotherapy, patients underwent surgical resection when feasible. This study (NUPAT-01) was a randomized phase II trial, and the primary endpoint was the R0 resection rate.. Fifty-one patients were enrolled in this study [FOLFIRINOX (n = 26) and GEM/nab-PTX (n = 25)]. A total of 84.3% (n = 43/51) of the patients eventually underwent surgery, and R0 resection was achieved in 67.4% (n = 33/ 51) of the patients. Adverse events (grade >3) due to neoadjuvant treatment were observed in 45.1% of the patients (n = 23/51), and major surgical complications occurred in 30.0% (n = 13/43), with no mortality noted. The intention-to-treat analysis showed that the 3-year overall survival rate was 54.7%, with a median survival time of 39.4 months, and a significant difference in overall survival was not observed between the FOLFIRINOX and GEM/nab-PTX groups.. These results indicate that neoadjuvant chemotherapy with FOLFIRINOX or GEM/nab-PTX is feasible and well tolerated, achieving an R0 resection rate of 67.4%. The survival of patients was even found to be favorable in the intention-to-treat analysis.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

A comprehensive analysis of peripheral immune cell phenotypes and tumor immune-gene expression profiles in locally advanced pancreatic cancer patients treated with neoadjuvant chemotherapy in a phase II clinical trial was carried out.. Patients were treated with neoadjuvant modified folinic acid, fluorouracil, irinotecan hydrochloride, oxaliplatin (mFOLFIRINOX) followed by surgery and adjuvant gemcitabine at the Asan Medical Center. Correlations between survival outcomes and baseline peripheral immune cells and their changes during preoperative chemotherapy were analyzed. Patients who had surgery were divided into two groups according to achievement of disease-free survival >10 months (achieved versus failed). Differential expression and pathway analysis of immune-related genes were carried out using the Nanostring platform, and immune cells within the tumor microenvironment were compared by immunohistochemistry.. Forty-four patients were treated in the phase II clinical trial. Higher baseline CD14+CD11c+HLA-DR+ monocytes (P = 0.044) and lower Foxp3+CD4+ T cells (P = 0.02) were associated with poor progression-free survival of neoadjuvant mFOLFIRINOX. During the preoperative chemotherapy, PD-1 T cells significantly decreased (P = 0.0110). Differential expression and pathway analysis of immune-genes from the resected tumor after neoadjuvant treatment revealed transforming growth factor-β pathway enrichment and higher expression of MARCO (adjusted P < 0.05) associated with early recurrence. Enrichment of the Th1 pathway and higher peritumoral CD8+ T cells (P = 0.0103) were associated with durable disease-free survival from surgery (>10 months) following neoadjuvant mFOLFIRINOX.. Our results identify potential immune biomarkers for locally advanced pancreatic cancer and provide insights into pancreatic cancer immunity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Phenotype; Transcriptome; Tumor Microenvironment

Pancreatic adenocarcinoma (PDAC) remains a refractory disease; however, modern cytotoxic chemotherapeutics can induce tumor regression and extend life. A blood-based, pharmacogenomic, chemosensitivity assay using gene expression profiling of circulating tumor and invasive cells (CTICs) to predict treatment response was previously developed. The combination regimen of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel (G/nab-P) are established frontline approaches for treating advanced PDAC; however, there are no validated biomarkers for treatment selection. A similar unmet need exists for choosing second-line therapy.. The chemosensitivity assay was evaluated in metastatic PDAC patients presenting for frontline treatment. A prospective study enrolled patients (n = 70) before receiving either FOLFIRINOX or G/nab-P at a 1:1 ratio. Six milliliters of peripheral blood was collected at baseline and at time of disease progression. CTICs were isolated, gene-expression profiling was performed, and the assay was used to predict effective and ineffective chemotherapeutic agents. Treating physicians were blinded to the assay prediction results.. Patients receiving an effective regimen as predicted by the chemosensitivity assay experienced significantly longer median progression-free survival (mPFS; 7.8 months vs. 4.2 months; hazard ratio [HR], 0.35; p = .0002) and median overall survival (mOS; 21.0 months vs. 9.7 months; HR, 0.40; p = .005), compared with an ineffective regimen. Assay prediction for effective second-line therapy was explored. The entire study cohort experienced favorable outcomes compared with historical controls, 7.1-month mPFS and 12.3-month mOS.. Chemosensitivity assay profiling is a promising tool for guiding therapy in advanced PDAC. Further prospective validation is under way (clinicaltrials.gov NCT03033927).

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Paclitaxel; Pancreatic Neoplasms; Prospective Studies

National guidelines endorse treatment with neoadjuvant therapy for borderline resectable pancreatic ductal adenocarcinoma (PDAC), but the optimal strategy remains unclear.. To compare treatment with neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) with or without hypofractionated radiation therapy with historical data and establish standards for therapy in borderline resectable PDAC.. This prospective, multicenter, randomized phase 2 clinical trial conducted from February 2017 to January 2019 among member institutions of National Clinical Trials Network cooperative groups used standardized quality control measures and included 126 patients, of whom 70 (55.6%) were registered to arm 1 (systemic therapy; 54 randomized, 16 following closure of arm 2 at interim analysis) and 56 (44.4%) to arm 2 (systemic therapy and sequential hypofractionated radiotherapy; all randomized before closure). Data were analyzed by the Alliance Statistics and Data Management Center during September 2021.. Arm 1: 8 treatment cycles of mFOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2) over 46 hours, administered every 2 weeks. Arm 2: 7 treatment cycles of mFOLFIRINOX followed by stereotactic body radiotherapy (33-40 Gy in 5 fractions) or hypofractionated image-guided radiotherapy (25 Gy in 5 fractions). Patients without disease progression underwent pancreatectomy, which was followed by 4 cycles of treatment with postoperative FOLFOX6 (oxaliplatin, 85 mg/m2; leucovorin, 400 mg/m2; bolus fluorouracil, 400 mg/m2; and infusional fluorouracil, 2400 mg/m2 over 46 hours).. Each treatment arm's 18-month overall survival (OS) rate was compared with a historical control rate of 50%. A planned interim analysis mandated closure of either arm for which 11 or fewer of the first 30 accrued patients underwent margin-negative (R0) resection.. Of 126 patients, 62 (49%) were women, and the median (range) age was 64 (37-83) years. Among the first 30 evaluable patients enrolled to each arm, 17 patients in arm 1 (57%) and 10 patients in arm 2 (33%) had undergone R0 resection, leading to closure of arm 2 but continuation to full enrollment in arm 1. The 18-month OS rate of evaluable patients was 66.7% (95% CI, 56.1%-79.4%) in arm 1 and 47.3% (95% CI 35.8%-62.5%) in arm 2. The median OS of evaluable patients in arm 1 and arm 2 was 29.8 (95% CI, 21.1-36.6) months and 17.1 (95% CI, 12.8-24.4) months, respectively.. This randomized clinical trial found that treatment with neoadjuvant mFOLFIRINOX alone was associated with favorable OS in patients with borderline resectable PDAC compared with mFOLFIRINOX treatment plus hypofractionated radiotherapy; thus, mFOLFIRINOX represents a reference regimen in this setting.. ClinicalTrials.gov Identifier: NCT02839343.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Prospective Studies

Early results at 3 years from the PRODIGE 24/Canadian Cancer Trials Group PA6 randomized clinical trial showed survival benefits with adjuvant treatment with modified FOLFIRINOX vs gemcitabine in patients with resected pancreatic ductal adenocarcinoma; mature data are now available.. To report 5-year outcomes and explore prognostic factors for overall survival.. This open-label, phase 3 randomized clinical trial was conducted at 77 hospitals in France and Canada and included patients aged 18 to 79 years with histologically confirmed pancreatic ductal adenocarcinoma who had undergone complete macroscopic (R0/R1) resection within 3 to 12 weeks before randomization. Patients were included from April 16, 2012, through October 3, 2016. The cutoff date for this analysis was June 28, 2021.. A total of 493 patients were randomized (1:1) to receive treatment with modified FOLFIRINOX (oxaliplatin, 85 mg/m2 of body surface area; irinotecan, 150-180 mg/m2; leucovorin, 400 mg/m2; and fluorouracil, 2400 mg/m2, every 2 weeks) or gemcitabine (1000 mg/m2, days 1, 8, and 15, every 4 weeks) as adjuvant therapy for 24 weeks.. Primary end point was disease-free survival. Secondary end points included overall survival, metastasis-free survival, and cancer-specific survival. Prognostic factors for overall survival were determined.. Of the 493 patients, 216 (43.8%) were women, and the mean (SD) age was 62.0 (8.9) years. At a median of 69.7 months' follow-up, 367 disease-free survival events were observed. In patients receiving chemotherapy with modified FOLFIRINOX vs gemcitabine, median disease-free survival was 21.4 months (95% CI, 17.5-26.7) vs 12.8 months (95% CI, 11.6-15.2) (hazard ratio [HR], 0.66; 95% CI, 0.54-0.82; P < .001) and 5-year disease-free survival was 26.1% vs 19.0%; median overall survival was 53.5 months (95% CI, 43.5-58.4) vs 35.5 months (95% CI, 30.1-40.3) (HR, 0.68; 95% CI, 0.54-0.85; P = .001), and 5-year overall survival was 43.2% vs 31.4%; median metastasis-free survival was 29.4 months (95% CI, 21.4-40.1) vs 17.7 months (95% CI, 14.0-21.2) (HR, 0.64; 95% CI, 0.52-0.80; P < .001); and median cancer-specific survival was 54.7 months (95% CI, 45.8-68.4) vs 36.3 months (95% CI, 30.5-43.9) (HR, 0.65; 95% CI, 0.51-0.82; P < .001). Multivariable analysis identified modified FOLFIRINOX, age, tumor grade, tumor staging, and larger-volume center as significant favorable prognostic factors for overall survival. Shorter relapse delay was an adverse prognostic factor.. The final 5-year results from the PRODIGE 24/Canadian Cancer Trials Group PA6 randomized clinical trial indicate that adjuvant treatment with modified FOLFIRINOX yields significantly longer survival than gemcitabine in patients with resected pancreatic ductal adenocarcinoma.. EudraCT: 2011-002026-52; ClinicalTrials.gov Identifier: NCT01526135.

Topics: Antineoplastic Combined Chemotherapy Protocols; Canada; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Neoplasm Recurrence, Local; Oxaliplatin; Pancreatic Neoplasms

In this phase I dose-escalation trial, we assess the maximum tolerated dose (MTD) of Bermekimab in combination with Nanoliposomal Irinotecan (Nal-Iri) and 5-Fluorouracil/Folinic Acid (5-FU/FA). Secondarily, we investigate effects on weight, lean body mass, quality-of-life, the gut microbiome composition, inflammatory biomarkers, progression-free survival, and overall survival. This was a single-arm, open-label adaptive Bayesian dose-escalation study of Bermekimab combined with Nal-Iri and 5FU/FA in patients with advanced or locally advanced PDAC who failed gemcitabine-based chemotherapy. 22 patients enrolled between 2017 and 2019. 3 of 21 patients experienced dose-limiting toxicities attributable to the chemotherapy backbone. 58% (10/17) of patients exhibited weight stability. Physical performance status was preserved among all subjects. Patients reported improvements in quality-of-life metrics via QLQ-PAN26 questioner (-3.6, p = 0.18) and functional well-being (1.78, p = 0.02). Subjects exhibited a decrease in inflammatory cytokines, notably, vascular endothelial growth factor (-0.86, p = 0.017) with Bermekimab. Bermekimab treatment was associated with an increased abundance of gut health-promoting bacterial genera Akkermansia, with 3.82 Log2-fold change from baseline. In sum, Bermekimab is safe to be used in conjunction with Nal-Iri and 5-FU/FA chemotherapy. This benign toxicological profile warrants further Phase I/II investigation of Bermekimab in combinatorial strategies, and the impact of anti-IL-1α antibodies on the gut microbiome.Clinical trials registration: NCT03207724 05/07/2017.

Topics: Adenocarcinoma; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Fluorouracil; Humans; Irinotecan; Leucovorin; Pancreatic Neoplasms; Vascular Endothelial Growth Factor A

The ability to detect circulating tumor DNA (ctDNA), a novel surrogate for minimal residual disease (MRD) for patients with solid tumors, has significantly evolved over the past decade. Several studies have shown that ctDNA may provide clinical insight into the biological dynamics of MRD. The CIRCULATE-US (NRG-GI008; NCT05174169) trial will aim to address the role of ctDNA for risk stratification to intensify and deintensify adjuvant chemotherapy for patients with early-stage colon cancer.. CIRCULATE-US, a prospective phase 2/3 randomized trial, is investigating the molecular dynamics and prognostic role of ctDNA (evaluated by Natera's Signatera assay) for patients with resected colon cancer. Patients with negative postoperative ctDNA will be enrolled in cohort A and randomized to receive either immediate treatment with 5-fluorouracil and folinic acid or capecitabine plus oxaliplatin (FOLFOX6 or CAPEOX; Arm 1) or serial ctDNA surveillance with delayed adjuvant therapy (Arm 2). Patients randomized to Arm 2 with subsequent positive ctDNA results will be enrolled in cohort B for a second randomization to receive either FOLFOX6/CAPEOX (Arm 3) or 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan (FOLFIRINOX; Arm 4) for 6 months. Patients with positive postoperative ctDNA results will be directly enrolled in cohort B and randomized to receive either FOLFOX6/CAPEOX (Arm 3) or FOLFIRINOX (Arm 4). Patients with stage II or stage IIIC colon cancer with positive ctDNA results (tested as standard of care with commercial testing) will be eligible for enrollment in cohort B. The primary end point for cohort A is time to positive ctDNA status for phase 2 and disease-free survival for phase 3 with a noninferiority design. The primary end point for cohort B is disease-free survival for both phase 2 and phase 3 with a superiority design.. CIRCULATE-US will aim to understand postoperative ctDNA dynamics in early-stage colon cancer and will investigate escalation and de-escalation approaches by using ctDNA status as a surrogate for MRD status.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Circulating Tumor DNA; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm, Residual; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prospective Studies

To compare the efficacy and safety of algenpantucel-L [HyperAcute-Pancreas algenpantucel-L (HAPa); IND# 12311] immunotherapy combined with standard of care (SOC) chemotherapy and chemoradiation to SOC chemotherapy and chemoradiation therapy alone in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (PDAC).. To date, immunotherapy has not been shown to benefit patients with borderline resectable or locally advanced unresectable PDAC. HAPa is a cancer vaccine consisting of allogeneic pancreatic cancer cells engineered to express the murine α(1,3)GT gene.. A multicenter, phase 3, open label, randomized (1:1) trial of patients with borderline resectable or locally advanced unresectable PDAC. Patients received neoadjuvant SOC chemotherapy (FOLFIRINOX or gemcitabine/nab-paclitaxel) followed by chemoradiation (standard group) or the same standard neoadjuvant regimen combined with HAPa immunotherapy (experimental group). The primary outcome was overall survival.. Between May 2013 and December 2015, 303 patients were randomized from 32 sites. Median (interquartile range) overall survival was 14.9 (12.2-17.8) months in the standard group (N = 158) and 14.3 (12.6-16.3) months in the experimental group (N = 145) [hazard ratio (HR) 1.02, 95% confidence intervals 0.66-1.58; P = 0.98]. Median progression-free survival was 13.4 months in the standard group and 12.4 months in the experimental group (HR 1.33, 95% confidence intervals 0.72-1.78; P = 0.59). Grade 3 or higher adverse events occurred in 105 of 140 patients (75%) in the standard group and in 115 of 142 patients (81%) in the experimental group (P > 0.05).. Algenpantucel-L immunotherapy did not improve survival in patients with borderline resectable or locally advanced unresectable PDAC receiving SOC neoadjuvant chemotherapy and chemoradiation.. ClinicalTrials.gov Identifier: NCT01836432.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Immunotherapy; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival; Standard of Care; Survival Analysis

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Deoxycytidine; Disease-Free Survival; Drug Therapy, Combination; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Markov Chains; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; United States

According to current guidelines, treatment of patients with hepatic oligometastasis in pancreatic cancer is not reflected and systemic chemotherapy is recommended in those patients. Retrospective data suggest beneficial outcomes in patients with hepatic oligometastasis, though prospective data from clinical trials addressing this particular patient group is not available.. In this single arm, phase-2 trial, survival data from patients receiving neoadjuvant chemotherapy followed by R0/R1 resection will be compared to historic data from patients with oligometastatic adenocarcinoma of the pancreas. The clinical trial will focus on a well-defined patient collective with metastatic load limited to the liver as target organ with a maximum of five metastases. The combination of liposomal irinotecan (nal-IRI), oxaliplatin (OX) and 5-fluouracil (5-FU)/folinic acid (FA) (nal-IRI + OX+ 5-FU/FA, NAPOX) was chosen as neoadjuvant chemotherapy; the choice was based on an ongoing clinical study in which NAPOX appeared manageable, with promising anti-tumor activity in first-line treatment of patients with metastatic pancreatic adenocarcinoma. In total 150 patients will be enrolled for this trial with an aim of 55 patients receiving a complete macroscopic synchronous tumor and metastatic resection.. This is the first clinical study to prospectively evaluate the value of multimodality therapy concepts in oligometastatic pancreatic cancer.. EudraCT 2019-002734-37 ; NCT04617457 .

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Female; Fluorouracil; Germany; Humans; Irinotecan; Leucovorin; Liposomes; Liver Neoplasms; Male; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Progression-Free Survival; Quality of Life

Nab-paclitaxel/gemcitabine (AG) and FOLFIRINOX (FFX) are promising drugs in metastatic pancreatic cancer (MPC). This study evaluated a new first-line sequential treatment (AG followed by FFX) in MPC that might overcome resistance to primary therapy and delay tumor progression.. Patients with histologically/cytologically confirmed MPC were included in a multicentric trial receiving AG (day 1, 8 and 15) followed by FFX (day 29 and 43). In phase Ib, three dose-levels were tested for maximum tolerated dose (MTD) and recommended phase II dose. In phase II, the main outcome was the objective response rate (ORR) and secondarily safety, progression-free survival (PFS) and overall survival (OS).. In phase Ib, we included 33 patients (31 assessable) of median age 61.0 years (range 42-75 years) and represented by 54.8% males. Five dose-limiting toxicities were reported without any death. The main grade 3/4 toxicities were neutropenia with spontaneous resolution (35.5%/32.3%), venous thromboembolism (grade 3: 22.6%) and thrombopenia (grade 3: 29.0%), while the MTD was not reached. In phase II, we included 58 patients of median age 60 years (range 34-72 years), 50% males and with Eastern Cooperative Oncology Group stage score 0 and 1 of 37.9% and 62.1%, respectively. They received a median of 4 (1-9) cycles in 8.5 months (0.5-19.8 months). The ORR was 64.9% [95% confidence interval (CI) 51.1% to 77.1%], and neurotoxicity was remarkably low. The main grade 3-4 toxicities were venous thromboembolism, thrombopenia, neutropenia/febrile neutropenia, nausea, diarrhea, weight loss and asthenia without any death. Tumor response was complete in 3.5% and partial in 61.4%, while disease was stable in 19.3% and progressive in 15.8% of patients. The median PFS was 10.5 months (95% CI 6.0-12.5 months) and median OS was 15.1 months (95% CI 10.6-20.1 months).. Sequential AG and FFX showed acceptable toxicity as first-line treatment with no limiting neurotoxicity, while high response rate and survival justify randomized trials.

Topics: Adenocarcinoma; Adult; Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

The prognosis of patients with advanced pancreatic cancer is poor despite the recent introduction of immune checkpoint inhibitors. Therefore, the development of new therapeutic approaches is urgently required. In the present phase I/II study, we have evaluated the safety, the efficacy and the prognostic factors of Wilms' tumor 1 (WT1) and/or mucin 1 (MUC1) peptide-loaded dendritic cell (DC) vaccination in combination with a chemotherapy employing gemcitabine plus nab-paclitaxel or a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) in patients with advanced or relapsed pancreatic ductal adenocarcinoma (PDAC). Forty-eight eligible patients were enrolled and received the vaccinations approximately every 2-4 weeks at least seven times. No severe adverse events related to the vaccinations were observed. Median progression free survival and overall survival were 8.1 months and 15.1 months, respectively. DC vaccinations augmented tumor specific immunity which might be related to clinical outcome. The multivariate analyses demonstrated that WT1 or MUC1-specific interferonɤ enzyme-linked immunospot number prior to DC vaccination was an independent prognostic factor related to overall survival. These results indicate that DC-based immunotherapy combined with a conventional chemotherapy is safe and has clinical benefits for patients in advanced stage of PDAC. The precise evaluation of the baseline antitumor specific immunity is critical to predict clinical outcome.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Dendritic Cells; Fluorouracil; Humans; Leucovorin; Mucin-1; Pancreatic Neoplasms; Peptides; Prognosis; Vaccination; WT1 Proteins

Background Treatment options for pancreatic ductal adenocarcinoma (PDAC) are limited and checkpoint blockade inhibitors have been disappointing in this disease. Pegilodecakin has demonstrated single agent anti-tumor activity in immune-sensitive tumors. Phase 1 and preclinical data indicate synergy of pegilodecakin with 5-FU and platins. We assessed the safety and activity of pegilodecakin+FOLFOX in patients with PDAC. Methods IVY (NCT02009449) was an open-label phase 1b trial in the United States. Here we report on all enrolled patients from cohort C. Heavily pretreated patients were treated with pegilodecakin (self-administered subcutaneously daily at 2.5, 5, or 10 μg/kg) + 5-flurouracil/leucovorin/oxaliplatin (FOLFOX), dosed per manufacturers prescribing information, until tumor progression. Eligible patients had measurable disease per immune-related response criteria (irRC), were ≥ 18 years of age, and had ECOG performance status of 0 or 1. Patients were evaluated for primary(safety) and secondary (tumor response per irRC) endpoints. Results From 5 August 2014-12 July 2016, 39 patients enrolled in cohort C. All patients were evaluable for safety. In this advanced population, regimen had manageable toxicities with no immune-related adverse events (irAEs) greater than grade 1. The most common grade 3/4/5 TEAEs were thrombocytopenia (21[53.8%] of 39) and anemia (17[43.6%] of 39). In evaluable PDAC patients, the best overall response of pegilodecakin+FOLFOX was 3(14%) with CRs in 2(9%) patients. Conclusions Pegilodecakin+FOLFOX had an acceptable tolerability profile in PDAC, with no substantial irAEs seen, and promising efficacy with the combination yielding a 2-year OS of 24% (95% CI 10-42). These data led to the phase 3 study with pegilodecakin+FOLFOX as second-line therapy of PDAC (SEQUOIA).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Dose-Response Relationship, Drug; Fluorouracil; Humans; Interleukin-10; Kaplan-Meier Estimate; Leucovorin; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Pancreatic Neoplasms; Polyethylene Glycols; Progression-Free Survival; Response Evaluation Criteria in Solid Tumors

Chemotherapy with or without radiotherapy is the standard in patients with initially nonmetastatic unresectable pancreatic cancer. Additional surgery is in discussion. The CONKO-007 multicenter randomized trial examines the value of radiotherapy. Our interim analysis showed a significant effect of surgery, which may be relevant to clinical practice.. One hundred eighty patients received induction chemotherapy (gemcitabine or FOLFIRINOX). Patients without tumor progression were randomized to either chemotherapy alone or to concurrent chemoradiotherapy. At the end of therapy, a panel of five independent pancreatic surgeons judged the resectability of the tumor.. Following induction chemotherapy, 126/180 patients (70.0%) were randomized to further treatment. Following study treatment, 36/126 patients (28.5%) underwent surgery; (R0: 25/126 [19.8%]; R1/R2/Rx [n = 11/126; 6.1%]). Disease-free survival (DFS) and overall survival (OS) were significantly better for patients with R0 resected tumors (median DFS and OS: 16.6 months and 26.5 months, respectively) than for nonoperated patients (median DFS and OS: 11.9 months and 16.5 months, respectively; p = 0.003). In the 25 patients with R0 resected tumors before treatment, only 6/113 (5.3%) of the recommendations of the panel surgeons recommended R0 resectability, compared with 17/48 (35.4%) after treatment (p < 0.001).. Tumor resectability of pancreatic cancer staged as unresectable at primary diagnosis should be reassessed after neoadjuvant treatment. The patient should undergo surgery if a resectability is reached, as this significantly improves their prognosis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Chemoradiotherapy; Deoxycytidine; Disease-Free Survival; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Postoperative Complications; Radiotherapy, Conformal; Radiotherapy, Intensity-Modulated; Survival Analysis

Chemotherapy dose modification to manage adverse events is commonplace in clinical practice. This exploratory analysis evaluates the impact of liposomal irinotecan dose modification on overall survival (OS) and progression-free survival (PFS) in the NAPOLI-1 clinical trial (NCT01494506).. Analysis includes only patients enrolled under protocol version 2 who received at least the first 2 scheduled doses of study drug. Within the liposomal irinotecan +5 fluorouracil/leucovorin (5 FU/LV) arm, patients were grouped according to whether or not they had a dose modification within the first 6 weeks. Dose reduction was defined as any decrease from initial dose; dose delay was any dosing delay >3 days from target date. OS and PFS (Kaplan-Meier estimates) were compared within the liposomal irinotecan+5-FU/LV arm and between treatment arms. Unstratified hazard ratios (HRs) were calculated using Cox regression analysis.. Of the 93 patients from the liposomal irinotecan+5 FU/LV arm included in the analysis, 53 experienced a dose modification (both delay and reduction, n = 30; delay only, n = 19; reduction only, n = 4). No apparent difference in median OS or PFS was observed between patients who did versus patients who did not have a dose modification (OS: 8.4 vs 6.7 months; HR, 0.89; PFS: 4.2 vs 3.1 months; HR, 0.74).. An early dose reduction or delay of liposomal irinotecan+5-FU/LV in the first 6 weeks does not significantly impact OS or PFS compared to patients without dose modifications. This finding suggests that tolerability-guided dose modification of liposomal irinotecan does not adversely affect efficacy outcomes.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liposomes; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Survival Analysis

To report the long-term outcome of a multicenter phase II study with FOLFIRINOX followed by stereotactic body radiotherapy (LAPC-1 trial) in patients with locally advanced pancreatic cancer (LAPC).. Patients with histological confirmation of LAPC inoperable at diagnosis were enrolled. Induction therapy with 8 cycles of FOLFIRINOX was administered. If no disease progression was found after chemotherapy, patients received stereotactic body radiotherapy (SBRT) at a total dose of 40 Gy in 5 fractions.. In LAPC-1 trial, 50 patients were included, but due to disease progression in 11 patients under chemotherapy, 39 patients received stereotactic SBRT after FOLFIRINOX treatment. In whole population, the 1- and 3-year overall survival (OS) were 62% and 10%, respectively. Median follow-up was 13 months. The SBRT group had median OS of 18 months (95% CI 13.2-21.5) versus 5 months (95% CI 4.1-6.7) in non-SBRT group (p<0.001). After chemoradiotherapy, seven patients underwent surgery achieving a radical resection. Patients who underwent surgery had a 3-years OS of 43% compared to 6.5% in the unresected group (p=0.03). Four patients developed grade ≥ 3 adverse events during SBRT.. Long-term survival has been found in patients with LAPC underwent FOLFIRINOX followed by SBRT. This approach increased the probability of a radical surgery. The resected patients achieved a significant better survival compared to unresected group.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Radiosurgery

Clinical outcomes after curative treatment of resectable pancreatic ductal adenocarcinoma (PDA) remain suboptimal. To assess the potential of early control of systemic disease with multiagent perioperative chemotherapy, we conducted a prospective trial.. To determine 2-year overall survival (OS) using perioperative chemotherapy for resectable PDA.. This was a randomized phase 2 trial of perioperative chemotherapy with a pick-the-winner design. It was conducted across the National Clinical Trials Network, including academic and community centers all across the US. Eligibility required patients with Zubrod Performance Score of 0 or 1, confirmed tissue diagnosis of PDA, and resectable disease per Intergroup criteria.. Perioperative (12 weeks preoperative, 12 weeks postoperative) chemotherapy with either fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX, arm 1) or gemcitabine/nab-paclitaxel (arm 2).. The primary outcome was 2-year overall survival (OS), using a pick-the-winner design; for 100 eligible patients, accrual up to 150 patients was planned to account for cases deemed ineligible at central radiology review.. From 2015 to 2018, 147 patients were enrolled; 43 patients (29%) had ineligible disease, beyond resectability criteria, at central radiology review. There were 102 eligible and evaluable patients, 55 in arm 1 and 47 in arm 2, of whom the median (range) age was 66 (44-76) and 64 (46-76) years, respectively; 36 patients (65%) in arm 1 and 24 (51%) in arm 2 were men. In arm 1, 34 (62%) had Zubrod Performance Score of 0, while in arm 2, 31 (66%) did; and 44 (80%) in arm 1 and 39 (83%) in arm 2 had head tumors. Of 102 patients, 84% and 85% completed preoperative chemotherapy, 73% and 70% underwent resection, and 49% and 40% completed all treatment. Adverse events were expected hematologic toxic effects, fatigue, and gastrointestinal toxicities. Two-year OS was 47% (95% CI, 31%-61%) for arm 1 and 48% (95% CI, 31%-63%) for arm 2; median OS was 23.2 months (95% CI, 17.6-45.9 months) and 23.6 months (95% CI, 17.8-31.7 months). Neither arm's 2-year OS estimate was significantly higher than the a priori threshold of 40%. Median disease-free survival after resection was 10.9 months in arm 1 and 14.2 months in arm 2.. This phase 2 randomized clinical trial did not demonstrate an improved OS with perioperative chemotherapy, compared with historical data from adjuvant trials in resectable pancreatic cancer. Two-year OS was 47% with mFOLFIRINOX and 48% with gemcitabine/nab-paclitaxel for all eligible patients starting treatment for resectable PDA. The trial also demonstrated adequate safety and high resectability rates with perioperative chemotherapy, and challenges in quality control for resectability criteria.. ClinicalTrials.gov Identifier: NCT02562716.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Fluorouracil; Humans; Leucovorin; Male; Pancreatic Neoplasms; Prospective Studies

SEQUOIA compared efficacy and safety of adding pegilodecakin (PEG), a pegylated recombinant human interleukin (IL)-10, with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) in patients following progression on first-line gemcitabine-containing therapy with metastatic pancreatic ductal adenocarcinoma (PDAC).. SEQUOIA, a randomized, global phase III study, compared FOLFOX with PEG + FOLFOX as second line in gemcitabine-refractory PDAC. Patients were randomly assigned 1:1 (PEG + FOLFOX:FOLFOX) and stratified by prior gemcitabine and region. Eligible patients had only one prior gemcitabine-containing treatment. Primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), response evaluation per Response Evaluation Criteria in Solid Tumor (RECIST) 1.1, and safety. Exploratory analyses included biomarkers related to immune activation.. Between March 1, 2017, and September 9, 2019, 567 patients were randomly assigned PEG + FOLFOX (n = 283) or FOLFOX (n = 284). Most (94.7%) patients received prior gemcitabine plus nab paclitaxel. OS was similar comparing PEG + FOLFOX versus FOLFOX (median: 5.8. PEG added to FOLFOX did not improve efficacy in advanced gemcitabine-refractory PDAC. Safety findings were consistent as previously observed from PEG with chemotherapy; toxicity was manageable and tolerable. Exploratory pharmacodynamic results were consistent with immunostimulatory signals of the IL-10R pathway.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Disease Progression; Drug Resistance, Neoplasm; Fatigue; Female; Fluorouracil; Gemcitabine; Humans; Interleukin-10; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Outcome Assessment, Health Care; Oxaliplatin; Pancreatic Neoplasms; Polyethylene Glycols; Thrombocytopenia

Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients.. This nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and ≤ 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as ≤90 degrees arterial and ≤ 270 degrees venous involvement without occlusion. Patients receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3 years and 1.5 years follow-up.. The PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer.. Primary registry and trial identifying number: EudraCT: 2017-002036-17 . Date of registration: March 6, 2018. Secondary identifying numbers: The Netherlands National Trial Register - NL7094 , NL61961.078.17, MEC-2018-004.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Randomized Controlled Trials as Topic

Poorly differentiated neuroendocrine carcinomas (NEC) are rare diseases with a poor prognosis. Platinum-etoposide (PE) has been the recommended first-line treatment for decades. FOLFIRINEC (NCT04325425) is a national multicenter randomized phase II study which aims to challenge this standard regimen.. The primary objective is to compare the median progression-free survival (PFS) under mFOLFIRINOX versus PE. The secondary objectives are to evaluate the objective response rates (ORR), median overall survival (OS), safety and quality of life. The associated real-time translational study will establish a molecular profile for each patient enrolled.. NEC of gastroenteropancreatic (GEP) or unknown origin, metastatic and RECIST 1.1 evaluable disease, tumor sample available and no contraindication to chemotherapy. Patients will be randomized 1:1 between PE every 21 days for 6-8 cycles and mFOLFIRINOX every 14 days for up to 12 cycles and stratified according to center, performance status, Ki67 and pathological subtype. This trial will randomize 218 patients (24 months of follow-up) to have 80% power to detect an improvement of the median PFS from 5 months under PE to 7.5 months under mFOLFIRINOX (HR of 0.67, α =5%, two-sided). An intermediate analysis is planned at 50% of events. Recruitment started on October 20, 2020.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Carcinoma, Neuroendocrine; Etoposide; Female; Fluorouracil; Humans; Intestinal Neoplasms; Irinotecan; Leucovorin; Male; Neoplasm Metastasis; Neoplasms, Unknown Primary; Neuroendocrine Tumors; Oxaliplatin; Pancreatic Neoplasms; Platinum Compounds; Progression-Free Survival; Prospective Studies; Quality of Life; Stomach Neoplasms; Survival Rate; Treatment Outcome

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Survival Rate

Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC.. Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with. A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen.. Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Male; Middle Aged; Nanoparticles; Pancreatic Neoplasms; Peptides

Metastatic pancreatic cancer (mPC) still harbors a dismal prognosis. Our previous trial (PRODIGE 4-ACCORD 11) demonstrated the superiority of 6-month chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) over gemcitabine for overall survival. The high limiting oxaliplatin-related neurotoxicity supports the evaluation of an oxaliplatin stop-and-go strategy and a sequential strategy in mPC.. In this phase II study, patients were randomly assigned to receive either 6 months of FOLFIRINOX (arm A), 4 months of FOLFIRINOX followed by leucovorin plus fluorouracil maintenance treatment for controlled patients (arm B), or a sequential treatment alternating gemcitabine and fluorouracil, leucovorin, and irinotecan every 2 months (arm C). The primary end point was progression-free survival at 6 months.. Between January 2015 and November 2016, 276 patients (mean age: 63 years; range: 40-76 years) were enrolled (A: 91, B: 92, and C: 90). Grade 3 or 4 neurotoxicity occurred in 10.2% of patients in arm A and 19.8% in arm B. The median ratio of received dose/targeted dose of oxaliplatin was 83% in arm A and 92% in arm B. The 6-month progression-free survival was 47.1% in A, 42.9% in B, and 34.1% in C. The median overall survival was 10.1 months in arm A, 11.2 in arm B, and 7.3 in arm C. Median survival without deterioration in quality-of-life scores was higher in the maintenance arm (11.4 months) than in arms A and C (7.2 and 7.5 months, respectively).. Maintenance with leucovorin plus fluorouracil appears to be feasible and effective in patients with mPC controlled after 4 months of induction chemotherapy with FOLFIRINOX. Severe neurotoxicity was higher in the maintenance therapy arm, probably because of the higher cumulative dose of oxaliplatin.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Pancreatic Neoplasms; Quality of Life

Preoperative therapy in borderline resectable pancreatic cancer (BRPC) is intended to increase R0 resection rates. An optimal approach in BRPC is yet to be defined.. Patients with BRPC, confirmed adenocarcinoma, performance status ≤1, and adequate organ function enrolled in a single-institution, phase 2 trial. Patients received FOLFIRINOX × 6 cycles, then radiation therapy (50 Gy in 25 fractions) concurrent with fixed-dose rate gemcitabine (1 g/m. Twenty-five patients with median age of 60 years (range, 47-77 years) enrolled from November 2011 through January 2017. Twenty-one (84%) completed FOLFIRINOX and 19 (76%) completed all protocol therapy. Treatment-related grade 3 to 4 toxicities included neutropenia (40%), nausea and vomiting (28%), diarrhea (16%), and fatigue (12%). Eighteen patients (72%) underwent laparotomy, 13 (52%) were resected (all R0). The median PFS and OS in 25 patients were 13.1 months (95% confidence interval [CI], 7.3-24.7) and 24.4 months (95% CI, 12.6-40.0), respectively. For resected patients, median PFS was 21.6 months (95% CI, 8.2-37.1) and OS was 37.1 months (95% CI, 15.4-not reached).. Neoadjuvant therapy with FOLFIRINOX, followed by intensity modulated radiation therapy concurrent with fixed-dose-rate gemcitabine in BRPC is feasible and tolerated. Although the alternate hypothesis was not met, the OS of the resected cohort was favorable.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Chemoradiotherapy; Deoxycytidine; Dose Fractionation, Radiation; Feasibility Studies; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neutropenia; Oxaliplatin; Pancreatic Neoplasms; Progression-Free Survival; Radiotherapy, Intensity-Modulated

Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). Tumor tissues from patients treated with pelareorep have shown reovirus replication, T-cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination with pembrolizumab and chemotherapy in patients with PDAC would be safe and effective.. A phase Ib single-arm study enrolled patients with PDAC who progressed after first-line treatment. Patients received pelareorep, pembrolizumab, and either 5-fluorouracil, gemcitabine, or irinotecan until disease progression or unacceptable toxicity. Study objectives included safety and dose-limiting toxicities, tumor response, evaluation for reovirus replication, and immune analysis in peripheral blood and tumor biopsies.. Eleven patients were enrolled. Disease control was achieved in three of the 10 efficacy-evaluable patients. One patient achieved partial response for 17.4 months. Two additional patients achieved stable disease, lasting 9 and 4 months, respectively. Treatment was well tolerated, with mostly grade 1 or 2 treatment-related adverse events, including flu-like symptoms. Viral replication was observed in on-treatment tumor biopsies. T-cell receptor sequencing from peripheral blood revealed the creation of new T-cell clones during treatment. High peripheral clonality and changes in the expression of immune genes were observed in patients with clinical benefit.. Pelareorep and pembrolizumab added to chemotherapy did not add significant toxicity and showed encouraging efficacy. Further evaluation of pelareorep and anti-PD-1 therapy is ongoing in follow-up studies. This research highlights the potential utility of several pretreatment and on-treatment biomarkers for pelareorep therapy warranting further investigation.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Combined Modality Therapy; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Oncolytic Virotherapy; Oncolytic Viruses; Pancreatic Neoplasms; Patient Safety; Treatment Outcome

This Phase IIb (NCT02195180) open-label study evaluated erythrocyte-encapsulated asparaginase (eryaspase) in combination with chemotherapy in second-line advanced pancreatic adenocarcinoma.. Eligible patients were randomized 2:1 to either eryaspase in combination with gemcitabine or mFOLFOX6 (eryaspase arm), or to gemcitabine or mFOLFOX6 alone (control arm). Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with low asparagine synthetase (ASNS) expression. Secondary endpoints included OS and PFS in the entire population.. 141 patients were randomized (eryaspase arm, n = 95; control arm, n = 46). Median OS and PFS in patients with low ASNS expression were 6.2 months (95% CI, 5.1-8.8) in the eryaspase arm versus 4.9 months (3.1-7.1) in the control arm (HR, 0.63; 95% CI, 0.39-1.01; P = 0.056) and 2.0 months (95% CI, 1.8-3.4) in the eryaspase arm versus 1.8 months (1.4-3.8) in the control arm (HR, 0.67; 95% CI, 0.40-1.12; P = 0.127), respectively. In the entire population, median OS and PFS for the eryaspase arm versus control were 6.0 months versus 4.4 months (HR, 0.60; P = 0.008) and 2.0 months versus 1.6 months (HR, 0.56; 95% CI, 0.37-0.84; P = 0.005), respectively. The combination of eryaspase and chemotherapy was well tolerated. The most frequent Grade 3/4 adverse events in the eryaspase arm (n = 93) were gamma-glutamyltransferase increase (16 [17.2%]), neutropenia (12 [12.9%]), and physical health deterioration (12 [12.9%]).. Eryaspase in combination with chemotherapy is associated with improvements in OS and PFS, irrespective of ASNS expression in second-line advanced pancreatic adenocarcinoma. A Phase III trial is underway.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Biopsy; Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Staging; Neutropenia; Organoplatinum Compounds; Pancreas; Pancreatic Neoplasms; Progression-Free Survival; Response Evaluation Criteria in Solid Tumors

The global, randomized NAPOLI-1 phase 3 trial reported a survival benefit with liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) after previous gemcitabine-based therapy. Median overall survival (OS) with nal-IRI+5-FU/LV was 6.1 vs 4.2 months with 5-FU/LV alone (unstratified hazard ratio [HR] = 0.67, P = .012). Herein, we report efficacy and safety results from a post-hoc subgroup analysis of Asian patients treated at Asian centers. Primary study endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Patients receiving nal-IRI+5-FU/LV (n = 34) had significantly longer median OS versus 5-FU/LV (n = 35) (8.9 vs 3.7 months; unstratified HR = 0.51, P = .025). Patients had significantly increased median PFS with nal-IRI+5-FU/LV versus 5-FU/LV (4.0 vs 1.4; unstratified HR = 0.48, P = .011), and increased ORR (8.8% vs 0; P = .114). nal-IRI monotherapy (n = 50) numerically improved efficacy endpoints versus 5-FU/LV (n = 48): median OS was 5.8 versus 4.3 months (HR = 0.83, P = .423) and median PFS was 2.8 versus 1.4 months (HR = 0.69, P = .155). Grade ≥3 neutropenia was reported more frequently with nal-IRI+5-FU/LV versus 5-FU/LV (54.5% vs 3.4%), and incidence of grade ≥3 diarrhea was comparable between the two arms (3.0% vs 6.9%). This subgroup analysis confirms nal-IRI+5-FU/LV as an efficacious treatment option that improves survival in Asian patients with mPDAC that progressed after gemcitabine-based therapy, with a safety profile agreeing with previous findings. The nal-IRI+5-FU/LV regimen should represent a new standard of care for these patients in Asia. (Clinicaltrials.gov: NCT01494506).

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Asian People; Endpoint Determination; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

The NAnoliPOsomaL Irinotecan (NAPOLI-1) study (NCT01494506) was the largest global phase 3 study in a post-gemcitabine metastatic pancreatic adenocarcinoma (mPAC) population (N = 417). The subanalyses reported here investigated the prognostic effect of tumor characteristics and disease stage, prior treatment characteristics, baseline patient characteristics on survival outcomes in NAPOLI-1, and whether liposomal irinotecan (nal-IRI) + 5-fluorouracil/leucovorin (5-FU/LV) benefited patients with mPAC across subgroups.. Post hoc analyses were performed in the NAPOLI-1 population (4 across tumor characteristics and disease stage, 6 across prior treatment characteristics, and 4 across patient baseline characteristics). Survival outcomes were estimated by Kaplan-Meier analysis and patient safety data were evaluated.. Mortality and morbidity risk was lower on nal-IRI+5-FU/LV treatment across subgroups. Exceptions were patients who had received prior nonliposomal irinotecan and those who had undergone prior Whipple procedure (overall survival hazard ratio = 1.25 and 1.23, respectively). Decreased appetite, liver metastases, and number of measurable metastatic lesions seemed to be prognostic of survival in this population. Subgroup safety data were generally comparable with those in the overall NAPOLI-1 safety population.. A diverse population of patients with mPAC that progressed on gemcitabine-based therapy benefited from nal-IRI+5-FU/LV versus 5-FU/LV, potentially helping guide treatment decisions for challenging cases.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liposomes; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Treatment Outcome

Topics: Abdominal Pain; Acute Disease; Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Data Analysis; Diarrhea; Fluorouracil; Humans; Irinotecan; Leucovorin; Middle Aged; Nausea; Organs at Risk; Oxaliplatin; Pancreatic Neoplasms; Prospective Studies; Radiation Dosage; Radiosurgery; Time Factors

Pancreatic ductal adenocarcinoma is a largely incurable cancer. Surgical resection remains the only potential option for cure. Even in surgically resectable patients, only about 10% to 20% are long-term survivors. Emerging data suggest a role for neoadjuvant therapy to target occult micrometastatic disease.. To report our institutional experience with a novel neoadjuvant chemoradiation (CRT) regimen in resectable and borderline resectable pancreatic cancer.. Patients were treated with 2 cycles of induction chemotherapy with FOLFOX and then received CRT with gemcitabine and intensity-modulated radiotherapy (IMRT).. From April 2014 to June 2017, 24 patients were enrolled. Eighteen patients were borderline resectable and 6 patients were resectable. All patients received induction chemotherapy with FOLFOX. Thirteen patients underwent pancreatectomy after CRT with a resection rate of 62%. R0 resection achieved in 11 patients (84.6%) and 2 patients had R1 resection (15.4%). For patients who underwent resection, the median progression-free survival (PFS) was 31 months, 1-year PFS rate was 69.2% (95% confidence interval [CI], 0.48-0.99), and 2-year PFS rate was 51.9% (95% CI, 0.3-0.89). Median overall survival (OS) was 34.8 months (95% CI, 1.045 to infinity), 1-year OS rate was 91.7% (95% CI, 0.77-1.0), and 2-year OS rate was 75% (95% CI, 0.54-1.0). Median CA 19-9 at screening for patients who underwent surgery was 659 (range, 18 to 2154), which decreased to 146.9 (range, 18 to 462) after CRT before resection.. Neoadjuvant therapy for borderline resectable and resectable pancreatic ductal adenocarcinoma with CRT facilitated R0 resection in 84% patients who underwent surgery.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Chemoradiotherapy; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Induction Chemotherapy; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Pancreatic Neoplasms; Radiotherapy, Intensity-Modulated

Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; CD8-Positive T-Lymphocytes; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Myeloid-Derived Suppressor Cells; Pancreatic Neoplasms; Peptides; Peritoneal Neoplasms; Receptors, CXCR4; Retroperitoneal Neoplasms; Survival Rate; T-Lymphocytes, Regulatory; Treatment Outcome

Management of metastatic pancreatic ductal adenocarcinoma (mPDA) places a significant financial burden on the U.S. health care system because of such factors as treatment with multidrug chemotherapy regimens, management of chemotherapy-related adverse events, and disease- or treatment-related hospitalizations. Depending on functional status, first-line chemotherapy regimens that are guideline recommended include. To describe health care costs following initiation of first-line treatment with AG or FFX among patients with mPDA.. Retrospective cohorts of first-line AG and FFX initiators were constructed from the MarketScan database (2014-2017). The index date was the date of first-line AG or FFX initiation. Included patients had insurance enrollment for 6 months before the index date. Total cumulative health care costs and costs from outpatient services, inpatient admissions, emergency department visits, chemotherapy administrations, and pharmacy dispensing were assessed within 12 months after the index date (i.e., 0-1, 0-2, …, 0-12 months). Patient-level cost data began accruing from the first paid claim and continued accruing until the censoring date.. A total of 2,199 patients with mPDA initiated first-line AG (n = 1,352) or FFX (n = 847). Compared with AG initiators, FFX patients were younger (mean age 59 vs. 63 years) and had better baseline health status, with fewer having diabetes (43% vs. 57%) or coronary artery disease (12% vs. 22%). Median follow-up was 5.4 and 7.2 months for AG and FFX, respectively. Median first-line treatment duration was 2.1 months with AG and 2.3 months with FFX. Six months following first-line treatment initiation, total cumulative health care costs (median) were $85,714 (95% CI = $79,683-$91,788) and $114,116 (95% CI = $105,816-$119,591) for AG and FFX initiators, respectively. Outpatient services contributed the largest fractional cost for both groups.. Total health care costs for patients with mPDA who initiated FFX or AG are driven mostly by outpatient rather than inpatient costs. Further research, using comparative methodology, is warranted to fully understand cost drivers and whether higher costs for FFX patients relate primarily to use of FFX or higher underlying use of outpatient care among FFX patients.. This study was funded by Halozyme Therapeutics. Oestreicher and Yeganegi were employees of Halozyme Therapeutics at the time of the study and were involved in study design, data interpretation, and the decision to submit the data for publication. Bullock reports advisory board fees from Eisai, Exelixis, Bayer, and Taiho and consulting fees from Halozyme Therapeutics, outside the submitted work. Rowan reports consulting fees from Halozyme Therapeutics, during the conduct of the study. Chiorean reports grants and consulting fees from Celgene and Halozyme Therapeutics; grants from Lilly, Stemline, Ignyta, Roche, Merck, Boehringer-Ingelheim, Bristol Meyer Squibb, Incyte, Macrogenics, Rafael, and AADi; and consulting fees from Astra Zeneca, Array, Eisai, Ipsen, Five Prime Therapeutics, Seattle Genetics, Vicus, and Legend, outside the submitted work.

Topics: Aged; Aged, 80 and over; Ambulatory Care; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cohort Studies; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Health Care Costs; Hospitalization; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

This phase II study tested granulocyte-macrophage colony-stimulating factor (GM-CSF)-allogeneic pancreatic tumor cells (GVAX) and ipilimumab in metastatic pancreatic ductal adenocarcinoma (PDA) in the maintenance setting.. Patients with PDA who were treated with front-line chemotherapy consisting of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the metastatic setting and had ongoing response or stable disease after 8-12 doses were eligible. Patients were randomized 1:1 to treatment with GVAX and ipilimumab given every 3 weeks for four doses then every 8 weeks (Arm A) or to FOLFIRINOX continuation (Arm B). The primary objective was to compare overall survival (OS) between the two arms.. Eighty-two patients were included in the final analysis (Arm A: 40; Arm B: 42). The study was stopped for futility after interim analysis. Median OS was 9.38 months [95% confidence interval (CI), 5.0-12.2] for Arm A and 14.7 months (95% CI, 11.6-20.0) for Arm B (HR, 1.75;. GVAX and ipilimumab maintenance therapy did not improve OS over continuation of chemotherapy and resulted in a numerically inferior survival in metastatic PDA. However, clinical responses and biological effects on immune cells were observed. Further study of novel combinations in the maintenance treatment of metastatic PDA is feasible.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Ipilimumab; Irinotecan; Leucovorin; Macrophages; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Pancreatic Neoplasms; Tumor Microenvironment

Chemotherapy is effective in metastatic pancreatic adenocarcinoma (mPA), but new approaches are still needed to improve patients' survival and quality of life. We have previously published good efficacy and tolerability results on a sequential treatment strategy of gemcitabine followed by an intensified FOLFIRI (5FU+irinotecan) regimen. In the present study, we evaluated the same sequence but replaced gemcitabine by the new gemcitabine + nab-paclitaxel standard first-line combination.. We randomised chemotherapy-naive patients with proven mPA, bilirubin levels ≤1.5 upper limit of normal values and performance status 0-2 to alternately receive gemcitabine + nab-paclitaxel for 2 months then FOLFIRI.3 for 2 months in arm A, or gemcitabine + nab-paclitaxel alone until progression in arm B. The primary objective was to increase the 6-month progression-free survival (PFS) rate from 40% (H. Between November 2015 and November 2016, 127 patients were enrolled. Main grade III-IV toxicities (% in arm A/B) were: diarrhoea (12.5/1.7), neutropenia (46.9/31, including febrile neutropenia: 1.6/0), skin toxicity (6.3/13.8), and peripheral neuropathy (6.3/8.6). No toxic deaths occurred. The objective response rate was 40.3% (95% confidence interval [CI]: 28.1-53.6) in arm A and 26.7% (95% CI: 16.1-39.7) in arm B. The primary end-point (6-month PFS rate) was 45.2% [one-sided 95% CI: 34.3-56.4] in arm A and 23.3% in arm B [one-sided 95% CI: 14.3-32.3] in the mITT population. In the PP population, median PFS and OS were 7.6 months and 6 months and 14.5 months and 12.2 months in arm A and B, respectively.. The FIRGEMAX strategy with gemcitabine + nab-paclitaxel alternating with FOLFIRI.3 every 2 months, appears feasible and effective, with manageable toxicities, in patients able to reach >2mo of treatment.. EudraCT: 2014-004449-28: NCT: 0282701.

Topics: Adenocarcinoma; Adult; Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Disease Progression; Drug Substitution; Female; Fluorouracil; France; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival; Treatment Outcome

Previously published work has demonstrated that combining gemcitabine with irreversible electroporation (IRE) results in increased drug delivery to pancreatic adenocarcinoma cells in vivo. This study assessed the efficacy of IRE + gemcitabine and IRE + FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), the impact of the superior regimen on survival, and the safety of electrochemotherapy in human subjects.. Histologic analysis was performed after in vitro and in vivo treatment of S2013 and Panc-1 pancreatic cancer cells and S2013 orthotopic tumors, respectively, and levels of apoptotic machinery and cell cycle proteins were evaluated using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot.. Electrochemotherapy (ECT) with IRE and FOLFIRINOX resulted in increased tumor cells apoptosis compared with gemcitabine, gemcitabine + IRE, and FOLFIRINOX alone, and significantly improved overall survival when compared with mice treated with IRE or FOLFIRINOX. Increased tumor cell apoptosis, caspase-3 mRNA, active caspase-3 protein, and decreased cell proliferation were noted at the time of death or euthanasia in the ECT group compared with folinic acid alone. In five patients, ECT with either FOLFIRINOX or gemcitabine was well-tolerated and resulted in no dose-limiting toxicities.. ECT thus results in synergistic antitumor activity compared with either treatment modality used alone, resulting in increased tumor cell apoptosis as well as decreased tumor cell proliferation and improved overall survival. Pilot data suggest that ECT represents a promising modality for the treatment of patients with locally advanced pancreatic cancer.. The human subject portion of this work was conducted as part of an investigator-initiated clinical trial at the University of Louisville (NCT03484299).

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Deoxycytidine; Disease Models, Animal; Electrochemotherapy; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Mice; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

The optimal neoadjuvant therapy for resectable pancreatic ductal adenocarcinoma (PDA) and the impact on surgical outcomes remains unclear.. S1505 (NCT02562716) was a randomized phase II study of perioperative chemotherapy with mFOLFIRINOX (Arm 1) or gemcitabine/nab-paclitaxel (Arm 2). Measured parameters included resection rate, margin positivity, pathologic response, and toxicity.. Between 2015 and 2018, 147 patients were randomized. Of these, 44 (30%) were deemed ineligible (43 by central review). Of the 103 eligible patients, 77 (76%) completed preoperative therapy and underwent surgery; reasons patients did not undergo surgery included toxicity related to preoperative therapy (n = 9), progression (n = 9), or other (n = 7). Of the 77, 73 (95%) underwent successful resection; 21 (29%) required vascular reconstruction, 62 (85%) had negative (R0) margins, and 24 (33%) had a complete or major pathologic response to therapy. The grade 3-5 postoperative complication rate was 16%. Of the 73 patients completing surgery, 57 (78%) started and 46 (63%) completed postoperative therapy. This study represents the first prospective trial evaluating modern systemic therapy delivered in a neoadjuvant/perioperative format for resectable PDA.. We have demonstrated: (1) Based on the high percentage of enrolled, but ineligible patients, it is clear that adherence to strict definitions of resectable PDA is challenging; (2) Patients can tolerate modern systemic therapy and undergo successful surgical resection without prohibitive perioperative complications; (3) Completion of adjuvant therapy in the perioperative format is difficult; (4) Major pathologic response rate of 33% is encouraging.

Topics: Aged; Albumins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Combined Modality Therapy; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Immunosuppressive Agents; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Paclitaxel; Pancreatectomy; Pancreatic Neoplasms; Perioperative Care; Prospective Studies; Treatment Outcome

Multiple clinical trials have established a role for adjuvant chemotherapy for patients with pancreatic ductal adenocarcinoma. Adjuvant FOLFIRINOX increases survival as compared with gemcitabine but with increased toxicity. FOLFOX+nab-paclitaxel (FOLFOX-A) was developed by the Brown University Oncology Research Group (BrUOG) as an alternative to FOLFIRINOX. This phase II trial explored the feasibility and toxicity of adjuvant FOLFOX-A in patients who have completed resection for pancreatic ductal adenocarcinoma.. Patients with resected pancreatic ductal adenocarcinoma were eligible. The primary objective was to determine the feasibility of adjuvant FOLFOX-A. Patients experiencing grade 2 neuropathy received a 20% reduction of oxaliplatin. Secondary end points were disease-free survival, and overall survival.. Between June 2014 and October 2018, 25 patients were enrolled following surgical resection. The median number of cycles completed was 9.5. Median disease-free survival was 19.7 months (95% confidence interval, 10.3 to not reached) and median overall survival was 53.5 months (95% confidence interval, 24.2 to not reached). The most common treatment-related grade 3 or greater adverse events were fatigue (58%), nausea (13%), and neutropenia (26%). Fourteen patients had grade 2 neuropathy (58%) and 1 patient (4%) had grade 3 neuropathy. Only 2 patients (8%) had grade 3 diarrhea.. Adjuvant FOLFOX-A is a feasible multi-agent adjuvant treatment regimen and, with further validation, could be an alternative to FOLFIRINOX.

Topics: Adult; Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Female; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms; Treatment Outcome

In the NAPOLI-1 phase 3 trial, liposomal irinotecan (nal-IRI) +5-fluorouracil/leucovorin (5-FU/LV) significantly increased mPFS versus 5-FU/LV (3.1 vs. 1.5 months [unstratified HR = 0.56, p = 0.0001]) in patients with mPAC that progressed on prior gemcitabine-based therapy. This randomized phase 2 trial evaluated nal-IRI+5-FU/LV tolerability (Part 1), safety, and efficacy (Part 2; outcomes reported here) in Japanese patients with mPAC that progressed on gemcitabine-based therapy.. Patients were randomized 1:1 and stratified by KPS (70 and 80 vs. ≥90) and baseline albumin (≥4.0 g/dl vs. <4.0 g/dl). Primary endpoint was PFS; secondary endpoints were ORR, DCR, OS, TTF, CA19-9 response, and QoL. The ITT population comprised all randomized patients.. Patient characteristics differed between nal-IRI+5-FU/LV (n = 40) and 5-FU/LV (n = 39) arms, including baseline hepatic lesions (63% vs. 51%), stage IV disease at diagnosis (78% vs. 51%), and post-study anticancer therapy (55% vs. 72%). Investigator-assessed mPFS increase with nal-IRI+5-FU/LV was clinically meaningful and statistically significant versus 5-FU/LV (2.7 vs. 1.5 months, HR = 0.60). Independently assessed mPFS showed similar trends (1.7 vs. 1.6 months, HR = 0.79). mOS was 6.3 months with nal-IRI+5-FU/LV and not reached with 5-FU/LV. ORR increased significantly with nal-IRI+5-FU/LV versus 5-FU/LV (18% vs. 0, rate difference 17.5). Commonly reported grade ≥3 treatment-emergent AEs were decreased neutrophil count (37% vs. 3%), decreased white blood cell count (20% vs. 0), and diarrhea (17% vs. 3%).. In conclusion, clinically meaningful and statistically significant gains in investigator-assessed PFS and ORR were observed with nal-IRI+5-FU/LV versus 5-FU/LV in Japanese patients, with no new or unexpected safety signals. (Clinicaltrials.gov ID: NCT02697058).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Drug Resistance, Neoplasm; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Japan; Leucovorin; Liposomes; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Pancreatic Neoplasms; Survival Rate

BACKGROUND Pancreatic cancer (PC) is a common digestive system tumor. For patients with advanced pancreatic cancer (APC), chemotherapy is still the predominant treatment. However, no large-scale clinical studies have been done of it as first-line therapy for APC. The goal of the present study was to assess real-world outcomes with chemotherapy in that setting. MATERIAL AND METHODS We retrospectively analyzed data from 322 patients with APC who were treated with chemotherapy at 4 hospitals in different cities in China. The first-line regimens used were AS (nab-paclitaxel and S-1), AG (nab-paclitaxel and gemcitabine), and FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin). RESULTS Of the patients, 232 received AS, 79 received AG, and 11 received FOLFIRINOX. The median number of chemotherapy cycles was 5. The median overall survival (mOS) was 9 months and the median progression-free survival (mPFS) was 5 months. The AS, AG, and FOLFIRINOX regimens were associated with mOS rates of 9 months, 9 months, and 10 months, respectively. The mPFS rates for the AS, AG, and FOLFIRINOX regimens were 5, 4, and 5 months, respectively. The differences between the PFS rates for the regimens were statistically significant. The overall response rate (ORR) and overall disease control rate (DCR) for chemotherapy were 38% and 81.8%, respectively. The ORRs for the AS, AG, and FOLFIRINOX regimens were 46.9%, 18.7%, and 0%, respectively. The DCRs for the AS, AG and FOLFIRINOX regimens were 87.2%, 69.3%, and 63.6%, respectively. The differences between the ORRs and DCRs for the regimens were statistically significant. The incidences of grade 3/4 adverse events (AEs) associated with the AS, AG, and FOLFIRINOX regimens were 29.9%, 25%, and 36.4%, respectively. CONCLUSIONS The AS regimen was associated with a higher ORR and DCR than the other 2 regimens, with a lower rate of AEs.

Topics: Adult; Aged; Albumins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; China; Deoxycytidine; Drug Combinations; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Oxonic Acid; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival; Retrospective Studies; Tegafur

Devimistat (CPI-613

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Caprylates; Female; Fluorouracil; Follow-Up Studies; Humans; International Agencies; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Prospective Studies; Sulfides; Survival Rate

Cancer antigen (CA)-125 influences progression, metastasis, and outcomes in pancreatic cancer. This phase I/II trial (NCT01959672) evaluated the safety, efficacy, and immunologic correlates of chemoimmunotherapy (CIT) with oregovomab (anti-CA-125), followed by stereotactic body radiotherapy (SBRT) with the radiosensitizer nelfinavir.. Following imaging, pathologic confirmation, and staging laparoscopy, subjects received three 3-week cycles of CIT (gemcitabine/leucovorin/fluorouracil/oregovomab). Thereafter, nelfinavir was delivered (1250 mg bid) for 5 weeks, with SBRT (40 Gy/5 fractions) occurring during the third week of nelfinavir. Following another cycle of CIT, pancreaticoduodenectomy was performed if resectable. Three more cycles of CIT were then delivered (total 7 cycles). In subjects with high (≥10 U/mL) CA-125, oregovomab (2 mg) was administered for 7 total doses (3 pre-SBRT, 1 between SBRT and resection, and 3 postoperatively). The enzyme-linked immunospot assay evaluated the development of CA-125-specific CD8 T-lymphocytes.. The trial was prematurely closed because gemcitabine/leucovorin/fluorouracil was replaced by FOLFIRINOX and gemcitabine/nab-paclitaxel as the standard of care. Median follow-up was 13 months. Of 11 enrolled patients, 10 had high CA-125; 1 patient suffered an unexpected cardiac-related death, so 9 subjects received oregovomab. Ten received SBRT and 4 underwent resection. Overall, 6/11 patients experienced any grade ≥3 event. The median survival and time to progression were 13 and 8.6 months, respectively. Five patients had samples available for immunospot testing, of whom 2 (40%) developed CA-125-specific CD8 T-lymphocytes.. A combined pancreatic cancer multimodality approach using CIT and radiosensitized radiotherapy is feasible and safe; delivery of immunotherapy can lead to T-cell immunity. Re-evaluation with modern systemic paradigms is recommended.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; CA-125 Antigen; Camptothecin; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leucovorin; Magnetic Resonance Imaging; Male; Membrane Proteins; Middle Aged; Nelfinavir; Neoadjuvant Therapy; Neoplasm Invasiveness; Organoplatinum Compounds; Pancreatic Neoplasms; Pancreaticoduodenectomy; Proportional Hazards Models; Radiosurgery; Risk Assessment; Survival Analysis; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

Local and distant disease recurrence are frequently observed following pancreatic cancer resection, but an improved understanding of resection margin assessment is required to aid tailored therapies.. Analyses were carried out to assess the association between clinical characteristics and margin involvement as well as the effects of individual margin involvement on site of recurrence and overall and recurrence-free survival using individual patient data from the European Study Group for Pancreatic Cancer (ESPAC)-3 randomized controlled trial.. There were 1151 patients, of whom 505 (43.9%) had an R1 resection. The median and 95% confidence interval (CI) overall survival was 24.9 (22.9-27.2) months for 646 (56.1%) patients with resection margin negative (R0 >1 mm) tumors, 25.4 (21.6-30.4) months for 146 (12.7%) patients with R1<1 mm positive resection margins, and 18.7 (17.2-21.1) months for 359 (31.2%) patients with R1-direct positive margins (P < 0.001). In multivariable analysis, overall R1-direct tumor margins, poor tumor differentiation, positive lymph node status, WHO performance status ≥1, maximum tumor size, and R1-direct posterior resection margin were all independently significantly associated with reduced overall and recurrence-free survival. Competing risks analysis showed that overall R1-direct positive resection margin status, positive lymph node status, WHO performance status 1, and R1-direct positive superior mesenteric/medial margin resection status were all significantly associated with local recurrence.. R1-direct resections were associated with significantly reduced overall and recurrence-free survival following pancreatic cancer resection. Resection margin involvement was also associated with an increased risk for local recurrence.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Margins of Excision; Neoplasm Recurrence, Local; Pancreatectomy; Pancreatic Neoplasms; Prognosis; Prospective Studies; Retrospective Studies; Survival Analysis

Purpose Our previous phase I trial suggested feasibility of addition of leucovorin (LV) to S-1 and gemcitabine therapy in advanced pancreatic cancer. The aim of this phase II trial was to assess the efficacy and toxicity of gemcitabine, S-1 and LV (GSL) combination therapy for advanced pancreatic cancer. Methods Chemotherapy-naïve patients with histologically or cytologically proven advanced pancreatic cancer were enrolled. Gemcitabine was administered at a dose of 1000 mg/m2 by 30 min infusion on days 1, S-1 40 mg/m2 orally twice daily and LV 25 mg orally twice daily on days 1 to 7 every 2 weeks. Primary end point was progression free survival (PFS). Results A total of 49 patients with advanced pancreatic cancer (19 locally advanced and 30 metastatic) were enrolled. Overall response rate and disease control rate were 32.7% and 87.8%. The median PFS and overall survival (OS) were 10.8 (95% confidence interval [CI], 7.4-13.5) and 20.7 (95% CI 13.0-NA) months with 1-year survival rate of 73.4%. Major Grade 3-4 toxicities were neutropenia (22.4%) and stomatitis (14.3%). No toxicity related death was observed. Conclusions In this single center, phase II trial, gemcitabine, S-1 and LV combination therapy was tolerable and can potentially be a treatment option for advanced pancreatic cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Drug Combinations; Female; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Oxonic Acid; Pancreatic Neoplasms; Peritoneal Neoplasms; Prognosis; Survival Rate; Tegafur

The NAPOLI-1 study (NCT01494506) reported that liposomal irinotecan plus 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) improved overall survival vs 5-FU/LV with manageable toxicity in patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-based therapy. Yet, clinicians need treatment strategies that also maintain the patient's health-related quality of life (HRQOL). Here, we report the HRQOL data.. Patients completed the European Organisation for Research and Treatment of Cancer QOL core questionnaire C30 (EORTC QLQ-C30) at baseline, every 6 weeks, and at 30 days after discontinuation of study treatment. Patient-reported outcomes (PROs) were scored according to EORTC guidelines. nal-IRI+5-FU/LV HRQOL was compared with 5-FU/LV. The PRO population comprised intent-to-treat patients who completed baseline and at least one subsequent assessment on the EORTC QLQ-C30. Data were also analysed for missingness.. Of 236 patients in the intent-to-treat population, 128 (54.2%) comprised the PRO population (71 in the nal-IRI+5-FU/LV arm; 57 the in 5-FU/LV arm). Of the remaining 108 patients (45.8%) not included in the PRO population, most progressed rapidly, making participation difficult. Median change from baseline was ≤10 points at weeks 6 and 12 in global health status or functional and symptom scale scores, except for fatigue, which deteriorated by 11.1 points with nal-IRI+5-FU/LV but did not change vs 5-FU/LV. The proportion of patients whose HRQOL improved or deteriorated was not significantly different between the arms.. In the NAPOLI-1 study, HRQOL was maintained with nal-IRI+5-FU/LV in patients with metastatic pancreatic adenocarcinoma previously treated with a gemcitabine-based regimen, while survival was significantly extended.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Disease Progression; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Patient Reported Outcome Measures; Progression-Free Survival; Quality of Life; Time Factors

In our previous randomised phase 2 study for patients with gemcitabine-refractory advanced pancreatic cancer, S-1 plus leucovorin improved progression-free survival compared with S-1 alone. Here, we evaluated the efficacy of TAS-118 (S-1 plus leucovorin) versus S-1 in overall survival (OS).. This randomised, open-label, phase 3 study was conducted at 58 centres in Japan and Korea. Patients with metastatic pancreatic cancer that progressed during first-line gemcitabine-based chemotherapy or recurred during or after post-operative gemcitabine-based adjuvant treatment were randomly assigned (1:1) to receive either S-1 (40-60 mg, twice daily for 4 weeks in a 6-week cycle) or TAS-118 (S-1 40-60 mg plus leucovorin 25 mg, twice daily for 1 week in a 2-week cycle). The primary end-point was OS.. A total of 603 patients were randomised, and 300 and 301 patients received TAS-118 and S-1, respectively. There was no difference in OS between groups (median OS for TAS-118 versus S-1, 7.6 months versus 7.9 months; hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.82-1.16]; P = 0.756). Progression-free survival was significantly longer with TAS-118 than S-1 (median, 3.9 months versus 2.8 months; HR, 0.80 [95% CI, 0.67-0.95]; P = 0.009). There were interactions between Japan and Korea (P = 0.004) and between unresectable and recurrent disease (P = 0.025) in OS. Incidence, profile and severity of adverse events were similar between groups.. TAS-118 did not improve OS in patients with gemcitabine-refractory advanced pancreatic cancer compared to S-1. Further studies are needed to find patients who have benefit from adding leucovorin to S-1.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Adenosquamous; Deoxycytidine; Disease Progression; Drug Combinations; Drug Resistance, Neoplasm; Female; Gemcitabine; Humans; Japan; Leucovorin; Male; Middle Aged; Oxonic Acid; Pancreatic Neoplasms; Progression-Free Survival; Republic of Korea; Tegafur; Time Factors

FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil, leucovorin) treatment significantly improved overall survival in the recent phase III study and became a standard therapy for metastatic pancreatic cancer. However, treatment for locally advanced pancreatic cancer is still controversial. We conducted subset analyses from a nation-wide multicenter observational study in Japan to evaluate the tolerability and efficacy of FOLFIRINOX in patients with locally advanced pancreatic cancer and to investigate independent prognostic factors with pre-treatment variables.. The study included 66 patients with unresectable locally advanced pancreatic cancer from 27 institutions in Japan who received FOLFIRINOX as first-line treatment between December 20, 2013 and December 19, 2014 and surveyed until December 2015.. The median age was 63 with the Eastern Cooperative Oncology Group performance status of 0 or 1. Major Grade 3 or 4 adverse events included neutropenia (64%), leukopenia (33%), febrile neutropenia (15%), and diarrhea (15%). Severe adverse event occurred in 14 patients (11%) without fatal event. The median overall survival and progression-free survival times were 18.5 and 7.6 months, respectively. The objective response rate 15.2% and the disease control rate was 81.9%. A high modified Glasgow prognostic score (mGPS, ≥1) (95%CI 1.96-12.5) and female (95%CI 0.20-0.97) were identified as independent poor prognostic factors.. First-line FOLFIRINOX treatment for locally advanced pancreatic cancer seems to be effective with acceptable toxicities. A high mGPS may be associated with poor survival in patients with locally advanced pancreatic cancer who receive FOLFIRINOX. This study was registered at the UMIN Clinical Trials Registry (UMIN000014658).

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Irinotecan; Japan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Prognosis

Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) is approved for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This approval was based on significantly improved median overall survival compared with 5-FU/LV alone (6.1 vs 4.2 months; hazard ratio [HR], 0.67) in the global phase 3 NAPOLI-1 trial. Here, we report the final survival analysis and baseline characteristics associated with long-term survivors (survival of ≥1 year) in the NAPOLI-1 trial.. Patients with mPDAC were randomised to receive nal-IRI + 5-FU/LV (n = 117), nal-IRI (n = 151), or 5-FU/LV (n = 149) for the first 4 weeks of 6-week cycles. Baseline characteristics and efficacy in the overall population were compared with those in patients who survived ≥1 year. Through 16th November 2015, 382 overall survival events had occurred.. The overall survival advantage for nal-IRI+5-FU/LV vs 5-FU/LV was maintained from the original nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1) analysis (6.2 vs 4.2 months, respectively; HR, 0.75; 95% confidence interval: 0.57-0.99). Median progression-free survival, objective response rate and disease control rate also favoured nal-IRI+5-FU/LV therapy. Estimated one-year overall survival rates were 26% with nal-IRI+5-FU/LV and 16% with 5-FU/LV. Baseline characteristics associated with long-term survival in the nal-IRI+5-FU/LV arm were Karnofsky performance status ≥90, age ≤65 years, lower CA19-9 levels, neutrophil-to-lymphocyte ratio ≤5 and no liver metastases. No new safety concerns were detected.. The survival benefits of nal-IRI+5-FU/LV versus 5-FU/LV were maintained over an extended follow-up, and prognostic markers of survival ≥1 year were identified.. NCT01494506.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Humans; Irinotecan; Karnofsky Performance Status; Leucovorin; Liposomes; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Progression-Free Survival; Proportional Hazards Models

Background The aim of the study was to evaluate diagnostic performance of functional parameters derived by conventional mono-exponential approach of diffusion weighted imaging (DWI) and by diffusion kurtosis imaging (DKI) in the assessment of pancreatic tumours treated with electrochemotherapy (ECT). Patients and methods Twenty-one consecutive patients with locally advanced pancreatic adenocarcinoma subjected to ECT were enrolled in a clinical approved trial. Among twenty-one enrolled patients, 13/21 (61.9%) patients were subjected to MRI before and after ECT. DWI was performed with a 1.5 T scanner; a free breathing axial single shot echo planar DWI pulse sequence parameters were acquired using seven b value = 0, 50, 100, 150, 400, 800, 1000 s/mm2. Apparent diffusion coefficient by conventional mono-exponential approach and mean of diffusion coefficient (MD) and mean of diffusional kurtosis (MK) by DKI approach were derived from DWI. Receiver operating characteristic (ROC) analysis was performed and sensitivity, specificity, positive and negative predictive value were calculated. Results Among investigated diffusion parameters, only the MD derived by DKI showed a significant variation of values between pre and post treatment (p = 0.02 at Wilcoxon test) and a significant statistically difference for percentage change between responders and not responders (p = 0.01 at Kruskal Wallis test). MD had a good diagnostic performance with a sensitivity of 80%, a specificity of 100% and area under ROC of 0.933. Conclusions MD derived by DKI allows identifying responders and not responders patients subject to ECT treatment. MD had higher diagnostic performance to assess ECT response compared to conventional DWI derived parameters.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Deoxycytidine; Diffusion Magnetic Resonance Imaging; Diffusion Tensor Imaging; Electrochemotherapy; Feasibility Studies; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Sensitivity and Specificity; Statistics, Nonparametric; Thermal Conductivity; Treatment Outcome

Pegylated recombinant human hyaluronidase (PEGPH20) degrades hyaluronan (HA) and, in combination with chemotherapy, prolongs survival in preclinical models. The activity of PEGPH20 with modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) was evaluated in patients with metastatic pancreatic cancer (mPC).. Patients had untreated mPC, a performance status of 0 to 1, and adequate organ function. Tumor HA status was not required for eligibility. After a phase Ib dose-finding study of mFOLFIRINOX plus PEGPH20, the phase II open-label study randomly assigned patients (1:1) to the combination arm or to mFOLFIRINOX alone (n = 138). The primary end point was overall survival (OS).. PEGPH20 dosages of 3 µg/kg every 2 weeks were more tolerable than twice-weekly dosages used in the phase I study, so 3 µg/kg every 2 weeks was the phase II dosage. An amendment instituted enoxaparin prophylaxis in the PEGPH20 combination arm as a result of increased thromboembolic (TE) events. The planned interim futility analysis when 35 deaths (of 103 analyzable patients) occurred resulted in an OS hazard ratio (HR) of 2.07 that favored the control arm, and the study was closed to accrual. The treatment-related grade 3 to 4 toxicity was significantly increased in the PEGPH20 combination arm relative to control (odds ratio, 2.7; 95% CI, 1.1 to 7.1). The median OS in the mFOLFIRINOX arm was 14.4 months (95% CI, 10.1 to 15.7 months) versus 7.7 months (95% CI, 4.6 to 9.3 months) in the PEGPH20 combination arm.. Addition of PEGPH20 to mFOLFIRINOX seems to be detrimental in patients unselected for tumor HA status. This combination caused increased toxicity (mostly GI and TE events) and resulted in decreased treatment duration compared with mFOLFIRINOX alone. The median OS in the mFOLFIRINOX control arm (14.4 months) is, to our knowledge, the longest yet reported and can be considered for patients with good PS.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Hyaluronic Acid; Hyaluronoglucosaminidase; Immunohistochemistry; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Pancreatic Neoplasms; Survival Rate

The HIV protease inhibitor nelfinavir (NFV) displays notable radiosensitizing effects. There have been no studies evaluating combined stereotactic body radiotherapy (SBRT) and NFV for borderline/unresectable pancreatic cancer. The primary objective of this phase I trial (NCT01068327) was to determine the maximum tolerated SBRT/NFV dose, and secondarily evaluate outcomes.. Following initial imaging, pathologic confirmation, and staging laparoscopy, subjects initially received three 3-week cycles of gemcitabine/leucovorin/fluorouracil; patients without radiologic progression received 5-fraction SBRT/NFV. Dose escalation was as follows: (1) 25 Gy/625 mg BID ×3wks; (2) 25 Gy/1250 mg BID ×3wks; (3) 30 Gy/1250 mg BID ×3wks; (4) 35 Gy/1250 mg BID ×3wks; (5) 35 Gy/1250 mg BID ×5wks; and (6) 40 Gy/1250 mg BID ×5wks. Pancreaticoduodenectomy was performed thereafter if resectable; if not, gemcitabine/leucovorin/fluorouracil was administered.. Forty-six patients enrolled (10/2008-5/2013); 39 received protocol-directed therapy. Sixteen (41%) experienced any grade ≥2 event during and 1 month after SBRT. Four grade 3 and both grade 4 events occurred in a single patient at the initial dose level. 40 Gy/1250 mg BID ×5wks was the maximum tolerated dose. Five patients had late gastrointestinal bleeding (n = 2 superior mesenteric artery pseudo-aneurysm, n = 1 disease progression, n = 1 lower GI tract, n = 1 unknown location). The median overall survival was 14.4 months. Six (15%) patients recurred locally; median local failure-free survival was not reached. The median distant failure-free survival was 11 months, and median all failure-free survival was 10 months.. Concurrent SBRT (40 Gy)/NFV (1250 mg BID) for locally advanced pancreatic cancer is feasible and safe, although careful attention to treatment planning parameters is recommended to reduce the incidence of late gastrointestinal bleeding.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy, Adjuvant; Deoxycytidine; Disease Progression; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Nelfinavir; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Pancreatic Neoplasms; Pancreaticoduodenectomy; Radiation-Sensitizing Agents; Radiosurgery

Pancreatic cancer is a highly lethal disease predominantly affecting older patients. Characterization of outcomes in these patients may help optimise treatment decisions. The global, phase 3 NAPOLI-1 trial (NCT01494506) demonstrated an overall survival (OS) benefit with liposomal irinotecan and 5-flurouracil/leucovorin (nal-IRI + 5-FU/LV) versus 5-FU/LV. This subgroup analysis explored impact of age on outcomes in NAPOLI-1 patients, and nal-IRI + 5-FU/LV efficacy and safety in older patients.. This exploratory, post-hoc analysis of the NAPOLI-1 trial included patients aged ≥eighteen years (no upper limit) with metastatic pancreatic adenocarcinoma that had progressed on gemcitabine-based therapy. Patients were stratified by age (cut-offs at 65, 70, and 75 years); OS and progression-free survival (PFS) were estimated by Kaplan-Meier analysis.. Of 417 randomized patients, 192 (46%), 110 (26%) and 43 (10%) were aged ≥65, ≥70 and ≥ 75 years, respectively. Mortality risk and risk of disease progression were similar in older and younger patients independent of treatment (HRs for median [m]OS/mPFS comparisons were 0.88/0.95 [<65 versus ≥65 years], 0.89/0.88 [<70 versus ≥70 years] and 1.04/0.98 [<75 versus ≥75 years]; P > .25). Reduced mortality/morbidity risk with nal-IRI + 5-FU/LV in older subgroups was in line with the wider population. No additional toxicities with nal-IRI + 5-FU/LV were observed in older patients: 86% of patients ≥75 years versus 69% <75 years required a dose delay or reduction due to toxicities (43% versus 32% dose reductions).. Results suggest that older patients with metastatic pancreatic adenocarcinoma that progressed on prior gemcitabine-based treatment can benefit from second-line therapy, supporting nal-IRI + 5-FU/LV treatment in older patients.

Topics: Adenocarcinoma; Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Middle Aged; Pancreatic Neoplasms

Patients with locally advanced pancreatic cancer have historically poor outcomes. Evaluation of a total neoadjuvant approach is warranted.. To evaluate the margin-negative (R0) resection rate of neoadjuvant FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and losartan followed by chemoradiotherapy for locally advanced pancreatic cancer.. A single-arm phase 2 clinical trial was conducted at a large academic hospital from August 22, 2013, to May 22, 2018, among 49 patients with previously untreated locally advanced unresectable pancreatic cancer as determined by multidisciplinary review. Patients had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 17.1 months (range, 5.0-53.7) among 27 patients still alive at study completion.. Patients received FOLFIRINOX and losartan for 8 cycles. Patients with radiographically resectable tumor after chemotherapy received short-course chemoradiotherapy (5 GyE × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy (50.4 Gy with a vascular boost to 58.8 Gy) with fluorouracil or capecitabine.. R0 resection rate.. Of the 49 patients (26 women and 23 men; median age 63 years [range, 42-78 years]), 39 completed 8 cycles of FOLFIRINOX and losartan; 10 patients had fewer than 8 cycles due to progression (5 patients), losartan intolerance (3 patients), and toxicity (2 patients). Seven patients (16%) had short-course chemoradiotherapy while 38 (84%) had long-course chemoradiotherapy. Forty-two (86%) patients underwent attempted surgery, with R0 resection achieved in 34 of 49 patients (69%; 95% CI, 55%-82%). Overall median progression-free survival was 17.5 months (95% CI: 13.9-22.7) and median overall survival was 31.4 months (95% CI, 18.1-38.5). Among patients who underwent resection, median progression-free survival was 21.3 months (95% CI, 16.6-28.2), and median overall survival was 33.0 months (95% CI, 31.4 to not reached).. Total neoadjuvant therapy with FOLFIRINOX, losartan, and chemoradiotherapy provides downstaging of locally advanced pancreatic ductal adenocarcinoma and is associated with an R0 resection rate of 61%.. ClinicalTrials.gov identifier: NCT01821729.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Losartan; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

The phase II AFUGEM GERCOR trial aimed to assess the efficacy of a first-line therapy combining nab-paclitaxel plus either gemcitabine (gemcitabine group) or simplified leucovorin and fluorouracil (sLV5FU2 group) in patients with previously untreated metastatic pancreatic cancer. Results of progression-free survival at 4 months (primary endpoint) were in favor of the sLV5FU2 group. This paper presents health-related quality of life (HRQoL) data as a secondary endpoint.. HRQoL was assessed using the EORTC QLQ-C30 questionnaire at baseline and at each chemotherapy cycle until the end of treatment. The HRQoL deterioration-free survival (QFS) was used as a modality of longitudinal analysis. QFS was defined as the time between randomization and the first definitive HRQoL score deterioration as compared to the baseline score, or death. Sensitivity analysis was performed excluding death as an event. Univariate Cox models were used to estimate hazard ratios (HRs) and 90% confidence intervals (CIs) of the treatment effect.. Between 2013 and 2014, 114 patients were randomized in a 1:2 ratio (39 in the gemcitabine group and 75 in the sLV5FU2 group). Patients in the sLV5FU2 group seemed to present longer QFS than those of the gemcitabine group for 14 out of 15 dimensions, with HRs < 1. Results of the sensitivity analysis excluding death as an event were significantly in favor of the sLV5FU2 group for physical functioning (HR = 0.51 [90% CI 0.27-0.97]) and pain (HR = 0.26 [90% CI 0.09-0.74]).. The nab-paclitaxel plus simplified leucovorin and fluorouracil combination had no negative impact in exploratory HRQoL analyses.

Topics: Aged; Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Paclitaxel; Pancreatic Neoplasms; Prognosis; Proportional Hazards Models; Quality of Life; Treatment Outcome

The outlook for patients with advanced pancreatic cancer remains poor, despite significant advances in our understanding of pancreatic tumor biology. One emerging theme highlights the distinct composition of the pancreatic tumor microenvironment. Hyaluronic acid is a hydrophilic glycosaminoglycan whose production within the tumor leads to increased interstitial tumor pressure, thereby limiting the access of potentially effective circulating anticancer drugs via reduced tumor perfusion. PEGylated rHuPH20 is a multiply PEGylated recombinant human hyaluronidase that has shown promising efficacy in preclinical models and early phase clinical trials in pancreatic cancer patients. Here, we discuss these findings, and the rationale for the ongoing randomized Phase III trial (HALO-109-301), which seeks to definitively define the efficacy of PEGylated rHuPH20 alongside gemcitabine and nab-paclitaxel in previously untreated, hyaluronic acid-high, stage IV pancreatic cancer.

Topics: Adult; Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease-Free Survival; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Gemcitabine; Humans; Hyaluronic Acid; Hyaluronoglucosaminidase; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organometallic Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Recombinant Proteins; Tumor Microenvironment

Patients with gastroenteropancreatic (GEP), metastatic or locally advanced, non-resectable, grade 3 poorly-differentiated neuroendocrine carcinoma (NEC) are treated with cisplatin (or carboplatin)-etoposide in first-line palliative chemotherapy (CT1). However, nearly all patients will develop resistance and there is no standard second-line treatment.. PRODIGE 41-BEVANEC is an academic randomized, phase II study designed to evaluate the efficacy of bevacizumab in combination with FOLFIRI after failure of CT1 in unknown primary NEC and GEP-NEC.. The main eligibility criteria are age ≥18 years, metastatic (synchronous or metachronous) or locally advanced, non-resectable, grade 3 GEP-NEC, and documented progressive disease during or after CT1 therapy.. A total of 124 patients will be randomly assigned (1:1) to receive either 5 mg/kg bevacizumab with FOLFIRI, or FOLFIRI alone, every 14 days until disease progression or unacceptable toxicity. The hypothesis is to demonstrate a 6-month overall survival for at least 50% of the patients in bevacizumab arm versus 35% in the control arm (FOLFIRI alone). Secondary endpoints are objective response, response duration, progression-free survival, toxicity, and biochemical response.. The study is currently opened in France (NCT02820857). The first patient was randomized on September 6, 2017.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma, Neuroendocrine; Drug Administration Schedule; Female; Fluorouracil; France; Humans; Intestinal Neoplasms; Leucovorin; Male; Neuroendocrine Tumors; Pancreatic Neoplasms; Research Design; Stomach Neoplasms; Survival Analysis; Treatment Outcome

In metastatic pancreatic ductal adenocarcinoma (mPDAC) treatment, erlotinib is known to be more effective in patients developing skin rash. Treatment with the FOLFIRINOX regimen is only performed in fit patients following defined inclusion criteria. The present study investigates the efficacy of gemcitabine plus erlotinib (gem/erlotinib) in rash-positive patients fit for FOLFIRINOX.. For this prospective phase II study, 150 patients were recruited in 20 centres. All patients received gem/erlotinib for 4 weeks (run-in phase); the subsequent treatment was determined by the development of skin rash: patients with rash grades 1-4 continued with gem/erlotinib, rash-negative patients were switched to FOLFIRINOX. Primary study end-point was to achieve a 1-year survival rate in rash-positive patients ≥40%.. Ninety patients were deemed positive for skin rash by the end of the run-in phase, showing a 1-year survival rate of 40.0% (95% confidence interval [CI] 29.8-50.9). Median overall survival (OS) was 10.1 months, progression-free survival (PFS) was 3.8 months and overall response rate (ORR) was 23.3%. Patients switched to FOLFIRINOX (n = 27) had a 1-year survival rate of 48.1% (95% CI 28.7-68.1), a median OS of 10.9 months, a median PFS of 6.6 months and an ORR of 33.3%. Rash-negative patients had a lower quality of life at baseline but seemed to experience an improved control of pain during FOLFIRINOX.. First-line treatment with gem/erlotinib was effective in fit, rash-positive mPDAC patients achieving a 1-year survival rate comparable to previous reports for FOLFIRINOX. The study was registered at clinicaltrials.gov (NCT0172948) and Eudra-CT (2011-005471-17).

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Drug Combinations; Drug Eruptions; Erlotinib Hydrochloride; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Progression-Free Survival; Proportional Hazards Models; Prospective Studies; Young Adult

Omega-3 fatty acids may improve cancer cachexia, but only in patients with pancreatic and bile duct cancer. Patients with pancreatic cancer commonly suffer from exocrine pancreatic insufficiency, and the ingestion of digestive enzyme supplements may improve absorption.. Racol®, an enteral nutrient formulated with omega-3 fatty acids, was administered to patients with unresectable pancreatic and bile duct cancer. The skeletal muscle mass and blood test data were taken pre-administration and at 4 and 8 weeks after. Patients with pancreatic cancer were given the digestive enzyme supplement LipaCreon® from the fifth week after the start of administration.. In all 27 patients, skeletal muscle mass was significantly increased at both 4 and 8 weeks after the start of administration versus pre-administration (p=0.006, p=0.002, respectively).. Omega-3 fatty acid supplementation in patients with unresectable pancreatic and bile duct cancer may improve cancer cachexia.

Topics: Aged; Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Cachexia; Camptothecin; Combined Modality Therapy; Deoxycytidine; Dietary Supplements; Drug Combinations; Fatty Acids, Omega-3; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Nutritional Support; Organoplatinum Compounds; Oxonic Acid; Paclitaxel; Pancreatic Neoplasms; Pyridines; Tegafur

Both FOLFIRINOX and gemcitabine/nab-paclitaxel (G-nP) are used increasingly in the neoadjuvant treatment (NAT) of pancreatic ductal adenocarcinoma (PDA). This study aimed to compare neoadjuvant FOLFIRINOX and G-nP in the treatment of resectable (R) and borderline resectable (BR) head PDA.. A single-institution retrospective review of R and BR patients undergoing pancreaticoduodenectomy after NAT with FOLFIRINOX or G-nP was performed. Comparative analysis was performed using inverse-probability-weighted (IPW) estimators. The end points of the study were overall survival (OS) and an 80% reduction in CA19-9 with NAT.. In this study, 193 patients were analyzed, with 73 patients receiving FOLFIRINOX and 120 patients receiving G-nP. The median OS was 38.7 months for FOLFIRINOX versus 28.6 months for G-nP (p = 0.214). The patients who received FOLFIRINOX were younger and had fewer comorbidities, more BR disease, and larger tumors than those treated with G-nP (all p < 0.05). The two regimens were equally effective in achieving an 80% decline in CA19-9 (p = 0.8). The R0 resection rates were similar (80%), but FOLFIRINOX was associated with a reduction in pN1 disease (56% vs. 72%; p = 0.028). The receipt of adjuvant therapy was similar (74 vs. 75%; p = 0.79). In the Cox regression analysis with adjustment for baseline and treatment-related variables (FOLFIRINOX vs. G-nP, age, gender, computed tomography (CT) tumor size, BR vs. R, pre-NAT CA19-9), regimen type was not associated with a survival benefit. In the IPW analysis of 166 patients, however, the average treatment effect of FOLFIRINOX was to increase OS by 4.9 months compared with G-nP (p = 0.012).. Both FOLFIRINOX and G-nP are viable options for neoadjuvant treatment of PDA. In this study, neoadjuvant FOLFIRINOX was associated with a 4.9-month improvement in survival compared with G-nP after adjustment for covariates.

Topics: Adenocarcinoma; Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Paclitaxel; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Survival Rate

Gemcitabine is one of the standard treatments for locally advanced pancreatic cancer. Recent studies on metastatic pancreatic cancer have shown that combination chemotherapy with oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel (GnP) prolonged the overall survival compared with gemcitabine alone. To select the most promising chemotherapy, a randomized phase II selection design trial was started in July 2016 to compare between modified FOLFIRINOX and GnP for patients with locally advanced pancreatic cancer. A total of 124 patients will be enrolled from 36 Japanese institutions within 2.5 years. The primary endpoint is the proportion of 1-year overall survival, and secondary endpoints are progression-free survival, distant metastasis-free survival, response rate in patients with target lesions, CA19-9 response, adverse events, treatment-related death, early death, grade 4 non-hematological toxicity, and dose intensity. This trial has been registered with the UMIN Clinical Trials Registry [http://www.umin.ac.jp/ctr/index.htm], and the registration number is UMIN000023143.

Topics: Albumins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Drug Combinations; Fluorouracil; Gemcitabine; Humans; Irinotecan; Japan; Leucovorin; Organometallic Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

In the phase 3 randomised NAPOLI-1 clinical study, a 45% increase in median overall survival (OS) was shown with liposomal irinotecan, 5-fluorouracil and leucovorin (nal-IRI+5-FU/LV) versus 5-FU/LV in patients with metastatic pancreatic cancer progressing after gemcitabine-based therapy. Here, we report data from a pre-specified, expanded analysis of outcomes in the per-protocol (PP) population.. The PP population comprised patients receiving ≥80% of planned treatment during the first 6 weeks, with no major protocol violations. A post-hoc analysis of the non-PP population was also performed.. For PP patients, median OS was 8.9 (95% confidence interval: 6.4-10.5) months with nal-IRI+5-FU/LV (n = 66) vs 5.1 (4.0-7.2) months with 5-FU/LV (n = 71; unstratified hazard ratio [HR] 0.57, p = 0.011). For non-PP patients, it was 4.4 (3.3-5.3) months with nal-IRI+5-FU/LV (n = 51) vs 2.8 (1.7-3.2) months with 5-FU/LV (n = 48; unstratified HR 0.64, p = 0.0648).. A statistically significant survival advantage was observed with nal-IRI+5-FU/LV vs 5-FU/LV in the PP patient population.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Drug Resistance, Neoplasm; Fluorouracil; Gastrointestinal Diseases; Gemcitabine; Hematologic Diseases; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liposomes; Middle Aged; Pancreatic Neoplasms; Polyethylene Glycols; Progression-Free Survival; Proportional Hazards Models

Among patients with metastatic pancreatic cancer, combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pancreatic cancer.. We randomly assigned 493 patients with resected pancreatic ductal adenocarcinoma to receive a modified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-surface area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a protocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety.. At a median follow-up of 33.6 months, the median disease-free survival was 21.6 months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified hazard ratio for cancer-related event, second cancer, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the modified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gemcitabine group died from toxic effects (interstitial pneumonitis).. Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. (Funded by R&D Unicancer and others; ClinicalTrials.gov number, NCT01526135 ; EudraCT number, 2011-002026-52 .).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Deoxycytidine; Disease-Free Survival; Drug Combinations; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Lung Diseases, Interstitial; Male; Middle Aged; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Proportional Hazards Models; Prospective Studies

Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting.. NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany.. The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research.. ClinicalTrials.gov : NCT02047513, 08/13/2014.

Topics: Adult; Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Clinical Trials, Phase II as Topic; Deoxycytidine; Disease Progression; Disease-Free Survival; Drug Combinations; Fluorouracil; Gemcitabine; Germany; Humans; Irinotecan; Leucovorin; Middle Aged; Multicenter Studies as Topic; Neoadjuvant Therapy; Organometallic Compounds; Oxaliplatin; Paclitaxel; Pancreatectomy; Pancreatic Neoplasms; Prognosis; Prospective Studies; Quality of Life; Randomized Controlled Trials as Topic; Survival Analysis; Young Adult

In the NAPOLI-1 Phase 3 trial, nal-IRI+5-fluorouracil and leucovorin (5-FU/LV) significantly improved median overall survival (6.1 vs 4.2 months, P=0.012) and progression-free survival (3.1 vs 1.5 months, P=0.0001) vs 5-FU/LV alone in metastatic pancreatic adenocarcinoma patients previously treated with gemcitabine-based therapy. This analysis evaluated between treatment differences in quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST).. Overall survival was partitioned into time with grade ⩾3 toxicity (TOX), disease progression (REL), and time without disease progression symptoms or grade ⩾3 toxicity (TWiST). Mean Q-TWiST was calculated by weighting time spent by a utility of 1.0 for TWiST and 0.5 for TOX and REL. In threshold analyses, utility for TOX and REL were varied from 0.0 to 1.0.. Patients in nal-IRI+5-FU/LV (n=117) vs 5-FU/LV (n=119) had significantly more mean time in TWiST (3.4 vs 2.4 months) and TOX (1.0 vs 0.3 months) but similar REL (2.5 vs 2.7 months). In the base case, nal-IRI+5-FU/LV patients had 1.3 months (95% CI, 0.4-2.1; 5.1 vs 3.9) greater Q-TWiST (threshold analyses range: 0.9-1.6 months).. Within NAPOLI-1, nal-IRI+5-FU/LV resulted in statistically significant and clinically meaningful gains in quality-adjusted survival vs 5-FU/LV alone.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Disease Progression; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Liposomes; Male; Middle Aged; Nanoparticles; Pancreatic Neoplasms; Quality of Life; Retreatment; Survival Rate

This study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicity, and efficacy of second-line chemotherapy with FOLFIRINOX after gemcitabine (GEM)-based chemotherapy failure in metastatic pancreatic cancer (MPC).. We studied 18 histopathologically proven MPC patients. The schedule was 85 mg/m oxaliplatin, irinotecan, and 400 mg/m leucovorin, followed by 400 mg/m 5-fluorouracil (5-FU) as a bolus on day 1 and 2400 mg/m 5-FU as a 46-hour continuous infusion biweekly. The dose of irinotecan was defined as follows: level 0: 100 mg/m, level 1: 125 mg/m, level 2: 150 mg/m, and level 3: 180 mg/m. The doses of other drugs were fixed. The primary endpoint of phase II study was the response rate (RR).. We initially evaluated 6 patients in a phase I study. One patient developed neutropenia and 1 patient developed hyperglycemia and severe infection. Accordingly, level 1 was chosen as the MTD. According to a phase II study, the RR was 22.2% and the disease control rate was 61.1%. The progression-free survival and overall survival were 2.8 (range, 0.7-19.1) and 9.8 (2.4-19.8) months, respectively. The most common severe adverse event was neutropenia (66.7%). Febrile neutropenia occurred in 1 (5.6%) case.. The recommended dose was 85 mg/m oxaliplatin, 100 mg/m irinotecan, and 400 mg/m leucovorin, followed by 400 mg/m 5-FU as a bolus on day 1 and 2400 mg/m 5-FU as a 46-hour continuous infusion. These results indicate that second-line FOLFIRINOX is a marginally effective treatment for GEM-based chemotherapy failure cases.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Retreatment; Treatment Outcome

Carbohydrate antigen 19-9 (CA19-9) is a sensitive and specific serum marker in pancreatic cancer. Our retrospective analysis aims to evaluate CA19-9 decrease in patients with metastatic pancreatic cancer treated in ACCORD11/PRODIGE4 (FOLFIRINOX vs. gemcitabine).. A total of 342 patients were treated. CA19-9 was measured at 8 weeks (±2) in 160 patients from a total of 282 with abnormal CA19-9 values at baseline (gemcitabine arm, n = 75; FOLFIRINOX arm, n = 85). In the present study, 8-week CA19-9 decrease or greater CA19-9 decrease according to the 20 and 90% thresholds were analyzed. Progression-free survival (PFS) and overall survival (OS) were estimated in each subgroup.. In the FOLFIRINOX arm, patients with an 8-week CA19-9 decrease or greater CA19-9 decrease ≥20% showed improved median OS, PFS, and objective response rate. In the overall study population, median OS and PFS were significantly improved in patients with an 8-week CA19-9 decrease ≥20% (vs. <20%). The 8-week CA19-9 decrease was predictive of PFS (interaction test significant according to treatment arm; p = 0.006).. An 8-week CA19-9 decrease ≥20% is a prognostic factor for OS and PFS. The 8-week CA19-9 decrease (20% threshold) is predictive of PFS. It could help to evaluate the efficacy of FOLFIRINOX and gemcitabine regimens.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Camptothecin; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Organoplatinum Compounds; Pancreatic Neoplasms; Prognosis; Retrospective Studies

The management of locally advanced pancreatic cancer (LAPC) is a major challenge. Although new drugs are available for the treatment of metastatic disease, the optimal treatment of non-metastatic cases remains controversial. The role of neoadjuvant therapy is still a question of debate in this setting. The aim of the study was to prospectively collect and analyse data on efficacy and safety of a modified FOLFIRINOX regimen in LAPC patients treated in a single institution. Another major objective was to assess the capability of FOLFIRINOX to render primary non-resectable cancer to resectable. No bolus fluorouracil was given and a 20% dose reduction of oxaliplatin and irinotecan was applied. Primary G-CSF prophylaxis was applied to prevent febrile neutropenia. Thirty-two patients (mean age 60.2 years, range: 40-77 years) have been enrolled into the study. All patients had ECOG performance status of 0 or 1. Best response to therapy was stable disease (SD) or partial regression (PR) in 18 (56.2%) and 6 (18.8%) cases. Two patients (6.3%) underwent surgical resection (100% R0). The most frequent grade 3/4 adverse events were nausea (18.8%), fatigue (12.5%) and diarrhea (12.5%). The incidence of severe neutropenia was 28.1%, with only one documented case of febrile neutropenia. The probability of disease progression was 25% and 50% after 75 and 160 days with 88.4% of possibility of disease progression after 500 days. OS probability was 92.1, 71.5% and 49.5% at 180-, 365 and 540 days. Our data does not support the capability of FOLFIRINOX to render primary non-resectable cancer to resectable. However, due to the high disease control rate observed, FOLFRINOX might be recommended as first line option for the palliative treatment of LAPC. Despite reduced chemotherapy doses significant toxicity has been seen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

In mouse models of pancreatic cancer, IPI-926, an oral Hedgehog inhibitor, increases chemotherapy delivery by depleting tumor-associated stroma. This multicenter phase Ib study evaluated IPI-926 in combination with FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) in patients with advanced pancreatic cancer.. Patients were treated with once-daily IPI-926 plus FOLFIRINOX. A 3 + 3 dose escalation design was used, with cohort expansion at the maximum tolerated dose. A subset of patients underwent perfusion computed tomography to assess changes in tumor perfusion.. The maximum tolerated dose was identified 1 dose level below standard FOLFIRINOX. Common treatment-related adverse events included liver function test abnormalities, neuropathy, nausea/vomiting, and diarrhea. Objective response rate was high (67%), and patients receiving IPI-926 maintenance showed further declines in CA19-9 levels even after FOLFIRINOX discontinuation. Treatment did not result in consistent increases in tumor perfusion. The study closed early when a separate phase II trial of IPI-926 plus gemcitabine indicated detrimental effects of this combination.. This is the first study to demonstrate the feasibility of using FOLFIRINOX as the chemotherapeutic backbone in a clinical trial design. Although robust antitumor activity and acceptable safety were observed with the addition of IPI-926 to this regimen, future development of Hedgehog inhibitors in pancreatic cancer seems unlikely.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Camptothecin; Diarrhea; Dose-Response Relationship, Drug; Feasibility Studies; Female; Fluorouracil; Hedgehog Proteins; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Nausea; Nervous System Diseases; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Signal Transduction; Treatment Outcome; Veratrum Alkaloids; Vomiting

The Brown University Oncology Research Group performed a phase I study to remove irinotecan from FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) and substitute nab-paclitaxel.. Patients with newly diagnosed advanced pancreatic adenocarcinoma were eligible. Patients received oxaliplatin 85 mg/m, leucovorin 400 mg/m, and 5-fluorouracil 2400 mg/m with 3 dose levels of nab-paclitaxel (125, 150, and 175 mg/m) every 2 weeks. Dose-limiting toxicities were assessed in the first 2 cycles of treatment. The final dose level was expanded to assess cumulative neurotoxicity.. Thirty-five patients were entered; 24 with metastatic and 11 with locally advanced pancreatic cancer. The maximum tolerated dose of nab-paclitaxel was 150 mg/m every 2 weeks with FOLFOX. Cumulative neuropathy was the most important toxicity. Grade 3 neuropathy developed in 2 of the first 6 patients at 10 and 11 cycles of FOLFOX-A. Following an amendment to reduce oxaliplatin to 65 mg/m if grade 2 neuropathy developed, no additional patients developed grade 3 neurotoxicity. Twenty-one of 35 patients (60%) had a partial response. The median survival for patients with metastatic disease was 15 months.. The maximum tolerated dose of nab-paclitaxel is 150 mg/m every 2 weeks with FOLFOX. The regimen of FOLFOX-A represents a promising treatment for pancreatic cancer.

Topics: Adenocarcinoma; Adult; Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Fluorouracil; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Leucovorin; Maximum Tolerated Dose; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Prognosis; Prospective Studies; Risk Assessment; Survival Analysis; Treatment Outcome

Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population.. We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1:1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m(2) every 3 weeks, equivalent to 100 mg/m(2) of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m(2), equivalent to 70 mg/m(2) of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1:1:1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506.. Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6.1 months (95% CI 4.8-8.9) vs 4.2 months (3.3-5.3) with fluorouracil and folinic acid (hazard ratio 0.67, 95% CI 0.49-0.92; p=0.012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4.9 months [4.2-5.6] vs 4.2 months [3.6-4.9]; 0.99, 0.77-1.28; p=0.94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]).. Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy. This agent represents a new treatment option for this population.. Merrimack Pharmaceuticals.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Deoxycytidine; Diarrhea; Fatigue; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liposomes; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Pancreatic Neoplasms; Treatment Outcome; Vomiting

We evaluated the efficacy and toxicity of adding oral leucovorin (LV) to S-1 when compared with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer (PC).. Gemcitabine-refractory PC patients were randomly assigned in a 1:1 ratio to receive S-1 at 40, 50, or 60 mg according to body surface area plus LV 25 mg, both given orally twice daily for 1 week, repeated every 2 weeks (SL group), or S-1 monotherapy at the same dose as the SL group for 4 weeks, repeated every 6 weeks (S-1 group). The primary end point was progression-free survival (PFS).. Among 142 patients enrolled, 140 were eligible for efficacy assessment (SL: n = 69 and S-1: n = 71). PFS was significantly longer in the SL group than in the S-1 group [median PFS, 3.8 versus 2.7 months; hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.37-0.85; P = 0.003]). The disease control rate was significantly higher in the SL group than in the S-1 group (91% versus 72%; P = 0.004). Overall survival (OS) was similar in both groups (median OS, 6.3 versus 6.1 months; HR, 0.82; 95% CI, 0.54-1.22; P = 0.463). After adjusting for patient background factors in a multivariate analysis, OS tended to be better in the SL group (HR, 0.71; 95% CI, 0.47-1.07; P = 0.099). Both treatments were well tolerated, although gastrointestinal toxicities were slightly more severe in the SL group.. The addition of LV to S-1 significantly improved PFS in patients with gemcitabine-refractory advanced PC, and a phase III trial has been initiated in a similar setting.. Japan Pharmaceutical Information Center: JapicCTI-111554.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease Progression; Disease-Free Survival; Drug Combinations; Drug Resistance, Neoplasm; Female; Gemcitabine; Humans; Japan; Leucovorin; Male; Middle Aged; Oxonic Acid; Pancreas; Pancreatic Neoplasms; Tegafur; Treatment Outcome

Pancreatic adenocarcinoma is the fourth leading cause of cancer death. Recently, MM-398 (nanoliposomal irinotecan) was shown to be associated with significant improvement in outcome measures with acceptable toxicities when combined with 5-fluorouracil (5-FU)/leucovorin (LV) compared to 5-FU/LV alone in patients failing one line of gemcitabine-based therapy. There is a paucity of data evaluating the role of irinotecan in combination with 5FU in advanced pancreas cancer (APC). We performed a retrospective analysis of all patients who received mFOLFIRI (minus bolus 5FU and LV). All patients with metastatic disease who had failed at least one line of gemcitabine-based therapy prior to receiving mFOLFIRI were included in this study. Descriptive statistics were used to assess the continuous variables and adverse events (AEs), and Kaplan-Meier methods were used to calculate the median progression-free survival (PFS) and overall survival (OS). Forty patients were included in this analysis. Patients received 1-5 lines of prior therapy (25 % with more than 3 lines of prior therapy). The mean age at diagnosis was 60, and 98 % had ECOG of 1. The mean CA 19-9 at the start of therapy was 33,169 U/ml. The median PFS was 2.59 months [95 % confidence interval (CI) (1.90, 3.54)], and OS was 4.75 months [95 % CI (3.14, 8.98)]. The most common AEs included fatigue (98 %), neuropathy (83 %), anorexia (68 %), nausea (60 %) and constipation (55 %). Grade 3 toxicities included fatigue (13 %) and rash (3 %). There were no observed grade 4 toxicities. In this single-institution retrospective analysis, mFOLFIRI was found to be both tolerable and relatively effective in a heavily pretreated patient population with APC. Future prospective studies should consider evaluating the role of mFOLFIRI in refractory APC.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Costs and Cost Analysis; Disease-Free Survival; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies; Treatment Outcome

Modifications of FOLFIRINOX are widely used despite the absence of prospective data validating efficacy in metastatic disease (metastatic pancreatic cancer (MPC)) or locally advanced pancreatic cancer (LAPC). We conducted a multicentre phase II study of modified FOLFIRINOX in advanced pancreatic cancer to assess the impact of dose attenuation in MPC and efficacy in LAPC.. Patients with untreated MPC or LAPC received modified FOLFIRINOX (irinotecan and bolus 5-fluorouracil reduced by 25%). Adverse events (AEs) were compared with full-dose FOLFIRINOX. Response rate (RR), median progression-free survival (PFS) and median overall survival (OS) were determined.. In total, 31 and 44 patients with LAPC and MPC were enrolled, respectively. In MPC, efficacy of modified FOLFIRINOX was comparable with FOLFIRINOX with RR 35.1%, OS 10.2 months (95% CI 7.65-14.32) and PFS 6.1 months (95% CI 5.19-8.31). In LAPC, efficacy was notable with RR 17.2%, resection rate 41.9%, PFS 17.8 months (95% CI 11.0-23.9) and OS 26.6 months (95% CI 16.7, NA). Neutropenia (P<0.0001), vomiting (P<0.001) and fatigue (P=0.01) were significantly decreased. [(18)F]-Fluorodeoxyglucose positron emission tomography imaging response did not correlate with PFS or OS.. In this first prospective study of modified FOLFIRINOX in MPC and LAPC, we observed decreased AEs compared with historical control patients. In MPC, the efficacy appears comparable with FOLFIRINOX. In LAPC, PFS and OS were prolonged and support the continued use of FOLFIRINOX in this setting.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Peritoneal Neoplasms; Prognosis; Prospective Studies; Survival Rate

In pancreatic ductal adenocarcinoma, the CCL2-CCR2 chemokine axis is used to recruit tumour-associated macrophages for construction of an immunosuppressive tumour microenvironment. This pathway has prognostic implications in pancreatic cancer, and blockade of CCR2 restores anti-tumour immunity in preclinical models. We aimed to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX chemotherapy (oxaliplatin and irinotecan plus leucovorin and fluorouracil).. We did this open-label, dose-finding, non-randomised, phase 1b study at one centre in the USA. We enrolled treatment-naive patients aged 18 years or older with borderline resectable or locally advanced biopsy-proven pancreatic ductal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1, and normal end-organ function. Patients were allocated to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), and bolus fluorouracil 400 mg/m(2), followed by 2400 mg/m(2) 46-h continuous infusion), administered every 2 weeks for a total of six treatment cycles, or in combination with oral PF-04136309, administered at a starting dose of 500 mg twice daily in a standard 3 + 3 dose de-escalation design. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 12 weeks. The primary endpoints were the safety, tolerability, and recommended phase 2 dose of PF-04136309 plus FOLFIRINOX, with an expansion phase planned at the recommended dose. We analysed the primary outcome by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01413022.. Between April 19, 2012, and Nov 12, 2014, we treated 47 patients with FOLFIRINOX alone (n=8) or with FOLFIRINOX plus PF-04136309 (n=39). One patient had a dose-limiting toxic effect in the dose de-escalation group receiving FOLFIRINOX plus PF-04136309 at 500 mg twice daily (n=6); this dose was established as the recommended phase 2 dose. We pooled patients in the expansion-phase group (n=33) with those in the dose de-escalation group that received PF-04136309 at the recommended phase 2 dose for assessment of treatment-related toxicity. Six (75%) of the eight patients receiving FOLFIRINOX alone were assessed for treatment toxicity, after exclusion of two (25%) patients due to insurance coverage issues. The median duration of follow-up for treatment toxicity was 72·0 days (IQR 49·5-89·0) in the FOLFIRINOX alone group and 77·0 days (70·0-90·5) in the FOLFIRINOX plus PF-04136309 group. No treatment-related deaths occurred. Two (5%) patients in the FOLFIRINOX plus PF-04136309 group stopped treatment earlier than planned due to treatment-related toxic effects. Grade 3 or higher adverse events reported in at least 10% of the patients receiving PF-04136309 included neutropenia (n=27), febrile neutropenia (n=7), lymphopenia (n=4), diarrhoea (n=6), and hypokalaemia (n=7). Grade 3 or higher adverse events reported in at least 10% of patients receiving FOLFIRINOX alone were neutropenia (n=6), febrile neutropenia (n=1), anaemia (n=2), lymphopenia (n=1), diarrhoea (n=2), hypoalbuminaemia (n=1), and hypokalaemia (n=3). Therapy was terminated because of treatment-related toxicity in one (17%) of the six patients receiving FOLFIRINOX alone. 16 (49%) of 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective tumour response, with local tumour control achieved in 32 (97%) patients. In the FOLFIRINOX alone group, none of the five patients with repeat imaging achieved an objective response, although four (80%) of those patients achieved stable disease.. CCR2-targeted therapy with PF-04136309 in combination with FOLFIRINOX is safe and tolerable.. Washington University-Pfizer Biomedical Collaborative.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Macrophages; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Pyrrolidines; Receptors, CCR2

Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported.. To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting.. A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50-76 years]; 55% female). Patients registered between May 29, 2013, and February 7, 2014.. Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2 of irinotecan hydrochloride, 400 mg/m2 of leucovorin calcium, and then 2400 mg/m2 of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2 orally twice daily) prior to pancreatectomy.. Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate.. The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%-83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%-88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins, 5 (33%) had specimens that had less than 5% residual cancer cells, and 2 (13%) had specimens that had pathologic complete responses. The median overall survival of all patients was 21.7 months (95% CI, 15.7 to not reached) from registration.. The successful completion of this collaborative study demonstrates the feasibility of conducting quality-controlled trials for this disease stage in the multi-institutional setting. The data generated by this study and the logistical elements that facilitated the trial's completion are currently being used to develop cooperative group trials with the goal of improving outcomes for this subset of patients.. clinicaltrials.gov Identifier: NCT01821612.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Carcinoma, Pancreatic Ductal; Chemoradiotherapy; Feasibility Studies; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Margins of Excision; Middle Aged; Neoadjuvant Therapy; Neoplasm, Residual; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Pilot Projects; Prospective Studies; Radiotherapy, Intensity-Modulated; Survival Rate

A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC.. A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV, and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT.. Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached).. The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemoradiotherapy; Dose Fractionation, Radiation; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Longitudinal Studies; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Radiation Injuries; Radiosurgery; Radiotherapy, Adjuvant; Treatment Outcome

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Quality of Life

We sought to assess the benefit-risk balance of FOLFIRINOX versus gemcitabine in patients with metastatic pancreatic adenocarcinoma.. We used generalized pairwise comparisons. This statistical method permits the simultaneous analysis of several prioritized outcome measures. The first priority outcome was survival time (OS). Differences in OS that exceeded two months were considered clinically relevant. The second priority outcome was toxicity. The overall treatment effect was quantified using the net chance of a better outcome, which can be interpreted as the net probability for a random patient treated in the FOLFIRINOX group to have a better overall outcome than a random patient in the gemcitabine group.. In this trial 342 patients received either FOLFIRINOX or gemcitabine. The net chance of a better outcome favored strongly and significantly the FOLFIRINOX group (24.7; P<.001), suggesting a favorable benefit-risk balance of FOLFIRINOX versus gemcitabine. The positive benefit-risk balance of FOLFIRINOX was observed throughout all sensitivity analyses.. Generalized pairwise comparisons are useful to perform a quantitative assessment of the benefit-risk balance of new treatments. It provides a clinically intuitive way of comparing patients with respect to all important efficacy and toxicity outcomes. Overall the benefit-risk balance of FOLFIRINOX was strongly positive.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Disease Progression; Disease-Free Survival; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Report the preliminary results on electrochemotherapy (ECT) in the treatment of locally advanced pancreatic cancer of a phase I/II study and described the new functional imaging tools to assess ECT response in Magnetic Resonance (MR) imaging compared to morphological Computer Tomography (CT), ultrasound (US) without and with contrast enhancement (CEUS) and MR Imaging.. Thirteen patients were enrolled in an ongoing clinical phase I/II study approved by Ethical Committee of National Cancer Institute G. Pascale Foundation - IRCCS of Naples. ECT with bleomycin was performed during open surgery. All patients underwent US and CT scan, before and after ECT treatment; 7 patients were evaluated using morphological and functional (dynamic contrast enhancement-DCE and diffusion weighted- DW) parameters in MR; 5 patients underwent CEUS. RECIST criteria were used to evaluate ECT response on US, CT and MR images. Functional parameters were also used to evaluate ECT response on MR images.. No acute (intraoperative) and/or postoperative serious adverse events related to electrochemotherapy were observed; no clinically significant electrocardiographic, hemodynamic, or serum biologic changes were noted. No clinically relevant elevation of amylase or lipase levels was observed and no bleeding or damage to surrounding viscera occurred. In three patients had seen splenic infarction without thrombosis of the splenic vessels.. Electrochemotherapy is feasible and safe treatment modality in patients with locally advanced pancreatic adenocarcinoma. Dynamic and diffusion MR imaging in comparison to MR morphological sequence alone and to UC and CT imaging is more suitable to assess ECT treatment response. CEUS is not indicated in follow up after ECT.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Camptothecin; Deoxycytidine; Electrochemotherapy; Female; Fluorouracil; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Middle Aged; Organoplatinum Compounds; Pancreatic Neoplasms; Prospective Studies; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography; Young Adult

The miniature biodegradable implant siG12D-LODER™ was inserted into a tumor and released a siRNA drug against KRAS(G12D) along four months. This novel siRNA based drug was studied, in combination with chemotherapy, as targeted therapy for Locally Advanced Pancreatic Cancer (LAPC).. An open-label Phase 1/2a study in the first-line setting of patients with non-operable LAPC was initiated. In this study patients were assigned to receive a single dose of siG12D-LODERs, in three escalating dose cohorts (0.025mg, 0.75mg and 3.0mg). Gemcitabine was given on a weekly basis, following the siG12D-LODERTM insertion, until disease progression. The recommended dose was further examined with modified FOLFIRINOX. The follow up period was eight weeks and survival until death.. Fifteen patients with LAPC were enrolled. Among the 15 treated patients, the most frequent adverse events observed were grade 1or 2 in severity (89%); five patients experienced serious adverse events (SAEs). In 12 patients analyzed by CT scans, none showed tumor progression, the majority (10/12) demonstrated stable disease and two showed partial response. Decrease in tumor marker CA19-9 was observed in 70% (7/10) of patients. Median overall survival was 15.12 months; 18 month survival was 38.5%.. The combination of siG12D-LODER™ and chemotherapy is well tolerated, safe and demonstrated a potential efficacy in patients with LAPC. NCT01188785.

Topics: Absorbable Implants; Aged; Aged, 80 and over; Antigens, Neoplasm; Antineoplastic Agents; Camptothecin; Carcinoma, Pancreatic Ductal; Combined Modality Therapy; Deoxycytidine; Disease-Free Survival; Drug Implants; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Molecular Targeted Therapy; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); RNA, Small Interfering; RNAi Therapeutics

Metastatic pancreatic adenocarcinoma (PAC) prognosis remains dismal and gemcitabine monotherapy has been the standard treatment over the last decade. Currently, two first-line regimens are used in this setting: FOLFIRINOX and nab-paclitaxel plus gemcitabine. Increasing translational data on the predictive value of hENT1 for determining gemcitabine efficacy suggest that a non-gemcitabine-based regimen is favored in about 60 % of patients with PAC due to high resistance of PAC to this cytotoxic drug. This study aims to evaluate the efficacy of weekly nab-paclitaxel combined with gemcitabine or a simplified (s) LV5FU2 regimen in patients with previously untreated metastatic PAC.. AFUGEM is a two-stage, open-label, randomized, multicenter, phase II trial. Patients with PAC who meet the inclusion criteria and provide written informed consent will be randomized in a 1:2 ratio to either nab-paclitaxel (125 mg/m(2)) plus gemcitabine (1000 mg/m(2)) given on days 1, 8, and 15 every 28 days or nab-paclitaxel (125 mg/m(2)) plus sLV5FU2 (leucovorin 400 mg/m(2) followed by bolus 400 mg/m(2) 5-fluorouracil and by 5-fluorouracil 2400 mg/m(2) as an 46-h intravenous infusion) given on days 1 and 15 every 28 days. A total of 114 patients will be randomized to one of the treatment arms. The primary endpoint is progression-free survival at 4 months. Secondary outcomes are rate and duration of response, disease control, overall survival, safety, and quality of life. Potential biomarkers of gemcitabine (hENT1, dCK) and 5-fluorouracil (TS) efficacy will be assessed.. The AFUGEM trial is designed to provide valuable information regarding efficacy and tolerability of nab-paclitaxel plus gemcitabine and nab-paclitaxel plus sLV5FU2 regimens. Identification of potential predictive biomarkers of gemcitabine and 5-fluorouracil is likely to drive therapeutic decisions in patients with metastatic PAC.. AFUGEM is registered at Clinicaltrials.gov: NCT01964534 , October 15, 2013.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Clinical Protocols; Deoxycytidine; Equilibrative Nucleoside Transporter 1; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Neoplasm Metastasis; Paclitaxel; Pancreatic Neoplasms; Translational Research, Biomedical

Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection.. Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided.. Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval [CI] = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (χ(2) 1=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (χ(2)₁= 9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (χ(2)₁ = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (χ(2)₁ = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ(2) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald χ(2) = 1.22; P = .27) patients.. Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Deoxycytidine; Disease-Free Survival; Equilibrative Nucleoside Transporter 1; Europe; Female; Fluorouracil; Gemcitabine; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Treatment Outcome

Advanced pancreatic cancer (APC), beside its high mortality, causes the highest rates of venous thromboembolic events (VTE). Enoxaparin, a low molecular weight heparin (LMWH), is effective in prevention and treatment of VTE. Some small studies indicated that this benefit might extend to patients with cancer and probably prolong survival due to independent mechanisms. We initiated this safety investigation to get feasibility information on intensified chemotherapy combined with LMWH in outpatients with APC treated in 1st line.. The trial was a prospective, open-label, single center investigation in outpatients with inoperable pancreatic cancer who were treated with intensified first-line chemotherapy along with concomitant application of subcutaneous LMWH. The combined chemotherapy consisted of gemcitabine 1 g/m2 (30 min), 5-FU 750 mg/m2 (24 h), folinic acid 200 mg/m2 (30 min), and Cisplatin 30 mg/m2 (90 min) on day 1 and 8; q3w for the first 12 weeks (GFFC) followed by gemcitabine alone in patients without cancer progression. The simultaneous application of prophylactic enoxaparin started on day 1 of chemotherapy with a fixed dose of 40 mg daily. Statistical analyses were performed using R 3.01 with software package CMPRSK and SPSS software v19.0.. The investigation was stopped after recruitment of 19 patients. At this time 15 patients had completed the required 12 weeks of treatment. Based on 71 cycles of GFFC + enoxaparin (median 4/pt [range: 2-4]) and 108 cycles of single-agent gemcitabine + enoxaparin (median 4/pt [range: 0-18]) the cumulative frequency of NCI-CTC toxicities grade 3/4 was below 10%. One case (5%) of a symptomatic non-lethal thromboembolic event was observed while receiving LMWH treatment. No severe bleeding event as defined in the protocol has been observed. The median overall survival was 10.05 [95% CI: 8.67-18.14] months.. The addition of enoxaparin to GFFC chemotherapy is feasible, safe and does not appear to affect the efficacy or the toxicity profile of the chemotherapy regimen in patients with advanced pancreatic adenocarcinoma. Based on these findings we have initiated the randomized CONKO-004 trial to examine whether enoxaparin reduces the incidence of thromboembolic events or increases overall outcome.. Clinical Trials NCT01945879.

Topics: Aged; Anticoagulants; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Deoxycytidine; Enoxaparin; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Pilot Projects; Prospective Studies; Thromboembolism

To assess the efficacy of a second-line regimen of oxaliplatin and folinic acid-modulated fluorouracil in patients with advanced pancreatic cancer who have experienced progression while receiving gemcitabine monotherapy.. A randomized, open-label, phase III study was conducted in 16 institutions throughout Germany. Recruitment ran from January 2004 until May 2007, and the last follow-up concluded in December 2012. Overall, 168 patients age 18 years or older who experienced disease progression during first-line gemcitabine therapy were randomly assigned to folinic acid and fluorouracil (FF) or oxaliplatin and FF (OFF). Patients were stratified according to the presence of metastases, duration of first-line therapy, and Karnofsky performance status.. Median follow-up was 54.1 months, and 160 patients were eligible for the primary analysis. The median overall survival in the OFF group (5.9 months; 95% CI, 4.1 to 7.4) versus the FF group (3.3 months; 95% CI, 2.7 to 4.0) was significantly improved (hazard ratio [HR], 0.66; 95% CI, 0.48 to 0.91; log-rank P = .010). Time to progression with OFF (2.9 months; 95% CI, 2.4 to 3.2) versus FF (2.0 months; 95% CI, 1.6 to 2.3) was significantly extended also (HR, 0.68; 95% CI, 0.50 to 0.94; log-rank P = .019). Rates of adverse events were similar between treatment arms, with the exception of grades 1 to 2 neurotoxicity, which were reported in 29 patients (38.2%) and six patients (7.1%) in the OFF and FF groups, respectively (P < .001).. Second-line OFF significantly extended the duration of overall survival when compared with FF alone in patients with advanced gemcitabine-refractory pancreatic cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease Progression; Drug Resistance, Neoplasm; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

In our previous randomized controlled trial, the addition of S-1 to gemcitabine for advanced pancreatic cancer did not prolong overall survival (OS) significantly, despite its higher response rate and longer progression-free survival (PFS). Leucovorin is known to enhance efficacy of S-1, and we conducted this phase I trial of combination therapy of gemcitabine, S-1 and leucovorin (GSL).. Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Gemcitabine was administered at an escalating dose of 600, 800 and 1,000 mg/m(2) over 30 min on day 1, and oral S-1 at a dose of 40 mg/m(2) twice daily and oral leucovorin at a dose of 25 mg twice daily on days 1-7, every 2 weeks. A standard "3 + 3" phase I dose escalation design was utilized.. Fifteen patients were enrolled across three dose levels. Three patients developed DLTs: two patients in level 1 (grade 3 anorexia in 1 and grade 3 anorexia, stomatitis and diarrhea in 1) and one patient in level 2 (grade 3 deep vein thrombosis). No DLT was observed in level 3. Response rate and the disease control rate were 33 and 93 %, respectively. The median PFS and OS were 5.4 and 16.6 months. Ten of 12 patients (83 %) with elevated CA19-9 at baseline had a ≥ 50 % decline.. RD of gemcitabine in GSL was determined as 1,000 mg/m(2). GSL was well tolerable and showed promising results in advanced pancreatic cancer.

Topics: Aged; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Female; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Oxonic Acid; Pancreatic Neoplasms; Stomatitis; Survival Analysis; Tegafur; Treatment Outcome; Venous Thrombosis

In this study, we compared the efficacy and safety of the oral fluoropyrimidine S-1 as monotherapy or in combination with leucovorin as the second-line treatment for patients with metastatic pancreatic cancer whose disease had progressed on gemcitabine treatment.. The study was a randomized, open-label, controlled study. Patients randomly received S-1 or S-1 in combination with leucovorin (SL arm) in 21-day cycles. The primary endpoint was the 6-month survival rate.. A total of 92 patients were randomized to S-1 (n = 47) and SL (n = 45). No statistically significant differences were observed between the two arms with regard to 6-month survival rates (40% vs. 49%), median overall survival (5.5 vs. 6.3 months), median progression-free survival (1.9 vs. 3.0 months), and overall response rate (4.7% vs. 8.3%). The rate of major grade 3-4 adverse events of digestive toxicity was significantly higher in the SL arm than in the S-1 arm.. Compared with S-1, SL did not improve the survival of patients with metastatic pancreatic cancer who had failed to benefit from prior gemcitabine treatment, but SL had a higher adverse event rate.

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease-Free Survival; Drug Combinations; Female; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Oxonic Acid; Pancreatic Neoplasms; Survival Rate; Tegafur; Treatment Outcome

Fluorouracil and irinotecan-based, and gemcitabine-based regimens, are the standard of care in the first-line treatment of patients with metastatic pancreatic cancer. New approaches are needed to improve survival and quality of life. Whether a sequential approach alternating irinotecan, fluorouracil and gemcitabine may be effective and tolerable in patients with metastatic pancreatic cancer is unknown.. In this randomised, multicentre, open-label, phase 2 trial, patients with metastatic pancreatic adenocarcinoma, World Health Organisation (WHO) performance status 0-1, and bilirubin levels <1.5 upper limit of normal values (ULN) were randomised 1:1 to receive as first-line treatment either FOLFIRI.3 (irinotecan, leucovorin and fluorouracil) alternating with fixed-dose rate gemcitabine as 2-month periods (FIRGEM, arm A), or fixed-dose rate gemcitabine alone (arm B). Treatment was continued until disease progression or limiting toxicity. The primary end-point was the crude progression-free survival (PFS) rate at 6 months. The study is registered with EudraCT (N° 2006-005703-34).. Between October 2007 and March 2011, 98 patients were enroled. The observed 6-month PFS rate was 43.5% (95% confidence interval (CI), [28.6-58.4%]) in arm A reaching the Fleming decision rules criteria to reject H0 and 26.1% (95% CI [12.9-39.3%]) in arm B. Objective response rates were 37% (23-51%) in arm A and 10% (1-19%) in arm B. Median PFS (5.0 versus 3.4 months, hazard ratio (HR)=0.59 [0.38-0.90]) and overall survival (11.0 versus 8.2 months, HR=0.71 [0.46-1.10]) were higher in arm A compared to arm B. The most frequent grade 3-4 toxicities were neutropenia (49%/24%; febrile neutropenia, 4%/0% in arms A/B), diarrhoea (arm A, 12% and arm B, 0%), and nausea/vomiting (8%/4%). No toxic deaths occurred.. The FIRGEM strategy appears to be effective and feasible in patients with metastatic pancreatic cancer.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Prospective Studies; Quality of Life; Treatment Outcome

Oxaliplatin is an effective and widely used chemotherapeutic agent in the treatment of many solid tumors. The most common side effects are peripheral neuropathy, gastrointestinal toxicity, and neutropenia. There have been some case reports about ototoxicity with oxaliplatin, but no clinical trials. In this trial, we explored whether or not oxaliplatin has ototoxic effects.. A total of 18 patients, 14 with colorectal cancer and 4 with pancreatic cancer, were included in this study. Four patients (22%) were treated with a capecitabine and oxaliplatin (CapeOx) regimen, and 14 patients (78%) were treated with fluorouracil, leucovorin, and oxaliplatin (FOLFOX-6). Patients' pretreatment and posttreatment hearing levels were assessed with high-frequency audiometry and otoacoustic emission tests.. The median time between the first and the last oxaliplatin doses was 3.2 months (range: 2-7 months). There was no hearing loss in tests conducted for both ears of patients at frequencies of 500, 1000, 2000, 4000, 6000, 8000, 12,000, and 16,000 Hz. There was no difference between the pretreatment and posttreatment otoacoustic emission tests.. Oxaliplatin is a reliable agent in terms of ototoxicity.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Cohort Studies; Colorectal Neoplasms; Deoxycytidine; Drug Administration Schedule; Female; Fluorouracil; Hearing Loss; Hearing Tests; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Disease-Free Survival; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

Despite median survival of less than 6 months, there is a significant proportion of advanced pancreatic cancer patients who progress on gemcitabine that remains fit, and these patients are candidates for second-line treatment.. The objective of this study is to evaluate the efficacy and safety of oxaliplatin plus 5-fluorouracil and folinic acid in patients with gemcitabine-pretreated advanced pancreatic cancer.. Thirty patients with advanced pancreatic cancer who were pretreated with gemcitabine received oxaliplatin (85 mg/m(2)) on days 1 and 15 followed by leucovorin (20 mg/m(2)) and 5-fluorouracil (500 mg/m(2)) on days 1, 8, and 15. The cycle was repeated every 3 weeks.. The majority of patients (80 %) had locally advanced disease. Median age was 63 years, and 60 % were males. The liver was the most common site of metastasis. Partial response was observed in 2 patients (6.7 %) and stable disease in 6 patients (20 %), while 12 patients progressed (40 %). Improved performance status was reported in 10 patients (33.3 %). The median duration of response was 13 weeks, and median overall survival was 22 weeks. There was no grade 4 toxicity apart from grade 4 neutropenia in 6.6 % of patients. Neutropenia (46.5 %) and neuropathy (43.2 %) were the most common toxicities, while hand-foot syndrome was the least frequent one (20 %). There were no treatment-related deaths. The 6-month survival rate was 30 %.. This regimen is feasible and active with an acceptable toxicity; however, further investigation in phase III trial is needed.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Survival Rate

Topics: Aged; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Benztropine; Camptothecin; Dexamethasone; Drug Combinations; Female; Fluorouracil; Haloperidol; Humans; Leucovorin; Male; Metoclopramide; Morpholines; Nausea; Organoplatinum Compounds; Pancreatic Neoplasms; Vomiting

The aims of this study were to establish the maximum tolerated dose (MTD) of oxaliplatin in combination with fixed doses of gemcitabine, irinotecan, and 5-fluorouracil/leucovorin (G-FLIE) in solid tumors, including advanced pancreatic cancer, and to evaluate the toxicity of the regimen.. Patients with metastatic solid tumors were treated with a regimen consisting of gemcitabine (500 mg/m(2) by fixed-dose-rate infusion), irinotecan (120 mg/m(2)), leucovorin 300 mg, bolus/infusion 5-fluorouracil (400 and 1,500 mg/m2, respectively), and oxaliplatin at doses from 50 to 85 mg/m(2) according to the escalation schema. Treatment was repeated every 14 days.. The study enrolled 25 patients with a median age of 64 years and median Karnofsky performance score of 80. Patients had metastatic adenocarcinomas of pancreas (n = 9), as well as gastroesointestinal, hepatobiliary, or unknown primary tumors. With only one dose limiting toxicity (neutropenia and constipation), the MTD of oxaliplatin was not reached up to the pre-specified maximum level of 85 mg/m(2). Other toxicities predictably included cytopenias, fatigue, sensory neuropathy, nausea/vomiting, diarrhea, and constipation. Four partial responses and ten disease stabilizations were observed. The overall median time to disease progression was 17 weeks (2-110 weeks) with median overall survival of 31.5 weeks (7-139 weeks).. G-FLIE is a tolerable multi-agent chemotherapy regimen with the oxaliplatin dose up to 85 mg/m(2). The combination of full-dose oxaliplatin with gemcitabine, irinotecan, and 5-fluorouracil is feasible with attenuated doses of the drugs, but further optimization is necessary before assessment of efficacy.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

To compare the quality of life (QoL) of patients receiving oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) or gemcitabine as first-line chemotherapy and to assess whether pretreatment QoL predicts survival in patients with metastatic pancreatic cancer.. Three hundred forty-two patients with performance status 0 or 1 were randomly assigned to receive FOLFIRINOX (oxaliplatin, 85 mg/m(2); irinotecan, 180 mg/m(2); leucovorin, 400 mg/m(2); and fluorouracil, 400 mg/m(2) bolus followed by 2,400 mg/m(2) 46-hour continuous infusion, once every 2 weeks) or gemcitabine 1,000 mg/m(2) weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. QoL was assessed using European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30 every 2 weeks.. Improvement in global health status (GHS; P < .001) was observed in the FOLFIRINOX arm and improvement in emotional functioning (P < .001) was observed in both arms, along with a decrease in pain, insomnia, anorexia, and constipation in both arms. A significant increase in diarrhea was observed in the FOLFIRINOX arm during the first 2 months of chemotherapy. Time until definitive deterioration ≥ 20 points was significantly longer for FOLFIRINOX compared with gemcitabine for GHS, physical, role, cognitive, and social functioning, and six symptom domains (fatigue, nausea/vomiting, pain, dyspnea, anorexia, and constipation). Physical functioning, constipation, and dyspnea were independent significant prognostic factors for survival with treatment arm, age older than 65 years, and low serum albumin.. FOLFIRINOX significantly reduces QoL impairment compared with gemcitabine in patients with metastatic pancreatic cancer. Furthermore, baseline QoL scores improved estimation of survival probability when added to baseline clinical and demographic variables.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Irinotecan; Leucovorin; Longitudinal Studies; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Quality of Life; Surveys and Questionnaires; Survival Rate

This prospective phase II trial aims to evaluate the sequential FOLFOX-6 and gemcitabine followed by adapted maintenance for advanced pancreatic cancer. Treatment included FOLFOX-6 for 4 cycles, followed sequentially by gemcitabine for 3 cycles. Patients, who show clinical benefit after both sequences, will receive maintenance treatment based on the investigator's discretion. From January 2005 to June 2008, 32 patients with median age of 63 were included; 75% of patients had metastatic disease, 81% had pure adenocarcinoma, while 19% had adenocarcinoma with a neuroendocrine component. There were 22% PR and 22% SD resulting in 44% tumor growth control. Under FOLFOX, grade 3/4 toxicities were neutropenia in 8 patients, thrombocytopenia and anemia in 3 patients each, and diarrhea in 2 patients. Under Gem, grade 3/4 neutropenia was observed in 4 patients, thrombocytopenia and anemia were observed in 2 patients, and hand-foot syndrome was observed in 3 patients. The median TTP and OS were 4 and 10 months, respectively. In APC, FOLFOX-6 regimen followed by gemcitabine achieved an interesting RR within a tolerable level of toxicity. This regimen seems to warrant further investigation to confirm its efficacy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Pancreatic Neoplasms; Prospective Studies

The purpose of the present study was to evaluate the activity and the tolerability of the FOLFIRI regimen, administered as second-line chemotherapy in patients with locally advanced or metastatic pancreatic cancer after the failure of a gemcitabine-based regimen.. Patients with locally advanced/metastatic disease who received a first-line chemotherapy (one line only) with gemcitabine ± platinoid (cisplatin, oxaliplatin) and who had measurable disease conform with the RECIST criteria were eligible for the study. FOLFIRI consists of irinotecan 180 mg/m(2) i.v. on day 1, leucovorin (l-form) 200 mg/m(2) i.v. on day 1 and 2, 5-FU 400 mg/m(2) i.v. bolus on days 1 and 2, and 5-FU 600 mg/m(2) i.v. by ci for 22 h on days 1 and 2, repeated every 2 weeks. The primary end point was the response rate.. Among the 50 enrolled patients, 4 partial responses (PR) (8%) and 14 stable diseases were observed, for a disease control rate of 18/50 (36%). Forty-one patients (82%) have been pretreated with cisplatin/oxaliplatin+gemcitabine as first-line chemotherapy. The median progression-free and overall survivals were 3.2 and 5 months, respectively. The 6-month survival rate was 32%. Grade 3-4 neutropenia and diarrhea occurred in 10 (20%) and 6 (12%) patients, respectively.. The FOLFIRI regimen showed a modest clinical activity in this quite heavily pretreated patients' population with locally advanced or metastatic pancreatic cancer with a manageable toxicity profile.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Survival Rate

Combination chemotherapy with FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) was shown to be effective in a large phase III trial.. The purpose of this study was to examine the tolerance and effectiveness of FOLFIRINOX as practiced outside of the confines of a clinical trial and to document any dose modifications used by practicing oncologists.. Data on patients with all stages of pancreatic adenocarcinoma treated with FOLFIRINOX at three institutions was analyzed for efficacy, tolerance, and use of any dose modifications.. Total of 61 patients was included in this review. Median age was 58 years (range: 37 to 72 years), 33 were male (54.1%) and majority had ECOG performance of 0 or 1 (86.9%, 53 patients). Thirty-eight (62.3%) had metastatic disease, while 23 (37.7%) were treated for locally advanced or borderline resectable disease. Patients were treated with a median number of four cycles of FOLFIRINOX, with dose modifications in 58.3% (176/302) of all cycles. Ten patients had stable disease (16.4%), four had a partial response (6.6%) while eight had progressive disease (13.1%) on best imaging following therapy. Median progression-free survival and overall survival were 7.5 months and 13.5 months, respectively. The most common grade 3-4 adverse event was neutropenia at 19.7% (12 cases), with 4.9% (3 cases) rate of febrile neutropenia. Twenty-one patients (34.4%) were hospitalized as a result of therapy but there were no therapy-related deaths. Twenty-three (37.7%) had therapy eventually discontinued as a result of adverse events.. Despite substantial rates of adverse events and use of dose modifications, FOLFIRINOX was found to be clinically effective in both metastatic and non-metastatic patients. Regimen toxicity did not detract from overall response and survival.

Topics: Abdominal Pain; Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

Adjuvant chemotherapy prolongs survival in patients with pancreatic cancer, but its benefit is limited. Long-term survival times of up to 44 months after adjuvant chemoradioimmunotherapy in phase II trials motivated the present study.. Between 2004 and 2007, 132 R0/R1 resected patients received either fluorouracil (FU), cisplatin, and interferon alfa-2b (IFN α-2b) plus radiotherapy followed by two cycles of FU (arm A, n=64) or six cycles of FU monotherapy (arm B, n=68). One hundred ten patients (arm A, n=53; arm B, n=57) received at least one dose of the study medication, and these patients composed the per-protocol (PP) population. Biomarkers were analyzed longitudinally for their predictive value.. Median survival for all randomly assigned patients was 26.5 months (95% CI, 21.6 to 39.5 months) in arm A and 28.5 months (95% CI, 20.4 to 38.6 months) in arm B. The hazard ratio was 1.04 (arm A v arm B: 95% CI, 0.66 to 1.53; P=.99). Median survival for the PP population was 32.1 months (95% CI, 22.8 to 42.2 months) in arm A and 28.5 months (95% CI, 19.5 to 38.6 months) in arm B (P=.49). Eighty-five percent of patients in arm A and 16% of patients in arm B experienced grade 3 or 4 toxicity. The quality of life was temporarily negatively affected in arm A.. The FU, cisplatin, and IFN α-2b plus radiotherapy regimen did not improve the survival compared with FU monotherapy. Given the substantial adverse effects, this treatment can currently not be recommended. Nevertheless, the outcome in both arms represents the best survival, to our knowledge, ever reported for patients with resected pancreatic cancer in randomized controlled trials. Future studies will demonstrate whether immune response to IFN α-2b challenge has a predictive value.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Chemotherapy, Adjuvant; Cisplatin; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Prognosis; Recombinant Proteins; Survival Analysis

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

To investigate the efficacy and toxicity of a short intensive Uracil/Tegafur (UFT) based chemoradiotherapy scheme combined with celecoxib in locally advanced pancreatic cancer.. The Academic Medical Centre, Amsterdam and the Erasmus Medical Centre, Rotterdam enrolled 83 eligible patients with unresectable pancreatic cancer in a prospective multicentre phase II study. Median age was 62 years, median tumour size 40 mm and the majority of the patients (85%) had pancreatic head cancers. Treatment consisted of 20×2.5 Gy radiotherapy combined with UFT 300 mg/m(2) per day, leucovorin (folinic acid) 30 mg and celecoxib 80 0mg for 28 days concomitant with radiotherapy. Four patients were lost to follow-up.. Full treatment compliance was achieved in 55% of patients, 80% received at least 3 weeks of treatment. No partial or complete response was observed. Median survival was 10.6 months and median time to progression 6.9 months. Toxicity was substantial with 28% grades III and IV gastro-intestinal toxicity and two early toxic deaths.. Based on the lack of response, the substantial toxicity of mainly gastro-intestinal origin and the reported mediocre overall and progression free survival, we cannot advise our short intensive chemoradiotherapy schedule combined with celecoxib as the standard treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Celecoxib; Combined Modality Therapy; Female; Humans; Leucovorin; Male; Medication Adherence; Middle Aged; Pancreatic Neoplasms; Prospective Studies; Pyrazoles; Sulfonamides; Tegafur; Uracil

Advanced pancreatic cancer has a bad prognosis, with a median overall survival (OS) no longer than 4-6 months. Since the end of last century, monotherapy with gemcitabine has remained the elective therapy, but new schedules are needed in order to improve these results. We aim to evaluate the efficacy of tegafur and levofolinic acid (LV) associated with gemcitabine, as well as its toxicity, progression-free survival and OS in advanced pancreatic cancer.. An open-label, multicentric, prospective, non-controlled trial was carried out on patients with advanced or disseminated pancreatic cancer. Gemcitabine 1250 mg/m² was administered on the 1st and 8th days of the cycle, tegafur 750 mg/m²/day for 21 consecutive days and LV 25 mg/day continuously, every 28 days, with a maximum of six cycles. The primary variable was tumour overall response rate (ORR). Secondarily, time to progression (TTP), OS and scheme toxicity were determined.. Forty patients were recruited; the male/female ratio was 30:10, with a mean age of 61 years. Forty percent had a Karnofsky index of 90% or 100%. Only 11 patients (27%) completed the six cycles of treatment, but more than 50% received three or more cycles. Dose intensity was 89.56% for gemcitabine and 87.36% for tegafur. Efficacy ORR was 22.5% (CI 95%, 6-37%). TTP was 3.87 months (CI 95%, 2.1-5.6), time to treatment failure was 2.97 months (CI 95%, 2.43-4.67) and OS 6.3 months (CI 95%, 4-7). The chemotherapeutic combination was well accepted; most haematologic and non-haematologic toxicities were grade 1 or 2. The most prevalent grade 3/4 toxicities were asthenia (30%), liver biochemistry disorders (25%), diarrhoea (15%) and stomatitis (12%).. The administration of gemcitabine, associated with oral tegafur and leucovorin, has activity against advanced pancreatic cancer, with an adequate toxicity profile.

Topics: Adenocarcinoma; Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease Progression; Female; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis; Tegafur; Treatment Outcome

This open-label, multi-center phase II study investigated the efficacy and safety of the combination of 5-fluorouracil (5-FU)/folinic acid (FA) plus gemcitabine (GFF) in patients with advanced pancreatic cancer. The study is based on our completed dose finding phase I trial.. A total of 90 patients (pts) were recruited between 02/2000 and 04/2002 to receive 5-FU 750 mg/m(2) (24 h, i.v.), FA 500 mg/m(2) (2 h, i.v.) and gemcitabine 1,000 mg/m(2) (30 min, i.v.) on days 1, 8, 15, and 22. Treatment was repeated on day 43 until disease progression. The primary objective was the 1-year survival rate. The trial was conducted in compliance with the Declaration of Helsinki.. The 1-year survival rate was 25% [95% CI: 16-34], median overall survival was 6.8 months [95% CI: 5.13-8.45], 9 patients showed partial responses (PR) so that the overall response rate was 10.3%. Overall control rate (PR + stable disease for at least 6 months) was 56%. Median time to progression was 4.6 months [95% CI: 3.68-5.52]. In 402 GFF cycles, we observed adverse events grade 3 in up to 10% of patients and grade 4 below 5% of patients.. The GFF combination appears to be effective and well tolerated. This intravenous regimen represents an intensified therapy with low frequency of toxicities and seems to be convenient for patients who are unable to get oral anti-neoplastic medication. After these encouraging results, the German CONKO-002 trial investigated the GFF regimen versus single-agent gemcitabine.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis

To evaluate the therapeutic efficacy of 3-month triplet induction chemotherapy (ICT) followed by concomitant chemoradiotherapy (CCRT) in patients with locally advanced pancreatic cancer (LAPC).. Chemonaïve patients with measurable, histologically confirmed LAPC were eligible. The ICT consisted of biweekly gemcitabine (800 mg/m2) infusion at a fixed dose rate (10 mg/m2/min), followed by 85 mg/m2 oxaliplatin and 48-h infusion of 5-fluorouracil/leucovorin (3000/150 mg/m2) for 6 cycles. Patients without disease progression 4 weeks after ICT would receive weekly 400 mg/m2 gemcitabine and 5040 cGy radiation in 28 fractions. After CCRT, patients were subjected for surgical intervention and/or maintenance chemotherapy until progression or intolerable toxicity.. Between December 2004 and August 2008, 50 patients were enrolled. The best responses after ICT were partial response (PR) in 9, stable disease in 26, and progressive disease or not evaluable in 15. Among the former 35 patients, 2 had disease progression before CCRT, and 3 declined to have CCRT. Of the 30 patients receiving CCRT, an additional 4 and 1 patient(s) achieved PR at the end of CCRT and during maintenance chemotherapy, respectively. On intent-to-treat analysis, the overall best response was PR in 14 patients and stable disease in 21. The overall response rate and disease control rate were 28% (95% confidence interval [CI], 16.2-42.5%) and 70% (95% CI, 44.4-99.2%), respectively. The median time to progression and overall survival of the intent-to-treat population was 9.3 (95% CI, 5.8-12.8) months and 14.5 (95% CI, 11.9-17.1) months, respectively. One- and two-year survival rates were 68% (95% CI, 55.1-80.9%) and 20.6% (95% CI, 8.7-32.5%), respectively. Neutropenia was the most common Grade 3-4 toxicity of both ICT and CCRT, with a frequency of 28% and 26.7%, respectively. Significant sensory neuropathy occurred in 9 patients (18%).. Three months of triplet ICT followed by gemcitabine-based CCRT is feasible, moderately active, and associated with encouraging survival in patients with LAPC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Deoxycytidine; Disease Progression; Drug Administration Schedule; Female; Fluorouracil; Gemcitabine; Humans; Induction Chemotherapy; Leucovorin; Maintenance Chemotherapy; Male; Middle Aged; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prospective Studies; Radiotherapy Dosage; Radiotherapy, Conformal; Survival Rate; Taiwan

Data are lacking on the efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer.. We randomly assigned 342 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival.. The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001).. As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. (Funded by the French government and others; ClinicalTrials.gov number, NCT00112658.).

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Proportional Hazards Models; Quality of Life; Severity of Illness Index; Survival Analysis

Gemcitabine usually given until progressive disease (PD) is the main first-line treatment option for patients with inoperable advanced pancreatic cancer (APC). Currently there is no accepted active regimen for second-line chemotherapy. Previous phase II studies suggest clinical relevant activity of oxaliplatin, folinic acid and 5-FU (OFF). We initiated a phase III multicentre study comparing OFF versus best supportive care (BSC) in patients with APC progressing while on gemcitabine therapy.. In this open randomized study, patients with CT and/or MRI confirmed progressive disease while on gemcitabine therapy were randomized 1:1 to OFF or BSC. Stratification included duration of first-line therapy (<3, 3 to 6 and >6 months), performance status (KPS 70-80%; 90-100%) and tumour stage (M1/M0). OFF consisted of folinic acid 200mg/m(2) followed by 5-fluorouracil 2g/m(2) (24h) on d1, d8, d15, d22 and oxaliplatin 85 mg/m(2) on days 8 and 22. After a rest of 3 weeks the next cycle was started on d43. A total of 165 patients were calculated to demonstrate a doubling of survival time after progression on first-line therapy.. After inclusion of forty six patients the trial was terminated according to predefined protocol regulations due to insufficient accrual (lack of acceptance of BSC by patients and physicians. Patient characteristics were well balanced between both study arms. The OFF regimen was well tolerated with more patients with grade I/II paraesthesia and grade II/III nausea/emesis and diarrhoea. Median second-line survival was 4.82 [95% Confidence Interval; 4.29-5.35] months for OFF treatment and 2.30 [95% CI; 1.76-2.83] months with BSC alone (0.45 [95% CI: 0.24-0.83], p = 0.008). Median overall survival for the sequence GEM-OFF was 9.09 [95% CI: 6.97-11.21] and 7.90 [95% CI: 4.95-10.84] months for GEM-BSC (0.50 [95% CI: 0.27-0.95], p = 0.031) respectively.. Although stopped prematurely, this randomized trial provides at first time evidence for the benefit of second-line chemotherapy as compared to BSC alone for patients with APC. OFF significantly prolonged survival time compared to BSC alone after failure of first-line therapy with gemcitabine.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease Progression; Female; Fluorouracil; Gemcitabine; Germany; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

Pancreatic endocrine carcinomas are rare and heterogeneous. Published results concerning treatment of advanced tumours are inconsistent and responses to standard chemotherapy remain unsatisfactory.. To investigate the ability of the FOLFIRI regimen to manage progressive unresectable metastatic well-differentiated endocrine carcinomas of the pancreas as first-line chemotherapy.. 20 patients with metastatic or advanced well-differentiated endocrine carcinomas of the pancreas and progressive disease were enrolled in a prospective multicentre phase II trial to receive chemotherapy with FOLFIRI schedule (irinotecan 180mg/m(2) infusion combined with simplified LV5FU2) every 14 days. The primary end point was the non-progression rate at 6 months.. The 6-month non-progression rate was 80% (95% confidence interval [56-94%]), with stabilisation in 15 patients and 1 objective response. Overall survival at 24 months was 65% [40-82%]. Median progression-free survival was 9.1 months [6.5-17.3 months]. The median number of administered cycles was 12 [range 1-28]. Grade 3/4 haematologic toxicity occurred in 5 patients (25%) and grade 3 digestive toxicity in 11.. The FOLFIRI regimen, as first-line chemotherapy, achieved stabilisation in most patients whose tumours had been progressing and was well-tolerated. It could be an alternative therapy for advanced well-differentiated endocrine carcinomas of the pancreas.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Disease-Free Survival; Female; Fluorouracil; Gastrointestinal Diseases; Hematologic Diseases; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neuroendocrine Tumors; Pancreatic Neoplasms; Treatment Outcome

The feasibility, safety, and efficacy of planned sequential administration of docetaxel and irinotecan with 5-fluorouracil (5-FU)/leucovorin in advanced upper gastrointestinal adenocarcinoma (UGIA) are unknown. Seventy-three patients with gastric (GC; n = 22), pancreatic (PC; n = 28) or biliary cancer (BC; n = 23) were randomised to start with 45 mg/m(2) docetaxel or 180 mg/m(2) irinotecan combined with 5-FU/leucovorin every 2nd week. After every 2nd course, the patients were crossed over to the other combination. Treatment was given for a maximum of 12 courses. Quality-of-life (QoL) was evaluated during the first two months using the EORTC QLQ-C30. Eighteen patients (25%; GC 32%, PC 21%, BC 22%) demonstrated partial response (PR) and 21 (29%) had prolonged stable disease. Mean QoL scores were low at baseline. Twenty-three (32%) patients had improved QoL using a summary measure and 13 were stable. Median time to progression was 4.4 months and overall survival 8.2 months. The treatments were reasonably well tolerated. Grade 3-4 toxicities were slightly more common for the docetaxel combination. There were two treatment-related deaths. Planned sequential treatment with docetaxel or irinotecan with 5-FU/leucovorin is feasible, reasonably tolerable and appears active in advanced UGIA.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Camptothecin; Digestive System Neoplasms; Docetaxel; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Quality of Life; Stomach Neoplasms; Taxoids; Treatment Outcome; Vitamin B Complex

Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer.. To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer.. The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up.. Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m(2), intravenous bolus injection, followed by fluorouracil, 425 mg/m(2) intravenous bolus injection given 1-5 days every 28 days) (n = 551) or gemcitabine (1000 mg/m(2) intravenous infusion once a week for 3 of every 4 weeks) (n = 537) for 6 months.. Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life.. Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (chi(1)(2) = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups.. Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer.. clinicaltrials.gov Identifier: NCT00058201.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Deoxycytidine; Disease Progression; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Quality of Life; Survival Analysis

Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma. Although the 5-fluorouracil (5FU), folinic acid and cisplatin combination (LV5FU2-CDDP) is an option, the optimal order of the regimens must be determined. The first strategic phase III trial comparing LV5FU2-CDDP followed by gemcitabine versus gemcitabine followed by LV5FU2-CDDP was conducted.. Patients with metastatic pancreatic adenocarcinoma, performance status (PS) 0-2, without prior chemotherapy were randomly assigned (1:1) to receive either LV5FU2-CDDP followed by gemcitabine at disease progression or toxicity (Arm A), or the opposite sequence (Arm B). 202 patients had to be included and 170 deaths had to be observed to detect an expected improvement in median overall survival (OS) from 6.5 to 10 months in Arm A (two-sided α = 5% and β = 20%).. 202 patients were included (Arm A, 102; Arm B, 100). Median age, male/female ratio, PS 0-1 and previous surgery were similar in the two arms. After a median follow-up of 44 months, median OS in Arm A was 6.6 months versus 8.0 months in Arm B (p = 0.85). Median progression-free survival was similar between Arms A and B. More grade 3/4 toxicities were observed when LV5FU2-CDDP was administered as a first-line treatment compared with gemcitabine: 79% versus 64% (p = 0.018).. This trial did not show any strategic advantage to using LV5FU2-CDDP as a first-line treatment and suggests that gemcitabine remains the standard first-line treatment. Sixty-one per cent of patients were able to receive a second line of chemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Deoxycytidine; Disease Progression; Drug Administration Schedule; Female; Fluorouracil; France; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

A phase II study was performed to assess the activity of oxaliplatin plus 5-fluorouracil (5-FU) modulated by leucovorin, as second-line treatment in locally advanced or metastatic pancreas adenocarcinoma pretreated with gemcitabine-containing schedule.. Patients received weekly intravenous infusions of oxaliplatin 40 mg/m, 5-FU 500 mg/m, and leucovorin 250 mg/m (3 weeks on, 1 week off).. Twenty-three patients affected with metastatic (16) or locally advanced (7) pancreas adenocarcinoma were involved in this study. A total of 148 weeks of chemotherapy was delivered (median 2 courses each patient). Among 17 assessable patients, no objective response was registered and 4 patients had stable disease, whereas 13 had tumor progression. Median duration of stable disease was 14 weeks. Median time to progression of disease (TTP) was 11.6 weeks [95% confidence interval (CI), 7.6-5.6]. Kaplan-Meier estimated median overall survival (OS) was 17.1 week (95% CI, 4.0-30.1) and 3 months survival rate was 69.6%. Seven patients experienced grade 3 to 4 toxicity. The regimen was associated with 36% clinical benefit.. The median TTP and median OS in this population with poor prognosis suggests some activity, however, only further investigations will be able to establish the clinical value of this combination.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Maximum Tolerated Dose; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Peritoneal Neoplasms; Prognosis; Salvage Therapy; Survival Rate; Treatment Outcome

This phase II trial investigated the efficacy and safety of oxaliplatin (O), 5-fluorouracil (5-FU), and folinic acid (FA) (OFF) as second-line treatment for patients with metastatic pancreatic adenocarcinoma after failure of first-line gemcitabine treatment.. 37 patients with confirmed progressive disease on gemcitabine therapy were treated with OFF (O 85 mg/m(2) days 8, 22; FA 500 mg/m(2), followed by 5-FU 2,600 mg/m(2) days 1, 8, 15, 22) every 6 weeks. Patients were treated on an outpatient basis and remained on treatment until disease progression.. All patients were assessable for toxicity and effectiveness. We observed moderate hematotoxicity, the most common non-hematologic toxicity was neurotoxicity. A total of 12 patients had grade 3 nonhematologic toxicities: nausea and vomiting (4 patients), reversible neurotoxicity (5 patients), and diarrhea (3 patients). No grade 4 toxicities were observed. Median time to progression was 12 (1-125) weeks. Survival in second line was 22 (4-326+) weeks. Overall disease control rate was 49% (complete remission = 3%; partial remission = 3%; stable disease > 12 weeks = 43%).. This regimen is feasible and active with an acceptable toxicity profile; it can be safely administered in an outpatient setting. There is an urgent need for further investigation in phase III trials.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Treatment Failure; Treatment Outcome

To evaluate the efficacy and safety profile of a triplet regimen consisting of gemcitabine, oxaliplatin, and infusional fluorouracil and leucovorin (LV) in advanced pancreatic carcinoma (APC).. Chemotherapy-naïve patients with histo-/cytologically proven unresectable APC, and bi-dimensionally measurable diseases were eligible. Treatment consisted of fixed-dose rate (10 mg/m(2)/min) infusion of 800 mg/m(2) gemcitabine followed by 2-h infusion of 85 mg/m(2) oxaliplatin and then 48-h infusion of fluorouracil and LV (3,000 and 300 mg/m(2), respectively) every 2 weeks (the GOFL regimen). The primary end-point was objective response rate.. Forty-five patients were enrolled and received a median of seven [95% confidence interval (CI) 6.4-8.8] cycles of treatment. On intent-to-treat analysis, the overall response and disease-control rates were 33.3% (95% CI 21.4-48.0%) and 68.9% (95% CI 54.8-83.0%), respectively. Clinical benefit response was observed in 46.2% of initially symptomatic patients. The median time-to-tumor progression and overall survival were 5.1 (95% CI 4.0-6.3) months and 8.7 (95% CI, 6.1-11.3) months, respectively. Major grade 3-4 toxicities were neutropenia (28.9%, with 4.4% complicated with fever), peripheral sensory neuropathy (15.6%), nausea/vomiting (13.3%), and diarrhea (6.7%).. The triplet regimen is feasible and exhibits promising activity against APC, deserving further exploration.

Topics: Adult; Aged; Antineoplastic Agents; Deoxycytidine; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Gemcitabine; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Survival Rate; Treatment Outcome

The European Study Group for Pancreatic Cancer (ESPAC-1) study is the largest study of adjuvant treatment for pancreatic ductal adenocarcinoma to date and confirmed a survival advantage for adjuvant chemotherapy but not for chemoradiation. The importance of parallel evaluation of survival and quality of life (QoL) has been recognized as fundamental and the aim was to assess QoL and quality adjusted survival. A longitudinal QoL study on a subset of ESPAC-1 patients who prospectively completed the EORTC QLQ C-30 questionnaire during treatment and follow-up. An integrated quality-survival product method was used to adjust any treatment effect on survival by a function of measured QoL, calculated over a restricted 24-month-period (QALM-24). Three hundred and sixteen patients completed 1,201 questionnaires. There were no differences between treatment groups in dimension scores at baseline (randomization). For the chemotherapy group, the mean Quality Adjusted Life Months over 24 months (QALM-24) was 9.6 (95% CI: 8.7, 11.2) months compared with the mean QALM-24 of 8.6 (95% CI: 7.6, 10.5) months for the no chemotherapy group. For the chemoradiation group, the mean QALM-24 was 7.1 (95% CI: 6.0, 9.0) months compared with the mean QALM-24 of 8.1 (95% CI: 7.0, 10.0) months for the no chemoradiation group. The previously reported survival advantage supporting the use of adjuvant chemotherapy is maintained when adjusted using quality adjusted survival methodology. Chemotherapy provided on average an additional 1.0 quality-adjusted life months within a restricted 2-year time period from the time of resection.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Longitudinal Studies; Male; Middle Aged; Pancreatic Neoplasms; Prognosis; Prospective Studies; Quality of Life; Radiotherapy, Adjuvant; Surveys and Questionnaires; Survival Rate; Treatment Outcome

Only a few clinical trials have been conducted in patients with advanced pancreatic cancer after failure of first-line gemcitabine-based chemotherapy. Therefore, there is no current consensus on the treatment of these patients. We conducted a randomised phase II study of the modified FOLFIRI.3 (mFOLFIRI.3; a regimen combining 5-fluorouracil (5-FU), folinic acid, and irinotecan) and modified FOLFOX (mFOLFOX; a regimen combining folinic acid, 5-FU, and oxaliplatin) regimens as second-line treatments in patients with gemcitabine-refractory pancreatic cancer.. The primary end point was the 6-month overall survival rate. The mFOlFIRI.3 regimen consisted of irinotecan (70 mg m(-2); days 1 and 3), leucovorin (400 mg m(-2); day 1), and 5-FU (2000 mg m(-2); days 1 and 2) every 2 weeks. The mFOLFOX regimen was composed of oxaliplatin (85 mg m(-2); day 1), leucovorin (400 mg m(-2); day 1), and 5-FU (2000 mg m(-2); days 1 and 2) every 2 weeks.. Sixty-one patients were randomised to mFOLFIRI.3 (n=31) or mFOLFOX (n=30) regimen. The six-month survival rates were 27% (95% confidence interval (CI)=13-46%) and 30% (95% CI=15-49%), respectively. The median overall survival periods were 16.6 and 14.9 weeks, respectively. Disease control was achieved in 23% (95% CI=10-42%) and 17% patients (95% CI=6-35%), respectively. The number of patients with at least one grade 3/4 toxicity was identical (11 patients, 38%) in both groups: neutropenia (7 patients under mFOLFIRI.3 regimen vs 6 patients under mFOLFOX regimen), asthaenia (1 vs 4), vomiting (3 in both), diarrhoea (2 vs 0), and mucositis (1 vs 2).. Both mFOLFIRI.3 and mFOLFOX regimens were tolerated with manageable toxicity, offering modest activities as second-line treatments for patients with advanced pancreatic cancer, previously treated with gemcitabine.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Survival Rate; Treatment Outcome

The standard beneficial chemotherapy proven for patients with advanced pancreatic cancer is a regimen containing gemcitabine. In the pregemcitabine era, 5-fluorouracil (5-FU) was the standard agent. Oral 5-FU can be added to gemcitabine to improve the efficacy of chemotherapy and to provide better patient convenience. The possibility to improve efficacy of gemcitabine by fixed dose rate infusion (FDRI) was proposed in addition to combining it with 5-FU. We tried a new chemotherapy combining FDRI of gemcitabine with doxifluridine and leucovorin. Eligibility criteria were pathologically proven, chemotherapy-naïve, and metastatic or nonoperable advanced pancreatic cancer. Gemcitabine 1,000 mg/m(2) was infused over 100 min (days 1, 8 and 15). Doxifluridine 200 mg/m(2) t.i.d. and leucovorin 15 mg b.i.d. were given orally (days 1-21). Chemotherapy was repeated every 28 days until a patient had received 6 cycles or progression was found. Twenty-nine patients were enrolled from October 2002 to December 2004. A total of 78 cycles were given at a mean of 2.7 cycles per patient. Response could be evaluated in 26 patients. Responses were partial remission in 4/26 patients (15.4%), stable disease in 8/26 (30.8%) and progression in 14/26 (53.8%). All patients progressed except for 2 in partial remission and 2 in stable disease. Toxicities could be assessed in 23 patients. Maximal hematological toxicities greater than grade 2 were leucopenia in 3 patients (11.5%), neutropenia in 2 (7.7%), anemia in 2 (7.7%), thrombocytopenia in 1 (3.8%) and febrile neutropenia in 3 (11.5%). Maximal nonhematological grade 3 or 4 toxicities were asthenia in 1 patient (3.8%), anorexia in 1 (3.8%), vomiting in 1 (3.8%), diarrhea in 2 (7.7%), allergic reaction in 1 (3.8%), hand-foot syndrome in 1 (3.8%) and hyperbilirubinemia in 1 (3.8%). All 29 patients were dead on last follow-up. Median progression-free survival was 3.91 months in 26 evaluable patients and median overall survival was 5.59 months in all patients. Combination chemotherapy including FDRI of gemcitabine seems minimally active for patients with advanced, nonoperable pancreatic cancer. Further research to improve effectiveness of chemotherapy for advanced pancreatic cancer is mandatory.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease-Free Survival; Female; Floxuridine; Follow-Up Studies; Gemcitabine; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Remission Induction; Survival Analysis; Treatment Outcome

The aim of this study is to identify the prognostic factors of a large group of patients with pancreatic cancer who underwent the same regimen of intra-arterial chemotherapy.. 5-fluorouracil (1000 mg/m2), leucovorin (100 mg/m2), epirubicin (60 mg/m2), and carboplatin (300 mg/m2) were administered every 3 weeks into celiac axis (FLEC regimen). Kaplan-Meyer survival curve for univariate analysis and Cox regression model for multivariate one were used to determine factors predictive of survival.. Data of 211 patients with advanced pancreatic cancer who underwent FLEC regimen were analyzed. Eighty-nine had locally advanced disease, and 112 had distant metastases. Median overall survival was 9.2 months. In both univariate and multivariate analyses, pain reduction after treatment (< or =30% of baseline level vs >30%; overall survival, 7.6 vs 11.5 months), stage of disease (III vs IV; overall survival, 10.5 vs 6.6 months), and number of administered cycles (< or =3 vs >3; overall survival, 5.9 vs 12.3 months) were significant and independent predictors of survival.. Pain reduction, stage of disease, and number of administered cycles are independent prognostic factors of overall survival in a multivariate analysis of patients with advanced pancreatic cancer receiving FLEC regimen intra-arterially.

Topics: Adenocarcinoma; Adult; Aged; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Epirubicin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Male; Middle Aged; Pain; Pancreatic Neoplasms; Prognosis; Survival Rate

GOLF is a triple translational combination chemotherapy regimen with gemcitabine, oxaliplatin, and 5-fluorouracil (5-FU) (plus levofolinic acid), cytotoxic drugs currently used in the treatment of pancreatic carcinoma. Considering its promising anti-tumor effects in patients with gastroenteric malignancies, we carried out the present study to investigate its toxicity and anti-tumor activity in patients with advanced pancreatic carcinoma. Twenty-seven patients were enrolled in the study, 15 males and 12 females with an average age of 61 years and a performance status (ECOG)

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Feasibility Studies; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prospective Studies

The purpose of the study was to prospectively evaluate the efficacy and tolerability of the FOLFIRI.3 regimen in patients with unresectable pancreatic adenocarcinoma.. Chemotherapy-naive patients with histologically proven advanced pancreatic adenocarcinoma were treated with the FOLFIRI.3 regimen, consisting of irinotecan 90 mg/m(2) as a 60-min infusion on day 1, leucovorin 400 mg/m(2) as a 2-h infusion on day 1, followed by 5-fluorouracil (5-FU) 2000 mg/m(2) as a 46-h infusion and irinotecan 90 mg/m(2), repeated on day 3, at the end of the 5-FU infusion, every 2 weeks.. Forty patients were enrolled, of whom 29 (73%) had metastatic disease. A total of 441 cycles were delivered (1-53). Grade 3-4 neutropenia occurred in 35% of the patients, accompanied by fever in two cases. Other relevant grade 3-4 toxic effects were nausea-vomiting (27%) and diarrhea (25%). Grade 2 alopecia occurred in 48% of the patients. There were no treatment-related deaths. The confirmed response rate was 37.5%. Stable disease was observed in 27.5% of the patients. The median progression-free and overall survivals were 5.6 months and 12.1 months, respectively. The 1-year survival rate was 51%.. The FOLFIRI.3 regimen seems to be active on advanced pancreatic cancer and to have a manageable toxicity profile. The lack of cross-resistance between FOLFIRI.3 and gemcitabine-based regimens allows efficient second-line therapies.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Paris; Prospective Studies; Time Factors; Treatment Outcome

Development of treatments to improve the outcomes achieved with single-agent gemcitabine therapy for metastatic pancreatic cancer remains a research priority. G-FLIP (gemcitabine, 5-fluorouracil, leucovorin and cisplatin) is a four-drug regimen designed to maximize sequence-dependent synergy, while attempting to minimize toxicity among the four drugs. The dose-limiting toxicities and maximum tolerated dose of irinotecan as part of the G-FLIP regimen have been published. For phase II testing, G-FLIP consisted of sequential gemcitabine 500 mg/m2 at a fixed rate of 10 mg/m2/min, irinotecan 120 mg/m2, bolus 5-fluorouracil 400 mg/m2 and leucovorin 300 mg, followed by a 24-h 5-fluorouracil infusion of 1500 mg/m2 on day 1 and cisplatin 35 mg/m2 on day 2. Cycles were repeated every 14 days. Thirty-three patients with metastatic pancreatic cancer (22 men and 11 women) were treated and 31 were evaluable. Median patient age was 63 years (range 44-78 years) and median Karnofsky performance status score was 70-80. Estimated median time to disease progression was 171 days (6.1 months) and Kaplan-Meir-estimated median overall survival was 229 days (8.1 months). Twelve- and 18-month survivals were 33 and 21%, respectively. As per Response Evaluation Criteria in Solid Tumors criteria, 13 patients had stable disease, seven (22%) attained a partial response, and 10 (32%) had disease progression. One patient attained a complete response and two were not evaluable (one withdrew consent and one died suddenly, each after cycle 1). Treatment generally was well tolerated. Grade 3-4 toxicities/patient were thrombocytopenia (3.1%), leukopenia (15%), neutropenia (21%), neutropenic fever (3%), fatigue (18%) and thrombosis (12.5%). Common grade 1-2 toxicities per patient included nausea/vomiting (69%), diarrhea (45%), constipation (21%) and fatigue (39%). In conclusion, G-FLIP is a feasible outpatient regimen with acceptable toxicity for metastatic pancreatic cancer patients. Disease control rate (stable disease rate plus partial or complete responses) and 1-year survival outcomes are encouraging.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Camptothecin; Cisplatin; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

Advanced pancreatic carcinoma (APC) has a poor prognosis and chemotherapy remains the most common approach. Gemcitabine was the only drug recently approved for use as single agent therapy in APC. However, the combination of oxaliplatin and 5-fluorouracil (5-FU) has shown some promising results. This phase II trial was conducted to investigate the efficacy of oxaliplatin, 5-FU, and folinic acid (FOLFOX-6) in previously untreated APC patients.. We studied response rate, time to progression, and toxicity profile. Treatment included oxaliplatin 100 mg/m2 and folinic acid 400 mg/m2 on day 1 followed by a 5-FU bolus 400 mg/m2 and a 46-hour infusion of 3000 mg/m2 every 2 weeks.. From January 2003 through December 2004, 30 eligible patients were included. Median age was 65 (range, 38-75). There were 22 patients who had metastatic disease and 29 had an adenocarcinoma. A total of 181 cycles were delivered with a mean of 6 cycles per patient. There were 23 patients evaluable for response. There were 8 patients with partial response (27.6% response rate) and 10 with stable disease status (34.5%), while tumor growth control was found in 62% of the patients. Recorded toxicities of grade 3/4 were: neutropenia (26.67%), thrombocytopenia and anemia (10% each), diarrhea (6.67%), and mucositis (3.33%). Neurosensory toxicity was mild. The median time to progression and the median survival were 4 and 7.5 months, respectively.. In patients with APC, FOLFOX-6 regimen achieved an interesting response rate within a tolerable level of toxicity. This regimen seems to warrant further controlled investigation to confirm its efficacy.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Neuroendocrine Tumors; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Patient Selection

To test the hypothesis that dual biochemical modulation of fluorouracil (FU) in combination with mitomycin improves the survival of patients with pancreas cancer.. Eligibility included stage II or III unresectable adenocarcinoma of the pancreas, performance status of 0 to 2, and adequate organ function. Treatment included FU 200 mg/m2/d via continuous intravenous infusion for 4 weeks followed by 1 week of rest; leucovorin 30 mg/m2 administered via intravenous bolus infusion on days 1, 8, 15, and 22, followed by 1 week rest; mitomycin 10 mg/m2 intravenous bolus infusion every 6 weeks for a total of four doses. Dipyridamole 75 mg was administered orally three times daily during the FU administration.. Fifty patients (median age, 61 years; 23 males, 27 females) with localized unresectable pancreatic cancer were eligible for this trial. Twenty-seven patients survived past 1 year for a 1-year survival probability of 54% (95% CI, 40% to 68%). Overall, the objective response rate was 26% (confirmed and unconfirmed) in the 47 patients with measurable disease, with two complete responders. Six of the responding patients underwent curative successful resection of the tumor. The most common toxicity to treatment was stomatitis. Three patients had reversible hemolytic uremic syndrome. Five patients experienced grade 4 toxicity. There were no treatment-related deaths.. Potential improvement in survival and resectability of localized unresectable pancreatic cancer may be attained without radiation. The strategy of dual biochemical modulation of FU warrants additional investigation in a randomized fashion.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dipyridamole; Disease Progression; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Pancreatic Neoplasms; Survival Analysis

The main aim of the present work was to determine response rates and time to progression in patients with locally advanced or metastatic pancreatic cancer treated with intra-arterial chemotherapy.. Nineteen chemotherapy-naive patients with measurable lesions were treated with intra-arterial 5-fluorouracil 1000 mg/m2, leucovorin 100 mg/m2, carboplatin 300 mg/m2 and epirubicin 60 mg/m2 (FLEC regimen) every 21 days. Prophylactic granulocyte colony-stimulating factors were administered on days 4-10 of each cycle.. There were 16 patients evaluable for response, of whom 4 (25%) had a partial response, 7 (44%) showed stable disease, and 5 (31%) progressed. Marker response rate was 43%. Median time to progression was 4 months and median overall survival was 6 months. One-year overall survival was 16%. No grade 4 toxicity or severe complications relating to the angiographic procedure were observed.. Our results show that intra-arterial FLEC is well tolerated and active against advanced pancreatic cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chemotherapy, Cancer, Regional Perfusion; Disease Progression; Epirubicin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Treatment Outcome

The present study was conducted to evaluate activity and toxicity of the FLEC (folinic acid 100 mg/m2; 5-fluorouracil 1000 mg/m2; carboplatin 300 mg/m2; epirubicin 60 mg/m2) schedule as second-line treatment for progressive locally advanced or metastatic pancreatic cancer (LAMPC). FLEC was administered every 3 weeks with an angiographic catheter introduced into the tumor vascular bed. Thirty-two patients were enrolled. Twenty patients had a PS of 2. Twenty-five patients had metastatic disease to liver. Seven (21.9%) partial responses were observed (WHO criteria). Fifteen patients (46.9%) had stable disease and ten patients (31.2%) had progressive disease. The median OS from the diagnosis was 11.8 months. PS (p=0.0308) and pain (WHO scale, p=0.0222; analogic scale, p=0.0446) significantly improved after therapy. No patient discontinued treatment because of toxicity (NCI-CTC criteria). The current study shows that intraarterial chemotherapy is a good therapeutic option in second-line treatment of LAMPC.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Carboplatin; Disease Progression; Epirubicin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Retrospective Studies; Time Factors; Treatment Outcome

The role of adjuvant therapy in pancreatic cancer remains controversial. Gemcitabine given systemically seems to be effective; intra-arterial chemotherapy (IAC) has a deep rationale.. The goal was to evaluate the impact of postoperative IAC followed or not by systemic gemcitabine in patients after curative resection for pancreatic adenocarcinoma. 5-fluoruracil 750 mg sq m(-1), leucovorin 75 mg sq m(-1), epirubicin 45 mg sq m(-1), carboplatin 225 mg sq m(-1) were administered every 3 weeks into celiac axis for three cycles (FLEC regimen), then gemcitabine at the dosage of 1 g sq m(-1) on days 1, 8 and 15 every 4 weeks for 3 months (FLECG regimen).. Forty-seven patients entered the study. The first 24 received only IAC (FLEC regimen), the other 23 received the same intra-arterial regimen followed by systemic gemcitabine (FLECG regimen). After a median follow-up of 16.9 months, 29 patients recurred (61.7%). Median disease free survival (DFS) was 18 months and median overall survival (OS) was 29.7 months. One-year DFS was 59.4% and 1-year OS was 75.5%. Main grade 3 toxicity related to IAC was only nausea/vomiting in 4%; regarding gemcitabine, grade 3 toxicities were anaemia 8%, leukopenia 8%, thrombocitopenia 17%, nausea/vomiting 4%.. FLEC regimen with or without gemcitabine is active with a very mild toxicity and results are very encouraging in an adjuvant setting.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chemotherapy, Adjuvant; Deoxycytidine; Disease-Free Survival; Epirubicin; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intra-Arterial; Karnofsky Performance Status; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms

Pancreatic cancer is a dismal disease. Few drugs, including gemcitabine and 5-fluorouracil (5-FU), have notable antitumor effects against advanced pancreatic cancer. The purpose of the present study was to determine the maximum tolerated dose (MTD) of 5-FU and the efficacy and toxicity profile of weekly gemcitabine plus infusional 5-FU/leucovorin in advanced pancreatic cancer.. Patients with histo-/cytologically confirmed, advanced pancreatic cancer were eligible. Treatment consisted of a 30-min infusion of gemcitabine (800 mg/m2), followed by a 24-h infusion of 5-FU and leucovorin (300 mg/m2) at day 1, day 8 and day 15 every 28 days, and was termed the GemFL24 regimen. The dose of 5-FU was escalated from 1600, 2000, to 2600 mg/m2 in the phase I study, and fixed MTD for subsequent enrolled patients.. Eighteen patients were enrolled in the phase I study, and 24 in phase II. The MTD of 5-FU was 2000 mg/m2, with major dose-limiting toxicities being febrile neutropenia and delayed recovery from neutropenia. The dose intensity of gemcitabine of the 35 patients with 5-FU dosage set at MTD was 593 mg/m2 per week. In the entire series of 42 patients, myelosuppression was the main toxicity, with grade 3 neutropenia in eight patients, and grade 3/4 thrombocytopenia in six. On an intention-to-treat analysis, the overall and clinical benefit response rates were 22% and 46%, respectively; with median progression-free and overall survival of 4.1 and 6.9 months, respectively.. The GemFL24 regimen is a feasible and moderately active treatment with manageable toxicities for advanced pancreatic cancer, and could be a basis for further combination with other anticancer drugs.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

Only a few drugs are active in the treatment of well-differentiated endocrine carcinomas (WDEC). We evaluated the combination of the so-called 'de Gramont schedule' and irinotecan in these tumors in a phase II study.. 20 patients were enrolled in the study. The combination regimen included irinotecan, 180 mg/m(2) on day 1, followed by 200 mg/m(2) folinic acid in a 2-hour infusion, an intravenous 10-min bolus of 400 mg/m(2) 5-fluorouracil (5FU) and finally 600 mg/m(2) 5FU in a 22-hour infusion. Folinic acid and 5FU were repeated on day 2. Clinical, biological and morphological parameters were assessed by CT every 8 weeks. The site of the primary tumor was the pancreas in 10 cases, the lung in 3 cases and other sites in 7 cases. Sixteen patients had previously received chemotherapy, and 6 of them had had two lines of treatment. Six patients had previously been treated with chemoembolization.. The median number of cycles administered was 8. Grade 3-4 neutropenia was observed in 8 patients, and 1 patient experienced febrile neutropenia. There was no toxicity-related death. No complete symptomatic response was observed in 7 evaluable patients; 4 patients had an objective biological response. One patient achieved a morphological objective response, stabilization was observed in 15, but progression occurred in 3 patients. Median survival was 15 months.. The above-mentioned combination of LV5FU2 + irinotecan does not yield major activity in heavily pretreated unresectable metastatic gastroenteropancreatic WDEC, and significant toxicity was observed.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Drug Administration Schedule; Enteroendocrine Cells; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Lung Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Prospective Studies; Survival Analysis; Treatment Failure; Treatment Outcome

To evaluate the feasibility and maximal tolerated dose (MTD) of oxaliplatin of a triplet regimen consisting of gemcitabine, oxaliplatin and infusional fluorouracil (5-FU)/leucovorin (LV) (GOFL) for advanced pancreatic cancer.. Patients with histologically proven metastatic or unresectable, locally advanced pancreatic adenocarcinoma were eligible to take part in the study. The treatment consisted of fixed-rate infusion (10 mg/m2/minute) of 800 mg/m2 gemcitabine followed by 2-h infusion of oxaliplatin and then 48-h infusion of 5-FU/LV day 1 and day 15 every 4 weeks. The oxaliplatin would be evaluated at three dose levels, 65, 75 and 85 mg/m2.. A total of 15 patients were enrolled at three dose levels. Dose-limiting toxicity of neutropenic fever and grade 4 thrombocytopenia occurred in one of each six patients at oxaliplatin dose level of 65 mg/m2 and 85 mg/m2, respectively. The MTD of oxaliplatin for this combination was 85 mg/m2. After a median four cycles of treatment, grade 3/4 neutropenia occurred in 46.7% of patients and thrombocytopenia in 13.3%. Non-hematological toxicities were generally of grade 1/2. Objective tumor response was observed in five patients (33.3%, 95% confidence interval, 6.3-60.4%).. Biweekly GOFL is a feasible regimen for advanced pancreatic cancer. For further phase II studies, the recommended dose of oxaliplatin is 85 mg/m2.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Drug Administration Schedule; Feasibility Studies; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Vitamin B Complex

To evaluate response rate and toxicity of irinotecan and oxaliplatin plus fluorouracil (FU) and leucovorin (Folfirinox) in advanced pancreatic adenocarcinoma (APA).. Chemotherapy-naive patients with histologically proven APA and bidimensionally measurable disease were treated with Folfirinox therapy every 2 weeks, which comprised oxaliplatin 85 mg/m(2) and irinotecan 180 mg/m(2) plus leucovorin 400 mg/m(2) followed by bolus FU 400 mg/m(2) on day 1, then FU 2,400 mg/m(2) as a 46-hour continuous infusion. Quality of life (QOL) was assessed using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30).. Forty-seven patients were entered, and 46 received treatment. Thirty-five patients (76%) had metastatic disease. A total of 356 cycles were delivered, with a median of eight cycles per patient (range, one to 24 cycles). All patients were assessable for safety. No toxic death occurred. Grade 3 to 4 neutropenia occurred in 52% of patients, including two patients with febrile neutropenia. Other relevant toxicities included grade 3 to 4 nausea (20%), vomiting (17%), and diarrhea (17%) and grade 3 neuropathy (15%; Levi's scale). The confirmed response rate was 26% (95% CI, 13% to 39%), including 4% complete responses. Median time to progression was 8.2 months (95% CI, 5.3 to 11.6 months), and median overall survival was 10.2 months (95% CI, 8.1 to 14.4 months). Between baseline and end of treatment, patients had improvement in all functional scales of the EORTC QLQ-C30, except cognitive functioning. Responders had major improvement in global QOL.. With a good safety profile, a promising response rate, and an improvement in QOL, Folfirinox will be further assessed in a phase III trial.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Drug Administration Schedule; Female; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Quality of Life; Survival Analysis

The present study was conducted to evaluate the efficacy and safety of the combination of Oxaliplatin, Leucovorin and 5-FU as second line therapy, following relapse to Gemcitabine, in patients with advanced adenocarcinoma of the pancreas.. Patients with advanced pancreatic cancer previously treated with Gemcitabine were included in the study. All patients had histologically or cytologically confirmed adenocarcinoma of the pancreas that was unresectable, locally advanced or metastatic. Treatment consisted of Oxaliplatin 50 mg/m(2) (2-hour iv infusion), followed by Leucovorin 50 mg/m(2) (i.v. bolus) and 500 mg/m(2) 5-FU (1-hour iv infusion), administered weekly, until unacceptable toxicity or disease progression. Objective tumour response and toxicity were evaluated according to World Health Organisation (WHO) criteria.. A total of 30 patients, 20 men and 10 women, median age 63 years (range 52-71 years) and Karnofsky Performance Status (PS) of > or =50 entered the study. The majority of patients (96%) had locally advanced disease. A total of 380 doses of chemotherapy were delivered, a median of 12 doses per patient. Partial responses were observed in 7 patients (PR 23.3%), stable disease in 9 (SD 30.0%), while 14 patients progressed (PD 46.7%). Improved PS was observed in 18 (42.8%) patients. Patients that had responded to first-line Gemcitabine treatment were found more likely to respond or stabilize their disease with second-line treatment. The median duration of response was 22 weeks, and median overall survival was 25 weeks, Grade 3/4 toxicity expressed per chemotherapy dose included leukopenia 16%, anemia 3.2%, thrombocytopenia 3.2%, diarrhea 14.2%, fatigue 16.1% and neurotoxicity 4.2%. Eight patients (27%) suffered a febrile neutropenic event managed successfully with oral antibiotic home therapy, while 17 patients required G-CSF support. There were no treatment related deaths.. The combination of Oxaliplatin, Leucovorin and 5-FU was tolerated with manageable toxicity, offering encouraging activity as second-line treatment of patients with advanced or metastatic pancreatic adenocarcinoma, previously treated with Gemcitabine. Additional studies are warranted with this regimen in Gemcitabine relapsed pancreatic cancer patients.

Topics: Adenocarcinoma; Aged; Anemia; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Leukopenia; Lymphatic Metastasis; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Salvage Therapy; Survival Analysis; Thrombocytopenia

Systemic palliative treatment with chemotherapy against advanced pancreas cancer has low effectiveness despite considerable toxicity.. To investigate the safety, toxicity and tumour response of intraperitoneal 5-Fluorouracil (5-FU) with intravenous Leucovorin and to monitor 5-FU pharmacokinetics in plasma during intraperitoneal instillation with and without vasopressin in patients with non-resectable pancreas cancer.. Between 1994 and 2003, 68 patients with non-resectable pancreas cancer TNM stage III and IV, were enrolled to receive intraperitoneal5-FU instillation 750-1500 mg/m2 and intravenous Leucovorin 100 mg/m2 for two days every third week. Tumour response, performance status and toxicity were recorded. Seventeen patients were also treated with intravenous vasopressin 0.1 IU/minute for 180 minutes, during intraperitoneal 5-FU instillation. Area under the curve (AUC) and peak concentration (Cmax) of 5-FU in plasma were analysed.. The treatment was well tolerated with minor toxicity. One complete response (54.1+ months) and 2 partial responses were observed. Time to progression was 4.4 months (0.8-54.1+), and median survival was 8.0 months (0.8-54.1+). There was a significant reduction of 5-FU Cmax in plasma the second day of treatment if vasopressin was used (3.4+/-2.5 and 6.1+/-5.4 mumol/l, respectively, p<0.05). 5-FU AUC in plasma was not significantly affected by vasopressin either day of treatment.. Intraperitoneal 5-FU is a safe treatment with low toxicity to patients with non-resectable pancreas cancer. Tumour response was 4.4% and median survival time 8.0 months. Addition of vasopressin did not significantly decrease plasma 5-FU AUC but reduced Cmax on day 2 of treatment.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Female; Fluorouracil; Hemostatics; Humans; Injections, Intraperitoneal; Injections, Intravenous; Leucovorin; Male; Middle Aged; Palliative Care; Pancreatic Neoplasms; Survival Rate; Vasopressins

The influence of type of surgery and occurrence of post-operative complications on survival following adjuvant therapy for pancreatic cancer are uncertain.. Cox proportional hazard modelling was used to investigate the influence of type of surgery and the presence of complications on survival in conjunction with clinico-pathological variables in the 550 patients of the ESPAC-1 adjuvant randomized controlled trial.. Standard Kausch-Whipple (KW) was performed in 282 (54%) patients, 186 (35%) had a pylorus-preserving (PP) KW, 39 (7%) had a distal pancreatectomy and 21 (4%) had a total pancreatectomy. Post-operative complications were reported in 140 (27%) patients. PP-KW patients survived longer with a median (95% CI) survival of 19.9 (17.3, 23.1) months compared to 14.8 (13.0, 16.7) for KW patients (chi(2)(LR) = 15.1, p < 0.001). KW patients were more likely however to have R1 margins (67 (24%) vs. 29 (16%), chi(2) = 4.59, p = 0.032), poorly differentiated tumours (70 (26%) vs. 19 (10%), chi(2) = 18.65, p < 0.001) and positive lymph nodes (165 (60%) vs. 81 (44%), chi(2) = 11.32, p < 0.001). Post-operative complications did not significantly affect survival. Independent prognostic factors were tumour grade, nodal status and tumour size but not type of surgery or post-operative complications. There was a survival benefit for chemotherapy irrespective of the type of surgery or post-operative complications.. The KW and PP-KW procedures did not significantly influence the hazard of death in the presence of tumour staging, demonstrating that ESPAC-1 surgeons showed good judgement in their choice of operation. Post-operative complications did not adversely affect the survival benefit from adjuvant chemotherapy.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Chi-Square Distribution; Digestive System Surgical Procedures; Europe; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Postoperative Complications; Prognosis; Proportional Hazards Models; Prospective Studies; Radiotherapy, Adjuvant; Survival Rate

This phase I trial was initiated based on encouraging clinical data with 5-fluorouracil (5-FU)/leucovorin (LV), gemcitabine and cisplatin (G-FLIP) in the therapy of solid tumors. In this trial, G-FLIP has been modified to facilitate outpatient administration and to optimize sequence-dependent synergistic activity. Treatment consisted of biweekly (once every 14 days) cycles of sequential gemcitabine 500 mg/m, irinotecan per dose escalation schedule, bolus 5-FU 400 mg/m and LV 300 mg on day 1 followed by a 24-h 5-FU infusion 1500 mg/m, followed by cisplatin 35 mg/m on day 2. The irinotecan starting dose was 80 mg/m and escalated by 20 mg/m in cohorts of three patients until the maximum tolerated dose (MTD) was defined. Twenty-three patients were enrolled (13 men/10 women) with the following cancers: 11 pancreatic, five gallbladder, three squamous cell carcinoma of the head and neck, one hepatocellular carcinoma, one melanoma, one gastric, and one breast cancer. Median patient age was 63 years (range 44-78) and median Karnofsky performance status (KPS) was 80. Patients received a median of 8 cycles (range 1-16) over five irinotecan dose levels (80, 100, 120, 140 and 160 mg/m). Dose-limiting toxicity consisting of grade 3 nausea/vomiting despite aggressive anti-emetic therapy occurred in one patient at dose level 1 and three patients at dose level 3. Grade 3-4 hematological toxicities per patient consisted of thrombocytopenia (3%), anemia (6%), thrombosis (23%), neutropenia (16%) and neutropenic fever (10%). Of 18 patients evaluable for response, one complete response (pancreatic) and eight partial responses (three gallbladder, two pancreatic, two head and neck, and one breast) were attained. Seven patients had disease stabilization (five pancreatic, one hepatocellular and one gastric) for a median of 16 weeks (range 10-22). Median time to disease progression among all 23 patients enrolled to the phase I portion of the trial was 20.5 weeks (range 4-37). We conclude that G-FLIP is a novel outpatient chemotherapy regimen with acceptable toxicity at the maximum tolerated irinotecan dose of 120 mg/m. The phase II trial of G-FLIP using an irinotecan dose of 120 mg/m for patients with metastatic pancreatic cancer is ongoing.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms

The purpose of this phase II multi-institutional study was to define the efficacy and toxicity of infusional 5-FU in combination with PALA and leucovorin in patients with advanced pancreatic cancer.. Patients were required to have histologically confirmed pancreatic cancer that was locally advanced, unresectable or disseminated. The treatment regimen consisted of weekly 5-FU 2600 mg/m(2) given concurrently with leucovorin at 500 mg/m(2). Both drugs were administered by 24-hour continuous infusion. PALA was administered 24 hours prior to the administration of 5-FU/LV at a dose of 250 mg/m(2) IV over 15 minutes weekly. Patients were continued on the assigned treatment regimen until progression of disease, unacceptable toxicity, or the patient declined further therapy.. This study accrued 30 patients. Four of these patients were ineligible. All 26 eligible patients were evaluated for toxicity. One patient had inadequate assessment of response and was considered a non-responder. Three of the twenty-six eligible patients had partial responses, for a response rate of 12% (95% confidence interval 2% to 30%). All 26 eligible patients have died and the median overall survival was 7 months (95% confidence interval: 5.2 to 9 months). Four patients experienced grade 4 toxicities, including bilirubin increase (2 patients), vomiting (1 patient) and non-local skin ulceration (1). Two patients discontinued therapy due to toxicity.. The dual modulation of 5-FU with PALA and leucovorin in the dose and schedule used here, has a response rate similar to other single agents in pancreatic cancer and can result in some long term survival while having relatively mild toxicity.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Phosphonoacetic Acid; Pilot Projects; Prospective Studies; Survival Rate; Treatment Outcome

Mitomycin C (MMC) in combination with infusional 5-fluorouracil (FU) plus folinic acid (FA) is an effective treatment for metastatic gastrointestinal cancer. Anthracyclines are commonly used in the treatment of upper gastrointestinal cancer. The aim of this study was to determine the maximum tolerated dose of liposomal, pegylated doxorubicin (Caelyx) in combination with infusional 5-FU/sodium FA and MMC. Escalating doses of Caelyx (15-25-30-35 mg m(-2) corresponding to dose levels I-IV) were applied on days 1 and 29, given to fixed doses of 24-h 5-FU (2000 mg m(-2)) and sodium FA (500 mg m(-2), mixed with 5-FU in one pump) weekly for 6 weeks, and MMC 7 mg m(-2) on days 8 and 36. At least three patients were treated at each dose level. A total of 25 patients are evaluable. No dose-limiting toxicity (DLT) was observed on level I (n=3). On level II, DLT occurred in three out of five patients (mucositis and leucopenia). Owing to the early DLTs at this dose, we added a 20 mg m(-2) Caelyx dose level (Ia). In total, 17 patients were treated at this dose level. Among these, only two patients experienced DLT in cycle one and 37 complete cycles have been administered in association with a low toxicity profile. The median dose intensity was 100% for each drug during the first course and no treatment delay exceeding 7 days was required. The recommended dose of 4-weekly Caelyx in combination with weekly 24-h 5-FU/sodium FA and 4-weekly MMC is 20 mg m(-2). Preliminary antitumour activity has been observed in patients with pretreated pancreatic cancer and in untreated gastric cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cholangiocarcinoma; Doxorubicin; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liposomes; Male; Maximum Tolerated Dose; Middle Aged; Mitomycin; Pancreatic Neoplasms; Stomach Neoplasms; Survival Analysis; Treatment Outcome

5-Fluorouracil (5-FU) and gemcitabine are the major active drugs in the treatment of pancreatic cancer.. Twenty-two patients with advanced pancreas cancer were treated with a new chemotherapy regimen consisting of infusional 5-FU and high-dose leucovorin with gemcitabine (GEMFUFOL).. A total of 200 cycles of chemotherapy were administered. The response rate was 27.3%, all responses being partial. The median survival time and 1-year survival rate were, respectively, 13 months and 60.4%. The toxicity was very low and severe hematological toxicity was exceptional.. The GEMFUFOL regimen can be an active regimen for the treatment of advanced pancreatic cancer and has a low toxicity.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Hematologic Diseases; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Survival Rate

The aim of the study was to assess the response rate and toxicity of high-dose 24 h infusion of 5-fluorouracil (5FU) in metastatic adenocarcinoma of the pancreas. Patients with measurable disease, performance status 0-2, and no prior chemotherapy were registered to receive cycles of leucovorin (LV) 500 mg/m2 (or l-LV 250 mg/m2 over 1 h followed by 5FU 2.6 g/m2 over 24 h, weekly for 6 weeks, followed by a 2-week rest. The main endpoints were the response rate and toxicity. From 37 patients, 36 were the analysed for toxicity, and 33 were eligible and analysed for response. The median age was 59 years (range 28-74 years), and the median performance status was 1. Partial response was observed in three patients (9%) (95% Confidential Interval (CI): [2-24]%). Main grade 3/4 National Cancer Institute (NCI) common toxicity criteria toxicities (patients) were diarrhoea (n = 3), vomiting (n = 2) and hand-foot syndrome (n = 5). Median time to progression was 7 weeks (95% CI: [6.4-11.7] weeks) and median survival 19 weeks (95% CI: [12-35] weeks). In conclusion, high-dose 5FU and folinic acid is well tolerated, but has only modest activity in pancreatic cancer.

Topics: Adult; Aged; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites, Antineoplastic; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms

Gemcitabine is considered the gold standard treatment for unresectable pancreatic adenocarcinoma. Intra-arterial drug administration had shown some interesting results in small phase II studies. In this study, patients were randomly assigned to receive gemcitabine at a dose of 1,000 mg/m2 over 30 minutes intravenously weekly for 7 weeks, followed by 1 week of rest, then weekly for 3 weeks every 4 weeks or FLEC: 5-fluoruracil 1,000 mg/m2, leucovorin 100 mg/m2, epirubicin 60 mg/m2, carboplatin 300 mg/m2 infused bolus intra-arterially into celiac axis at a 3-week interval 3 times or 5-fluorouracil 400 mg/m2 plus folinic acid 20 mg/m2 for 5 days every 4 weeks for 6 cycles. The primary endpoint was overall survival, while time to treatment failure, response rate, clinical benefit response were secondary endpoints. Sixty-seven patients were randomly allocated gemcitabine and 71 were allocated FLEC intra-arterially. Patients treated with FLEC lived for significantly longer than patients on gemcitabine (p=0.036). Survival at 1 year increased from 21% in the gemcitabine group to 35% in the FLEC group. Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group. Median time to treatment failure was longer with FLEC (5.3 vs 4.2 months for FLEC vs gemcitabine respectively; p=0.013). Clinical benefit was similar in both groups (17.9% for gemcitabine and 26.7% for FLEC; p=NS). CT-scan partial response was similar in both groups (5.9% for gemcitabine and 14% for FLEC; p=NS). Toxicity profiles were different. Compared with gemcitabine, the FLEC regimen given intra-arterially improved survival in patients with unresectable pancreatic adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Deoxycytidine; Epirubicin; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

Pancreatic adenocarcinoma is a common disease considered to be poorly responsive to antiblastic treatment. Recent clinical and preclinical results suggest that a combined treatment of gemcitabine (GEM), 5-flurouracil (5-FU) and folinic acid (FA) offers a clinical benefit in patients with advanced pancreas adenocarcinoma. The aim of this phase II clinical trial was to evaluate the antitumour activity and toxicity of a novel biweekly schedule of this combination in patients with pancreatic adenocarcinoma. A total of 42 patients received a 30 min infusion of FA (100 mg m(-2)) and 5-FU (400 mg m(-2)) (FUFA) on days 1-3, and GEM 1000 mg m(-2) on day 1 every 15 days. We observed 13 objective responses (two complete, 11 partial) and 23 stable diseases. The median time to progression was 9.75 months (95% Confidence Interval (CI), 6.88-12.62) and the median overall survival was 13.10 months (95% CI 9.64-16.56). There were seven cases of each grade III gastroenteric and haematological toxicity. The GEM plus FUFA combination appears to be well tolerated and very active in patients with pancreatic carcinoma.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease Progression; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

To determine the predictive value of carbohydrate antigen (CA) 19-9 in pancreatic cancer treated with radiochemotherapy.. Ninety-five patients with locally advanced unresectable adenocarcinoma of the pancreas were treated with hyperfractionated accelerated radiotherapy to a total dose of 44.8 Gy combined with 5-fluorouracil and folinic acid. CA 19-9 was measured before therapy, each week during therapy, and every 4 weeks during the follow-up period.. The median CA 19-9 before treatment was 420 U/mL; in the responder group it was 117 U/mL, and in the nonresponder group it was 806 U/mL. Patients with a pretreatment CA 19-9 less than the median had not only a significantly better tumor response (45.8%) but also a better survival prognosis (median survival 12.3 months) than those with a level higher than the median (tumor response 12.8%; median survival 7.1 months). The posttreatment median CA 19-9 for all patients also exhibited prognostic significance. The median survival of patients with a CA 19-9 level lower than the posttreatment median of 293 U/mL was 13.5 months, compared with 7.2 months for those with a CA 19-9 level greater than the median. To detect recurrent disease during follow-up, the sensitivity of CA 19-9 was 100% and the specificity 88%.. Our results indicate that CA 19-9 is of predictive value for prognosis, response, and detecting recurrence of pancreatic cancer in patients undergoing combined radiochemotherapy. Therefore, we recommend the routine implementation of CA 19-9 observation during the clinical course of treatment for patients with pancreatic cancer undergoing radiochemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Austria; CA-19-9 Antigen; Combined Modality Therapy; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Reproducibility of Results; Sensitivity and Specificity; Survival Analysis

Phase II studies have suggested an improved response rate and acceptable toxicity profile associated with gemcitabine combinations compared to gemcitabine alone for treatment of metastatic adenocarcinoma of the pancreas. The GFP regimen (gemcitabine, 5-fluorouracil, leucovorin, and cisplatin) is based on laboratory evidence of disease-specific chemotherapy interaction. This retrospective analysis examined the outcome of 49 consecutive patients with histologically confirmed metastatic pancreatic adenocarcinoma treated between July 1998 and September 2000. Day 1 treatment consisted of gemcitabine 500 mg/m2 over 30 minutes and then leucovorin 300 mg bolus, 5-fluorouracil (5-FU) 400 mg/m2 bolus, followed by infusional 5-FU 600 mg/m2 over 8 hours. Day 2 consisted of leucovorin 300 mg bolus, 5-FU 400 mg/m2 bolus, followed by cisplatin 50-75 mg/m2 over 30 minutes and then infusional 5-FU 600 mg/m2 over 8 hours. Treatment was administered every 2 weeks. Median patient age was 61.5 years, 74% were men, and 20 patients had refractory disease (11 patients had disease progression upon gemcitabine-based therapy). Grade 3-4 toxic effects (% patients) consisted of neutropenia (30%), thrombocytopenia (14%), anemia (8%), and neutropenic fever (2%). Grade 3-4 nonhematological toxicities (% patients) consisted of neuropathy (14%), ototoxicity (8%), nephrotoxicity (6%), nausea/vomiting (14%), and mucositis (10%). The majority of dose reductions were made for neuropathy or cytopenias. Filgrastim and erythropoietin were given as needed to promote dose intensity. Eight patients attained a partial response (PR) by RECIST criteria. Fourteen had stable disease (SD). Two patients attaining PR and two attaining SD had progressive disease with prior gemcitabine-based therapy. The median time to disease progression (TTP) from GFP start was 9 weeks. For all 49 patients, the median overall survival (OS) from GFP start was 10.6 months, 12-month survival was 46%, and 24-month survival was 30%. Notably, upon disease progression, 31 patients continued to receive the GFP regimen with irinotecan 80 mg/m2 inserted on day 1 following gemcitabine, the G-FLIP regimen (gemcitabine, 5-fluorouracil, leucovorin, irinotecan, and cisplatin). Measured from G-FLIP initiation, the TTP for the 31 patients treated sequentially was 10 weeks, and for the 14 patients attaining SD or PR the TTP was 25 weeks. The median overall survival measured from GFP initiation was 11.8 months. The response rate, non-cross r

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Deoxycytidine; Drug Administration Schedule; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Retrospective Studies; Survival Analysis; Treatment Outcome

Advanced pancreatic cancer has limited treatment options. 5-fluorouracil (5-FU) is frequently used in the treatment of pancreatic cancer. Preclinical studies suggest synergism between trimetrexate (TMTX),5-FU, and leucovorin (NFL).. We conducted a phase II trial to evaluate the activity and safety of NFL in pancreatic cancer.. Eligible patients (n = 21) with untreated advanced pancreatic cancer were treated with 110 mg/m2 intravenous (IV) THTX on day 1 and 200 mg/m2 IV leucovorin prior to 500 mg/m2 IV 5-FU on day 2. Oral leucovorin (15 mg every 6 h for seven doses) started intravenous 24 h later.. Treatment was administered for 6 wk followed by a 2-wk rest period. Response was evaluated every 8 wk. All patients were evaluable for response and toxicity. Most patients (80%) had distant metastases. Forty-five cycles of chemotherapy were administered. The most common serious toxicities were Grade 3 diarrhea (23.8%) and nausea and vomiting (14.2%). The response rate was 4.1% (95% CI, 0-23%), median survival was 6.8 mo, and 1-yr survival was 19%.. Treatment with NFL is well-tolerated in patients with advanced pancreatic cancer. The median survival and 1-yr survival in these patients with poor prognosis compares favorably with other treatment options.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Nausea; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome; Trimetrexate; Vomiting

Gemcitabine is considered the golden standard treatment for unresectable pancreatic adenocarcinoma. Intra-arte-rial drug administration had shown a deep rationale with some interesting results. In a multicenter phase III trial, we compared gemcitabine given weekly with a combination of 5-fluoruracil, leucovorin, epirubicin, carboplatin (FLEC) administered intra-arteriously as first-line therapy in unresectable pancreatic adenocarcinoma. Patients were randomly assigned to receive gemcitabine at a dose of 1,000 mg/m2 over 30 minutes intravenously weekly for 7 weeks, followed by 1 week of rest, then weekly for 3 weeks every 4 weeks or 5-fluoruracil 1,000 mg/m2, leucovorin 100 mg/m2, epirubicin 60 mg/m2, carboplatin 300 mg/m2 infused bolus intra-arteriously at three-weekly interval for 3 times. The primary end point was overall survival, while time to treatment failure, response rate, clinical benefit response were secondary endpoints. Sixty-seven patients were randomly allocated gemcitabine and 71 were allocated FLEC intra-arterially. Patients treated with FLEC lived for significantly longer than patients on gemcitabine (p=.036). Survival at 1 year was increased from 21% in the gemcitabine group to 35% in the FLEC group. Median survival was 7.9 months in the FLEC group and 5.8 months in the gemcitabine group. Median time to treatment failure was longer with FLEC (5.3 vs 4.2 months for FLEC vs gemcitabine respectively; p=.013). Clinical benefit was similar in both groups (17.9% for gemcitabine and 26.7% for FLEC; p=NS). CT-scan partial response was similar in both group (5.9% for gemcitabine and 14% for FLEC; p=NS). Toxicity profiles were different. Compared with gemcitabine, FLEC regimen given intra-arteriously, improved survival in patient with unresectable pancreatic adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Deoxycytidine; Disease-Free Survival; Epirubicin; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intra-Arterial; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

Patients with pancreatic cancer often present initially in advanced disease with many compromising factors, and yet they may still be responsive to chemotherapy.. The response of 23 patients with advanced pancreatic cancer to continuous infusion therapy was investigated.. From September 1995 to February 1998, 23 patients with advanced pancreatic cancer, many with compromising factors, were treated with a MEFLEP regimen: biweekly 24-hour infusions of etoposide, 5-fluorouracil, leucovorin, epirubicin, and cisplatin, all given through an infusion pump, plus megestrol acetate, 160 mg/d, taken daily. A total of 145 courses were given. Overall response rate was 21% (4/19) for assessable chemo-naive patients; median survival for all 23 patients was 6 months; 22% of patients were alive at 1 year; and a clinical response benefit was attained in 35%.. Toxicity was manageable; grade 3 or 4 leukopenia occurred in 1 patient each, 1 patient had fever and grade 3 infection, and grade 3 and 4 hyperammonemic encephalopathy developed in 3 and 1 patients, respectively. All four of the latter patients recovered uneventfully within 2 days of initiation of therapy. Nine patients were evaluated by fluorescence in situ hybridization for the Her-2/neu oncogene, but for only one patient did amplification of the gene occur. She attained complete remission with treatment and lived for 26.7 months after diagnosis.. Biweekly MEFLEP is an active and manageable regimen for patients with advanced pancreatic cancer with compromised clinical status.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Epirubicin; Etoposide; Female; Fluorouracil; Gene Amplification; Humans; Leucovorin; Male; Middle Aged; Palliative Care; Pancreatic Neoplasms; Receptor, ErbB-2

The combination of gemcitabine with protracted 5-fluorouracil (5-FU) in the treatment of metastatic pancreatic cancer has shown activity with tolerable toxicity. The administration of UFT may simulate the effects of a protracted infusion of 5-FU. Patients with previously untreated metastatic or unresectable measurable pancreatic adenocarcinoma received gemcitabine (800 mg/m2 i.v., administered as an 80-min infusion on days 1, 8 and 15), UFT (200 mg/m2/day, on days 1 to 21), and oral leucovorin (90 mg/day, on days 1 to 21). Thirty patients were enrolled in this study. Five patients had partial responses, with an overall response rate of 17% (5/30), using the intent-to-treat principle (95% confidence interval (CI), 3-30%). Nine out of 25 (36%) patients experienced clinical benefit responses (95% CI; 17-55%). The median time to progression was 3.0 months, and the median overall survival was 7.2 months. The principal adverse event was neutropenia. The combination of gemcitabine, UFT, plus oral leucovorin shows significant antitumor activity and a beneficial clinical effect with an acceptable level of toxicity.

Topics: Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Tegafur; Uracil

Gemcitabine alone or 5-fluorouracil (5-FU) according to several schedules are used for palliation of metastatic and locally advanced (LA) pancreatic adenocarcinoma. This study was designed to test the efficacy of the leucovorin 5-FU and gemcitabine combination.. This phase II trial combined a simplified bimonthly LV5FU2 with gemcitabine: leucovorin 400 mg/m2 in a two-hour infusion, followed by 5-fluorouracil 400 mg/m2 bolus and 2 or 3 g/m2 continuous infusion over 46 hours; gemcitabine 1 g/m2 was infused over 30 min on day 3 after 5-FU. Treatment was repeated every two weeks. Gemcitabine dose could be increased (250 mg/m2 every two cycles up to 1500 mg/m2) in the absence of NCI-CTC toxicity > 2.. Among the 62 patients included in this study, 22 had LA and 40 had metastatic disease. Objective response rate for the 54 patients with measurable disease was 25.9% (95% confidence interval (CI): 14%-37.8%) and 22.6% (95% CI: 12%-33.2%) in the intent-to-treat population: the clinical benefit rate for the 59 assessable patients was 49.2%. Median progression-free survival and median overall survival were 4.8 and 9 months, respectively, with 32.3% of patients alive at 1 year. The most frequent toxicity (grade 3-4) was neutropenia (56.5%) usually asymptomatic (1.1% febrile neutropenia), but requiring decreases of 5-FU and gemcitabine doses. Unexpected complete alopecia occurred in 97% of patients.. Palliative effects, response rate and survival observed in this multicenter study seem to be superior to those obtained with gemcitabine or 5-FU alone, despite a limiting hematological toxicity.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Middle Aged; Neutropenia; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

The primary goal of this phase II study was to determine the efficacy of gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) plus 5-fluorouracil in patients with pancreatic cancer. Eligibility criteria included nonresectable locally advanced or metastatic pancreatic adenocarcinoma and measurable disease. Gemcitabine at 1,000 mg/m(2) and leucovorin at 20 mg/m(2) were administered intravenously 30 minutes before 5-fluorouracil 600 mg/m(2), weekly for 3 of every 4 weeks. Twenty nine patients were enrolled. The overall response rate was 21% (95% confidence interval: 8% to 40%), consisting of one complete response and five partial responses; 16 patients (55%) had stable disease. Median survival was 8.4 months (95% confidence interval: 2.6 to 14.2), and actuarial 1-year survival was 36%. Neutropenia (grade 3 only) was reported in 3.4% of patients, but was generally of short duration. No thrombocytopenia or evidence of cumulative myelosuppression was observed. The only significant nonhematologic events were grade 3 diarrhea and alopecia (both 3.4%). Gemcitabine plus 5-fluorouracil is active and well tolerated compared with results reported for each of these single agents. Thus, this combination justifies future comparative clinical trials. Semin Oncol 28 (suppl 10):44-49.

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Pancreatic Neoplasms; Survival Analysis

In patients with non-colon digestive carcinomas, various schedules and doses of 5-fluorouracil (5-FU) and leucovorin combined with cisplatin (CDDP) have been used extensively. The present study explored the toxicity and activity of a weekly 24-h infusion of high dose 5-FU modulated by high dose leucovorin with bi-weekly CDDP. 59 patients with measurable disease were treated with a weekly infusion of high dose 5-FU (2 or 2.6 g/m2)+leucovorin 500 mg/m2 for 6 weeks and a bi-weekly dose of CDDP (50 mg/m2). All patients had metastatic or locoregionally advanced disease and had a performance status < or =3. All patients were evaluable for toxicity and 58 for response. Toxicity was different according to the schedule of 5-FU. Serious adverse events occurred most frequently when 5-FU was given at a dose of 2.6 g/m2 with a high incidence of grade 3/4 neutropenia (16%) and febrile neutropenia (13%), and led to dose reductions in both CDDP and 5-FU in 13 patients (34%). For patients who started 5-FU at a dose of 2 g/m2, no reduction in 5-FU was required, and only 4 patients required a dose reduction of CDDP (19%). Grade 3/4 neutropenia was seen in 10% of patients of this group and only 1 patient required hospitalisation for febrile neutropenia. Other grade 3/4 toxicities were rare in both groups. Renal toxicity was infrequent and mild and did not require dose adjustments. The overall response rate was 33%; 19 patients achieved a partial responses (PR). No patient had a complete response (CR). The median duration of response was 5.7 months (range 2-24 months) and the median survival was 7.9 months ( range: 1-30, 95% confidence interval (CI): 7-9). The combination of weekly 24-h infusion of high dose 5-FU with leucovorin and bi-weekly cisplatin seems a well-tolerated and active treatment in non-colon digestive carcinomas. A dose of 2 g/m2 of 5-FU seems to be recommended.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Cisplatin; Digestive System Neoplasms; Drug Administration Schedule; Esophageal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Stomach Neoplasms; Treatment Outcome

The aim of the study was to evaluate the effectiveness and safety of a combined treatment modality including systemic chemotherapy with 5-fluorouracil (FU), leucovorin, cisplatin and external beam radiotherapy in patients with locally advanced pancreatic cancer. Systemic chemotherapy consisted of FU 400 mg m(-2) and leucovorin 20 mg m(-2) both given as intravenous bolus injection on days 1-4, plus cisplatin 20 mg m(-2) administered as 90-min infusion on days 1-4. Treatment courses were repeated every 4 weeks x 6 unless prior evidence of progressive disease. Radiation therapy using megavolt irradiation of > or = 6 MV photons with a 3- or 4-field technique was delivered during the second and third chemotherapy course, that was reduced in dose by 25%. Between October 1994 and July 1996, a total of 38 patients were entered onto this trial, all of whom were assessable for toxicity and survival. Eighteen of these (47%) had objective remissions to combined radiochemotherapy, including four CR (11%), 13 (34%) had stable disease and seven patients (18%) showed tumour progression during treatment. The median progression-free interval of the entire study population was 10 months (range 3-32), and median overall survival was 14.0 months (range 3-45+ months); 53% of all patients were alive at 12 months, and 18% of patients were alive at 24 months respectively. Severe haematological side-effects comprised neutropenia in 18%, thrombocytopenia in 8% and anaemia in 11%. The most frequent non-haematological side-effects were nausea/vomiting (WHO grade 3: 18%), and diarrhoea (grade 3: 13%). This combined radiochemotherapy regimen was tolerable and effective in patients with locally advanced pancreatic cancer. Since therapeutic results, in fact, compare favourably with other series, including surgical treatment of potentially resectable tumours, further evaluation of combined treatment modalities in the neoadjuvant setting seems warranted.

Topics: Adenocarcinoma; Adult; Aged; Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neutropenia; Pancreatic Neoplasms; Radiotherapy Dosage; Thrombocytopenia

A phase II study was performed to evaluate the activity and toxicity of 5-fluorouracil (5-FU), leucovorin, and inteferon alpha-2a in metastatic pancreatic carcinoma. Twenty-three patients were entered in this study. Four patients withdrew before receiving treatment and one patient was nonevaluable for response because of treatment-related toxicity. The most common significant toxicity was nausea and vomiting. Treatment-related hospitalization was significant. Of 18 evaluable patients, 4 maintained stable disease and 14 had disease progression. None had an objective clinical response. We conclude that this biochemically modulated 5-FU regimen is ineffective treatment for advanced pancreatic carcinoma, with significant toxicity even in highly selected patients with an ambulatory performance status.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Recombinant Proteins

The objective of this trial was to evaluate the activity and tolerability of biomodulation of 5-fluorouracil by leucovorin, methotrexate, and platinum in patients with advanced measurable disease. Thirty-five patients with histologically or cytologically proven adenocarcinoma of the pancreas were treated with methotrexate (100 mg/m2 in 500 ml 5% dextrose in a 2-hour infusion, day 1), 5-fluorouracil (800 mg/m2/day, i.v. in continuous infusion from days 2 to 5) plus 1-leucovorin (7.5 mg/m2 given per os every 6 hours, from days 2 to 5) and platinum (60 mg/m2 i.v., day 2), every 28 days. Four partial responses (12%; exact 95% confidence interval: 1-23%) were obtained in 34 evaluable patients with a median survival time of 49 weeks (range, 20-77 weeks). Ten (29%) of 34 patients had stable disease. Median time to treatment failure from the beginning of therapy was 11 weeks (range, 4-59 weeks) and median survival time was 20 weeks (range, 4-77 weeks). The most common grade III-IV toxicities were diarrhea (15%), stomatitis (41%), and vomiting (17%). Hematologic toxicity was mild. There were no therapy-related deaths. In conclusion, this trial did not report an increase or improvement in response rate and survival rates, and this regimen cannot be recommended as effective therapy for advanced pancreatic cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Fluorouracil; Humans; Immunologic Factors; Italy; Leucovorin; Male; Methotrexate; Middle Aged; Pancreatic Neoplasms; Survival Rate; Treatment Failure

This Phase I study combines tegafur and uracil (UFT) with leucovorin and conventional radiation for the treatment of pancreatic cancer. The design seeks to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of this regimen as well as to define a future Phase II dose level.. Patients with locally advanced and unresectable pancreatic cancer were treated with 45 Gy of radiation therapy. The initial UFT dose was 150 mg/m(2)/day given with leucovorin 90 mg/day, both divided into 3 daily doses for 35 days concurrent with radiation. UFT doses were escalated at increments of 50 mg/m(2)/day. Dose-limiting toxicity (DLT) was defined as Grade 3 or greater nausea, vomiting or diarrhea despite medical intervention; or Grade 3 or greater neutropenia/thrombocytopenia; or Grade 3 or greater hepatic toxicity; or inability of the patient to take 75% or more of the planned UFT/leucovorin; or radiotherapy interruption of greater than 1 week. The MTD for UFT/leucovorin was exceeded by one dose level when a certain dose caused DLT in 2 or more patients of 6.. Five evaluable patients had Stage I resectable disease but had pathologic adenopathy. Seven had Stage II unresectable disease. Compliance with therapy was excellent. At a daily dose of 300 mg/m(2) of UFT, we noticed minimal diarrhea and hematologic toxicity with mild-moderate nausea, anorexia, and fatigue. Three patients had Grade 4 toxicity: 1 had neutropenia on Day 38, 1 had diarrhea on Day 55, and 1 had vomiting on Day 15.. Oral UFT/leucovorin and radiation therapy offers patients a viable treatment option for pancreatic cancer. The major known toxicity of diarrhea was tolerable. The MTD was not reached in this study. Our current plan is to expand this into a Phase I/II trial beginning at a UFT dose of 300 mg/m(2) and correlate this with clinical pharmacologic parameters. The potential benefit of long bioavailability and oral delivery of UFT compares favorably with continuous infusion regimens without the added morbidity of a catheter and pump.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Diarrhea; Female; Humans; Leucovorin; Male; Middle Aged; Neutropenia; Pancreatic Neoplasms; Tegafur; Uracil

A phase II trial of a new intra-arterial chemotherapy regimen for unresectable pancreatic cancer (UPC).. Ninety-six patients with UPC were treated with intra-arterial chemotherapy at three-weekly intervals. The schedule used was FLEC: 5-fluorouracil 1000 mg/m2, folinic acid 100 mg/m2, carboplatin 300 mg/m2; epirubicin 60 mg/m2.. The overall response rates by CT-scan evaluation were: 15% partial response (PR), 44% stable disease (SD), 17% progressive disease (PD). The overall median survival was 9.9 months, and 10.6 and 6.8 for UICC stage III and IV, respectively. Pain reduction occurred in 42% of patients. A weight gain > 7% from baseline occurred in 8% of patients. A total of 341 courses of FLEC were administered. Grade 3-4 hematological toxicity was seen in 25% of patients; ematemesis in 4%; grade 3 gastrointestinal toxicity in 3%; and grade 3 alopecia in 16%. One sudden death, a pre-infarction angina, and a transitory ischemic attack were observed. The only complication related to the angiographic procedure was an intimal dissection of the iliac artery.. The intra-arterial FLEC regimen was well tolerated and active. It requires only one day of hospitalization. Efficacy could only be assessed in a randomized study against a gemcitabine containing regimen.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Catheters, Indwelling; Epirubicin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Male; Middle Aged; Pain; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

Adenocarcinomas of the pancreas and biliary tract are highly malignant neoplasms, which are found in the advanced stage. Chemotherapy commonly plays a palliative role in the treatment of pancreatic and biliary tract cancers. 5-Fluorouracil (5-FU) is the most widely studied single agent; the response rate of 5-FU is only 20%. Recently, some reports presented interesting results, in which 5-FU, modulated with levofolinic acid (leucovorin), was active in patients with colorectal cancer. In relation, we performed a phase II study of 5-FU, modulated with leucovorin, in patients affected by advanced pancreatic or biliary tract cancer. Fifty-one patients with nonresectable carcinomas of the pancreas or biliary tract admitted to Korea University Hospital between May 1995 and December 1998 were included in this study. Chemotherapy consisted of leucovorin 25 mg/m2/day by 2-hour intravenous infusion, followed by 5-FU 375 mg/m2/day by bolus intravenous infusion, from day I to day 5. The treatment was repeated every 3 to 4 weeks. A total of 51 eligible patients with advanced adenocarcinoma of the pancreas or biliary tract were enrolled. Of 23 enrolled patients with pancreatic adenocarcinoma, one patient showed complete remission with a survival duration of 13 months (response duration was 9 months). Three patients had partial responses (PRs) with survival times of 6, 12, and 15 months, respectively. The overall response rate was 17.4% (95% confidence interval [CI], 7.2%-36.2%). The median time of overall survival was 6 months (range: 1-15 months). Of 28 enrolled patients with biliary tract cancer, complete responses were observed in 2 patients (7.1%) with survival time of 14 and 16 months, respectively. Seven patients had PRs with a median survival of 8 months. The overall response rate was 32.1% (95% CI, 20.3%-57.5%). The median time of overall survival was 6 months (range: 1-16 months). The most prominent toxicity was mucositis. Hematologic toxicity was less severe. 5-Fluorouracil in modulation with intravenous leucovorin is well tolerated by patients with stage IV pancreatic adenocarcinoma or biliary tract cancer. Although the response rate for patients with pancreatic adenocarcinoma is not better than that achieved using 5-FU monochemotherapy, the 32.1% overall response rate achieved in patients with biliary tract cancer suggests that 5-FU modulation with leucovorin is active in biliary tract cancer.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Confidence Intervals; Drug Interactions; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mucous Membrane; Neoplasm Staging; Palliative Care; Pancreatic Neoplasms; Remission Induction; Survival Rate

Chemotherapeutic treatments using combinations of etoposide, leucovorin and 5-FU (ELF) have shown activity in the treatment of gastrointestinal malignancies. Interferon alpha 2b is known to have antiproliferative effects on several cell lines and has well documented in vitro evidence of synergism with 5-FU. It was postulated that the combination of ELF and interferon alpha 2b would improve response rates and survival in patients with pancreas cancer.. Fifty-five eligible patients with locally-advanced or metastatic pancreatic adenocarcinoma received a regimen consisting of: i.v. leucovorin at 300 mg/m2/day on Days 1-3 (of 28-day cycle), i.v. etoposide at 80 mg/m2/day on Days 1-3, i.v. 5-FU at 500 mg/m2/day on Days 1-3, subcutaneous interferon alpha 2b at 3 million units TIW, and subcutaneous G-CSF at 5 microg/kg/day on Days 4-14 (or until WBC exceeds 10,000/microl). Patients with no evidence of disease progression continued on treatment for a total of 6 cycles.. Complete response was demonstrated in 1 patient, partial response in 5 patients (11% confirmed response rate). The median survival was 5 months, and the six-month survival rate was 40%. Ten patients completed all 6 cycles of treatment. Toxicity-related dose delays and reductions were necessary for most patients.. Although the combination of ELF and interferon alpha 2b (ELFI) has modest activity in pancreatic cancer, it is a toxic and complex regimen that is not superior to other currently available approaches for the chemotherapeutic management of pancreatic cancer. ELFI cannot be recommended as a standard therapy.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Etoposide; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Recombinant Proteins

There continues to be a need for new systemic approaches for the treatment of advanced pancreatic cancer. The purpose of this study was to compare the antitumor activity of the somatostatin analogue octreotide to 5-fluorouracil chemotherapy in a Phase III setting. Eighty-four patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and limited tumor volume were randomized to receive octreotide 200 microg three times daily or 5-fluorouracil with or without leucovorin. After the first 12 patients had been randomized to octreotide, we increased the dose in the remaining patients to 500 microg three times daily. This change was based on early reports in other studies, suggesting that our original dose may not have been effective and that higher doses of octreotide were well tolerated. A planned interim analysis performed after 84 patients were enrolled demonstrated inferior time to progression and survival for the patients randomized to octreotide. Further accrual to the octreotide arm of this protocol was therefore terminated. Octreotide in doses of 200-500 microg three times daily does not delay progression or extend survival in patients with advanced pancreatic cancer compared with treatment with 5-fluorouracil with or without leucovorin.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Disease Progression; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Octreotide; Pancreatic Neoplasms; Survival Rate

At present there remains a need for more effective systemic therapy in advanced pancreatic cancer. Some studies have suggested that infusional chemotherapy schedules and biomodulation of 5-fluorouracil (5-FU) may improve the therapeutic outcome in advanced colon cancer. One such regimen that uses continuous infusion 5-FU, weekly leucovorin, daily dipyridamole, and intermittent mitomycin-C has activity in both colon and unresectable pancreatic carcinoma. The intent of this trial was to test the effectiveness of this four-drug regimen in advanced pancreatic cancer. Patients received 5-FU 200 mg/m2 daily by continuous infusion, leucovorin 30 mg/m2 IV weekly, mitomycin-C 10 mg/m2 day 1, and dipyridamole 75 mg orally four times daily for 5 weeks. After a 1-week break, treatment cycles were repeated every 6 weeks. Eligibility included biopsy-proven advanced measurable pancreatic cancer, Eastern Cooperative Oncology Group performance status 0 and 2, and no prior systemic chemotherapy. Of 46 evaluable patients, 9 partial responses and 1 complete tumor response were seen, for an overall response rate of 22% (95% confidence interval 11-36%). The median survival in the group of 50 patients registered to this trial was 4.6 months, with a range of 0.33 to 40.2 months. Toxicity was manageable, with the most common toxicities (> or =grade III National Cancer Institute Common Toxicity Criteria) being anorexia (13%), stomatitis (17%), and hand-foot syndrome (13%). Of note, little severe hematologic toxicity and no significant headaches were reported. Although some patients did respond, the therapeutic results are not encouraging enough to take this regimen to phase III testing.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dipyridamole; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Pancreatic Neoplasms; Survival Analysis; Treatment Failure

Gemcitabine (Gemzar) and 5-fluorouracil (5-FU) plus folinic acid (FA) both have proven activity in the treatment of patients with advanced pancreatic cancer. The present study was initiated to investigate the efficacy of gemcitabine in combination with 5-FU-FA.. Thirty-eight patients, median age 60 years (range 34-70) with inoperable, stage IV, pancreatic cancer were enrolled into the study and treated on an outpatient basis. All except one patient received at least one cycle of treatment with gemcitabine (1000 mg/m2), followed by FA (200 mg/m2) and 5-FU (750 mg/m2) administered as a 24-hour continuous infusion on days 1, 8, 15 and 22 of a 42-day schedule. No patient had received prior chemotherapy or radiotherapy. All 38 patients were assessed for efficacy, toxicity and time to progressive disease.. Two patients (5%), achieved a partial response and thirty-four patients (89%) achieved stable disease. There were two early deaths (< or = 4 weeks). The median time to progression was 7.1 months (range 0.4-18.1+; 95% confidence interval (95% CI): 5.3-7.9 months). Three patients had a progression-free interval of greater than 12 months and 12 of 38 patients (32%) survived longer than 12 months. The median overall survival was 9.3 months (range 0.5-26.5; 95% CI: 7.3-13.0 months). The incidence of grade 3 and 4 toxicities was low.. The combination of gemcitabine and 5-FU-FA is active and well tolerated and seems to offer an improvement in progression-free interval over both gemcitabine monotherapy and 5-FU-FA therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms

Forty-seven patients with pancreatic cancer were treated with two different schedules of 5-fluorouracil (5FU) and leucovorin (LCV): standard and dose-intense schedules. The standard regimen was monthly and the dose intense was biweekly. Partial response was observed in one patient (4%), no change in 12 (48%) and progression of disease in another 12 patients. Clinical benefit, measured by symptomatic improvement, was observed in 19% of all the patients, in 12% of those treated with the standard regimen and in 27% of the intense group. Median survival was 8 months for all the patients. The 1-year survival rate was 32%. Toxicity was mild. There was no survival benefit for the dose intense regimen. These results indicate that clinical benefit can be obtained with 5FU and LCV regimens despite the lack of objective response and that a dose-intense schedule is of little benefit in treating pancreatic cancer.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Survival Rate; Treatment Outcome

Leucovorin modulates the cytotoxic effects of 5-fluorouracil (5-FU) in the treatment of cancer. 24-hour infusion of 5-FU has been shown to enhance antitumor activity in colorectal cancer compared to bolus infusion. According to experimental data cyclophosphamide and tamoxifen may enhance the effectiveness of leucovorin and 5-FU. A phase II trial was initiated to evaluate the effect of a combination of low-dose cyclophosphamide (C), leucovorin (L), 5-FU (F) and tamoxifen (T) (CLFT) in advanced pancreatic cancer. Fifty patients were treated monthly with 300 mg/m2 cyclophosphamide and weekly with 500 mg/m2 leucovorin followed by a 24-hour infusion of 2000 mg/m2 5-FU and tamoxifen 20 mg bid. Three patients had a partial response (6%), two a minor response (4%) and 32 (64%) no change of disease. The median survival time was 8.5 months for all patients, the median time to progression of disease was 4.6 months and the 1-year survival rate was 28%. CLFT was fairly well tolerated. These data suggest that biochemical modulation of 24-hour infusional 5-FU with leucovorin together with cyclophosphamide and tamoxifen has some positive effects in the treatment of pancreatic cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Prognosis; Survival Rate; Tamoxifen

Twenty-two patients, with locally advanced unresectable and/or metastatic pancreatic carcinoma, received weekly administration of cisplatin 40 mg m(-2), 5-fluorouracil 500 mg m(-2), epidoxorubicin 35 mg m(-2), 6S stereoisomer of leucovorin 250 mg m(-2) and glutathione 1.5 mg m(-2), supported by a daily administration of lenograstim at a dose of 5 microg kg(-1). Nineteen patients were men and three were women. Median age was 63 years (range 47-70). At study entry, pain was present in 15 out of 22 patients (68%) with a mean value of Scott-Huskisson scale of 27.6+/-23.8, whereas a weight loss >10% was present in 15 patients. After eight weekly treatments, three partial responses were achieved for a response rate of 13% (95% CI 0-26%), five patients had stable disease and 14 progressed on therapy. Pain was present in 9 out of 22 patients (40%) with a mean value of Scott-Huskisson scale of 12.3+/-18.4. Eight patients (36%) (three partial response and five stable disease) had a positive weight change. Toxicity was mild: WHO grade III or IV toxicity was recorded in terms of anaemia in 7 out of 188 cycles (3.7%), of neutropenia in 9 out of 188 cycles (4.7%) and of thrombocytopenia in 3 out of 188 cycles (1.5%). Median survival of all patients was 6 months. The outcome of this intensive chemotherapy regimen does not support its use in pancreatic cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Carcinoma; Cisplatin; Drug Administration Schedule; Epirubicin; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Lenograstim; Leucovorin; Male; Middle Aged; Pain; Palliative Care; Pancreatic Neoplasms; Recombinant Proteins; Survival Analysis; Treatment Outcome

A phase I, single-center, open-label, dose-escalation study (University of Alabama [UAB] 9614) has been undertaken to evaluate the feasibility and safety of uracil and tegafur (in a molar ratio of 4:1 [UFT]) plus oral calcium folinate (Orzel) plus radiotherapy in patients with pancreatic cancer. A total of 11 patients with a median age of 59 years have been treated for 35 days with 150 mg/m2/day of UFT and 90 mg/day of oral calcium folinate, divided into three daily doses. Radiotherapy began on day 1, to a total dose of 45 Gy at 1.8 Gy per day (for approximately 5 weeks). Dose escalation of UFT will be performed until the maximum tolerated dose is defined. Overall, therapy has been well tolerated and the maximum tolerated dose has not yet been reached.

Topics: Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Therapy, Combination; Follow-Up Studies; Humans; Leucovorin; Middle Aged; Pancreatic Neoplasms; Radiotherapy, Adjuvant; Safety; Survival Rate; Tegafur; Treatment Outcome; Uracil

Gemcitabine (Gemzar) has a significant impact upon survival and quality of life for patients with pancreatic cancer, compared with 5-fluorouracil (5-FU). This phase I study was initiated to define the recommended dose of 5-FU delivered as a 24 h infusion in combination with gemcitabine (1000 mg/m2) and folinic acid (200 mg/m2) in patients with inoperable pancreatic cancer, treated on an outpatient basis. Drugs were administered weekly for 4 weeks out of 6 weeks. Sixteen chemonaive patients (median age 59 years, range 51-66) were enrolled, 15 had stage IV and one stage III disease. The median Karnofsky performance score (KPS) was 70 (range 60-80). Six patients received 5-FU 750 mg/m2, eight received 5-FU 1000 mg/m2 and two received 5-FU 1250 mg/m2. The maximum tolerated dose of 5-FU was 1000 mg/m2. Hepatotoxicity was dose limiting. One patient who received 5-FU 1250 mg/m2 died as a result of hepatorenal failure. There was one partial response, nine patients had stable disease for more than 3 months and 13 patients had improved KPS. The median time to progressive disease was 31 weeks (range 5-50 weeks). A phase 11 trial is underway to further assess the activity of this combination at the recommended dose of 750 mg/m2 5-FU.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Drug Therapy, Combination; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Leucovorin; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Time Factors; Treatment Outcome

The somatostatin analog, octreotide, is effective in treating diarrhea associated with cancer chemotherapy. This study was undertaken to determine whether octreotide could be used as prophylaxis against chemotherapy-induced diarrhea and, thereby, permit increased dose intensity. Adult cancer patients were treated with a standard regimen of intravenous 5-fluorouracil (5-FU) (600 mg/m2) plus leucovorin (LV) (500 mg/m2) weekly x 6 weeks. In addition, 150 microg of octreotide was administered subcutaneously twice daily, beginning on the first day of chemotherapy and continuing for 43 days. Escalation of 5-FU was planned for successive cohorts based upon toxicity. Eleven patients were treated at the initial 5-FU dose level. In 10 evaluable patients, dose-limiting toxicities were diarrhea (two patients), fatigue (one patient), and hyperbilirubinemia (one patient). Diarrhea was experienced by six of 10 patients, and only three patients were able to receive six weekly chemotherapy treatments without dose reduction or delay. At a dose of 150 microg twice daily, octreotide did not prevent diarrhea associated with 5-FU plus LV, and 5-FU dose escalation was not possible. While octreotide is successful in the treatment of 5-FU-induced diarrhea, we were unable to demonstrate a role in toxicity prophylaxis.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Diarrhea; Female; Fluorouracil; Gastrointestinal Agents; Humans; Leucovorin; Male; Middle Aged; Octreotide; Pancreatic Neoplasms

Because of the poor response of pancreatic cancer to conventional therapy, the authors performed a phase II pilot study to evaluate whether beta-interferon and retinoids, added to active chemotherapeutic agents, could increase response rate and survival in a group of patients who had metastatic disease. Twenty-three chemotherapy-naive patients were treated as follows: epirubicin, 60 mg/m2, and mitomycin C, 10 mg/m2, intravenously on day 1; folinic acid, 200 mg/m2, and 5-fluorouracil (5-FU), 370 mg/m2, intravenously for 5 consecutive days. beta-Interferon, 1 x 10(6) IU/m2, subcutaneously three times a week, and retinol palmitate, 50,000 IU orally twice a day, were given between chemotherapy cycles. Patients having responses and disease stabilization were maintained with the same dose of beta-interferon and retinol palmitate. Treatment was given every 4 weeks for four courses or until onset of progression. A median of three courses of chemotherapy was delivered to each patient. All patients were evaluable. Eight patients responded (35%) and 8 (35%) had stable disease. Median time to progression and survival for all patients were, respectively, 6.1 months and 11 months. Toxicity was severe: 60% of patients had hematologic toxicity, 40% had gastrointestinal toxicity, 13% had cardiac toxicity, and 1 patient had a hemolitic-uremic syndrome. The combination of chemotherapy, beta-interferon, and retinoids shows activity in metastatic pancreatic carcinoma. Toxicity was high but patients who had responses and disease stabilization had prolonged symptom palliation.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Diterpenes; Epirubicin; Female; Fluorouracil; Humans; Interferon-beta; Leucovorin; Male; Middle Aged; Mitomycin; Pancreatic Neoplasms; Retinyl Esters; Survival Rate; Vitamin A

Unresectable adenocarcinoma of the biliary tree are associated with a very poor prognosis. 5-fluorouracil (5-FU) combination regimens have produced objective response rates in approximately 10-20% of patients. Leucovorin increases the selective cytotoxicity of 5-FU. There also are encouraging reports of carboplatin in combination with 5-FU in other gastrointestinal tract malignancies.. Fourteen consecutive eligible patients were treated with a combination of carboplatin, 300 mg/m2, intravenously (i.v.) on Day 1 only and 5-FU, 400 mg/m2, i.v. with leucovorin, 25 mg/m2, i.v. on Days 1-4. All patients were required to have a histologically confirmed diagnosis and measurable disease. Patients were evaluated for response, survival, and toxicity.. A total of 48 cycles of therapy were delivered. The median survival was 5 months. One patient achieved complete remission and two others partial remission, for a total response rate of 21.4%. Four additional patients had stable disease for a median duration of 4 months. The therapy was well tolerated, with moderate myelosuppression as the main dose-limiting toxicity.. The current combination regimen of leucovorin-modulated 5-FU with carboplatin is well tolerated with appropriate supportive care, produces significant objective responses in 21% of patients with biliary tree carcinoma, and should be considered for the treatment of this disease.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Carboplatin; Cholangiocarcinoma; Drug Interactions; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms

In this Phase I study, the maximally tolerated doses (MTDs) of i.p. iododeoxyuridine (IdUrd) alone and in combination with i.v. calcium leucovorin (LV) were determined. The pharmacokinetics and pharmacological advantage of IdUrd were evaluated, and flow cytometric analysis allowed examination of the extent of incorporation of IdUrd into tumor cells with and without the addition of i.v. LV. Thirty-nine patients with advanced neoplasms primarily confined to the peritoneal space were enrolled in a dose-escalation trial using 4-h dwells of IdUrd administered i.p. daily for 4 days with and without an i.v. infusion of LV 500 mg/m2/day for 4.5 days. Twenty-three patients received single-agent therapy, and 13 patients received i.p. IdUrd in combination with i.v. LV. The MTD of single-agent IdUrd administered on this schedule was 4125 mg/m2/day for 4 days; and that of the IdUrd in combination was 3438 mg/m2/day. Dose-limiting toxicities were myelosuppression and stomatitis. During the period of the dwell, the peritoneal AUC (area under the curve) of IdUrd exceeded the plasma AUC of IdUrd by one or two orders of magnitude in all patients at all doses tested; there was a possible effect of LV on peritoneal AUC. The geometric mean pharmacological advantage (AUCperitoneal/ AUCplasma) was 181 at 625 mg/m2/day and 90 at 4538 mg/m2/day. Flow cytometric analysis suggests saturation of IdUrd measured in DNA at the 2500-3125 mg/m2 dose level, without an increase after the addition of LV. Twelve patients received 4-12 courses of therapy. One patient with recurrent ovarian cancer who received 16 courses of therapy experienced complete resolution of her ascites, near normalization of CA-125 levels, and improved quality of life; two patients with high-risk tumors receiving "adjuvant" therapy are disease-free at 3 and 6 years after treatment; other patients experienced transient clearing of ascites. The recommended Phase II dose of i.p. IdUrd using a 4-h dwell daily for 4 days is 3750 mg/m2/day alone or 3125 mg/m2/day in combination with continuous i.v. LV at 500 mg/m2/day for 4.5 days. Although flow cytometric data suggest that DNA incorporation of IdUrd is not affected by the addition of LV, the cytotoxicity of the combination regimen may be increased due to LV-enhanced, IdUrd-related inhibition of thymidylate synthase. For this reason, we recommend that efficacy studies of the combination continue in parallel with studies of IdUrd alone.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; CA-125 Antigen; DNA, Neoplasm; Drug Administration Schedule; Drug Therapy, Combination; Female; Gastrointestinal Neoplasms; Humans; Idoxuridine; Injections, Intraperitoneal; Injections, Intravenous; Leucovorin; Male; Middle Aged; Ovarian Neoplasms; Pancreatic Neoplasms; Peritoneal Neoplasms

The combination of 5-fluorouracil (5-FU) and folinic acid (FA) has demonstrated activity in most gastrointestinal tumors. The addition of epirubicin (EPI) may increase the efficacy of the combination for cancers of the upper gastrointestinal tract, such as advanced pancreatic cancer. We examined two groups of patients, explaining the potential benefits and limitations of therapy, and those patients who agreed to undergo chemotherapy formed Group A and the remaining formed Group B. Therefore, the study was a non-randomized prospective comparison between patients receiving chemotherapy and those offered the best supportive care. Group A consisted of 42 patients; 19 underwent Roux-en-Y operation, and 23 were inoperable. Group B consisted of 48 patients who refused chemotherapy; 18 underwent Roux-en-Y operation, and 30 were considered inoperable. Chemotherapy consisted of FA 200 mg/m2/day, 5-FU 600 mg/m2/day both for 5 days, and EPI 35 mg/m2/day before FA-5-FU administration on days 1 and 2, every 28 days. All patients were evaluable for response and toxicity. Objective tumor responses (partial responses) in Group A were seen in 8 patients (19%) (6 women and 2 men), and 6 (14%) had stable disease. The estimated median survival was 27.6 weeks (mean 27.5) for Group A and 22.5 weeks (mean 24) (p=0.01) for Group B. From the onset of therapy, median duration of response was 16.6 weeks and median time to progression 11.8 weeks in Group A. Toxicity consisted primarily of myelosuppression, nausea and vomiting, diarrhea, alopecia, and mucositis. In Group A 12/42 patients became free from pain for a median duration of 10 months, 14/42 had improved appetite, and 15/42 had improved performance status in comparison to Group B, where no patients had improved performance status or symptoms. We conclude that the combination of EPI+FA+5-FU has moderate activity and increased toxicity in the treatment of advanced pancreatic cancer.

Topics: Adult; Aged; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Epirubicin; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Prospective Studies; Treatment Outcome

Uracil and tegafur in a 4:1 molar concentration ratio (UFT; Bristol-Myers Squibb, Wallingford, CT) has broad anti-tumor activity for cancers arising from the gastrointestinal tract. However, there are no published data regarding the efficacy of leucovorin-modulated UFT in patients with pancreatic cancer. The objective of this trial was to determine the activity and evaluate the toxicity of UFT plus oral calcium leucovorin in patients with advanced pancreatic adenocarcinoma.. Fourteen patients with advanced measurable adenocarcinoma of the pancreas were enrolled onto the trial. Patients received 300 mg/m2/d UFT plus 90 mg/d leucovorin administered orally in divided doses every eight hours for 28 days repeated every 35 days. Objective tumor response was evaluated after two courses of therapy.. Fourteen patients were evaluable for response and toxicity. No objective responses were seen. The median (range) time to progression and survival were 14 (1.6-37), and 15 (1.9-62) weeks, respectively. Toxicity was mild with severe (grade 3 or 4) hyperbilirubinemia, pain, diarrhea, transaminitis, venous thrombus, weakness, renal failure, confusion, and edema/ascites seen in three (21%), one (7%), two (14%), one (7%), one (7%), one (7%), one (7%), one (7%), and two (14%) patients, respectively.. In the 14 patients evaluable, UFT 300 mg/m2/d plus oral leucovorin 90 mg/d administered for 28 days did not demonstrate anti-tumor activity against advanced pancreatic adenocarcinoma; however, this oral regimen was well tolerated and devoid of neutropenia, significant oral mucositis or diarrhea.

Topics: Adenocarcinoma; Aged; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leucovorin; Male; Nausea; Pancreatic Neoplasms; Tegafur; Treatment Outcome; Uracil

Carcinoma of unknown primary site (CUPS) accounts for 5-10% of all malignancies. Forty patients with metastatic CUPS or advanced oesophagogastric/pancreatic adenocarcinomas were recruited. Eligibility included ECOG performance status 0-2, minimum life expectancy of 3 months and measurable disease. The regimen consisted of bolus intravenous 5 fluorouracil (5-FU) and leucovorin (20 mg m-2) days 1-5 and carboplatin (AUC5) on day 3. The leucovorin/carboplatin/5-FU (LCF) was repeated every 4 weeks. The starting dose of 5-FU was 350 mg m-2 day-1 with escalation to 370 and then 400 mg m-2 day -1 after the toxicity at the previous level had been assessed. The maximum tolerated dose (MTD) was defined as the dosage of 5-FU that achieved 60% grade 3/4 toxicity. In addition, objective and symptomatic responses, quality of life and survival were assessed. The MTD of 5-FU in the LCF regimen was 370 mg m-2. The predominant toxicity was asymptomatic marrow toxicity. The 350 mg m-2 level was then expanded. There were two toxic deaths due to neutropenic sepsis, one at 370 mg m-2 after one course and one at 350 mg m-2 after four courses. The objective response rate was 25% with one complete response (CR) and nine partial responses (PRs). The median duration of response was 3.4 months (range 1-10). The CR and eight of the nine PRs were in CUPS patients. Twelve patients developed progressive disease on LCF. Median survival for all 40 patients was 7.8 months (10 months median survival for those treated at 350 mg m-2). The majority of patients described a symptomatic improvement with LCF chemotherapy. The recommended dose of 5-FU for future studies is 350 mg m-2 combined with leucovorin 20 mg m-2 and carboplatin (AUC5).

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carboplatin; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasms, Unknown Primary; Pancreatic Neoplasms; Quality of Life; Survival Rate; Treatment Outcome

Previous laboratory and clinical studies support the ability of interferon (IFN) to enhance the antitumor properties of chemotherapy agents, including cisplatin and 5-fluorouracil (5-FU). A phase I-II clinical trial was initiated to treat several tumor types with IFN-alpha-2b, cisplatin, 5-FU, and leucovorin (LV), given daily for 5 days of a 28-day cycle. Because of preliminary results, this was continued as a phase II trial in 18 patients with metastatic adenocarcinoma of the pancreas. Each treatment day consisted of IFN 5 million u/m2 s.c. (maximum, 10 million U), CDDP 20 mg/m2 i.v. over 1 h, LV 20 mg/m2 i.v.p., and 5-FU 250-275 mg/m2 i.v.p. All patients had measurable disease with no prior chemotherapy for metastatic disease, and all had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Six of the 16 patients evaluable for response had partial responses (PRs) (37.5%) with a median response duration of 4 months, and all responding patients survived > or = 8 months. Median survival of all 18 treated patients was 5 months. Severe gastrointestinal toxicity (nausea, diarrhea, or requirement for i.v. hydration) was common. Grade 4 hematologic toxicity was seen in six patients. The response rate observed is promising and supports the concept that IFN may potentiate the effects of standard chemotherapy agents. However, the toxicities observed with this dosage schedule were considerable and further studies are needed to develop a less toxic regimen.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Recombinant Proteins; Survival Analysis

The ESPAC-1 trial is the largest study of its kind in pancreatic cancer and should definitively address the question of the role of conventional methods of adjuvant treatment in pancreatic cancer.. At the joint International Association of Pancreatology and the European Pancreatic Club meeting in Mannheim, Germany (June 12-15, 1996) a satellite meeting of the European Study Group for Pancreatic Cancer (ESPAC) met to discuss the progress of the ESPAC-1 trial.. A randomized multicenter study to address which, if any, of the following adjuvant treatments are of benefit in patients with resectable pancreatic cancer: radiotherapy (40 Gy with 5-FU as a sensitizing agent), 6 mo of chemotherapy (5-FU and folinic acid), or a combination of these treatments.. From February 1994 to June 1996 (the time of the Mannheim meeting) 221 patients so far have been recruited into the three treatment arms and one control arm.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Chemotherapy, Adjuvant; Clinical Protocols; Combined Modality Therapy; Europe; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Radiation-Sensitizing Agents; Radiotherapy, Adjuvant

Preclinical data suggest that the levorotatory isomer of leucovorin (1-LV) can augment the cytotoxic effects of 5-fluorouracil (5-FU) more effectively than racemic LV. A phase II study was initiated to evaluate the effect of a combination of the pure L-isomer of LV and 5-FU along with epirubicin in patients with advanced pancreatic cancer.. Twenty-eight consecutive, previously untreated patients with measurable metastatic adenocarcinoma of the pancreas were enrolled in this study. Treatment consisted of epirubicin 50 mg/m2 on day 1 and 5-FU 400 mg/m2 plus 1-LV 100 mg/m2 both administered on days 1 to 5. Treatment cycles were repeated every four weeks for a total of six months unless progressive disease was documented earlier. The study endpoints were survival, toxicity, objective response as well as palliative beneficial effects of the regimen in terms of performance status, body weight and pain.. Six patients had a partial response (21%; 95% CI, 8% to 44%) and 10 (36%) stable disease (35%), while the remaining 12 patients (43%) progressed during treatment. The median time to treatment failure was 2.9 months (range 1.2-13.7 months), and the median survival time was six months (range 1.8-19 months), with three patients (11%) being alive after one year. Beneficial palliative effects in terms of performance status, body weight and/or pain were seen in 12 of 28 patients (43%): an improvement in performance status was recorded in four patients, pain was attenuated and/or analgetic consumption reduced by > or = 50% in eight patients, and five patients had weight gain of > 5% of their pretreatment body weight. Treatment-associated side effects were generally mild to moderate. Severe adverse reactions included (asymptomatic) granulocytopenia in five, mucositis and/or diarrhea WHO grade 3 in four patients.. Our data suggest that epirubicin plus 5-FU and 1-LV is a tolerable regimen that has some positive effects in the treatment of pancreatic cancer. Since this regimen, however, is unlikely to offer any major therapeutic advantage compared to monochemotherapy or other combination regimens, the search for novel and more effective cytotoxic agents must continue.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Epirubicin; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Palliative Care; Pancreatic Neoplasms

UFT (tegafur and uracil) has been studied extensively in Japan, with documented efficacy in hepatobiliary and pancreatic cancer. In the United States, UFT with or without leucovorin has not undergone phase II testing in these malignancies. Our current trial is designed primarily to assess the efficacy in terms of response rates to UFT with leucovorin in patients with advanced hepatobiliary and pancreatic cancer. Secondary objectives include determining response duration, time to disease progression, overall survival, quality of life, and toxicity.

Topics: Adenocarcinoma; Adult; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Cholangiocarcinoma; Drug Combinations; Humans; Leucovorin; Liver Neoplasms; Pancreatic Neoplasms; Quality of Life; Tegafur; Treatment Outcome; Uracil

To improve the dismal prognosis of patients (pts) with pancreatic cancer we treated 32 patients with non-resectable (UICC III, 17 pts; UICC IV, 15 pts--group 1) and 20 patients with resected (UICC I, 1 pt; UICC II, 3 pts; UICC III, 16 pts--group 2) pancreatic cancer with palliative (group I) and adjuvant post-operative (group II) coeliac axis intra-arterial cyclic infusions (CAI). CAI consisted of mitoxantrone 10 mg/m2 on day 1, folinic acid 170 mg/m2 and 5-FU 600 mg/m2 during days 2-4, and cis-platinum 60 mg/m2 on day 5 for up to 11 (group I) or six (group II) cycles. In a total of 211 cycles toxicities at the level of WHO III occurred in 0-6% and of WHO IV in 0%. The median survival times, compared with institutional historical controls (treated vs controls), were 12 vs 4.8 months in UICC III (P < 0.006) and 4 vs 2.9 months in UICC IV (P < 0.05) group I pts, and 21 vs 9.3 months in group II (P < 0.0003). Hepatic disease progression appeared to be suppressed with CAI, which also appears to be effective for palliative and adjuvant treatment in non-resectable and resected pancreatic cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Case-Control Studies; Celiac Artery; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Male; Middle Aged; Mitoxantrone; Palliative Care; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

To evaluate the toxicities of a Phase I study of radiation therapy with concurrent 5-fluorouracil (5FU) and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma.. Twenty-seven patients with locally advanced carcinoma of the pancreas (n = 19), bile duct (n = 7), and gall bladder (n = 1) were entered into a Phase I study of combined radiation therapy, 5FU, and folinic acid. Radiation was given as a split course of 40 Gy in 20 daily fractions with a gap of 2 weeks after 20 Gy. 5-Fluorouracil, 300 to 375 mg/m2/day and folinic acid, 20 mg/m2/day were given as an i.v. bolus daily for 5 days beginning on day 1 and again on day 29.. Eight patients developed Grade 3 or 4 toxicities (National Cancer Institute common toxicity criteria) including nausea and vomiting (n = 4), oral mucositis (n = 4), myelosuppression (n = 2), infection (n = 2), and diarrhea (n = 1). Four patients did not complete the planned protocol due to treatment toxicities. There were two treatment deaths secondary to septic neutropenia. Treatment toxicity appeared to be related to age (> 70), performance status (ECOG = 2), and 5FU dose (> 350 mg/m2/day).. This protocol is poorly tolerated by elderly patients or those with poor performance status, and 350 mg/m2/day is our recommended dose for 5FU as given in this protocol.

Topics: Adult; Aged; Aged, 80 and over; Antidotes; Antimetabolites, Antineoplastic; Bile Duct Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Radiotherapy Dosage; Survival Analysis

The Italian Oncology Group for Clinical Research (GOIRC) randomized 55 naive patients with advanced pancreatic cancer (APC) between intravenous fluorouracil (5FU) 400 mg/m2, days 1-5 and folinic acid (FA) 200 mg/m2, days 1-5 alone, using Machover's schedule, or with FU, FA, and ifosfamide (IFO) 5 g/m2, day 1 and Mesna. In both arms, treatment was repeated every 28 days. Fifty-one patients were evaluable for response. The overall response rate was 6% (3 out of 51), 1 out of 29 (3%) complete response (CR) in the arm with FU plus FA, and 2 out of 22 (9%) partial responses (PR) in the arm with IFO. The duration of response rate was 39, 55, and 74 weeks, respectively. Median survival time was 21 weeks (range, 4-83 weeks) for 5FU/FA and 16 weeks (range, 3-106 weeks) for the FU/FA/IFO arm. Diarrhea, mucositis, and vomiting occurred in the majority of patients. One patient died due to toxicity. The combination of 5FU plus FA failed to demonstrate therapeutic activity in patients with APC and was associated with moderate to severe toxicity that could lower the quality of life of these patients. Ifosfamide did not potentiate the activity of this combination. Neither of these combinations should be considered for treatment of patients with APC.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Ifosfamide; Leucovorin; Male; Mesna; Middle Aged; Pancreatic Neoplasms

To describe the toxicities of a combined modality adjuvant regimen for patients with resectable periampullary adenocarcinoma.. Fourteen patients with surgically resected periampullary adenocarcinoma were treated with adjuvant therapy consisting of prophylactic hepatic irradiation and pancreatic bed irradiation and concurrent infusional 5-fluorouracil and leucovorin (5-FU/LV). Starting within 60 days of surgery, patients received radiation treatments of 1.8 Gy per fraction to the liver and pancreatic bed (13 fractions), followed by 1.8 Gy per fraction to the pancreatic region (15 fractions). All radiation treatments were given with infusional 5-FU (200 mg/m2/day) and leucovorin (5 mg/m2/day) for 5 out of every 7 days during the 38-day treatment sequence. After a 1-month break, patients were scheduled to receive four cycles of infusional 5-FU/LV (2 weeks on/2 weeks off).. All 14 patients completed the initial combination treatment. Toxicities were tolerable; three patients had Grade 3/4 toxicities that were primarily gastrointestinal in nature. Six patients required hospitalization during therapy for treatment-related toxicities. Two patients required radiation treatment breaks of less than 1 week, and two others had radiation held for 2-4 weeks. Three patients required chemotherapy dose reductions secondary to toxicities. Toxicities in the subsequent chemotherapy-alone cycles were few and primarily manifested by Grade 2 rises in liver injury tests. Higher toxicity grades were associated with tumor progression. Twelve patients have developed recurrent disease with an equal number of recurrences occurring in the pancreatic bed as in the liver over the 12-month median follow-up. Median survival for this cohort is 417 days, not significantly different from previously reported adjuvant trials in this patient population.. These data indicate that adjuvant therapy with concomitant large-field radiation and infusional chemotherapy is feasible and associated with mangeable toxicities in patients undergoing pancreaticoduodenectomy for periampullary adenocarcinoma. Improvement in survival over other adjuvant regimens has not thus far been observed. Modification of this strategy may be required.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Liver; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Pancreaticoduodenectomy; Survival Analysis

Advanced pancreatic adenocarcinoma is a rapidly fatal disease for which an active chemotherapy regimen is sought. Here we report the outcome of a phase II trial to assess the toxicity and efficacy of a combination of 5-fluorouracil (5-FU), leucovorin and cisplatin (CDDP).. A regimen combining leucovorin (200 mg/m2/d x 5d), 5-FU (375 mg/m2/d x 5d in a 2-hour infusion) and CDDP (15 mg/m2/d x 5d) was given to 52 patients with histologically-proven, previously untreated, locally advanced (n = 13) and/or metastatic (n = 39) pancreatic adenocarcinoma.. Of 48 patients evaluable for response, 10 achieved partial responses, for an overall response rate of 21% (95% CI 9.5%-32.5%), and a palliative effect was observed in 52%. The median survival was 9.5 months (18 months for locally-advanced and 5 months for metastatic disease) with a 1-year survival of 34.6% and a median progression-free survival of 4.5 months. Chemotherapy was well tolerated with grades 3 or 4 nausea/vomiting in 12%, diarrhea in 6%, anaemia in 17%, neutropenia in 12%, and thrombocytopenia in 10%. Eleven patients (21%) had Grade 2 peripheral neuropathy.. The combination of leucovorin, 5-FU and CDDP seems to be an effective palliative treatment, with moderate toxic effects, in advanced pancreatic adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Palliative Care; Pancreatic Neoplasms; Prospective Studies; Survival Rate; Treatment Outcome

To date there is no established chemotherapeutic treatment for patients with unresectable locally advanced and/or metastatic carcinomas of the exocrine pancreas or the gallbladder. A multicenter Phase II trial has been performed by the Southern Italy Oncology Group with the aim of evaluating the clinical effectiveness and tolerability of weekly 5-fluorouracil (5-FU) in modulation with intravenous (i.v.) high dose levofolinic acid and oral hydroxyurea.. A total of 70 patients fulfilling the standard eligibility for a Phase II study were enrolled in the trial. Forty patients had advanced pancreatic adenocarcinoma and 30 had advanced gallbladder carcinoma. The treatment schedule was: levofolinic acid, 100 mg/m2, in 500 mL of normal saline over 2-hour infusion followed by 5-FU, 600 mg/m2 i.v. bolus, and oral hydroxyurea, 1000 mg/m2, for 1 day every week for 6 consecutive weeks followed by 15 days of rest.. Among the 40 patients with pancreatic adenocarcinoma, 5 (12.5%; 95% confidence level [CL], 8.5-16.5%) showed a partial response with a median duration of 5.6+ months, and 13 had stable disease. Twenty-two patients progressed. Median survival was 5.8 months. Among patients with advanced gallbladder carcinoma, 9 of 30 had a partial response (30%; 95% CL, 26-34%) with a median duration of 6.5 months, and 8 (27%) had stabilization of disease. Thirteen patients showed progressive disease. Median overall survival was 8 months. Toxicity was mild, with Grade 1 to 2 leukopenia and gastrointestinal toxicity the most frequent side effects. No chemotherapy-related deaths were observed.. 5-FU in modulation with i.v. levofolinic acid and oral hydroxyurea on a weekly schedule is well tolerated by the vast majority of patients with locally advanced and/or metastatic carcinoma of the pancreas or the gallbladder. Although response rate and overall survival for patients with pancreatic adenocarcinoma are far from acceptable, the 30% overall response rate achieved in patients with advanced gallbladder carcinoma suggests that 5-FU in modulation with levofolinic acid and hydroxyurea is active in this neoplasm. The combination of modulated 5-FU with other antineoplastic drugs seems worthy of clinical testing in further controlled trials.

Topics: Adenocarcinoma; Administration, Oral; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Disease Progression; Drug Administration Schedule; Female; Fluorouracil; Gallbladder Neoplasms; Humans; Hydroxyurea; Infusions, Intravenous; Injections, Intravenous; Italy; Leucovorin; Leukopenia; Male; Middle Aged; Pancreatic Neoplasms; Remission Induction; Survival Rate

In certain patients with pancreatic and biliary cancer, chemotherapy may relieve tumour-related symptoms, improve quality of life and possibly prolong survival. The extent of these improvements is not completely known in spite of the extensive use of this treatment modality. The aim of this study was to estimate any gain in the quantity and quality of life produced by chemotherapy in patients with pancreatic and biliary cancer.. Between January 1991 and February 1995, 90 eligible patients with pancreatic or biliary cancer were randomized to either chemotherapy in addition to best supportive care or to best supportive care. Chemotherapy was allowed in the latter group if the supportive measures did not lead to palliation. Chemotherapy was either sequential 5-fluorouracil/leucovorin combined with etoposide (FELv) or, in elderly and poor performance patients, the same regimen without etoposide (FLv). Quality of life was evaluated with the EORTC-QLQ-C30 instrument.. Mean scale scores in the QLQ-C30 improved more often/deteriorated less frequently in the chemotherapy group than in the best supportive care group. More patients in the chemotherapy group (36%, 17/49) had an improved or prolonged high quality of life for a minimum period of 4 months compared to those in the best supportive care group (10%, 4/41, P < 0.01). Overall survival was significantly longer in the chemotherapy group (median 6 vs. 2.5 months, P < 0.01). Also, the quality-adjusted survival time was longer for patients randomized to chemotherapy (median 4 vs. 1 months, P < 0.01). The effects were seen both in pancreatic and biliary cancer.. The results show that chemotherapy can add to both quantity and quality of life in advanced pancreatic and biliary cancer. The number of patients who benefit from treatment is, however, still limited; for this reason careful selection before, and close monitoring during, treatment are necessary.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Palliative Care; Pancreatic Neoplasms; Pilot Projects; Quality of Life; Survival Analysis

Previous trials in patients with colorectal carcinoma have indicated that enhancement of 5-fluorouracil (5-FU) by leucovorin (LV) can result in an improved response rate and increased survival.. Phase II trials were performed with patients who had either gastric or papcreatic adenocarcinoma with inetastases. Forty-one gastric carcinoma patients and 31 pancreatic carcinoma patients with measurable disease were treated with 5-FU, 425 mg/m2 intraveneosly (i.v.) on Days 1-5 plus LV, 20 mg/m2 i.v., on Days 1-5, reported at 4 and 8 weeks, and then every 5 weeks thereafter.. The patients with metastatic gastric carcinoma had a median survival of 4.8 months. There was a 22% objective response rate, including a 4.9% complete response rate and a 17.1% partial response rate. Among the 31 patients with pancreatic carcinoma, there was a median survival of 5.7 months. No patients in this group showed a response.. The response rate for patients with metastatic gastric adenocarcinoma was modest and this regimen may provide temporary palliation for some patients. However, 5-FU and LV treatment is ineffective against metastatic pancreatic carcinoma.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cause of Death; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Stomach Neoplasms

Interferon alpha-2a (IFN-alpha) and folinic acid (FA) have been shown to modulate the cytotoxic effects of 5-fluorouracil (5-FU) in the treatment of cancer. A phase II study was initiated to evaluate the effect of a combination of 5-FU/FA/IFN-alpha in patients with advanced pancreatic cancer. Sixty previously untreated patients with advanced adenocarcinoma of the pancreas were treated with 500 mg m-2 FU via an intravenous bolus 1 h after the initiation of a 2 h infusion of 500 mg m-2 FA. Before starting the FA infusion, 6 million units (MU) of IFN-alpha was administered subcutaneously. The treatment was repeated once a week. Of 57 evaluable patients, eight (14%) had a partial response (PR), eight (14%) a minor response (MR) and 28 (49%) no change of disease (NC). Thirteen patients (23%) had progressive disease (PD). The median survival time was 10 months for all patients, 22 months for patients with partial remission and 5 months for patients with progressive disease. Many patients with tumour-related pain whose tumours were affected in terms of PR, MR, NC were free of pain during treatment with this regimen (22/36 patients). The common toxicities observed were fever (56%), nausea (37%) and diarrhoea (33%). These data suggest that biochemical modulation of 5-FU with FA and IFN-alpha has some positive effects in the treatment of pancreatic cancer of moderate toxicity.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Recombinant Proteins

Carcinoma of the pancreas is a virulent malignancy. We performed a Phase II survival study by treating 30 patients with pancreatic cancer with leucovorin, 200 mg/m2 x 5 days immediately followed by 5-fluorouracil, 370 mg/m2 every 4 weeks. We examined the survival of our 30 study patients with patients drawn from the Manitoba Tumor Registry, matched for important prognostic criteria. Classical response rates were also evaluated in those patients who had measurable tumors. The response rate was 13% with two complete remissions and one partial remission, with 40 patients (7.8%) demonstrating stable disease for 2 months, and 39% of patients demonstrating progressive disease while on treatment. The mean survival of the Phase II-treated group was 16 weeks, compared to 12 weeks in the matched controls, which indicated an increase in survival of 30%. This was significant at the p = .001 level. Toxicity was not as great as expected. This trial demonstrates that there may be marginal survival benefit with 5FU leucovorin in pancreatic cancer, but more profound prolongation needs to be seen with chemotherapy regimens before instituting randomized trials.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Registries; Remission Induction; Survival Analysis

Patients unable to undergo a pancreatoduodenectomy for adenocarcinoma of the pancreas are often treated with radiation therapy. A randomized trial by the Gastrointestinal Tumor Study Group has shown an advantage in combining it with chemotherapy. A similar size retrospective study at a large community radiation therapy center assessed this finding in the nonprotocol setting. The study population consisted of 86 patients treated with primary radiation therapy between 1982 and 1992; 62 of them also received chemotherapy. The overall probability of survival was 39% and 13% at 12 and 24 months respectively. Patients receiving chemotherapy had a significantly (p = .018) longer survival (44% versus 25% at 12 months). Results confirm the Study Group's findings and suggest that they be applied to the community setting.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Doxorubicin; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Radiotherapy, High-Energy; Retrospective Studies; Streptozocin; Survival Rate

Increased activity against colorectal cancer by 5-fluorouracil (5-Fu) modulation with leucovorin (LV) and/or interferon (IFN) has been reported. In this study 22 patients with measurable advanced pancreatic cancer received 5-Fu 375 mg/m2 and LV 20 mg/m2 by i.v. bolus daily x 5 every 28 days plus IFN-alpha 3 million units/m2 s.c. There were three out of 21 (14%) responses lasting from 4 to 8 months. Sixteen patients (73%) had one or more episodes of grade 3 or greater toxicity (stomatitis, diarrhea or fatigue). While this combination has some activity against pancreatic cancer, its toxicity limits its potential as a palliative treatment.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Middle Aged; Pancreatic Neoplasms; Recombinant Proteins

On the basis of data suggesting the possibility of maximizing the efficacy of 5-FU by LV and IFN, a pilot clinical trial was initiated in advanced pancreatic cancer.. Twenty-four patients received weekly 5-FU 600 mg/m2 bolus 1 hour after the initiation of a 2-hour infusion of 500 mg/m2 of leucovorin. Three MU of interferon alpha 2b was administered subcutaneously three times a week.. Two of 22 evaluable patients obtained partial responses (8%, confidence interval 3%-33%). Toxicity was severe. Diarrhea and stomatitis were the most common side effects, occurring in 50% and 25% of patients, respectively.. Because of the presence of severe toxicity we suggest that further clinical trials in pancreatic cancer be attempted only after a better definition in preclinical studies of interactions among 5-FU, leucovorin and interferon.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Interferon-alpha; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Pilot Projects; Prognosis

A Phase I study was conducted to determine whether the addition of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to a combined 5-fluorouracil (5-FU) and folinic acid (FA) regimen would allow an escalated starting dose of 5-FU. FA (500 mg/m2) was administered as a 2-hour infusion on days 1 through 5, with 5-FU administered as a bolus injection 1 hour after the initiation of FA. Fifteen patients were enrolled in the trial; six were entered at a dose level of 375 mg/m2 of 5-FU, six at 450 mg/m2, and three at 540 mg/m2. rhGM-CSF was administered subcutaneously on days 6 through 15. A course of therapy was repeated every 28 days. Serious toxicity was observed at 450 mg/m2, with two patients developing grade 3 mucositis and one, grade 4 mucositis. Dose-limiting toxicity occurred at 540 mg/m2, at which point three patients developed grade 4 mucositis. One patient with metastatic colon cancer who received 5-FU at 540 mg/m2 achieved a partial response. Because of this persistent mucositis, the addition of rhGM-CSF used in this schedule would not allow an increased starting dose of 5-FU.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Pancreatic Neoplasms; Recombinant Proteins

Preclinical and clinical data suggest that both leucovorin (LV) and interferon (IFN) can augment the cytotoxic effects of 5-fluorouracil (5-FU). Based on the rationale of biochemical double modulation, the current Phase II study was undertaken.. Thirty-two previously untreated patients with advanced adenocarcinoma of the pancreas were treated with subcutaneous recombinant alpha-2b-IFN at a dose of 10 million units on 3 consecutive days; LV (200 mg) plus 5-FU (20 mg/kg) were administered as intravenous bolus doses on day 3. Treatment courses were repeated as tolerated in 2-to-3-week intervals, depending on the patient's complete blood count.. Of 32 evaluable patients, 4 (12.5%) had a partial response (95% confidence limit, 4-30%) of 4, +6, 7.5, and 9 months' duration, and 13 (40.5%) had stable disease. The median duration of survival for all patients from the start of therapy was 5.5 months. The most common toxicities observed were IFN-related fever during the first course (69%), mild leukopenia (53%), and gastrointestinal symptoms (28%).. Although the combination of 5-FU, LV, and recombinant alpha-2b-IFN in patients with advanced pancreatic adenocarcinoma has some activity and generally was well tolerated, the observed response rate and median survival were not superior to 5-FU monotherapy.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Evaluation; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Recombinant Proteins

We conducted a phase I trial of fluorouracil (5-FU), leucovorin, (LCV), and recombinant interferon-alpha-2b (rIFN-alpha-2b). The doses of each of the three agents were escalated sequentially. 5-FU and LCV were administered by IV bolus, weekly for 6 weeks and rIFN-alpha-2b was administered by subcutaneous injection, three times weekly for 6 weeks. Twenty-nine patients with advanced cancer (75% colon or pancreatic cancer) were treated. Partial remissions were observed in three patients (10%) with previously untreated colon cancer, colon cancer refractory to 5-FU plus LCV and previously untreated pancreatic cancer, respectively. An additional three patients with pancreatic, prostate, and rectal cancer had a 50% reduction in tumor markers but no change in objective tumor measurements. The toxicity of this regimen was tolerable. The most common toxicities were diarrhea, fatigue, flu-like symptoms, nausea/vomiting, and mucositis. However, no fatal or life-threatening toxicities were observed. We conclude that the combination of 5-FU, LCV, and rIFN-alpha-2b can be safely administered and recommend further evaluation of this regimen in patients with tumors of gastrointestinal origin using doses of 5-FU 600 mg/m2, LCV 500 mg/m2, and rIFN-alpha-2b 10 x 10(6) U.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Evaluation; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Kidney Neoplasms; Leucovorin; Male; Middle Aged; Neoplasms; Pancreatic Neoplasms; Recombinant Proteins

Based on promising results with 5-FU/FA or 5-FU/IFN-alpha in colorectal cancer, a pilot study was initiated to evaluate the effects of the combination 5-FU/FA/interferon alfa (IFN-alpha) in patients with advanced pancreatic cancer. Patients received 9 million units (MU) IFN-alpha subcutaneously three times a week or 6 MU IFN-alpha once a week; 500 mg/m2 5-FU via an intravenous bolus 1 hour after the initiation of a 2-hour infusion of 500 mg/m2 of FA, once a week. Fourteen patients, all previously untreated with chemotherapy, were enrolled; 13 (two females/11 males) were evaluable for response and toxicity (one too early). The median performance status was 80% (range, 60 to 100) and the median age 62 years. Besides the inoperable primary tumor, metastatic sites were liver, lung, and peritoneum. Three of 13 patients had a partial remission, three of 13 patients a minor response, and four of 13 patients no change. Three patients had progressive disease. Until now, no complete remission was seen. Median duration of response was 4+ months; median survival has not been reached yet. Of all patients there were three instances of World Health Organization grade 3 toxicity: fatigue (one of 13), nausea (one of 13), and diarrhea (one of 13); grade 4 toxicity did not occur. Although overall toxicity was moderate, most patients experienced a reduction of well-being. Therefore in all patients the dose of IFN was reduced (from 3 x 9 MU/week to 1 x 6 MU/week). Our preliminary data suggest that biochemical modulation of 5-FU with FA and IFN-alpha (reduced dosage) is effective in pancreatic cancer with moderate toxicity, warranting further study.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Infusions, Intravenous; Interferon alpha-2; Interferon-alpha; Leucovorin; Liver Neoplasms; Lung Neoplasms; Middle Aged; Pancreatic Neoplasms; Pilot Projects; Recombinant Proteins

Forty-two previously untreated patients with advanced, measurable adenocarcinoma of the pancreas were treated with weekly fluorouracil (5-FU; 600 mg/m2 intravenous [IV]) and leucovorin 500 mg/m2 IV for 6 weeks followed by a 2-week rest. A median of 11 (range, one to 76) doses were given. There were three partial responses (three of 42 [7%]; exact 95% confidence interval, 1% to 19%) and no complete responses. Median survival was 6.2 months, with seven patients surviving longer than 12 months. The most common toxicity was diarrhea; there was one treatment-related death. Despite promising results in patients with advanced colorectal cancer, this dose schedule of 5-FU and leucovorin does not appear to be superior to 5-FU alone for the treatment of advanced pancreatic cancer. Alternative investigative approaches are needed.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis

Chemotherapy with leucovorin (100 to 200 mg) and 5-fluorouracil (30 mg/kg) every 2 wk produced four (three complete) objective responses among a group of eight patients with early metastatic pancreatic primary and unknown cancers. Complete remissions were associated with exceptionally long durations of survival, one in a patient failing prior combination chemotherapy. This treatment warrants testing because of its ease, scientific rationale, and the large population of patients with early metastatic pancreatic cancer for whom there is no accepted treatment. Early metastatic disease is defined as small metastatic lesions not immediately life threatening found in a physiologically intact patient. Controlled trials, demonstrating benefit associated with other 5-fluorouracil-containing regimens for patients with nonmetastatic stages of pancreatic cancer, provide a rationale for extending testing of leucovorin and 5-fluorouracil to other early stages of pancreatic cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Clinical Trials as Topic; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Middle Aged; Neoplasms, Unknown Primary; Pancreatic Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Fluorouracil; Humans; Leucovorin; Pancreatic Neoplasms; Stomach Neoplasms

Locally advanced (unresectable) pancreatic cancer (LAPC) is surgically unresectable and often treated with chemotherapy. Most previous studies, that have evaluated conversion surgery after chemotherapy, included heterogeneous patients and chemotherapy regimens, making it challenging to determine the impact of FOLFIRINOX. The present study evaluated the survival benefit of conversion surgery in patients with LAPC who received FOLFIRINOX chemotherapy, and analyzed the prognostic factors.. Patients with LAPC who received FOLFIRINOX as first-line therapy for at least four cycles were included. During chemotherapy, surgical eligibility was determined based on radiologic and metabolic response to the treatment. Clinicopathologic characteristics were compared between the curative-intent surgery and non-resection groups, and the prognostic factors were analyzed.. A total of 279 patients were included. The rates of partial response (PR) and stable disease (SD) were 34.1% and 51.4%, respectively, and 16.8% patients underwent curative-intent surgery. The median survival was significantly longer in the resection group than in the non-resection group (56 vs 21 months, P < .001). In a multivariate analysis, curative-intent surgery (HR 0.260; P < .001) was the most important factor.. Conversion surgery after FOLFIRINOX chemotherapy effectively rescues patients with LAPC. Patients without progression after FOLFIRINOX could be considered as potential candidates for conversion surgery.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Pancreatic Neoplasms

We aimed to assess the role of adjuvant FOLFIRINOX, in comparison with other adjuvant therapy, in patients who received neoadjuvant FOLFIRINOX and surgery for borderline resectable or locally advanced pancreatic cancer (BRPC or LAPC).. Our target population was patients with BRPC or LAPC, who received adjuvant therapy following neoadjuvant FOLFIRINOX and surgery between June 2013 and October 2020. Multivariable Cox proportional-hazard model was used to identify factors associated with overall survival (OS) and recurrence free survival (RFS).. Among 244 patients with BRPC or LAPC who received neoadjuvant FOLFIRINOX, 79 patients underwent subsequent surgery. Among them, 58 who received adjuvant therapy [median age, 63 years; 33 females (56.9%)] were included. Thirty patients received adjuvant modified FOLFIRINOX (mFOLFIRINOX), while 28 received adjuvant therapy other than FOLFIRINOX. In multivariable analysis, mFOLFIRINOX and post-treatment carbohydrate antigen 19-9 (CA 19-9) were significantly associated with OS and RFS. According to mFOLFIRINOX vs. other adjuvant therapy, median OS was not reached at 37.5 months of follow-up vs. 29.7 months (P = .012); and median RFS was 30.5 vs. 11.0 months (P = .028). According to post-treatment CA 19-9 (< 37 vs. ≥ 37 U/mL), median OS was 46.0 vs. 25.5 months (P = .022); and median RFS was 25.9 vs. 7.6 months (P = .012).. Continued adjuvant mFOLFIRINOX and post-treatment CA 19-9 level were associated with survival in patients with BRPC or LAPC who received neoadjuvant FOLFIRINOX and surgery. Continued adjuvant mFOLFIRINOX after neoadjuvant FOLFIRINOX could be considered for patients with good performance.

Topics: Adjuvants, Immunologic; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoadjuvant Therapy; Pancreatic Neoplasms; Retrospective Studies

Treatments for patients suffering from pancreatic cancer with oligo-hepatic metastasis have always been a cause of certain controversy. Herein, we reported 15 pancreatic cancer patients with oligo-hepatic metastasis who accepted sequential therapy of chemotherapy, radiofrequency ablation (RFA), and radical resection of the primary tumor.. A total of 87 pancreatic cancer patients with synchronous oligo-metastatic hepatic lesions who received treatments in the 2nd Affiliated Hospital of Zhejiang University between January 2017 and July 2020 were enrolled. The chemotherapy regimens included modified folfirinox (54/87) and gemcitabine plus nab-paclitaxel (33/87). Test of blood tumor markers and contrast-enhanced computed tomography (CT) or magnetic resonance (MR) scan was performed at diagnosis and after eight weeks of chemotherapy.. Thirty-five patients received just chemotherapy because of poor reaction to the first round of chemotherapy(Overall survival (OS), 6.47±1.80 months); 15 patients reassessed as stable disease (SD)/partial response (PR) continued chemotherapy (OS, 10.35±3.15); nine patients reassessed as progressive disease (PD) after RFA and continued chemotherapy (OS, 10.90±2.60). The primary tumors in 13 patients were unresectable after chemotherapy and RFA (OS, 12.92±2.47), while 15 patients completed the sequential therapy of chemotherapy, radio-frequency ablation, and radical resection (OS, 16.76±6.55).. Sequential chemotherapy and RFA is a good treatment strategy to select the best candidates for surgical treatment among patients with pancreatic cancer with oligo-hepatic metastasis.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

Use of neoadjuvant (NA) chemotherapy is recommended when pancreatic ductal adenocarcinoma (PDAC) is borderline resectable METHOD: A retrospective analysis of consecutive patients with localized PDAC between January 2016 and March 2019 within the Australasian Pancreatic Cancer Registry (PURPLE, Pancreatic cancer: Understanding Routine Practice and Lifting End results) was performed. Clinicopathological characteristics, treatment, and outcome were analyzed. Overall survival (OS) comparison was performed using log-rank model and Kaplan-Meier analysis.. The PURPLE database included 754 cases with localised PDAC, including 148 (20%) cases with borderline resectable pancreatic cancer (BRPC). Of the 148 BRPC patients, 44 (30%) underwent immediate surgery, 80 (54%) received NA chemotherapy, and 24 (16%) were inoperable. The median age of NA therapy patients was 63 years and FOLFIRINOX (53%) was more often used as NA therapy than gemcitabine/nab-paclitaxel (31%). Patients who received FOLFIRINOX were younger than those who received gemcitabine/nab-paclitaxel (60 years vs. 67 years, p = .01). Surgery was performed in 54% (43 of 80) of BRPC patients receiving NA chemotherapy, with 53% (16 of 30) achieving R0 resections. BRPC patients undergoing surgery had a median OS of 30 months, and 38% (9 of 24) achieved R0 resection. NA chemotherapy patients had a median OS of 20 months, improving to 24 months versus 10 months for patients receiving FOLFIRINOX compared to gemcitabine/nab-paclitaxel (Hazard Ratio (HR) .3, p < .0001).. NA chemotherapy use in BRPC is increasing in Australia. One half of patients receiving NA chemotherapy proceed to curative resection, with 53% achieving R0 resections. Patients receiving Infusional 5-flurouracil, Irinotecan and Oxaliplatin (FOLIRINOX) had increased survival than gemcitabine/nab-paclitaxel. Treatment strategies are being explored in the MASTERPLAN and DYNAMIC-Pancreas trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Middle Aged; Neoadjuvant Therapy; Pancreatic Neoplasms; Retrospective Studies

There is no prospective, randomised head-to-head trial comparing first-line FOLFIRINOX and gemcitabine/nab-paclitaxel in advanced pancreatic cancer. We assess real-world effectiveness and quality of life (QoL) of both regimens using a new prognostic score. This analysis includes 1540 patients with advanced pancreatic cancer from the prospective, clinical cohort study Tumour Registry Pancreatic Cancer separated into learning (n = 1027) and validation sample (n = 513). The Pancreatic Cancer Score (PCS) was developed using multivariate Cox regression. We compared overall survival (OS) and time to deterioration (TTD) for longitudinal QoL between first-line FOLFIRINOX (n = 407) and gemcitabine/nab-paclitaxel (n = 655) according to patients' prognostic risk, after inverse probability of treatment weighting (IPTW) by propensity score analysis. The PCS includes nine independent prognostic factors for survival: female sex, BMI ≥24/unknown, ECOG performance status ≥1, Charlson comorbidity index ≥1, tumour staging IV/unknown at primary diagnosis, liver metastases, bilirubin >1.5× upper limit of normal (ULN), leukocytes >ULN and neutrophil-to-lymphocyte ratio ≥4. Median OS of the validation sample was 11.4 (95% confidence interval [CI]: 10.4-14.4), 8.5 (95% CI: 6.8-9.6) and 5.9 months (95% CI: 4.0-7.4) for favourable- (0-3 risk factors), intermediate- (4-5 factors) and poor-risk group (6-9 factors), respectively. After IPTW, only poor-risk patients had significantly longer median OS and TTD of overall QoL with FOLFIRINOX (OS: 6.9 months, 95% CI: 3.9-13.3; TTD: 10.6 months, 95% CI: 2.0-14.1) vs gemcitabine/nab-paclitaxel (OS: 4.0 months, 95% CI: 2.8-4.8; TTD: 4.1 months, 95% CI: 2.4-4.5). Our novel PCS may facilitate treatment decisions in clinical routine of advanced pancreatic cancer, since only poor-risk, but not favourable-risk patients, seem to benefit from intensified treatment with FOLFIRINOX.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Paclitaxel; Pancreatic Neoplasms; Prognosis; Quality of Life

Effective chemotherapy (CTx) protocols as induction treatment provide increasing opportunities for surgical resection of locally advanced pancreatic cancer (LAPC). Although improved survival after resection of LAPC with CTx has been reported for selected patients, reliable recommendations on the indication for conversion surgery after induction treatment are currently lacking. We investigated the factors predictive of prognosis in resected LAPC after FOLFIRINOX.. Consecutive patients with LAPC undergoing curative resection after FOLFIRINOX between 2011 and 2018 were identified from a prospectively maintained database. Relevant clinical parameters and CT findings were examined. A scoring system was developed based on the ratio of hazard ratios for overall survival of all significant predictors.. A total of 62 patients with LAPC who underwent oncologic resection after FOLFIRINOX were analyzed. Tumor shrinkage, tumor density, and postchemotherapy CA19-9 serum levels were independently associated with overall survival (multivariate analysis: HR = 0.31, 0.17, and 0.18, respectively). One, two, and two points were allocated to these three factors in the proposed scoring system, respectively. The median overall survival of patients with a score from 0 to 2 was significantly shorter than that of patients with a score from 3 to 5 (22.1 months vs. 53.2 months, P < 0.001).. Tumor density is a novel predictive marker for the prognosis of patients with resected LAPC after FOLFIRINOX. A simple scoring model incorporating tumor density, the tumor shrinkage rate, and CA 19-9 levels identifies patients with a low score, who may be candidates for additional treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Induction Chemotherapy; Leucovorin; Neoadjuvant Therapy; Pancreatic Neoplasms; Prognosis

Original FOLFIRINOX (oFFX) is more toxic than other regimens for patients with metastatic pancreatic cancer (mPC); therefore, a modified FFX (mFFX) regimen with a reduced dosage has been used in Japanese clinical practice. However, very few studies have compared these two regimens.. This study was conducted as part of a multicenter retrospective study of 318 patients with mPC across 14 centers in Japan (NAPOLEON study). To control for potential bias and confounders, we conducted a propensity score-adjusted analysis of patient characteristics and clinical outcomes.. oFFX and mFFX were administered to 48 and 54 patients. More patients with younger age and poorer performance status were included in the oFFX group. The overall survival (OS; median, 11.6 vs. 11.3 months; hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.60-1.40; p = 0.67), progression-free survival (PFS) (median, 6.3 vs. 5.7 months; HR, 0.85; 95% CI, 0.56-1.28; p = 0.44), and overall response rate (29 vs. 26%, p = 0.71) were not significantly different for the oFFX and mFFX groups. Thrombopenia and liver dysfunction were significantly more frequent with oFFX than with mFFX. The median received dose intensity of CPT-11 was higher with oFFX than with mFFX (299 vs. 270 mg/m2/week, p < 0.01). The propensity score-adjusted analysis revealed no statistically significant differences in OS and PFS between the two groups.. In our data, there was no significant difference in efficacy between mFFX and oFFX, and mFFX has fewer adverse events.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Fluorouracil; Humans; Irinotecan; Leucovorin; Pancreatic Neoplasms; Retrospective Studies

Fluorouracil (5-FU) pharmacokinetics are variable, leading to a risk of toxicity in some patients and underdosing in others. Therapeutic drug monitoring of 5-FU was shown to reduce toxicity and increase efficacy. This study assessed the clinical utility of starting treatment with 70-80% of BSA calculated dose and titrating according to 5-FU blood levels and toxicity.. A retrospective analysis of a prospectively collected database of 126 patients treated with regimens containing 5-FU bolus and continuous infusion for 46 h for whom the 5-FU blood level was collected at least once. Response,and date of progression, and death were collected for patients with colon and pancreatic cancer.. In multivariate analysis, 5-FU blood levels were correlated with 5-FU dose and with age, albeit a small effect size (coefficient = 0.007). Of patients with colon cancer treated with an initial lower 5-FU dose, 18% had a therapeutic 5-FU blood level. The median survival was similar in patients with metastatic colon cancer treated with lower doses and those treated with a full dose. Of patients with pancreatic cancer treated with lower doses, 40% had therapeutic blood levels. The median survival was 13 months in patients with metastatic pancreatic cancer treated with lower 5-FU doses.. Starting treatment with low 5-FU dose was associated with patient survival comparable to other published data, and a sizeable percentage of patients had therapeutic blood levels. This approach can be considered, especially in elderly and frail patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Pancreatic Neoplasms; Retrospective Studies; Treatment Outcome

Irinotecan is a useful anticancer drug for colorectal cancer treatment. UGT1A1*28 and *6 gene polymorphisms are known risk factors for irinotecan-associated toxicity. However, severe adverse effects due to irinotecan have been observed even in patients who do not harbor UGT1A1*28 or *6. We investigated gene polymorphisms in the whole exome to identify useful biomarkers for irinotecan toxicity other than UGT1A.. A total of 178 patients with metastatic colorectal cancer (mCRC) and 87 patients with pancreatic cancer were treated with FOLFIRI, FOLFOX, FOLFOXIRI, modified FOLFIRINOX, or gemcitabine plus nab-paclitaxel. Genome-wide screening was performed using whole-exome sequencing (WES), and validation analysis was performed using qPCR with a hydrolysis probe.. Using WES after a doublet chemotherapy regimen comprising irinotecan and 5-fluorouracil (n = 15), seven single nucleotide polymorphisms (SNPs) were identified as candidate biomarkers for irinotecan-associated toxicity of neutropenia. Among the seven SNPs, an SNP in R3H domain and coiled-coil containing 1 (R3HCC1; c.919G > A, rs2272761) showed a significant association with neutropenia (>grade 3) after doublet chemotherapy. Patients receiving irinotecan including triplet chemotherapy, FOLFOXIRI for mCRC (n = 23) or modified FOLFIRINOX for pancreatic cancer (n = 40), also showed significant linear trends between R3HCC1 polymorphism and neutropenia (p = 0.017 and 0.046, respectively). No significant association was observed in patients treated with irinotecan-free regimens, FOLFOX for mCRC (n = 66), and gemcitabine plus nab-paclitaxel for pancreatic cancer (n = 47).. Thus, an SNP in the R3HCC1 gene may be a useful biomarker for the toxicity of irinotecan-containing chemotherapy for mCRC and pancreatic cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Neutropenia; Pancreatic Neoplasms; Polymorphism, Single Nucleotide; Rectal Neoplasms

Sinonasal intestinal-type adenocarcinoma (ITAC) is a rare tumor, typically found in the ethmoid or upper nasal cavity. There is no standard systemic treatment for metastatic/locally advanced disease ineligible for upfront surgery or radiotherapy.. Patients treated between 2015 and 2021 in our institution with a fluoropyrimidine plus oxaliplatin and/or irinotecan for advanced ITAC were retrospectively assessed for overall survival (OS), progression-free survival (PFS) and tumoral responses.. Six patients without meningeal involvement received chemotherapy (three FOLFOX, two FOLFIRI, one FOLFIRINOX). All achieved a response, including those with brain extension. Median PFS with FOLFOX and FOLFIRI was similar (6.0 months, 95%CI 5.8-NR; 5.8 months, 95%CI 5.8-NR respectively). Three patients had meningeal involvement with meningitis symptoms and received first-line therapy. All had rapid disease progression (median PFS 1.2 months, 95%CI 1.0-NR) DISCUSSION: FOLFOX, FOLFIRI or FOLFIRINOX appear to have anti-tumor efficacy for metastatic or locally advanced unresectable ITAC, except in cases of carcinomatous meningitis. These regimens require further evaluation.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

There is no agreed upon standard of care for borderline-resectable pancreatic cancer (BRPC) or locally-advanced pancreatic cancer (LAPC) patients regarding the benefit of chemotherapy or radiation alone or in combination.. We completed a retrospective cohort analysis of BRPC and LAPC patients at a cancer center with expertise in multi-disciplinary pancreatic ductal adenocarcinoma (PDAC) treatment over a 5-year period from 03/01/2014 to 03/01/2019 (cut-off date). The total evaluable newly diagnosed, treatment naïve, BRPC, and LAPC patients with adequate organ function and ability to obtain treatment after multidisciplinary review was 52 patients. After analysis, patients were evaluated for rates of resection, extent of resection (R0 or R1), median progression-free survival (mPFS), and median overall survival (mOS).. Patients were treated with chemotherapy alone (gemcitabine and nab-paclitaxel = 77% (20/26); FOLFIRINOX = 19% (5/26); single agent gemcitabine 3.8% (1/26)), or chemotherapy followed by chemoradiation (gemcitabine +5 Gy × 5 weeks), or chemoradiation alone prior to re-staging and potential resection. Of the 29% (15/52) of patients who went on to surgical resection, 73% (11/15) achieved R0 resection. An R0 resection was achieved in 35% (9/26) of patients treated with chemotherapy alone, 7.6% (1/13) in a patient treated with chemotherapy followed by radiation, and 7.6% (1/13) with concurrent chemoradiotherapy alone. Chemotherapy alone achieved a mPFS of 16.4 months (p  < 0.0025) and mOS of 26.2 months (p  < 0.0001), chemotherapy followed by chemoradiation was 13.0 months and 14.9 months respectively, while concurrent chemoradiotherapy was 6.9 months and 7.3 months.. BRPC and LAPC patients capable of surgery after only receiving neoadjuvant treatment with chemotherapy had higher rates of R0 resection with prolonged median PFS and OS compared with any patient needing combination chemotherapy with radiotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Neoadjuvant Therapy; Pancreatic Neoplasms; Retrospective Studies

Preoperative FOLFIRINOX chemotherapy is increasingly administered to patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) to improve overall survival (OS). Multicenter studies reporting on the impact from the number of preoperative cycles and the use of adjuvant chemotherapy in relation to outcomes in this setting are lacking. This study aimed to assess the outcome of pancreatectomy after preoperative FOLFIRINOX, including predictors of OS.. This international multicenter retrospective cohort study included patients from 31 centers in 19 European countries and the United States undergoing pancreatectomy after preoperative FOLFIRINOX chemotherapy (2012-2016). The primary end point was OS from diagnosis. Survival was assessed using Kaplan-Meier analysis and Cox regression.. The study included 423 patients who underwent pancreatectomy after a median of six (IQR 5-8) preoperative cycles of FOLFIRINOX. Postoperative major morbidity occurred for 88 (20.8%) patients and 90-day mortality for 12 (2.8%) patients. An R0 resection was achieved for 243 (57.4%) patients, and 259 (61.2%) patients received adjuvant chemotherapy. The median OS was 38 months (95% confidence interval [CI] 34-42 months) for BRPC and 33 months (95% CI 27-45 months) for LAPC. Overall survival was significantly associated with R0 resection (hazard ratio [HR] 1.63; 95% CI 1.20-2.20) and tumor differentiation (HR 1.43; 95% CI 1.08-1.91). Neither the number of preoperative chemotherapy cycles nor the use adjuvant chemotherapy was associated with OS.. This international multicenter study found that pancreatectomy after FOLFIRINOX chemotherapy is associated with favorable outcomes for patients with BRPC and those with LAPC. Future studies should confirm that the number of neoadjuvant cycles and the use adjuvant chemotherapy have no relation to OS after resection.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Neoadjuvant Therapy; Pancreatic Neoplasms; Retrospective Studies

Pancreatic adenosquamous carcinoma (PASC) account for <5% of pancreatic malignancies. The efficacy of modern chemotherapy regimens in patients with advanced PASC is unknown. Patients with advanced PASC from 2008 to 2021 were consecutively included in this retrospective multicenter study. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method. Ninety-four PASC from 16 French centers were included (median age, 67.3 years; males, 56.4%; metastatic disease, 85.1%). The first-line treatment was chemotherapy for 79 patients (84.0%) (37 FOLFIRINOX (FX), 7 Gemcitabine-nab paclitaxel (GN) and 35 for all other regimen) or best supportive care (BSC) alone for 15 patients (16.0%). No significant difference was observed between FX and GN in terms of PFS (P = .67) or OS (P = .5). Modern regimens pooled together (FX and GN) as compared to all others chemotherapy regimens showed an improvement of overall response rate (39.5% and 9.7%, P = .002), PFS (median, 7.8 vs 4.7 months, P = .02) and OS (median, 12.7 vs 9.2 months, P = .35). This large study evaluating first-line treatment regimens in advanced PASC suggests that modern regimens as FX or GN may be preferable to all other chemotherapy regimens. These results deserve confirmation in prospective studies.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Adenosquamous; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Paclitaxel; Pancreatic Neoplasms; Prospective Studies; Retrospective Studies

To emulate a hypothetical target trial assessing the effect of initiating 5-fluorouracil, folinic acid, irinotecan, and oxaliplatin (FOLFIRINOX) versus gemcitabine plus nab-paclitaxel (GN) within 8 weeks of diagnosis on overall survival.. An observational cohort study was conducted using population-level data from Alberta, Canada. Individuals diagnosed with advanced pancreatic cancer between April 2015 and December 2019 were identified through the provincial cancer registry and followed until March 2021. Records were linked to other administrative databases containing information on relevant variables. Individuals were excluded if they did not have adequate hemoglobin, platelet, white blood cell, and serum creatinine measures or if they received prior therapy. The observational analog of the per-protocol effect was estimated using inverse probability weighted Kaplan-Meier curves with bootstrapped 95% confidence intervals.. Four hundred seven individuals were eligible. The weighted median overall survival was 8.3 months (95% CI, 5.7-11.9) for FOLFIRINOX and 5.1 months (95% CI: 4.3 to 5.8) for GN. The adjusted difference in median overall survival was 3.2 months (95% CI, 1.1-7.4) and the mortality hazard ratio was 0.78 (95% CI, 0.61-0.97).. Our estimates favored the initiation of FOLFIRINOX over GN with respect to overall survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms

5-fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) is promising in treating patients with pancreatic ductal adenocarcinoma. However, many patients and physicians are reluctant to start FOLFIRINOX due to its high toxicity and limited clinical response rates. In this study, we investigated the effect of a single FOLFIRINOX cycle, in combination with a granulocyte colony-stimulating factor, on the blood immune transcriptome of patients with pancreatic ductal adenocarcinoma. We aimed to identify an early circulating biomarker to predict the lack of FOLFIRINOX response.. Blood samples of 68 patients from all disease stages, who received at least four FOLFIRINOX cycles, were collected at baseline and after the first cycle. The response to treatment was radiologically evaluated following the Response Evaluation Criteria in Solid Tumours criteria 1.1. Targeted immune-gene expression profiling (GEP) was performed using NanoString technologies. To predict the lack of FOLFIRINOX response, we developed a FOLFIRINOX delta GEP (FFX-ΔGEP) score.. A single FOLFIRINOX cycle significantly altered 395 genes, correlating to 30 significant alterations in relative immune cell abundances and pathway activities. The eight-gene (BID, FOXP3, KIR3DL1, MAF, PDGFRB, RRAD, SIGLEC1 and TGFB2) FFX-ΔGEP score predicted the lack of FOLFIRINOX response with a leave-one-out cross-validated area under the curve (95% confidence interval) of 0.87 (0.60-0.98), thereby outperforming the predictiveness of absolute and proportional Δcarbohydrate antigen19-9 values.. A single FOLFIRINOX cycle, combined with granulocyte colony-stimulating factor, alters the peripheral immune transcriptome indisputably. Our novel FFX-ΔGEP is, to our knowledge, the first multigene early circulating biomarker that predicts the lack of FOLFIRINOX response after one cycle. Validation in a larger independent patient cohort is crucial before clinical implementation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Carcinoma, Pancreatic Ductal; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms

We aimed to evaluate the long-term outcomes of the association of neoadjuvant chemotherapy with pancreatectomy with vascular resection in patients with locally advanced pancreatic cancer.. Clinical data from patients who underwent pancreatic resection after neoadjuvant FOLFIRINOX were retrospectively reviewed. Cox analyses were used to identify factors prognostic of overall survival (OS).. FOLFIRINOX protocol was administered pre-operatively with a median number of nine cycles (range 2-18) in 98 patients. Types of resections included pancreaticoduodenectomy (n = 53), total pancreatectomy (n = 17), and distal spleno-pancreatectomy (n = 28). Venous resection and arterial resections were performed in 85 (86.7%) and 64 patients (65.3%), respectively. The overall 90-day mortality and morbidity rates were 6.1% (n = 6) and 47% (n = 47), respectively. The median OS was 31.08 months after surgery. OS rates at one, three, five, and 10 years were 82%, 47%, 28%, and 21%, respectively. According to the type of vascular resection, median OS and 5-year survival rates were exclusive venous resection (31.08 months; 23%) and arterial resections (24.7 months; 27%). Multivariate Cox analysis found lymph node involvement, venous invasion, and total pancreatectomy as independent prognostic factors for OS. According to the presence of 0 or 1-3 risk factors, 5-year survival (85% vs 16%) and median overall survival rates (not reached versus 24.7 months, respectively) were statistically significantly different (p < 0.0001).. A multimodal treatment, including neoadjuvant FOLFIRINOX combined with pancreatectomy with venous and arterial resection, achieves long term survival rates in patients with locally advanced disease. Surgery, in experienced centers, should be integrated into the treatment of patients with locally advanced pancreatic adenocarcinomas.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Neoadjuvant Therapy; Pancreatic Neoplasms; Retrospective Studies; Survival Rate

Nanoliposomal irinotecan plus fluorouracil/leucovorin (5-FU/LV) is a standard second-line therapy for patients with pancreatic cancer. Identification of biomarkers is important to determine appropriate treatment strategies. We investigated the clinical practice outcomes and biomarkers associated with the nanoliposomal irinotecan plus 5-FU/LV regimen.. We retrospectively reviewed the data of patients treated with nanoliposomal irinotecan plus 5-FU/LV as a second or subsequent treatment after gemcitabine-based therapy between June 2020 and March 2021 at Shizuoka Cancer Center.. We analyzed 55 consecutive patients who met the selection criteria. At a median of 9.4 months, median progression-free survival (PFS) and median overall survival (OS) were 2.3 and 6.6 months, respectively. Multivariate analysis showed that Glasgow prognostic score (GPS) was significantly associated with PFS (hazard ratio [HR] 2.16; 95% confidence interval [CI] 1.09-4.30; P = 0.028) and OS (0 vs. 1 or 2: HR 2.46; 95% CI 1.15-5.25; P = 0.029). The OS was significantly longer in patients with CA19-9 response than in those without CA19-9 response (12.6 vs. 5.6 months; HR 0.24; 95% CI 0.08-0.75; P = 0.014).. Nanoliposomal irinotecan was efficacious and tolerable in clinical practice. GPS and CA19-9 response were good candidates as predictive biomarkers, whereas GPS was a good candidate prognostic biomarker for the nanoliposomal irinotecan plus 5-FU/LV regimen.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; CA-19-9 Antigen; Camptothecin; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Pancreatic Neoplasms; Retrospective Studies; Treatment Outcome

Nab-paclitaxel plus gemcitabine (AG) and modified FOLFIRINOX (FFX) are two systemic therapies that have been widely used as standard first-line chemotherapy regimens in metastatic pancreatic cancer. However, since there is no clinical trial to directly compare the efficacy and safety of the two regimens, it is not clear which regimen is more effective. In this study, we aim to examine and compare the efficacy and safety of AG and FFX as first-line chemotherapy regimens in Chinese patients with metastatic pancreatic cancer in a real-world setting.. We retrospectively evaluated the outcomes of 44 patients who were diagnosed with metastatic pancreatic cancer and were treated with either AG (n = 24) or FFX (n = 20) as first-line chemotherapy between March 2017 and February 2022 at Zhongnan Hospital of Wuhan University. Prognostic nutrition index (PNI) was calculated based on the serum albumin level and peripheral lymphocyte count. According to the optimal cutoff value of PNI, patients were divided into low PNI group (PNI < 43.70) and high PNI group (PNI ≥ 43.70).. Of 44 patients in this study, 24 were treated with AG, and 20 were treated with FFX as first-line chemotherapy. No significant differences in baseline characteristics were found between the two groups. The objective response rate (ORR) was 16.7% in the AG group and 20.0% in the FFX group. The disease control rate (DCR) was 70.8% in the AG group and 60.0% in the FFX group. There was no significant difference in PFS or OS between the AG group and the FFX group. The median progression-free survival (PFS) was 4.67 months (95% confidence interval [CI], 2.91-6.42) in the AG group and 3.33 months (95% CI, 1.87-4.79, p = 0.106) in the FFX group. The median overall survival (OS) was 9.00 months (95% CI, 7.86-12.19) in the AG group and 10.00 months (95% CI, 7.70-12.27, p = 0.608) in the FFX group. The second-line treatment rate was 62.5% in the AG group and 55.0% in the FFX group. Immune checkpoint inhibitors (ICIs) based regimens are common second-line treatment options whether in AG or FFX group. Significantly more grade 3-4 peripheral neuropathy occurred in the AG than FFX groups (4 (20.8%) vs 0 (0.0%), p = 0.030*). The patients in the PNI (Prognostic nutrition index) ≥ 43.7 group had a significant longer median OS (PNI ≥ 43.7 vs PNI < 43.7: 10.33 vs 8.00 months, p = 0.019).. AG and FFX showed comparable efficacy outcomes in patients with metastatic pancreatic cancer. Pancreatic cancer patients receiving first-line chemotherapy with good nutritional status are likely to have a better prognosis.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Fluorouracil; Humans; Leucovorin; Pancreatic Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Fluorouracil; Humans; Leucovorin; Pancreatic Neoplasms

FOLFIRINOX is increasingly used in the management of pancreatic ductal adenocarcinoma (PDAC). However, neoadjuvant therapy is associated with toxicity, possible disease progression, and biopsy-related and biliary complications that may preclude operative exploration. Data on the true attrition rate outside of clinical trials or resected surgical series are lacking.. Patients with nonmetastatic PDAC who initiated FOLFIRINOX from 2015 to 2020 were identified from our institution's pharmacy records. Multivariable regression and Cox proportional hazard models were used for adjusted analyses of categorical and survival outcomes, respectively.. Of 254 patients who initiated first-line neoadjuvant FOLFIRINOX, 199 (78.3%) underwent exploration, and 54 (21.3%) did not complete their chemotherapy cycles due to poor tolerability (46.3%), poor response (31.5%), or disease progression (14.8%), among other causes (7.4%). A total of 109 (42.9%) patients experienced grade 3/4 FOLFIRINOX-related toxicity, of whom 73 (28.7%) and 100 (39.4%) required an emergency department visit or inpatient admission, respectively. Finally, not undergoing surgical exploration was associated with impaired overall survival (hazard ratio 7.0; 95% CI 3.8 to 12.8; p < 0.001). Independent predictors of not undergoing exploration were remote history of chemotherapy receipt (odds ratio [OR] 0.06; p = 0.02), inability to complete FOLFIRINOX cycles (OR 0.2, p = 0.003), increase in ECOG score (OR 0.2, p < 0.001), and being single or divorced (OR 0.3, p = 0.018).. Among 254 patients with nonmetastatic PDAC initiated on FOLFIRINOX, of whom 52% were locally advanced, a total of 199 (78.3%) were explored, 142 (71.4%) underwent successful resection, and 129 (90.8%) were resected with negative margins. Despite 109 (42.9)% of patients experiencing significant toxicity, most patients could be managed through treatment-related complications to complete planned neoadjuvant chemotherapy and undergo planned surgical exploration.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Disease Progression; Fluorouracil; Humans; Leucovorin; Neoadjuvant Therapy; Pancreatic Neoplasms; Retrospective Studies

Response to second-line (2L) neoadjuvant therapy for operable pancreatic cancer (PC) is understudied. This study examined carbohydrate antigen 19-9 (CA19-9) response to first-line (1L) and 2L chemotherapy.. The study identified patients with operable PC and elevated CA19-9 (≥ 35 U/mL with total bilirubin < 2 mg/dL) who received 1L FOLFIRINOX (FFX). The patients were restaged after 2 months and based on response, received additional FFX or gemcitabine/nab-paclitaxel (GnP) as part of total neoadjuvant therapy. Response was defined as a decrease in tumor size on computed tomography (CT) imaging or a decline in CA19-9 of 50% or more and preserved performance status.. For operable PC with an elevated CA19-9, 108 patients received 1L FFX. After 2 months of chemotherapy, the decision was made to continue FFX (FFX ≥ FFX) for 76 (70%) of the 108 patients and switch to GnP (FFX ≥ GnP)) for 32 (30%) of the patients. Of the 32 FFX ≥ GnP patients, 27 had no evidence of radiographic or biochemical (CA19-9) response to 1L FFX. Of these 27 patients, 26 (96%) demonstrated a response to 2L GnP. After 4 months of chemotherapy, 62 (82%) of the 76 FFX ≥ FFX patients had a CA19-9 response compared with 31 (97%) of the 32 FFX ≥ GnP patients (p = 0.04).. Lack of biochemical response to 2 months of 1L FFX may identify a subgroup of patients with a very high rate of response to 2L GnP, emphasizing the importance of assessing treatment response at 2-month intervals.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Neoadjuvant Therapy; Paclitaxel; Pancreatic Neoplasms

First-line FOLFIRINOX (FOLinic acid, Fluorouracil, IRINotecan, and OXaliplatin) and gemcitabine plus nab-paclitaxel (GnP) have been publicly funded for patients with unresectable locally advanced pancreatic cancer (uLAPC) in Ontario, Canada. We examined the overall survival and surgical resection rate after first-line FOLFIRINOX or GnP and determined the association between resection and overall survival in patients with uLAPC.. We conducted a retrospective population-based study including patients with uLAPC who received first-line treatment FOLFIRINOX or GnP from April 2015 to March 2019. The cohort was linked to administrative databases to ascertain demographic and clinical characteristics. Propensity score methods were used to balance differences between FOLFIRINOX and GnP. The Kaplan-Meier method was used to calculate overall survival. Cox regression was used to determine the association between receipt of treatment and overall survival, adjusting for time-dependent surgical resections.. We identified 723 patients with uLAPC (mean age = 65.8, 43.5% female) who received FOLFIRINOX (55.2%) or GnP (44.8%). The median overall survival and 1-year overall survival probability were higher for FOLFIRINOX (13.7 months, 54.6%) than for GnP (8.7 months, 34.0%). Post-chemotherapy surgical resection occurred in 89 (12.3%) patients (FOLFIRINOX: 74 [18.5%] versus GnP: 15 [4.6%]), with no difference in survival since surgery between FOLFIRINOX and GnP (P = 0.29). After adjusting time-dependent post-treatment surgical resection, FOLFIRINOX (inverse probability treatment weighting hazard ratio 0.72, 95% confidence interval 0.61, 0.84) was independently associated with improved overall survival.. In this real-world population-based study of patients with uLAPC, FOLFIRINOX was associated with improved survival and higher resection rates. FOLFIRINOX was associated with improved survival in patients with uLAPC after accounting for the effect of post-chemotherapy surgical resection, suggesting the benefit of FOLFIRINOX was not solely due to improving resectability.

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Ontario; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

Subgroup analyses of the NAPOLI-1 study identified that among patients who were irinotecan naïve prior to entering the clinical trial, a survival benefit was observed between the study arm and control arm. This treatment benefit was not observed among those previously exposed to irinotecan. This study sought to understand the impact of prior exposure to irinotecan on clinical outcomes among patients treated with liposomal irinotecan in the real-world setting.. This retrospective observational study utilized a nationwide electronic health record (EHR)-derived deidentified database. Data for adult patients with mPDAC treated with liposomal irinotecan-based regimens between January 2016 and October 2020 were analyzed. Patient characteristics, overall survival (OS), and progression-free survival (PFS) were assessed. Cox proportional hazard methods were used to calculate hazard ratios (HRs). HRs were adjusted for demographics and relevant clinical covariates.. Six hundred and seventy-five patients with mPDAC treated with a liposomal irinotecan-based regimen were included. The unadjusted OS HR was 1.3 (95% CI: 1.1-1.6, p < 0.001) and unadjusted PFS was HR 1.4 (95% CI: 1.2-1.7, p < 0.001). After adjustment for baseline characteristics, the adjusted OS HR was 1.0 (95% CI: 0.8-1.3, p = 0.8836) and the adjusted PFS HR was 1.1 (95% CI: 0.8-1.4, p = 0.5626).. Prior irinotecan was not found to be a significant predictor of patient outcomes in those later treated with liposomal irinotecan. Thus, the results may inform the rationale for utilizing liposomal irinotecan combination therapy following prior irinotecan exposure in mPDAC, in particular where the prior irinotecan exposure was more distant in time.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Pancreatic Neoplasms

Recent advances in chemotherapy have made significant progress in conversion surgery (CS) for unresectable pancreatic cancer (uPC). However, the success rate and efficacy of CS have not been fully demonstrated in patients with uPC treated with FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (GnP).. We retrospectively reviewed the records of 318 patients with uPC who received FFX or GnP as first-line chemotherapy. The efficacy in the CS group, defined as undergoing complete resection after chemotherapy, was analyzed, and compared with the non-CS group; then, contributing factors to achieving CS were extracted. We also analyzed differences in the efficacy of CS between locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC).. Overall, CS was achieved in 4.3% of cases, eight patients (13.3%) with LAPC and five (2.1%) with MPC. Contributing factors to CS were LAPC, no liver metastasis, CA19-9 ≤37, and chemotherapy response. After adjusting for these, overall survival was significantly better in the CS group than in the non-CS group [median of 32.9 vs. 11.3 months; adjusted hazard ratio (HR)=0.32; 95% confidence interval (CI)=0.14-0.70; p<0.01]. Median relapse-free survival duration after CS was 19.1 and 18.1 months in the LAPC-CS and MPC-CS group, respectively (p=0.84). The median post-conversion survival was 27.6 months in the entire CS group, 43.8 months in the LAPC-CS group and 21.3 months in the MPC-CS group.. CS was achieved in 13.3% of LAPC and 2.1% of MPC cases. If possible, CS can markedly improve prognosis, even in MPC.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Neoplasm Recurrence, Local; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

A high systemic immune-inflammation index (SIII) at diagnosis of various cancers, including pancreatic cancer, is associated with poor prognosis. The impact of FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) chemotherapy or stereotactic body radiotherapy on this index is unknown. In addition, the prognostic value of changes in the SIII during treatment is unclear. In this retrospective analysis, we aimed to find answers regarding patients with advanced pancreatic cancer.. Patients with advanced pancreatic cancer treated with FOLFIRINOX chemotherapy alone or with FOLFIRINOX chemotherapy followed by stereotactic body radiotherapy between 2015 and 2021 in 2 tertiary referral centers were included. Baseline characteristics, laboratory values at 3 time points during treatment, and survival outcomes were collected. The patient-specific evolutions of SIII and their association with mortality were assessed with joint models for longitudinal and time-to-event data.. Data of 141 patients were analyzed. At a median follow-up time of 23.0 months (95% CI: 14.6-31.3), 97 (69%) patients had died. Median overall survival was 13.2 months (95% CI: 11.0-15.5). During treatment with FOLFIRINOX, the log (SIII) was reduced by -0.588 (95% CI: -0.0978, -0.197; P = 0.003). One unit increase in log (SIII) increased the hazard ratio of dying by 1.604 (95% CI: 1.068-2.409; P = 0.023).. In addition to carbohydrate antigen 19-9, the SIII is a reliable biomarker in patients with advanced pancreatic cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Fluorouracil; Humans; Inflammation; Leucovorin; Pancreatic Neoplasms; Retrospective Studies

/Objectives: Effects of chemotherapy on gut microbiota have been reported in various carcinomas. The current study aimed to evaluate the changes in the gut microbiota before and after neoadjuvant chemotherapy (NAC) in patients with resectable (R) and borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) and understand their clinical implications.. Twenty patients diagnosed with R/BR-PDAC were included in this study. Stool samples were collected at two points, before and after NAC, for microbiota analysis using 16S ribosomal RNA (16S rRNA) gene sequences.. Of the 20 patients, 18 (90%) were treated with gemcitabine plus S-1 as NAC, and the remaining patients received gemcitabine plus nab-paclitaxel and a fluorouracil, leucovorin, irinotecan, and oxaliplatin combination. No significant differences were observed in the α- and β-diversity before and after NAC. Bacterial diversity was not associated with Evans classification (histological grade of tumor destruction by NAC) or postoperative complications. The relative abundance of Actinobacteria phylum after NAC was significantly lower than that before NAC (P = 0.02). At the genus level, the relative abundance of Bifidobacterium before NAC in patients with Evans grade 2 disease was significantly higher than that in patients with Evans grade 1 disease (P = 0.03). Patients with Evans grade 2 lost significantly more Bifidobacterium than patients with Evans grade 1 (P = 0.01).. The diversity of gut microbiota was neither decreased by NAC for R/BR-PDAC nor associated with postoperative complications. Lower incidence of Bifidobacterium genus before NAC may be associated with a lower pathological response to NAC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Fluorouracil; Gastrointestinal Microbiome; Humans; Leucovorin; Neoadjuvant Therapy; Pancreatic Neoplasms; RNA, Ribosomal, 16S

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Pancreatic Neoplasms

Despite a potentially curative treatment, the prognosis after upfront surgery and adjuvant chemotherapy for patients with resectable pancreatic ductal adenocarcinoma (PDAC) is poor. Modified FOLFIRINOX (mFOLFIRINOX) is a cornerstone in the systemic treatment of PDAC, including the neoadjuvant setting. Pharmacokinetic-guided (PKG) dosing has demonstrated beneficial effects in other tumors, but scarce data is available in pancreatic cancer.. Forty-six patients with resected PDAC after mFOLFIRINOX neoadjuvant approach and included in an institutional protocol for anticancer drug monitoring were retrospectively analyzed. 5-Fluorouracil (5-FU) dosage was adjusted throughout neoadjuvant treatment according to pharmacokinetic parameters and Irinotecan (CPT-11) pharmacokinetic variables were retrospectively estimated.. By exploratory univariate analyses, a significantly longer progression-free survival was observed for patients with either 5-FU area under the curve (AUC) above 28 mcg·h/mL or CPT-11 AUC values below 10 mcg·h/mL. In the multivariate analyses adjusted by age, gender, performance status and resectability after stratification according to both pharmacokinetic parameters, the risk of progression was significantly reduced in patients with 5-FU AUC ≥28 mcg·h/mL [HR = 0.251, 95% CI 0.096-0.656; p = 0.005] and CPT-11 AUC <10 mcg·h/mL [HR = 0.189, 95% CI 0.073-0.486, p = 0.001].. Pharmacokinetically-guided dose adjustment of standard chemotherapy treatments might improve survival outcomes in patients with pancreatic ductal adenocarcinoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Drug Monitoring; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

This study aimed to clarify the treatment patterns of pancreatic cancer patients receiving systemic chemotherapy in Japan and to estimate the direct medical costs in actual practice.. This retrospective cohort study used electronic health record data between April 2008 and December 2018 in Japan. Participants had a confirmed pancreatic cancer diagnosis and received at least one systemic chemotherapy, including FOLFIRINOX, gemcitabine plus nab-paclitaxel, gemcitabine, and S-1. The outcomes were treatment patterns and monthly medical costs and the distribution of monthly medical costs across healthcare resource categories.. Of the 4514 selected patients, 40.7%, 7.1%, 24.4%, and 21.3% used gemcitabine plus nab-paclitaxel, FOLFIRINOX, gemcitabine, and S-1 as first-line chemotherapy, respectively. The median monthly medical costs were the highest in the first month, with gemcitabine plus nab-paclitaxel ranking first (6813 USD), followed by FOLFIRINOX, gemcitabine, and S-1. The health resource categories with the highest shares of monthly medical costs during the first-line treatment period with gemcitabine plus nab-paclitaxel and FOLFIRINOX were hospitalization costs (FOLFIRINOX: 41%-37%; gemcitabine plus nab-paclitaxel: 40%-34%) and medicine costs (FOLFIRINOX: 51%-42%; gemcitabine plus nab-paclitaxel: 49%-38%).. This study sheds light on the current treatment patterns and direct medical costs of systemic chemotherapy for pancreatic cancer in Japan.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Japan; Leucovorin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

Patients with metastatic pancreatic cancer refractory to first-line chemotherapy (CTx) have few treatment options. It is unclear what kind of patients could be brought about survival benefit by 2nd-line CTx after refractory to gemcitabine + nab-PTX (GnP) or FOLFIRINOX.. This analysis was conducted as part of a multicenter retrospective study of GnP or FOLFIRINOX in patients with metastatic pancreatic cancer. Excluding censored cases, 156 and 77 patients, respectively, received second-line chemotherapy (CTx) and best supportive care (BSC). Using prognostic factors for post-discontinuation survivals (PDSs) at the first-line determination in multivariate analysis, we developed a scoring system to demonstrate the benefit of second-line CTx.. The second-line CTx group had a median PDS of 5.2 months, whereas the BSC group had a median PDS of 2.7 months (hazard ratio 0.42; 95% confidence interval [CI] 0.31-0.57; p < 0.01). According to the Cox regression model, serum albumin levels below 3.5 g/dL, and CA19-9 levels above 1000 U/mL were independent prognostic factors (p < 0.01). Serum albumin (≥ and < 3.5 g/dL allotted to scores 0 and 1) and CA19-9 (< and ≥ 1000 U/mL allotted to scores 0 and 1) at first-line determination were used to develop the scoring system. The PDSs of patients with scores of 0 and 1 were significantly better than those of the BSC group; however, there was no significant difference between the PDSs of patients with score 2 and the BSC group.. The survival advantage of second-line CTx, was observed in patients with scores of 0 and 1 but not in those with score 2.

Topics: Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies; Serum Albumin

The NAPOLI-I trial showed better outcome of nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) compared to 5-FU/LV in patients with advanced pancreatic ductal adenocarcinoma cancer (advPDAC) progressed to gemcitabine-based therapy. This study aims to explore the real-world efficacy and safety of 5-FU/LV-nal-IRI.. This is a retrospective multicenter analysis including advPDAC patients receiving 5-FU/LV-nal-IRI after failure of gemcitabine-based therapy. Survival analyses were performed using Kaplan-Meier method, univariate and multivariate analyses by Cox regression.. A total of 296 patients (median age 64.4 years, ECOG PS ≥1 in 56% of cases) were treated at 11 Italian institutions between 2016 and 2018. 34% of them underwent primary tumor resection, and 79% received gemcitabine-nabpaclitaxel as first line. 5-FU/LV-nal-IRI was administered as second-line in 73% of cases. Objective response and disease control rate were 12% and 41%, respectively. Treatment was well tolerated with dose reductions in 50% of patients but no one permanent discontinuation; the commonest grade ≥3 toxicities were neutropenia (14%) and diarrhea (12%). Median PFS and OS from 5-FU/LV-nal-IRI initiation was 3.2 and 7.1 months, respectively.. These real-world data confirm the 5-FU/LV-nal-IRI efficacy and safety in advPDAC patients progressed to gemcitabine-based therapy, with outcomes comparable to NAPOLI-1, even in a less-selected population and with more modern therapeutic algorithm.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Continuity of Patient Care; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Middle Aged; Pancreatic Neoplasms

The treatment of pancreatic cancer has evolved; however, real-world data on treatment trends remain scarce. This study investigated treatment patterns for pancreatic cancer and patient survival using a nationwide population-based study in Korea.. Using the National Health Insurance database, data from 78,920 patients diagnosed with pancreatic cancer in Korea between 2006 and 2019 were extracted. Treatment patterns and survival by age group and year of diagnosis were examined.. Primary treatment was delivered as follows: 16,562 patients (21.0%) underwent surgery, 20,998 patients (26.6%) received chemotherapy, 1332 patients (1.7%) received chemoradiotherapy, and 40,040 patients (50.7%) received supportive care only. The proportion of patients undergoing surgery or chemotherapy increased gradually in all age groups over time. The commonly used anti-cancer drugs have changed from gemcitabine±erlotinib to gemcitabine+nab-paclitaxel and FOLFIRINOX. Survival improved mainly in patients who underwent surgery or chemotherapy. Median overall survival for all patients improved from 5.5 months in 2006-2008 to 9.8 months in 2018-2019, with greater improvement observed in younger age groups: 8.8-18.8 months, age ≤59 years, 6.8-14.6 months, age 60-69 years, 4.2-8.3 months, age 70-79 years and 2.4-3.4 months, age ≥80 years (all p < 0.0001).. An increase in the rates of surgery and chemotherapy for pancreatic cancer was observed. Survival rates for pancreatic cancer have generally improved over the past decade and are greater in patients undergoing surgery or chemotherapy and in younger age groups.

Topics: Aged; Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Infant; Leucovorin; Middle Aged; Paclitaxel; Pancreatic Neoplasms; Republic of Korea; Retrospective Studies

Pancreatic cancer (PC) represents an aggressive disease with median overall survival (OS) of less than 1 year in the front-line setting. FOLFIRINOX and gemcitabine and paclitaxel (GP) are standard of care options for these patients; however, optimal selection of therapy is challenging.. Comprehensive genomic profiling was performed on 8358 PC patients. Outcomes were available for 1149 metastatic PC patients treated with 1L FOLFIRINOX or GP. A scar-based measure of HRD was called using a machine learning-based algorithm incorporating copy number and indel features.. A scar-based HRD signature (HRDsig) was identified in 9% of patients. HRDsig significantly co-occurred with biallelic alterations in BRCA1/2, PALB2, BARD1, and RAD51C/D, but encompassed a larger population than that defined by BRCA1/BRCA2/PALB2 (9% vs. 6%). HRDsig was predictive of 1L FOLFIRNOX chemotherapy benefit with doubled OS relative to gemcitabine and paclitaxel (GP) (rwOS aHR 0.37 [0.22-0.62]), including 25% of the population with long-term (2 year+) survival in a real-world cohort of patients. Less benefit from FOLFIRINOX was observed in the HRDsig(-) population. Predictive value was seen in both the BRCA1/2/PALB2 mutant and wildtype populations, suggesting additional value to mutational profiling.. A scar-based HRD biomarker was identified in a significant fraction of PC patients and is predictive of FOLFIRINOX benefit. Incorporating a biomarker like HRDsig could identify the right patients for platinum chemotherapy and potentially reduce FOLFIRINOX use by over 40%, minimizing toxicities with similar survival outcomes. Confirmatory studies should be performed.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; BRCA2 Protein; Cicatrix; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

Nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU)/levo-leucovorin (Levo-LV) was approved for unresectable pancreatic cancer (UR-PC) in March 2020 in Japan. Levo-LV is administered by intravenous infusion over 120 min following 90 min intravenous infusion of nal-IRI (conventional method), causing a significant burden on both patients and the outpatient chemotherapy room owing to the prolonged administration time. Thus, from July 2021, we introduced the simultaneous intravenous administration of nal-IRI and Levo-LV (parallel method) with the approval of the institutional regimen committee.. We retrospectively reviewed the data of 69 patients with UR-PC who received nal-IRI plus 5-FU/Levo-LV at our hospital between June 2020 and October 2021. We examined the safety of the parallel method and compared the treatment outcomes and administration times between the two methods.. The median age was 66 years (54%, male). Disease statuses were locally advanced, metastatic, and postoperative recurrence after pancreatectomy in 7, 50, and 12 patients, respectively. Nal-IRI plus 5-FU/Levo-LV treatment was second and third-line or later in 35 and 34 patients, respectively. No intravenous line problems were observed during the parallel administration of nal-IRI and Levo-LV. Although there were no significant differences in response rates and adverse events between the two methods, the administration time was significantly shorter in the parallel method than in the conventional method.. The parallel administration of nal-IRI and Levo-LV is clinically safe and not inferior in efficacy. Moreover, parallel administration may offer convenience to patients and healthcare workers by reducing administration time.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Levoleucovorin; Liposomes; Male; Pancreatic Neoplasms; Retrospective Studies

Pancreatic cancer is mostly diagnosed in an advanced stage and treated with systemic therapy with palliative intent. Nowadays, the doublet chemotherapy of Gemcitabine and nab-paclitaxel (Gem-Nab) is one of the most frequently used regimens worldwide, but is not ubiquitarily available or reimbursed. Therefore, we compared the clinical efficacy of Gem-Nab to a historical control of patients treated with gemcitabine and oxaliplatin (Gem-Ox) at our tertiary cancer center, which was the standard treatment prior to the introduction of FOLFIRINOX.. This single-center retrospective real world study includes 121 patients diagnosed with locally advanced or primary metastatic pancreatic adenocarcinoma who were treated with chemotherapy doublet, with either Gem-Nab or Gem-Ox in palliative first-line. Survival rates were analyzed using the Kaplan-Meier method, and comparisons were made with log-rank tests. Gem-Ox was considered as standard first line therapy at our institution for patients who were deemed fit for doublet chemotherapy between the years 2006 to 2012. These patients were compared to a cohort of patients treated with the new standard first-line therapy of Gem-Nab between 2013 and 2020.. A total of 554 patients with pancreatic cancer of all stages were screened, and 73 patients treated with Gem-Nab and 48 patients treated with Gem-Ox in the palliative first-line setting were identified and included in this analysis. Patients receiving Gem-Ox had a statistically significantly better performance score (ECOG PS) when compared to the Gem-Nab group (Odds ratio (OR) 0.28, 95% CI 0.12-0.65, p = 0.005), more often suffered from locally advanced than metastatic disease (OR 3.10, 95% CI 1.27-7.91, p = 0.019) and were younger in age (OR 0.95, 95% CI 0.91-0.99, p = 0.013). Median overall survival (OS) of the whole study cohort was 10.3 months (95% CI 8.5-11.6). No statistically significant difference in OS could be observed between the Gem-Nab and the Gem-Ox cohort (median OS: 8.9 months (95% CI 6.4-13.5) versus 10.9 months (95% CI 9.5-13.87, p = 0.794, HR 1.27, 95% CI 0.85-1.91)). Median progression-free survival (PFS) was 6.8 months in the entire cohort (95% CI 4.9-8.4). No statistically significant difference in PFS could be observed between the Gem-Nab and the Gem-Ox cohort (median PFS: 5.8 months (95% CI 4.3-8.2) versus 7.9 months (95% CI 5.4-9.5) p = 0.536, HR 1.11, 95% CI 0.74-1.67). Zero-truncated negative binomial regressions on OS and PFS adjusting for gender, age, performance status (ECOG PS), and CA19-9 levels yielded no significant difference between Gem-Nab or Gem-Ox.. From our analysis, we could evidence no difference in outcome parameters in this retrospective analysis despite the worse prognostic pattern for GemOX. Therefore, we suggest Gem-Ox as potential first line treatment option for inoperable locally advanced or metastatic pancreatic cancer, especially if Gem-Nab is not available.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Gemcitabine; Humans; Leucovorin; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

Patients with resectable and borderline resectable pancreatic ductal adenocarcinoma increasingly receive neoadjuvant therapy prior to surgery. However, the effect of neoadjuvant therapy on the immune microenvironment remains largely unknown. We analyzed the immune microenvironment in pancreatic cancer tumor tissue samples from patients treated with neoadjuvant therapy compared to patients after upfront surgery to gain knowledge about the immunological environment after therapy.. Multispectral imaging was performed on tissue from resected specimens from patients with PDAC who underwent upfront surgery (n = 10), neoadjuvant FOLFIRINOX (n = 10) or gemcitabine + radiotherapy (gem-RT) (n = 9) followed by surgery. The samples were selected by a dedicated pancreas pathologist from both the central part and the invasive front of the tumor (by the resected vein or venous surface) and subsequently analyzed using the Vectra Polaris.. Patients receiving neoadjuvant FOLFIRINOX display a more pro-inflammatory immune profile, with less regulatory T cells and more CD8 T cells in the tumor tissue compared to patients receiving neoadjuvant gem-RTgem-RT or undergoing upfront surgery. Furthermore, CD163. Patients receiving neoadjuvant FOLFIRINOX display a more pro-inflammatory immune profile compared to patients receiving neoadjuvant gem-RT or undergoing upfront surgery. Furthermore, in all treatment groups, a more immune suppressive microenvironment was found in the tumor tissue compared to the adjacent non-tumorous tissue.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Fluorouracil; Gemcitabine; Humans; Leucovorin; Neoadjuvant Therapy; Pancreatic Neoplasms; Tumor Microenvironment

Vitamin D analogues remodel the desmoplastic stroma, and improve vascularity and efficacy of chemotherapy in preclinical pancreas cancer models.. We conducted a pilot study to evaluate the safety and preliminary efficacy of the vitamin D analogue paricalcitol in combination with nanoliposomal irinotecan (Nal-iri) plus 5-fluorouracil/leucovorin (5-FU/LV) in patients with advanced pancreatic cancer who had progressed on gemcitabine-based therapy. Two dose levels (DL) of paricalcitol were tested: fixed dose weekly (75 mcg, DL1) and weight-based weekly (7 mcg/kg, /DL2). The primary endpoint was safety, and secondary endpoints included overall response rate, progression-free survival (PFS), and overall survival (OS). Correlative objectives aimed to identify molecular predictors of response and alterations in the tumor stroma.. Twenty patients (10 each in DL1 and DL2) enrolled between March 2019 and May 2021. No grade 3/4 adverse events related to paricalcitol were observed. The most common toxicities were nausea, diarrhea and fatigue, which were similar in both cohorts. Three patients discontinued study after one cycle and were not radiographically evaluable. Of the remaining 17 evaluable patients, 2 had partial response and 12 had stable disease. The median PFS for response-evaluable patients in DL1 was 4.14 months, for DL2 was 4.83 months. Intent-to-treat median OS was 6.15 and 6.66 months for DL1 and DL2, respectively. Correlative studies showed increased tumor vascularity in posttreatment samples in patients receiving the higher dose of paricalcitol (DL2).. Paricalcitol at 7 mcg/kg/week in combination with Nal-iri/ 5-FU/LV is safely tolerated, may increase tumor vascularity and warrants further investigation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Ergocalciferols; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Liposomes; Pancreatic Neoplasms; Pilot Projects

Combination therapies such as FOLFIRINOX or gemcitabine-nanoparticle albumin-bound paclitaxel (GnP) are recommended for the first-line treatment of patients with advanced pancreatic cancer. The purpose of this study was to evaluate the efficacy of gemcitabine-based second-line therapies in patients whose disease progressed on FOLFIRINOX.. Patients diagnosed with advanced pancreatic cancer in 7 tertiary hospitals in Turkey were included. Patients were divided into 3 different groups according to their treatment regimens: GnP, gemcitabine doublet (gemcitabine-cisplatin or gemcitabine-capecitabine), and gemcitabine monotherapy.. A total of 144 patients were included in the study. In the second-line treatment, 65% of patients were given GnP, 20% were given gemcitabine doublet, and 15% were given gemcitabine monotherapy. The median exposure of the patients to gemcitabine-based therapy was 3 cycles, whereas the median progression-free survival was calculated as 3.4 months. The median overall survival for patients who received GnP was 4.6 months, 6.4 months for patients who received gemcitabine doublet therapy, and 3.7 months for patients who received gemcitabine monotherapy ( P = 0.248).. In conclusion, it has been shown that gemcitabine-based second-line treatments contribute to survival in patients with advanced pancreatic cancer. In addition, there was no difference in efficacy between gemcitabine monotherapy or combination treatments.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Gemcitabine; Humans; Leucovorin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

A retrospective study was conducted to analyze which translational therapy, palliative chemotherapy and surgery is the best treatment for locally advanced and advanced pancreatic cancer, and to screen out the dominant population for the best treatment. A total of 83 patients with pancreatic cancer, including locally advanced and advanced pancreatic cancer, who had lost the opportunity for radical surgery and were admitted to Zhejiang Provincial People's Hospital between January 2015 and July 2021 were collected. A total of 39 patients received palliative chemotherapy, 25 patients received conversion therapy and 19 patients tried surgery at the first visit. We conducted survival follow-up and prognostic evaluation of 83 patients. The median overall survival (mOS) and median progression-free survival (mPFS) of 25 pancreatic cancer patients who received conversion therapy were longer than those of pancreatic cancer patients who received palliative chemotherapy (mOS: 16 months vs. 9 months, P = 0.001; mPFS: 11 months vs. 7.5 months, P = 0.038) and surgery (mOS: 16 months vs. 9 months, P = 0.018; mPFS: 11 months vs. 5.5 months, P < 0.001). Multivariate and Kaplan-Meier analysis showed that age, distant metastasis, and the degree of CA199 declined after chemotherapy were independent factors affecting overall survival (OS) of pancreatic cancer patients who received conversion therapy. Conversion therapy can improve OS and progression-free survival in patients with locally advanced or advanced pancreatic cancer to a certain extent. Some patients with advanced pancreatic cancer have surprising results after receiving conversion therapy.

Topics: Age Factors; Aged; Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Oxaliplatin; Palliative Care; Pancreatic Neoplasms; Progression-Free Survival; Retrospective Studies

Pancreatic cancer is digestive cancer with limited therapeutic options and a poor outcome. Pancreatic cancer has a high mortality rate, with a 5-year survival rate of less than 5%. The median survival after metastasis of the disease is less than 6 months. Studies have revealed that the standard treatment, including palliative chemotherapy or immunotherapy, is not significantly effective for pancreatic cancer. Herein, we report a case of pancreatic cancer who benefited from a combination of anti-PD-1 immunotherapy and chemotherapy.

Topics: Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Fluorouracil; Humans; Immune Checkpoint Inhibitors; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms

Although improvements have been made in the management of pancreatic adenocarcinoma (PDAC) during the past 20 years, the prognosis of this deadly disease remains poor with an overall 5-year survival under 10%. Treatment with FOLFIRINOX, a combined regimen of 5-fluorouracil, irinotecan (SN-38) and oxaliplatin, is nonetheless associated with an excellent initial tumour response and its use has allowed numerous patients to go through surgery while their tumour was initially considered unresectable. These discrepancies between initial tumour response and very low long-term survival are the consequences of rapidly acquired chemoresistance and represent a major therapeutic frontier. To our knowledge, a model of resistance to the combined three drugs has never been described due to the difficulty of modelling the FOLFIRINOX protocol both in vitro and in vivo. Patient-derived tumour organoids (PDO) are the missing link that has long been lacking in the wide range of epithelial cancer models between 2D adherent cultures and in vivo xenografts. In this work we sought to set up a model of PDO with resistance to FOLFIRINOX regimen that we could compare to the paired naive PDO.. We first extrapolated physiological concentrations of the three drugs using previous pharmacodynamics studies and bi-compartmental elimination models of oxaliplatin and SN-38. We then treated PaTa-1818x naive PDAC organoids with six cycles of 72 h-FOLFIRINOX treatment followed by 96 h interruption. Thereafter, we systematically compared treated organoids to PaTa-1818x naive organoids in terms of growth, proliferation, viability and expression of genes involved in cancer stemness and aggressiveness.. We reproductively obtained resistant organoids FoxR that significantly showed less sensitivity to FOLFORINOX treatment than the PaTa-1818x naive organoids from which they were derived. Our resistant model is representative of the sequential steps of chemoresistance observed in patients in terms of growth arrest (proliferation blockade), residual disease (cell quiescence/dormancy) and relapse.. To our knowledge, this is the first genuine in vitro model of resistance to the three drugs in combined therapy. This new PDO model will be a great asset for the discovery of acquired chemoresistance mechanisms, knowledge that is mandatory before offering new therapeutic strategies for pancreatic cancer.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoids; Oxaliplatin; Pancreatic Neoplasms

Positive para-aortic lymph nodes (PALN) (station 16) are commonly detected in the final pathologic examination (ranging from 15 to 26%) among patients who undergo upfront pancreatoduodenectomy for resectable pancreatic ductal adenocarcinoma. However, after neoadjuvant treatment (NAT) the role of positive PALN as a watershed for surgical resection remains unclear. We aimed to determine the incidence of intraoperative detection of PALN after NAT with FOLFIRINOX for pancreatic head adenocarcinoma and its impact on survival, as our policy was to not resect the tumor in such situations.. From January 2014 to December 2020, 136 patients with non-metastatic cancer who received neoadjuvant FOLFIRINOX and underwent explorative laparotomy were included.. Intraoperative positive PALN were observed in 7 patients (5%). Patients had resectable (n = 5) or locally advanced (n = 2) disease at the time of surgery, but none of them underwent surgical resection. Positive PALN were significantly associated with a lower median number of FOLFIRINOX cycles (4 vs. 6, P = 0.05). There was no significant difference in overall survival between patients with positive loco-regional lymph nodes after resection and patients with non-resection owing to positive PALN (22 versus 16 months, P = 0.16), Overall survival with positive PALN, carcinomatosis, and liver metastasis was 16, 14, and 10 months, respectively (P > 0.05).. Our results suggest that NAT may lower PALN involvement. We have modified our policy, positive PALN after NAT are no longer a contraindication to resection, rather a holistic picture of the disease guides management.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Frozen Sections; Humans; Irinotecan; Leucovorin; Lymph Nodes; Lymphatic Metastasis; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Retrospective Studies

Patients with locally advanced pancreatic adenocarcinoma (PDAC) receive induction chemotherapy with or without radiation, with the goal of R0 resection and improving survival. Herein, we evaluate the outcomes of patients who presented with Stage III PDAC and received induction FOLFIRINOX.. An institutional database was queried for consecutive patients who received induction FOLFIRINOX for locally unresectable PDAC between 2010 and 2016. Clinical and radiographic parameters were assessed pre- and posttreatment, and clinical outcomes were evaluated.. There were 200 patients who met the inclusion criteria. The median number of cycles of FOLFIRINOX was 8, 70% (n = 140) received radiation, and 18% (n = 36) underwent resection. Median overall survival (OS) in resected patients was 36 months (95% confidence interval [CI]: 24-56), and this group had improved OS compared to patients that did not undergo resection (hazard ratio (95% CI): 0.41 (0.26-0.64), p < 0.001). Patients (n = 112) who did not progress on induction therapy but remained unresectable had a median OS of 23.9 months (95% CI: 21.1-25.4).. Nearly 20% of patients with locally advanced PDAC responded sufficiently to induction FOLFIRINOX to undergo resection, which was associated with improved OS compared to patients that did not undergo resection. Patients with stable disease who remain unresectable represent a group of patients with locally advanced PDAC who may benefit from optimization of additional nonoperative treatment.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cohort Studies; Combined Modality Therapy; Female; Fluorouracil; Humans; Induction Chemotherapy; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Survival Rate; Treatment Outcome

Quality of life in cancer patients might be affected by chemotherapy-induced toxicity. Especially in patients with pancreatic ductal adenocarcinoma (PDAC), with a short life expectancy, fear of poor quality of life is often a reason for both patients and medical oncologists to refrain from further treatment. In this study, we investigated quality of life (QoL), pain, sleep, and activity levels in locally advanced pancreatic cancer (LAPC) patients after FOLFIRINOX treatment.. A total of 41 LAPC patients with stable disease or partial response were included after completion of at least four cycles of FOLFIRINOX. QoL was measured with the EORTC QLQ-C30 and NRS pain scores. Patients completed the Richards-Campbell Sleep Questionnaire (RCSQ) for five consecutive nights and wore a GENEActiv tri-axial accelerometer (Actiwatch) for 7 days, registering sleep duration, efficiency, and activity.. Mean EORTC QLQ-C30 score for global health status was 78.3 (± 17.3), higher than reference values for cancer patients (P < 0.001) and general population (P = 0.045). LAPC patients reported few disease-related symptoms. Two patients (5%) reported pain scores > 3. Mean sleep duration was 8 h/night (± 1.2 h) and sleep efficiency 70% (± 9%) with high patient-reported quality of sleep (mean RCSQ score 72.0 ± 11.4). Mean duration of moderate-vigorous activity was 37 min/week (± 103 min/week).. QoL is very good in most LAPC patients with disease control after FOLFIRINOX, measured with validated questionnaires and Actiwatch registration. The fear of clinical deterioration after FOLFIRINOX is not substantiated by this study and should not be a reason to refrain from treatment.. Dutch trial register NL7578.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Quality of Life

While irresectable pancreatic cancer has still a dismal overall prognosis, evidence about the optimal chemotherapy sequence is scarce. After treatment with FOLFIRINOX in first-line, gemcitabine monotherapy was established for years. As a potential treatment alternative after failure of FOLFIRINOX therapy, combination of gemcitabine and nab-paclitaxel is used. However, this combination has formally not yet been approved for second-line treatment and investigation of efficiency and treatment tolerance is the aim of this trial.. Therefore, we investigated 225 patients with histologically confirmed local advanced or metastatic pancreatic cancer in this retrospective monocentre study (November 2010 - July 2019). Of this, 44 patients received FOLFIRINOX therapy and outcome was further analysed. The primary end point of this cohort was overall survival (OS), and secondary end points included progression-free survival (PFS), response rate, and safety.. In most of the patients, FOLFIRINOX as first-line treatment of irresectable pancreatic cancer resulted in temporary cancer control (partial response [PR]: 50% and stable disease [SD]: 18%), whereas tumour progression was observed in 23% of the patients. The median PFS time for FOLFIRINOX treatment was 7.3 months and median OS 10.3 months. Seven (16%) patients received additional local radio chemotherapy of the pancreatic tumour. During first-line therapy, in 8 (18%) patients, laparotomy was performed to proof resectability of the tumour. Hereby, in 3 patients R0- and in 3 patients R1 resection was achieved, whereas 2 patients stayed irresectable. Twenty-five of the 44 patients (57%) received second-line therapy, namely, 24 patients gemcitabine/nab-paclitaxel and 1 patient gemcitabine and erlotinib. Hereby, gemcitabine/nab-paclitaxel led again to temporary tumour control in 46% of the patients (PR: 21%, SD: 25%), while in 29% of the patients, disease progression was observed. Corresponding median PFS for gemcitabine and nab-paclitaxel treatment was 3.5 months. Patients who received second-line treatment with nab-paclitaxel and gemcitabine had a more favourable prognosis (median OS: 17 vs. 9.2 months; HR 0.32 [0.14-0.70], p < 0.001) than patients who were not eligible for second-line treatment. Moreover, in multivariate analyses association with patients' survival and tumour response to chemotherapy in both therapeutic lines and µGT concentrations below 100 IU/L in first-line FOLFIRINOX chemotherapy were observed.. These real-world data suggest that gemcitabine/nab-paclitaxel may be feasible after FOLFIRINOX therapy in patients with irresectable pancreatic cancer. However, prospective randomized data about the superiority to gemcitabine monotherapy are needed.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Prospective Studies; Retrospective Studies

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Rectal Neoplasms

Although second-line treatment for pancreatic cancer has been proven to have survival benefit, it is not clear which is the most preferred regimen. This study compared the efficacy and safety of modified FOLFIRINOX (mFOLFIRINOX) and sequential chemotherapy (FOLFIRI/FOLFOX) as a second-line treatment regimen for unresectable pancreatic cancer.. This was a retrospective single-center analysis of all patients who initiated treatment with mFOLFIRINOX or sequential chemotherapy from December 2014 to May 2019 as a second-line treatment for unresectable pancreatic cancer. The sequential chemotherapy group included all patients who initiated sequential chemotherapy. For efficacy analysis, the primary endpoint was overall survival (OS) of all patients, excluding those with locally advanced pancreatic cancer. For safety analysis, we assessed the incidence of grade ≥3 adverse events in all patients.. Seventy-four patients (mFOLFIRINOX group, n = 44; sequential chemotherapy group, n = 30) were included. OS tended to be slightly prolonged in the mFOLFIRINOX group than in the sequential chemotherapy group (median 10.6 [95% confidence interval {CI} 5.9-13.8] vs. 8.5 [95% CI 5.0-12.2] months; hazard ratio 1.40 [95% CI 0.71-2.71]). The objective response rate and disease control rate were 8.1% and 64.9%, respectively, in the mFOLFIRINOX group and 3.8% and 42.3%, respectively, in the sequential chemotherapy group. In safety analysis, the grade ≥3 rates of neutropenia, febrile neutropenia, and anorexia were 40.9%, 6.8%, and 18.2%, respectively, in the mFOLFIRINOX group and 3.3%, 0%, and 3.3%, respectively, in the sequential chemotherapy group.. Whereas efficacy tended to be slightly better in the mFOLFIRINOX group than in the sequential chemotherapy group, given the higher incidence of grade ≥3 adverse events with mFOLFIRINOX than with sequential chemotherapy, sequential chemotherapy is a regimen with better risk-benefit balance than mFOLFIRINOX, and can be considered a second-line treatment option for patients with unresectable pancreatic cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

No reliable nomogram has been developed until date for predicting the survival in patients with unresectable pancreatic cancer undergoing treatment with gemcitabine plus nab-paclitaxel (GnP) or FOLFIRINOX.. This analysis was conducted using clinical data of Japanese patients with unresectable pancreatic cancer undergoing GnP or FOLFIRINOX treatment obtained from a multicenter study (NAPOLEON study). A Cox proportional hazards model was used to identify the independent prognostic factors. A nomogram to predict 6-, 12-, and 18-month survival probabilities was generated, validated by using the concordance index (C-index), and calibrated by the bootstrapping method. And then, we attempted risk stratification for survival by classifying the patients according to the sum of the scores on the nomogram (total nomogram points).. A total of 318 patients were enrolled. A prognostic nomogram was generated using data on the Eastern Cooperative Oncology Group performance status, liver metastasis, serum LDH, serum CRP, and serum CA19-9. The C-indexes of the nomogram were 0.77, 0.72 and 0.70 for 6-, 12-, and 18-month survival, respectively. The calibration plot showed optimal agreement at all points. Risk stratification based on tertiles of the total nomogram points yielded clear separations of the survival curves. The median survival times in the low-, moderate-, and high-risk groups were 15.8, 12.8 and 7.8 months (P<0.05), respectively.. Our nomogram might be a convenient and inexpensive tool to accurately predict survival in Japanese patients with unresectable pancreatic cancer undergoing treatment with GnP or FOLFIRINOX, and will help clinicians in selecting appropriate therapeutic strategies for individualized management.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Japan; Leucovorin; Male; Middle Aged; Nomograms; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Treatment Outcome

Pancreas cancer (PCa) is one of the mortal cancer types with ranking as fourth leading cancer death in both sexes together. FOLFIRINOX (FFX) and Gemcitabine plus nab-paclitaxel (GNP) are approved as first-line metastatic treatment in PCa. The aim of this study was to compare the clinical outcomes, treated with FFX and GNP as first-line metastatic PCa. Medical records of patients diagnosed with metastatic PCa, from January 2010 to December 2020 were analyzed. This study was a retrospective cohort, multi-institution analysis. The focus of the present study was to compare the efficiency of FFX and GNP chemotherapy combinations in the first-line treatment of PCa. Efficacy had been measured by progression-free survival (PFS) and overall survival (OS). 182 patients diagnosed with PCa receiving metastatic first-line treatment were retrospectively analyzed. Patients were divided into two groups one hundred and three (56.6%) patients treated with FFX and seventy-nine (43.4%) patients treated with GNP. Patients in the FFX group were younger and had a better ECOG performance status. Overall response rate (ORR) was 69.9% in FFX and 37.9% in GNP group (p: 0.000). Disease control rate (DCR) was 73.7% in patients treated with FFX and 39.2% in GNP group (p: 0.000). The median PFS was 8.3 months (FFX 9.1 vs. GNP 6.7, HR = 0.25, 95% CI: 0.16-0.38) the median OS was 12.2 months (FFX 14.1 vs. GNP 9.6, HR = 0.48, 95% CI: 0.31-0.72). Guidelines recommend both FFX and GNP regimens as a first-line treatment of metastatic PCa. In clinical routine, it is still unclear which regiment is more effective. The present study showed increased survival parameters with FFX versus GNP with similar toxicity profiles.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

Advanced pancreatic cancer (APC) disproportionately impacts older adults. Randomized trials demonstrate improved overall survival (OS) with combination chemotherapy including 5-fluorouracil, irinotecan, leucovorin, and oxaliplatin (FOLFIRINOX) or nab-paclitaxel and gemcitabine compared with gemcitabine alone, but with increased toxicity. Older adults are at increased risk of side effects from chemotherapy. The aim of this study was to assess the efficacy and toxicity of chemotherapy in older adults with APC.. Patients diagnosed with APC from 2011 to 2016 were identified using the Manitoba Cancer Registry. Patient and treatment characteristics, toxicity, and outcomes of patients 65 years of age and above treated with palliative chemotherapy were compared by treatment regimen. OS was assessed using the Kaplan-Meier method. A Cox regression was used to identify independent predictors of OS.. A total of 87 patients aged 65 years and above received palliative chemotherapy: 52 (59.7%) FOLFIRINOX, 21 (24.1%) nab-paclitaxel and gemcitabine, and 14 (16.1%) gemcitabine, with a median age of 69 (65 to 84), 75 (65 to 88), and 73 (67 to 82), Eastern Cooperative Oncology Group (ECOG) performance status difference in hematologic toxicity between regimens (P=0.807). An increase in nonhematologic toxicity was seen with FOLFIRINOX (P<0.001), specifically neuropathy (P=0.008), fatigue (P<0.001), and nausea/vomiting (P=0.008). FOLFIRINOX was associated with improved radiologic response (P=0.05) and OS (P=0.035). PS, baseline carbohydrate antigen 19-9 level, and chemotherapy regimen were independent predictors of survival.. FOLFIRINOX is associated with improved response and OS in older adults with APC. FOLFIRINOX has a manageable safety profile in this population and should be considered in fit older adults with APC.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Nausea; Oxaliplatin; Paclitaxel; Palliative Care; Pancreatic Neoplasms; Treatment Outcome; Vomiting

Gemcitabine (Gem) alone or with Nab-paclitaxel (Gem-Nab) is used as second-line treatment for metastatic pancreatic adenocarcinoma (mPA) after FOLFIRINOX (FFX) failure; however, no comparative data exist. This study evaluates the efficacy and safety of adding Nab-paclitaxel to Gem for mPA after FFX failure.. In this retrospective real-world multicenter study, from 2011 to 2019, patients with mPA receiving Gem-Nab (Gem 1000 mg/m² + Nab 125 mg/m², 3 out of 4 weeks) or Gem alone were included after progression on FFX.. A total of 427 patients were included. Patients receiving Gem-Nab had more metastatic sites, peritoneal disease and less PS 2 (24% vs. 35%). After median follow-up of 22 months, Gem-Nab was associated with better disease control rate (DCR) (56% vs. 32%; P < 0.001), progression-free survival (PFS) (3.5 vs. 2.3 months; 95% CI: 0.43-0.65) and overall survival (OS) (7.1 vs. 4.7 months; 95% CI: 0.53-0.86). After multivariate analysis, Gem-Nab and PS 0/1 were associated with better OS and PFS. Grade 3/4 toxicity was more frequent with Gem-Nab (44% vs. 29%).. In this study, Gem-Nab was associated with better DCR, PFS and OS compared with Gem alone in patients with mPA after FFX failure, at the cost of higher toxicity.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

The 2020 National Comprehensive Cancer Network guidelines recommend neoadjuvant FOLFIRINOX or neoadjuvant gemcitabine plus nab-paclitaxel (G-nP) for borderline resectable/locally advanced pancreatic ductal adenocarcinoma (BR/LA PDAC).. The purpose of our study was to compare treatment outcomes, toxicity profiles, costs, and quality-of-life measures between these two treatments to further inform clinical decision-making.. We developed a decision-analytic mathematical model to compare the total cost and health outcomes of neoadjuvant FOLFIRINOX against G-nP over 12 years. The model inputs were estimated using clinical trial data and published literature. The primary endpoint was incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay threshold of $100 000 per quality-adjusted-life-year (QALY). Secondary endpoints included overall (OS) and progression-free survival (PFS), total cost of care, QALYs, PDAC resection rate, and monthly treatment-related adverse events (TRAE) costs (USD). FOLFIRINOX was the cost-effective strategy, with an ICER of $60856.47 per QALY when compared to G-nP. G-nP had an ICER of $44639.71 per QALY when compared to natural history. For clinical outcomes, more patients underwent an "R0" resection with FOLFIRINOX compared to G-nP (84.9 vs. 81.0%), but FOLFIRINOX had higher TRAE costs than G-nP ($10905.19 vs. $4894.11). A one-way sensitivity analysis found that the ICER of FOLFIRINOX exceeded the threshold when TRAE costs were higher or PDAC recurrence rates were lower.. Our modeling analysis suggests that FOLFIRNOX is the cost-effective treatment compared to G-nP for BR/LA PDAC despite having a higher cost of total care due to TRAE costs. Trial data with sufficient follow-up are needed to confirm our findings.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cost-Benefit Analysis; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bias; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

Large pragmatic studies of patients who received 5-fluorouracil with leucovorin, irinotecan, and oxaliplatin ([m]FOLFIRINOX) as initial treatment for localized pancreatic ductal adenocarcinoma (PDAC) are lacking. This study aimed to provide realistic estimates of oncologic outcomes in these patients.. This international retrospective cohort study included all consecutive patients presenting with localized PDAC who received at least 1 cycle of (m)FOLFIRINOX as initial treatment in 5 referral centers from the United States and the Netherlands (2012-2019). Primary outcome was median overall survival (OS), calculated from the date of tissue diagnosis, assessed using Kaplan-Meier estimates. Log-rank test was used to compare OS between groups. A Cox proportional hazards regression model was used to assess prognostic baseline factors for OS. All statistical tests were 2-sided.. Overall, 1835 patients were included, of whom 958 (52.2%) had locally advanced (LA), 531 (28.9%) had borderline resectable (BR), and 346 (18.9%) had potentially resectable (PR) PDAC. The median number of (m)FOLFIRINOX cycles was 6 (interquartile range = 4-8). Subsequent treatment included second chemotherapy (12.9%), radiotherapy (49.0%), and resection (37.9%). The resection rate was 17.6% for LA, 53.1% for BR, and 70.5% for PR PDAC (P < .001). The margin-negative resection rate (>1 mm) was 55.2% for LA, 62.6% for BR, and 79.2% for PR PDAC (P < .001). The median OS was 18.7 months (95% confidence interval [CI] = 17.7 to 19.9 months) for LA, 23.2 months (95% CI = 21.0 to 25.7 months) for BR, and 31.2 months (95% CI = 26.2 to 36.6 months) for PR PDAC (P < .001). The median OS for 695 patients who underwent a resection was 38.3 months (95% CI = 36.1 to 42.0 months). Independent prognostic factors at baseline for worse OS were more advanced stage, worse performance status, baseline carbohydrate antigen (CA) 19-9 > 500 U/mL, and body mass index ≤18.5 kg/m2.. This large international cohort study provides realistic estimates of resection rates and survival in patients with LA, BR, and PR PDAC who started (m)FOLFIRINOX treatment in PDAC referral centers.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cohort Studies; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

Both modified FOLFIRINOX (mFFX) and gemcitabine/nab-paclitaxel chemotherapy regimens have been shown to improve clinical outcomes in patients with pancreatic cancer, and are often used interchangeably as the standard of care. Preclinical studies often do not use these regimens, since administering these multiagent approaches can be difficult. In this study, we assessed the feasibility of administering these two chemotherapy regimens in spontaneous pancreatic tumors using KPC mice with the ultimate goal of advancing preclinical studies.. In total, 92 mice were included. The median OS in the FFX X2 group was slightly longer that the median OS in the FFX X1 group (15 days vs 11 days, P = 0.003). Mice in the GEM/AB X2 group had longer OS when compared to mice in the GEM/AB X1 group (33.5 vs 13 days, P = 0.001). Mice treated with chemotherapy survived longer than untreated control animals (median OS: 6.5 days, P < 0.001). Moreover, in mice treated with chemotherapy, mice that received 2 cycles of GEM/AB X2 had the longest survival, while the FFX X1 group had the poorest OS (P < 0.001). The addition of chemotherapy was associated with reduced number of myeloid and lymphoid cell types, except for CD4 + cells whose levels were largely unaltered only in tumors treated with gemcitabine/nab-paclitaxel. Lastly, chemotherapy followed by consolidative SBRT trended towards increased local control and survival.. We demonstrate the utility and feasibility of clinically relevant mFOLFIRINOX and gemcitabine/nab-paclitaxel in preclinical models of pancreatic cancer.

Topics: Albumins; Animals; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease Models, Animal; Feasibility Studies; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Mice; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

Recent studies have suggested the suboptimal efficacy of liposomal irinotecan plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in metastatic pancreatic ductal adenocarcinoma (mPDAC) patients previously treated with conventional irinotecan. This study investigated the effect of conventional irinotecan treatment in mPDAC patients receiving nal-IRI+5-FU/LV by analyzing a population-based dataset.. We reviewed 667 consecutive mPDAC patients treated with nal-IRI+5-FU/LV between August 2018 and November 2020 at Taiwanese medical centers. Eighty-six patients previously treated with conventional irinotecan were matched to 86 patients not treated with conventional irinotecan, following propensity matching for age, sex, performance status, metastatic organ site, pre-treatment carbohydrate antigen 19-9 level, lines of prior chemotherapy treatment, and time from first-line treatment to nal-IRI+5-FU/LV therapy.. The median overall survival and time-to-treatment failure were 4.8 and 2.6 vs 4.1 and 2.1 months, respectively, for patients who were and were not previously treated with conventional irinotecan. The tumor response and disease control rates were 5.8% and 32.6% vs 5.8% and 37.2%, respectively, for patients previously treated and not treated with conventional irinotecan. No significant differences were observed in survival times and tumor response rates between the two groups.. Previous conventional irinotecan treatment does not compromise the efficacy of subsequent nal-IRI+5-FU/LV treatment in mPDAC patients.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Pancreatic Neoplasms; Treatment Outcome

The prognosis of initially unresectable pancreatic cancer (UR-PC) has improved since the introduction of FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (GNP) treatment. Nonetheless, the indications and optimal timing for conversion to resection remain unclear for UR-PC. The aim of this study is to evaluate the characteristics of cases with initially UR-PC who received modified FFX or GNP treatment.. This retrospective study reviewed 454 consecutive Japanese UR-PC cases who received modified FFX/GNP treatment. Cases were categorized according to resection status, and overall survival (OS) was evaluated using a multivariable prognostic scoring model (0-4 points, higher score indicating more favorable prognostic factors).. The overall resection rate was 16% for locally advanced UR-PC (UR-LA) and 5% for metastatic UR-PC (UR-M). The resection group had better OS than the nonresection group (median OS time: not reached versus 13.0 months, P < 0.001). The independent prognostic factors were normalized CA19-9 concentration, modified Glasgow prognostic score of 0, tumor shrinkage after chemotherapy, chemotherapy duration ≥ 8 months, and resection. Cases were grouped according to their prognostic score, and the results suggested that candidates for resection might have prognostic scores of 4 points in UR-M cases or 2-4 points in UR-LA cases.. Stratification according to prognostic score was useful in predicting the outcomes of UR-PC cases and may aid in identifying cases who might benefit from surgical treatment after responding to chemotherapy.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Japan; Leucovorin; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

Chemotherapy-related adverse events (AEs) can negatively impact the care of patients. The prevention and management of AEs often require additional medications. This study evaluated the percentages of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) undergoing second-line therapy with 5-fluorouracil (5-FU)-based regimens that experienced AEs during treatment and received medication to manage those AEs.. We conducted a retrospective observational analysis utilizing the Flatiron Health database of adult patients with mPDAC who started second-line therapy between January 2016 and August 2020. The occurrence of diarrhea, fatigue, nausea and vomiting, neuropathy, and hematologic AEs including G3/G4 anemia, neutropenia, and thrombocytopenia was assessed. The use of concomitant medications including atropine and granulocyte colony stimulating factor (G-CSF) was assessed.. Of the 825 eligible patients, 29.0% (. In patients with mPDAC who received second-line therapy, those who received liposomal irinotecan-based regimens had the lowest rates of anemia, neutropenia, and thrombocytopenia compared to FOLFIRI, FOLFIRINOX, and FOLFOX, while requiring a similar or lower level of medication to treat and manage those adverse events. Patients treated with FOLFIRI received the highest dose of pegfilgrastim to manage neutropenia. The results of this real-world analysis are consistent with prior evaluations of patients with mPDAC and highlight the importance of managing adverse events and associated cost implications.

Topics: Adenocarcinoma; Adult; Anemia; Antineoplastic Combined Chemotherapy Protocols; Atropine Derivatives; Camptothecin; Diarrhea; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Irinotecan; Leucovorin; Nausea; Neutropenia; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Thrombocytopenia; Vomiting

Surgery and systemic therapy provide the best option for long-term cancer control in localized resectable pancreas cancer. The present study assessed the efficacy and safety of neoadjuvant treatment with FOLFIRINOX in patients with borderline resectable (BR) and locally advanced (LA) pancreas cancer (PDAC).. This was a prospective noninterventional observational trial of neoadjuvant FOLFIRINOX in BR and LA PDAC. The primary objective was the R0/R1 surgical resection rate. Secondary objectives included progression free survival (PFS) and overall survival (OS), tolerability, and toxicity.. Forty-nine patients were enrolled between 2013 and 2019; the majority had LA disease (59.2%). Median age was 61 years, and median Ca 19-9 level pretreatment was 523.4 μmol/L. Following neoadjuvant FOLFIRINOX, 11 patients (22.5%) underwent surgical resection, the majority of which were BR at diagnosis (72.7%). Median OS and PFS for the entire group were 25 (95% CI: 17.2-32.8) and 12 months (95% CI: 9.7-13.3), respectively. Median PFS in BR patients was 14 (95% CI: 10.5-17.5) compared to 12 months (95% CI: 5.2-18.8) in patients with LA patients. Median OS and PFS were not reached in patients who underwent surgical resection as compared to 22 (95% CI: 18.6-25.4) and 9 months (95% CI: 4.2-13.9) in those who did not, respectively. Grade 3/4 neutropenia, leukopenia, neuropathy, nausea/vomiting, and diarrhea occurred in 6.3%, 2.1%, 10.4%, 4.2%, and 8.3%, respectively.. Neoadjuvant FOLFIRINOX is an active regimen for patients with LA/BR PDAC with a resection rate of 22.5%. These results are in line with prior data.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoadjuvant Therapy; Pancreatic Neoplasms; Prospective Studies

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

Identifying pretreatment blood markers that distinguish prognostic groups of patients with advanced pancreatic ductal adenocarcinoma (PDAC) under first-line FOLFIRINOX chemotherapy has the potential to improve management of this condition. Aim of this study was to determine the prognostic utility of a range of pretreatment, inflammation-related, blood cell markers in this group of patients.. Data from a training cohort were analyzed to identify potential pretreatment blood markers correlating to survival outcomes. The most informative markers were further analyzed in a validation cohort comprised patients from a geographically separate cancer center undergoing the same treatment.. A total of 138 consecutive patients receiving FOLFIRINOX chemotherapy between 2010 and 2019, constituted the training cohort. Neutrophil/lymphocyte (NLR), monocyte/lymphocyte (MLR), and platelet/lymphocyte ratio (PLR) as well as the systemic inflammatory response index (SIRI) and CA19.9 showed prognostic significance in addition to tumor stage. A pretreatment SIRI score cutoff of 2.35 differentiated between a poor prognostic group with median overall survival (mOS) 5.1 months and a better prognostic group, mOS 12.5 months. SIRI ≤/> 2.35 was predictive of mOS in patients with locally advanced and metastatic PDAC. SIRI was confirmed as a prognostic marker in a validation cohort of 67 patients with mOS of 13.4 months and 6.3 months for those with SIRI ≤ 2.35 and >2.35, respectively. Additional analysis revealed baseline SIRI as being prognostic within additional subgroups of patients in both cohorts.. This large, retrospective, analysis of real-world patients receiving first-line FOLFIRINOX chemotherapy for advanced PDAC has identified the pretreatment blood SIRI as a strong prognostic marker for survival. This will allow better counseling of patients with regards to the benefits of treatment, improved stratification within clinical trials, and potentially identify groups of patients for novel therapy trials as first-line treatment.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Fluorouracil; Humans; Inflammation; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Retrospective Studies

Salvage chemotherapy for patients with unresectable pancreatic cancer (UR-PC) who have been treated with gemcitabine and nab-paclitaxel (GnP), and 5-fluorouracil (5-FU)/l-leucovorin (LV) plus nanoliposomal irinotecan (nal-IRI), has not been fully established. We retrospectively reviewed data from 17 patients with UR-PC who initiated 5-FU/l-LV plus oxaliplatin (FOLFOX) as salvage chemotherapy at our hospital between June 2020 and August 2021, after treatment with GnP and 5-FU/LV plus nal-IRI. The primary endpoint was tumor response. The secondary endpoints were progression-free survival (PFS) and adverse events (AEs). The response and disease control rates were 5.9% (1/17) and 17.6% (3/17), respectively. The median PFS was 1.8 months (range: 0.4-5.2 months). Eight patients (47.1%) experienced grade 3 nonhematologic AEs, while none experienced grade 3 hematologic AEs. Two patients with controlled disease had homologous recombination deficiency (HRD)-associated gene mutations in cancer panel testing. The FOLFOX regimen benefit for UR-PC patients treated with GnP and 5-FU/LV plus nal-IRI may be limited to patients with HRD-associated gene mutations.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

A woman in her 50s previously treated for early-stage breast cancer, parotid mucoepidermoid carcinoma and Caroli's disease was diagnosed with stage IV pancreatic ductal adenocarcinoma (PDAC) metastatic to the liver and was found to harbour a

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; Carcinoma, Pancreatic Ductal; Carcinoma, Squamous Cell; Female; Fluorouracil; Germ-Line Mutation; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Tongue Neoplasms

Pancreatic cancer is one of the most recalcitrant cancers, and more effective therapy is needed. Pre-clinical studies have shown that patient-derived orthotopic xenograft (PDOX) mouse models of pancreatic cancer are effectively treated with oral recombinant methioninase (o-rMETase).. A 62-year-old woman diagnosed with stage IV pancreatic cancer was treated with the combination of 5-fluorouracil/leucovorin, irinotecan, and oxaliplatinum (FOLFIRINOX) every two weeks and o-rMETase twice a day as a supplement. The patient was also on a low-methionine diet. Disease progression was monitored by CA19-9 and computed tomography. The patient initially responded to FOLFIRINOX, shown by a great reduction in CA19-9 levels, with tumor shrinkage shown by computed tomography. The patient began taking o-rMETase and went on a low-methionine diet one year after diagnosis which she has maintained without side effects for 7 months. The patient's CA19-9 level and tumor size remain stable 19 months after diagnosis. The patient is alive and has maintained a high performance status. Historical data show that less than 5% of stage IV pancreatic-cancer patients on FOLFIRINOX have stable disease 1.5 years after diagnosis.. The combination of o-rMETase and FOLFIRINOX may be synergistic in stage IV pancreatic cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Carbon-Sulfur Lyases; Disease Models, Animal; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Methionine; Mice; Mice, Nude; Oxaliplatin; Pancreatic Neoplasms; Xenograft Model Antitumor Assays

Pancreatic acinar cell carcinoma is rare; it accounts for 1% of all malignant pancreatic exocrine tumors. Although surgical resection is an option for curative treatment, the safety and efficacy of conversion surgery in patients with pancreatic acinar cell carcinoma with metastasis remain unknown.. A 67-year-old man with epigastric pain and a pancreatic tumor was referred to our hospital. Computed tomography revealed a large tumor with a maximum diameter of 67 mm at the pancreatic head and a 23-mm mass in the left upper abdominal cavity. Because a definitive diagnosis could not be made based on endoscopic ultrasonography-guided fine needle aspiration biopsy findings, a diagnostic laparoscopy was performed. The tumor in the greater omentum at the left upper abdomen, resected under laparoscopy, was histopathologically diagnosed as pancreatic acinar cell carcinoma. Therefore, the pancreatic tumor was diagnosed as an unresectable pancreatic acinar cell carcinoma with a solitary peritoneal dissemination. The size of the main pancreatic tumor decreased to 15 mm after 18 courses of FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin). Subsequently, the patient underwent conversion surgery, and the initial diagnosis of pancreatic acinar cell carcinoma was confirmed on pathological examination. The patient was discharged 31 days postoperatively, following which he received adjuvant chemotherapy with S-1. No sign of recurrence has been observed for 32 months after surgical resection.. FOLFIRINOX may be effective in patients with pancreatic acinar cell carcinoma, and conversion surgery after FOLFIRINOX may be applicable to selective patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Acinar Cell; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Oxaliplatin; Pancreatic Neoplasms

FOLFIRINOX (leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) and gemcitabine plus nab-paclitaxel are the 2 common first-line therapies for metastatic adenocarcinoma of the pancreas (mPC), but they have not been directly compared in a clinical trial, and comparative clinical data analyses on their effectiveness are limited.. To compare the FOLFIRINOX and gemcitabine plus nab-paclitaxel treatments of mPC in clinical data and evaluate whether there are differences in overall survival and posttreatment complications between them.. This retrospective, nonrandomized comparative effectiveness study used data from the AIM Specialty Health-Anthem Cancer Care Quality Program and from administrative claims of commercially insured patients, spanning 388 outpatient centers and clinics for medical oncology located in 44 states across the US. Effectiveness and safety of the treatments were analyzed by matching or adjusting for age, Charlson Comorbidity Index, ECOG performance status (PS) score, Social Deprivation Index (SDI), liver and lymph node metastasis, prior radiotherapy or surgical procedures, and year of treatment. Patients with mPC treated between January 1, 2016, and December 31, 2019, and followed up until June 30, 2020, were included in the analysis.. Initiation of treatment with FOLFIRINOX or gemcitabine plus nab-paclitaxel.. Outcomes were overall survival and posttreatment costs and hospitalization. Median survival time was calculated using Kaplan-Meier estimates adjusted with inverse probability of treatment weighting and 1:1 matching.. Among the 1102 patients included in the analysis (618 men [56.1%]; median age, 60.0 [IQR, 55.5-63.7] years), those treated with FOLFIRINOX were younger (median age, 59.1 [IQR, 53.9-63.3] vs 61.2 [IQR, 57.2-64.3] years; P < .001), with better PS scores (226 [39.9%] with PS of 0 in the FOLFIRINOX group vs 176 [32.8%] in the gemcitabine plus nab-paclitaxel group; P = .02), fewer comorbidities (median Charlson Comorbidity Index, 0.0 [IQR, 0.0-1.0] vs 1.0 [IQR, 0.0-1.0]), and lower SDI (median, 36.0 [IQR, 16.2-61.0] vs 42.0 [IQR, 23.8-66.2]). After adjustments, the median overall survival was 9.27 (IQR, 8.74-9.76) and 6.87 (IQR, 6.41-7.66) months for patients treated with FOLFIRINOX and gemcitabine plus nab-paclitaxel, respectively (P < .001). This survival benefit was observed among all subgroups, including different ECOG PS scores, ages, SDIs, and metastatic sites. FOLFIRINOX-treated patients also had 17.3% fewer posttreatment hospitalizations (P = .03) and 20% lower posttreatment costs (P < .001).. In this comparative effectiveness cohort study, FOLFIRINOX was associated with improved survival of approximately 2 months compared with gemcitabine plus nab-paclitaxel and was also associated with fewer posttreatment complications. A randomized clinical trial comparing these first-line treatments is warranted to test the survival and posttreatment hospitalization (or complications) benefit of FOLFIRINOX compared with gemcitabine plus nab-paclitaxel.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

Nab -paclitaxel and gemcitabine (GnP) or FOLFIRINOX (a combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin [FFX]) is currently recognized as the standard first-line regimen for unresectable pancreatic ductal adenocarcinoma (PDAC). Class III β-tubulin (TUBB3) has the potential to predict resistance to taxane in various tumors; therefore, this study aimed to clarify whether TUBB3 is a predictive marker for GnP response.. We retrospectively reviewed 113 patients with PDAC who received GnP or FFX as first-line chemotherapy and examined immunohistochemically the TUBB3 expression in specimens obtained by endoscopic ultrasound-guided fine-needle aspiration.. High TUBB3 expression was associated with a significantly lower disease control rate ( P = 0.017) and shorter progression-free survival (PFS) ( P = 0.019), and multivariate analysis revealed that TUBB3 expression was an independent variable for PFS in the GnP first-line group ( P = 0.045). In addition, in the FFX first-line group, TUBB3 expression was not correlated with PFS or overall survival (OS). In all 113 patients, TUBB3 expression was not also associated with OS.. Class III β-tubulin might be a predictive factor for the response of GnP, but not a prognostic factor for OS, helping the selection of an optimized first-line chemotherapy regimen for unresectable PDAC.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Flavonoids; Fluorouracil; Gemcitabine; Humans; Leucovorin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies; Tubulin

The preferred regimen for unresectable pancreatic cancer following gemcitabine-based chemotherapy is not well-established. This study compared the efficacy of (ⅰ) liposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU)/leucovorin (LV) (nal-IRI/5-FU/LV) versus modified FOLFIRINOX (mFFX) and (ⅱ) nal-IRI/5-FU/LV versus FOLFIRI, respectively, and the safety of the three regimens each other, as second-line chemotherapies for unresectable pancreatic cancer.. This was a retrospective single-center analysis of all patients who were administered nal-IRI/5-FU/LV, mFFX, or FOLFIRI from December 2014 to July 2021 as second-line chemotherapy for pancreatic cancer. The primary endpoint was the overall survival (OS) of all patients, excluding those with locally advanced pancreatic cancer. Regarding safety, we assessed the incidence of grade ≥3 adverse events of interest in all patients.. A total of 137 patients (nal-IRI/5-FU/LV, n = 55; mFFX, n = 39; FOLFIRI, n = 43) were included. The median OS in the nal-IRI/5-FU/LV group, the mFFX group, and the FOLFIRI group was 7.4, 11.8, and 8.4 months, respectively. Compared with the nal-IRI/5-FU/LV group, the mFFX and FOLFIRI groups displayed a hazard ratio of 0.66 [95% confidence interval 0.40-1.08] and 0.87 [95% confidence interval 0.55-1.39], respectively. In the FOLFIRI group, the incidence of grade ≥3 treatment-related adverse events tended to be low among all three groups.. Given the trend toward longer OS in the mFFX group and the lower incidence of adverse events in the FOLFIRI group, both mFFX and FOLFIRI, as well as nal-IRI/5-FU/LV, can be treatment options for second-line chemotherapy for unresectable pancreatic cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

BACKGROUND Studies are ongoing to determine the optimal adjuvant chemotherapy (ACT) for resected pancreatic carcinoma (PC). FOLFIRINOX is a chemotherapy regimen including oxaliplatin, irinotecan, leucovorin, and 5-fluorouracil (5-FU). S-1 is a fluoropyrimidine derivative widely used as ACT for gastrointestinal malignancy. This single-center retrospective study aimed to compare the efficacy and safety of modified FOLFIRINOX (mFOLFIRINOX) with S-1 as ACT for resected PC. MATERIAL AND METHODS A total of 71 patients with PC who accepted ACT after R0 resection between February 2016 and January 2019 were enrolled in this retrospective study. Among these patients, 34 received mFOLFIRINOX regimen chemotherapy (mFFX group), while 37 received S-1 monochemotherapy (S-1 group). The mFOLFIRINOX regimen included oxaliplatin 65 mg/m², leucovorin 400 mg/m², irinotecan 150 mg/m², 5-FU 400 mg/m², and continuous 5-FU 2400 mg/m² (for 46 h), in a 2-week schedule. The S-1 monochemotherapy (80-120 mg/day according to body surface area [BSA], in 2 divided doses for 2 week) was administrated every 3 weeks. We followed up these patients and analyzed the relapse-free survival (RFS), overall survival (OS), and chemotherapy-induced adverse events (AEs). RESULTS The mFFX group demonstrated a markedly higher 3-year RFS (P=0.0332) and OS (P=0.0346) than the S-1 group. Patients in the mFFX group experienced significantly more common and severe thrombocytopenia (P=0.0372), fatigue (P=0.0226), nausea/vomiting (P=0.0337), and diarrhea (P=0.0018). No chemotherapy-induced death was documented. CONCLUSIONS This retrospective study indicated that if dose adjustment and adverse events management are properly administrated, mFOLFIRINOX regimen chemotherapy could result in an improved survival compared with S-1 monochemotherapy for resected PC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Recurrence, Local; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

To evaluate response rate, toxicity, and efficacy of the novel combination of nab-paclitaxel, oxaliplatin, 5-fluorouracil, and leucovorin [FOLFOX-A] in patients with advanced pancreatic ductal adenocarcinoma [PDAC].. BrUOG-292 and BrUOG-318 were two concurrently run, prospective, single-arm phase II studies evaluating FOLFOX-A as first-line therapy in patients with metastatic and locally advanced/borderline resectable PDAC respectively. The FOLFOX-A regimen consisted of 5-fluorouracil, 1200 mg/m 2 /d as a continuous intravenous (IV) infusion over 46 hours, leucovorin 400 mg/m 2 IV, oxaliplatin 85 mg/m 2 IV, and nab-paclitaxel 150 mg/m 2 IV on day 1 every 14 days up to a maximum of 12 cycles. Patients with locally advanced or borderline resectable disease were permitted to stop treatment after 6 cycles and receive radiation therapy and/or surgical exploration if feasible. The primary end point was overall response rate [ORR]. Secondary end points were median progression-free survival [PFS], median overall survival [OS], and safety.. Seventy-eight patients with previously untreated PDAC were enrolled between June 2014 and November 2019; 76 patients were evaluable. The median follow-up was 40 months and 32 months, respectively. overall response rate was 34%. Among the patients enrolled on BrUOG-292 [48 patients], the PFS was 5 months and OS was 11 months, respectively. For those enrolled on BrUOG 318 [28 patients], the PFS was 11 months and OS was 22 months. Treatment-related toxicities included grade 3 fatigue [40%], diarrhea [14%], and neuropathy [2%].. The combination of FOLFOX-A has promising activity in PDAC and may represent an alternative to FOLFIRINOX when reduction of gastrointestinal toxicity is required.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Prospective Studies

There are no randomized control trials (RCTs) comparing gemcitabine and nab-paclitaxel (Gem-Nab) and fluorouracil, folinic acid, irinotecan, oxaliplatin (FOLFIRINOX) for advanced pancreatic cancer (APC). Although it is well known that RCT-based efficacy often does not translate to real-world effectiveness, there is limited literature investigating comparative cost-effectiveness of Gem-Nab vs FOLFIRINOX for APC. We aimed to examine the real-world cost-effectiveness of Gem-Nab vs FOLFIRINOX for APC in Ontario, Canada.. This study compared patients treated with first-line Gem-Nab or FOLFIRINOX for APC in Ontario from April 2015 to March 2019. Patients were linked to administrative databases. Using propensity scores and a stabilizing weights method, an inverse probability of treatment weighted cohort was developed. Mean survival and total costs were calculated over a 5-year time horizon, adjusted for censoring, and discounted at 1.5%. Incremental cost-effectiveness ratio and net monetary benefit were computed to estimate cost-effectiveness from the public health-care payer's perspective. Sensitivity analysis was conducted using the propensity score matching method.. A total of 1988 patients were identified (Gem-Nab: n = 928; FOLFIRINOX: n = 1060). Mean survival was lower for patients in the Gem-Nab than the FOLFIRINOX group (0.98 vs 1.26 life-years; incremental effectiveness = -0.28 life-years [95% confidence interval = -0.47 to -0.13]). Patients in the Gem-Nab group incurred greater mean 5-year total costs (Gem-Nab: $103 884; FOLFIRINOX: $101 518). Key cost contributors include ambulatory cancer care, acute inpatient hospitalization, and systemic therapy drug acquisition. Gem-Nab was dominated by FOLFIRINOX, as it was less effective and more costly. Results from the sensitivity analysis were similar.. Gem-Nab is likely more costly and less effective than FOLFIRINOX and therefore not considered cost-effective at commonly accepted willingness-to-pay thresholds.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Ontario; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

Over the last few years, the role of PDL1/PD-1 in pancreatic cancer development has received increasing attention, and this article is aimed at opening up new ideas for the medicine-based treatment of pancreatic cancer.. To investigate the efficacy and safety of PDL1/PD-1 inhibitors versus FOLFIRINOX regimen in the treatment of advanced pancreatic cancer and its impact on patient survival and to provide a reference basis for clinical treatment of pancreatic cancer.. The 116 pancreatic cancer patients treated in our hospital from September 2019 to September 2021 were selected and divided into 58 cases each in the (instance of watching, noticing, or making a statement) group and the comparison group according to the method based on random number table. The comparison group was treated with FOLFIRINOX, and the group was treated with PDL1/PD-1 stopper. The effectiveness, safety, and hit/effect on survival of the patients in the two groups were compared.. The median chemotherapy cycle for all patients was 4 (1-6), and the combined objective remission rate (0RR) was 36% and the disease control rate (DCR) was 80% after no chemotherapy in 116 patients, with 37.5% 0RR and 81.3% DCR in the observation group and 33.3% 0RR and 77.8% DCR in the comparison group. The greatest number of all patients reached SD, 44%; in the observation group, 43.8%; and in the comparison group, 44.5%. The rate of adverse reactions such as hematological toxicity, neutropenia, anemia, thrombocytopenia, nonhematological toxicity, vomiting, fatigue, infection, diarrhea, intestinal obstruction, and peripheral neuropathy was lower in 10.3% of patients in the observation group than in 25.8% of patients in the comparison group, which was significantly different by. PDL1/PD-1 inhibitors in combination with FOLFIRINOX regimens have shown longer survival than treatment with FOLFIRINOX regimens for pancreatic cancer patients, with reliable clinical efficacy, tolerable adverse effects, and a high safety profile for patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Immune Checkpoint Inhibitors; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Programmed Cell Death 1 Receptor

Systemic chemotherapy plays important role in pancreatic cancer not only for palliative treatment of unresectable disease, but also for neoadjuvant and adjuvant treatment of resectable disease. Most clinical trials of systemic chemotherapy have been conducted in non-elderly patients, and the results cannot always be extrapolated to elderly patients because of the uniqueness of this population. The number of elderly patients with pancreatic cancer has increased in an aging society; therefore, there is an urgent need to develop specific treatments for elderly patients with pancreatic cancer. Gemcitabine or S-1 monotherapy is generally considered appropriate even for vulnerable elderly patients. FOLFIRINOX is considered inapplicable based on its safety profile. Gemcitabine plus nab-paclitaxel and nanoliposomal irinotecan with fluorouracil plus folinic acid can be administered to elderly patients, because the phase III trials have shown the efficacy and safety for patients including those who were 75 years or older. However, the feasibility of these therapies for elderly patients is still under debate since the number of elderly populations was relatively small in these studies. To determine the indication for these regimens in the elderly, the background of each patient should be considered. Geriatric assessment such as the Geriatric 8 and the Geriatric Nutritional Risk Index can identify vulnerabilities and are therefore recommended in daily clinical practice as well as in clinical studies of elderly patients. It is expected that geriatric assessment will elucidate the eligibility criteria for those regimens in elderly individuals. Randomized clinical trials are ongoing to establish a standard treatment in the vulnerable elderly with advanced pancreatic cancer, who cannot tolerate the same regimen as in the non-elderly patients.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Paclitaxel; Pancreatic Neoplasms

This retrospective study investigated the efficacy and safety of nano-liposomal irinotecan (nal-IRI) plus 5-fluorouracil/L-leucovorin (5-FU/l-LV) treatment in the second-line or later setting for advanced pancreatic cancer under real-world conditions.. Between June 2020 and September 2021, a total of 44 patients with unresectable advanced pancreatic cancer treated with nal-IRI + 5-FU/l-LV in our affiliated hospitals were included. The prognosis, predictive factors (including systemic inflammation-based prognostic indicators), and adverse events were investigated.. The median age was 68 (interquartile range 62-73) years old, and 22 patients (50.0%) were male. Concerning tumor factors, 9 patients (20.5%) had local advanced disease and 35 patients (79.5%) had metastases. Twenty-five of the 44 patients were receiving second-line treatment, and 19 were receiving third-line or later treatment. The median overall survival (OS) and progression-free survival were 9.0 (range, 0.7-15.4) months and 4.4 (range, 0.6-15.4) months, respectively. The overall response rate was 5.3%. The disease control rate was 44.7%. Patients with a neutrophil-to-lymphocyte ratio of ≥2.7 had a significant risk of a poor OS (HR = 0.275, p = 0.017). Adverse events were manageable, although gastrointestinal symptoms and neutropenia were observed. The most common grade ≥3 adverse event was neutropenia, which was reported in 20% of patients.. Nal-IRI + 5-FU/l-LV therapy was considered to be a useful regimen as second-line or later treatment for unresectable advanced pancreatic cancer, even in clinical practice.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Male; Middle Aged; Neutropenia; Pancreatic Neoplasms; Retrospective Studies

The value of neoadjuvant radiotherapy (RT) after 5-fluorouracil with leucovorin, oxaliplatin, and irinotecan, with or without dose modifications [(m)FOLFIRINOX], for patients with borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) is uncertain.. We conducted an international retrospective cohort study including consecutive patients with BR PDAC who received (m)FOLFIRINOX as initial treatment (2012-2019) from the Trans-Atlantic Pancreatic Surgery Consortium. Because the decision to administer RT is made after chemotherapy, patients with metastases or deterioration after (m)FOLFIRINOX or a performance score ≥2 were excluded. Patients who received RT after (m)FOLFIRINOX were matched 1:1 by nearest neighbor propensity scores with patients who did not receive RT. Propensity scores were calculated using sex, age (≤70 vs >70 years), WHO performance score (0 vs 1), tumor size (0-20 vs 21-40 vs >40 mm), tumor location (head/uncinate vs body/tail), number of cycles (1-4 vs 5-8 vs >8), and baseline CA 19-9 level (≤500 vs >500 U/mL). Primary outcome was overall survival (OS) from diagnosis.. Of 531 patients who received neoadjuvant (m)FOLFIRINOX for BR PDAC, 424 met inclusion criteria and 300 (70.8%) were propensity score-matched. After matching, median OS was 26.2 months (95% CI, 24.0-38.4) with RT versus 32.8 months (95% CI, 25.3-42.0) without RT (P=.71). RT was associated with a lower resection rate (55.3% vs 72.7%; P=.002). In patients who underwent a resection, RT was associated with a comparable margin-negative resection rate (>1 mm) (70.6% vs 64.8%; P=.51), more node-negative disease (57.3% vs 37.6%; P=.01), and more major pathologic response with <5% tumor viability (24.7% vs 8.3%; P=.006). The OS associated with conventional and stereotactic body RT approaches was similar (median OS, 25.7 vs 26.0 months; P=.92).. In patients with BR PDAC, neoadjuvant RT following (m)FOLFIRINOX was associated with more node-negative disease and better pathologic response in patients who underwent resection, yet no difference in OS was found. Routine use of RT cannot be recommended based on these data.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cohort Studies; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

There is increased use of neoadjuvant fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the management of localized pancreatic ductal adenocarcinoma (PDAC), yet there are few validated biomarkers of treatment response.. Consecutive patients (n = 196) with resectable, borderline resectable or locally advanced PDAC (2012-2019) receiving FOLFIRINOX as initial treatment and with targeted sequencing of a pretreatment biopsy were identified in a prospective institutional database. Genomic alterations were determined in the 4 driver mutations (KRAS, TP53, CDKN2A, SMAD4), and associations between genomic alterations and clinical outcomes were assessed.. Alterations in KRAS (n = 172, 87.8%) and TP53 (n = 131, 66.8%) were common; alterations in CDKN2A (n = 49, 25.0%) and SMAD4 (n = 36, 18.4%) were less frequently observed. A total of 105 patients (53.6%) were able to undergo resection, of whom 8 (7.6%) had a complete/near-complete pathologic response. There were no somatic alterations associated with major pathologic response. Alterations in SMAD4 were associated with a lower rate of surgical resection (27.8% vs 59.4%, p < 0.001); this was additionally observed in a multivariable regression model accounting for resectability status (OR 0.35, 95% confidence interval [CI] 0.15-0.85). Thirty-three patients (16.8%) developed metastatic disease while on neoadjuvant therapy. SMAD4 alterations were associated with a significant risk of metastatic progression on therapy when controlling for resectability status (OR 3.31, 95% CI 1.44-7.60).. SMAD4 alterations are associated with more frequent development of metastasis during neoadjuvant FOLFIRINOX and lower probability of reaching surgical resection. Evaluation of alternative chemotherapy regimens in patients with SMAD4 alterations will be important to distinguish whether this represents a prognostic or predictive biomarker.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Neoplasm Staging; Oxaliplatin; Pancreatic Neoplasms; Prospective Studies; Proto-Oncogene Proteins p21(ras); Retrospective Studies

The regimen of nanoliposomal irinotecan plus 5-fluorouracil and leucovorin (Nal-IRI/FL) was approved in Japan as second-line chemotherapy after gemcitabine-based treatment for pancreatic ductal adenocarcinoma (PDAC) in 2020. We examined the difference in outcome between patients treated with second-line folinic acid, fluorouracil, irinotecan hydrochloride and oxaliplatin (FOLFIRINOX) and those treated with nal-IRI/FL after first-line gemcitabine and nab-paclitaxel (GnP).. The outcomes of 34 patients with PDAC who received second-line FOLFIRINOX (n=21) or nal-IRI/FL (n=13) after GnP at our Department from January 2016 to June 2021 were reviewed retrospectively.. Patient backgrounds did not differ between the groups. Dose reduction was more frequently required for treatment with FOLFIRINOX than with nal-IRI/FL (86% vs. 46%, p=0.022). Pegfilgrastim and aprepitant were used more frequently in the FOLFIRINOX group (both p<0.01). Progression-free survival (5.9 vs. 8.3 months) and overall survival (9.1 vs. 11.2 months) did not differ significantly between the groups. The frequency of grade 3 (Common Terminology Criteria for Adverse Events) or higher adverse events was similar between the groups. All-grade peripheral neuropathy was more common in the FOLFIRINOX group (100% vs. 77%, p=0.048).. FOLFIRINOX and nal-IRI/FL as second-line therapy after GnP provided similar prognoses, although supportive treatment and dose reduction were more frequently required for FOLFIRINOX.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

Objective S-1 and modified FOLFIRINOX (mFFX) were often used as the second-line chemotherapies after failure of gemcitabine plus nab-paclitaxel (GnP) in unresectable pancreatic cancer (UPC) until nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy was approved as an alternative in Japan in 2020. However, the clinical outcomes of S-1 and mFFX after GnP have scarcely been reported. Therefore, we retrospectively studied them. Methods We extracted the clinical data of 86 patients with UPC who received second-line chemotherapy after GnP between 2015 and 2020. Among the patients who had a good organ functions and no massive ascites, 41 patients treated with S-1 and 21 treated with mFFX were enrolled. Results Compared to S-1, mFFX tended to be used for younger patients with a good general condition (median age, 63 vs. 71 years, p<0.01; and performance status 0, 67% vs. 37%, p<0.05). The median progression-free and overall survival were similar between the S-1 (3.7 and 7.2 months, respectively) and mFFX (3.3 and 7.4 months, respectively) groups. The response rate in patients with measurable lesions was 4% (n=1/23) in the S-1 group and 17% (n=2/12) in the mFFX group. The incidence of grade 3 or 4 adverse events was 20% in the S-1 group and 57% (neutrophil count decreased in 43%) in the mFFX group (p<0.01). Conclusion S-1 and mFFX were both acceptable second-line chemotherapies after GnP therapy for UPC, although attention should be paid to myelosuppression during mFFX treatment. Further studies involving nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy are necessary to facilitate the selection of the optimal regimen for each patient.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Middle Aged; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

First-line palliative chemotherapy regimens in advanced pancreatic ductal adenocarcinoma (PDAC) have not been compared in head-to-head phase III randomised controlled trials (RCT). Data on optimum first-line treatment and subsequent sequencing is lacking.. To compare overall survival (OS) between first-line treatment regimens in a real-world population to determine if an optimal therapeutic sequence is associated with survival benefit.. A retrospective analysis of prospectively collated data from the Australasian PURPLE pancreatic cancer registry was undertaken.. From 2016 to 2020, of 1551 pancreatic cancer patients, 615 received palliative-intent chemotherapy. Patients with early-stage resected disease without recurrence (n = 369), radiotherapy alone (n = 43), received supportive care alone (n = 458) or had less than 3 months follow-up (n = 66) were excluded. Median OS was comparable between patients receiving first-line Gemcitabine/Nab-Paclitaxel (n = 376) and those receiving FOLFIRINOX (n = 73) (11.3 versus 12.3 months, P = 0.37), with 38% proceeding to second-line chemotherapy which was associated with longer mOS compared to first-line treatment alone (17.4 versus 8.2 months, P < 0.001). With second-line treatment following prior FOLFIRINOX (n = 29) or Gemcitabine/Nab-Paclitaxel (n = 101), mOS did not differ significantly (17.3 versus 15.9 months, P = 0.92), respectively, whilst median progression-free survival was longer with prior FOLFIRINOX (5.2 versus 2.9 months, P = 0.03).. There was no significant difference in overall survival between either first-line chemotherapy choice, despite patients receiving FOLFIRINOX being younger, fitter, and more likely to have localised disease. However, FOLFIRINOX was associated with delayed progression. In the absence of phase III RCT data, clinicians should be comfortable using either Gemcitabine/Nab-Paclitaxel or FOLFIRINOX as first-line therapy in advanced PDAC.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Registries

Biomarkers predicting treatment response may be used to stratify patients with pancreatic ductal adenocarcinoma (PDAC) for available therapies. The aim of this study was to evaluate the association of circulating cytokines with FOLFIRINOX response and with overall survival (OS).. Serum samples were collected before start and after the first cycle of FOLFIRINOX from patients with PDAC (. Patients with high serum IL-1RA concentrations after one cycle of chemotherapy were less likely to have tumor progression during FOLFIRINOX (OR 0.25,. Circulating IL-1RA, IL-7, IL-18, and MIP-1β concentrations are biomarkers associated with FOLFIRINOX response in PDAC patients, suggesting an important role for specific immune cells in chemotherapy response and PDAC progression. Cytokine-based treatment might improve patient outcome and should be evaluated in future studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Chemokine CCL4; Cytokines; Fluorouracil; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-18; Interleukin-7; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms

Pharmacological ascorbate (P-AscH - , high-dose, intravenous vitamin C) has shown promise as an adjuvant therapy for pancreatic ductal adenocarcinoma (PDAC) treatment. The objective of this study was to determine the effects of P-AscH - when combined with PDAC chemotherapies.. Clonogenic survival, combination indices, and DNA damage were determined in human PDAC cell lines treated with P-AscH - in combination with 5-fluorouracil, paclitaxel, or FOLFIRINOX (combination of leucovorin, 5-fluorouracil, irinotecan, oxaliplatin). Tumor volume changes, overall survival, blood analysis, and plasma ascorbate concentration were determined in vivo in mice treated with P-AscH - with or without FOLFIRINOX.. P-AscH - combined with 5-fluorouracil, paclitaxel, or FOLFIRINOX significantly reduced clonogenic survival in vitro. The DNA damage, measured by γH2AX protein expression, was increased after treatment with P-AscH - , FOLFIRINOX, and their combination. In vivo, tumor growth rate was significantly reduced by P-AscH - , FOLFIRINOX, and their combination. Overall survival was significantly increased by the combination of P-AscH - and FOLFIRINOX. Treatment with P-AscH - increased red blood cell and hemoglobin values but had no effect on white blood cell counts. Plasma ascorbate concentrations were significantly elevated in mice treated with P-AscH - with or without FOLFIRINOX.. The addition of P-AscH - to standard of care chemotherapy has the potential to be an effective adjuvant for PDAC treatment.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Carcinoma, Pancreatic Ductal; Fluorouracil; Humans; Irinotecan; Leucovorin; Mice; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

To compare the treatment outcomes of nanoliposomal-irinotecan (nal-IRI) plus fluorouracil and leucovorin (5-FU/LV) and modified FOLFIRINOX (mFFX) as second-line treatment after gemcitabine with nab-paclitaxel (GnP) for metastatic and recurrent pancreatic cancer.. We retrospectively analyzed consecutive patients with metastatic or recurrent pancreatic cancer treated with nal-IRI plus 5-FU/LV or mFFX after first-line GnP treatment between March 2014 and October 2021 in our hospital. Patient characteristics, treatment outcomes and adverse events were extracted for comparison.. Two hundred sixteen patients were included (nal-IRI plus 5-FU/LV/mFFX: 50/166). Patients in the nal-IRI plus 5-FU/LV group were older, had poorer ECOG PS, and a higher rate of peritoneal metastasis than those in the mFFX group. Median overall survival was 9.5 and 9.8 months (P = 0.97), respectively, and the median progression-free survival was 4.5 vs 4.8 months (P = 0.61), respectively. Anorexia, fatigue and peripheral neuropathy were more common in the mFFX group, but there was no difference in grade 3/4 adverse events between the two groups.. There was no significant difference in efficacy between nal-IRI plus 5-FU/LV and mFFX after GnP. Nal-IRI plus 5-FU/LV appears to be a viable alternative to mFFX as second-line treatment after GnP.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Liposomes; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies; Treatment Outcome

Although FOLFIRINOX (L-Leucovorin/5-FU/Irinotecan/Oxaliplatin) is established as one of the standard therapies for patients with metastatic pancreatic cancer, the modified FOLFIRINOX (mFOLFIRINOX) is often used in clinical practice to reduce the incidence of toxicities. Febrile neutropenia (FN) and severe neutropenia during FOLFIRINOX are especially frequently observed in Japanese patients. In this study, we evaluated the incidence of FN and severe neutropenia, and explored the risk factors for severe neutropenia in patients receiving treatment with mFOLFIRINOX. The data of patients who had received mFOLFIRINOX between December 2013 and December 2014 at the National Cancer Center Hospital East were reviewed retrospectively. We graded the neutropenia severity and defined ≥ Grade 3 neutropenia as severe neutropenia. Univariate and multivariate analysis were undertaken to evaluate the associations with risk of development of severe neutropenia. A total of 122 patients were enrolled in this study. Sixty two patients (51%) and 10 patients (8%) developed severe neutropenia and FN, respectively. Multivariate analysis identified a low baseline white blood cell count (odds ratio [OR], 14.50; 95% confidence interval (CI), 3.27-111.14; p = 0.002) and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism (OR, 2.84; 95% CI, 1.18-7.17; p = 0.023) as independent risk factors for severe neutropenia. The incidences of severe neutropenia and FN in patients receiving mFOLFIRINOX in our clinical practice were comparable to previous reports. The risk factors for severe neutropenia in patients receiving mFOLFIRINOX were a low baseline white blood cell count and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Incidence; Irinotecan; Leucovorin; Neutropenia; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Risk Factors

Annually, approx. 4000 patients are diagnosed with pancreatic cancer in Poland, and the number of deaths is close to the number of diagnoses. Such a high morbidity/mortality ratio is caused by a high percentage of unresectable lesions (about 80%) and chemoresistance, which, among other things, is due to the specific desmoplastic environment. Currently, there are 2 main systemic treatment regimens for pancreatic cancer: FOLFIRINOX (which is a combination of folic acid, fluorouracil (5-FU), irinotecan, and oxaliplatin) and combined treatment with nab-paclitaxel plus gemcitabine (NPXL+GMC).. In order to increase the effectiveness of systemic treatments for individual patients, cell lines derived from resected pancreatic tumors were developed and their chemosensitivity to various agents was examined. The hypothesis was that patients may benefit from individualization of chemotherapy.. Patients with histopathologically confirmed pancreatic cancer were operated on using irreversible electroporation (IRE) procedure. After isolating and establishing individual cell lines, chemosensitivity to 5-FU, GMC and NPXL was determined using MTT assay in primary and metastatic cell cultures.. Three primary cell lines were isolated for the prediction of chemosensitivity. Gemcitabine was shown to be more effective at lower doses compared to 5-FU, while NPXL was more effective than 5-FU, and both of these were less effective in metastatic cells. Pancreatic cancer cell chemoresistance was confirmed in stage IV.. Determination of chemosensitivity profiles using cell lines may help in the selection of systemic treatments for individual patients. This method can be the basis for a personalized planned chemotherapeutic protocol.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms

Pancreatic panniculitis is characterized by subcutaneous fat necrosis and is a rare presentation of an underlying pancreatic disease, appearing in approximately 2-3% of all patients with a pancreatic disease. The nodules usually involve the lower extremities. Pancreatic panniculitis is commonly associated with acute or chronic pancreatitis, and occasionally with pancreatic cancer, especially acinar cell carcinoma.. A 77-year-old Caucasian woman with no significant medical history was referred to our center with multiple painful, itchy, and warm red/blue cutaneous nodules on the left lower leg. These skin lesions were consistent with the clinical diagnosis of panniculitis. The skin biopsy obtained showed a predominantly lobular panniculitis with fat necrosis of which the aspect was highly suspicious for pancreatic panniculitis. Further analysis revealed high lipase serum of > 3000 U/L (normal range < 60 U/L), and on computed tomography scan a mass located between the stomach and the left pancreas was seen. Endoscopic ultrasonography-guided fine-needle biopsy confirmed the diagnosis of acinar cell carcinoma. After discussing the patient in the pancreatobiliary multidisciplinary team meeting, laparoscopic distal pancreatectomy including splenectomy and en bloc wedge resection of the stomach due to tumor in-growth was performed. The cutaneous nodules on both legs disappeared 1-2 days after surgery. No long-term complications were reported during follow-up. One year after surgery, the patient presented with similar symptoms as preoperatively. Computed tomography scan showed local recurrence and distal metastases, which were subsequently confirmed by biopsy. She started with palliative folinic acid-fluorouracil-irinotecan-oxaliplatin chemotherapy but stopped after two cycles because of disease progression. The patient died 2 months later, 13 months after surgical resection.. This case illustrates the importance of clinically recognizing cutaneous nodules and pathological recognizing the specific microscopic changes as sign of a (malignant) pancreatic disease.

Topics: Acinar Cells; Aged; Carcinoma, Acinar Cell; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Lipase; Lower Extremity; Oxaliplatin; Pancreatic Diseases; Pancreatic Neoplasms; Panniculitis

The multi-drug combination regime, FOLFIRINOX, is a standard of care chemotherapeutic therapy for pancreatic cancer patients. However, systematic evaluation of potential pharmacodynamic interactions among multi-drug therapy has not been reported previously. Here, pharmacodynamic interactions of the FOLFIRINOX agents (5-fluorouracil (5-FU), oxaliplatin (Oxa) and SN-38, the active metabolite of irinotecan) were assessed across a panel of primary and established pancreatic cancer cells. Inhibition of cell proliferation was quantified for each drug, alone and in combination, to obtain quantitative, drug-specific interaction parameters and assess the nature of drug interactions. The experimental data were analysed assuming Bliss independent interactions, and nonlinear regression model fitting was conducted in SAS. Estimates of the drug interaction term, psi (ψ), revealed that the Oxa/SN-38 combination appeared synergistic in PANC-1 (ψ = 0.6, 95% CI = 0.4, 0.9) and modestly synergistic, close to additive, in MIAPaCa-2 (ψ = 0.8, 95% CI = 0.6, 1.0) in 2D assays. The triple combination was strongly synergistic in MIAPaCa-2 (ψ = 0.2, 95% CI = 0.1, 0.3) and modestly synergistic/borderline additive in PANC-1 2D (ψ = 0.8, 95% CI = 0.6, 1.0). The triple combination showed antagonistic interactions in the primary PIN-127 and 3D PANC-1 model (ψ > 1). Quantitative pharmacodynamic interactions have not been described for the FOLFIRINOX regimen; this analysis suggests a complex interplay among the three chemotherapeutic agents. Extension of this pharmacodynamic analysis approach to clinical/translational studies of the FOLFIRINOX combination could reveal additional pharmacodynamic interactions and guide further refinement of this regimen to achieve optimal clinical responses.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Culture Techniques; Drug Combinations; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms

Topics: Adenocarcinoma; DNA-Binding Proteins; Female; Germ-Line Mutation; Humans; Leucovorin; Middle Aged; Nivolumab; Pancreatic Neoplasms

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Fluorouracil; Humans; Irinotecan; Leucovorin; Pancreatic Neoplasms

We hereby report a case in which a patient with multiple lung metastases of pancreatic cancer continued chemotherapy and maintained good performance status(PS)for 48 months after recurrence. But her disease progressed rapidly after withdrawal of chemotherapy, resulting in her death in a short period of time. The patient was a 66-year-old woman who underwent a substomach preserving pancreaticoduodenectomy for pancreatic head cancer at the age of 60 years. She was diagnosed as fT3N1M0, fStage ⅡB. During postoperative adjuvant chemotherapy S-1, multiple lung metastases were noted on CT scan 2 years after surgery. Thereafter, she was treated with gemcitabine(GEM)alone, GEM plus nab-paclitaxel(GnP), nal-CPT-11 plus 5-FU plus Leucovorin, and FOLFIRINOX for 48 months sequentially. Each of which achieved a best overall response SD or better. However, Trousseau syndrome developed following community-acquired pneumonia during chemotherapy withdrawal due to myelosuppression. The disease progressed rapidly and resulted in her death 50 months after relapse. The results suggest that chemotherapy may have contributed significantly to disease control in this case.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Pancreatic Neoplasms

The aim of the study is to compare the efficacy and safety of 3 chemotherapy regimens used as first-line treatments in the real-life management of metastatic pancreatic cancer.. A total of 218 patients were included in this multicenter study. Gemcitabine (Gem, n = 71), gemcitabine-cisplatin (Gem-Cis, n = 91), and FOLFIRINOX (a combination of leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin [FFX], n = 56) treatments were compared.. Overall response rate was significantly higher in the FFX group (50.0%) than in the Gem (28.2%) and Gem-Cis (27.5%) groups (P = 0.010). Median progression-free survival (8.4 vs 4.6 and 5.5 months, respectively, P < 0.001) and overall survival (16.4 vs 8.1 and 8.7 months, respectively, P = 0.002) were significantly longer in the FFX group than in the Gem and Gem-Cis groups. Toxicity of any grade was noted in 46 (64.8%), 56 (61.5%), and 49 (87.5%) patients in the Gem, Gem-Cis, and FFX groups, respectively (P = 0.003).. In our study, FFX regimen provides a significant advantage over the other treatment regimens in terms of response rates and survival. Treatment toxicity was more frequent but manageable with the FFX regimen.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival

Recent advances in prophylactic anticoagulation and antineoplastic treatment for advanced pancreatic cancer (aPC) warrant an updated reassessment of thromboembolic risk in this population. This multicenter retrospective cohort study aims to comprehensively characterize incidence, risk factors, and outcomes of venous (VTE) and arterial thromboembolism (ATE) in homogenously treated patients with aPC.. Four hundred and fifty-five patients with aPC undergoing palliative first-line chemotherapy (Gemcitabine/nab-Paclitaxel (GN) or FOLIRINOX) were included. Primary outcomes were objectively confirmed VTE and/or ATE.. Patients with aPC undergoing palliative first-line chemotherapy with FOLFIRINOX or GN face a high risk for VTE/ATE and its diagnosis is linked to worse clinical outcomes. VTE-risk prediction models have limited ability to sub-stratify thrombotic events in this high-risk scenario.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies; Venous Thromboembolism

FOLFIRINOX and FOLFOXIRI are combination chemotherapy treatments that incorporate the same drug cocktail (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) but exploit an altered dosing regimen when used in the management of pancreatic and colorectal cancer, respectively. Both have proven effective in extending life when used to treat patients with metastatic disease but are accompanied by significant adverse effects. To facilitate improved tumour-targeting of this drug combination, an ultrasound responsive microbubble formulation loaded with 5-fluorouridine, irinotecan and oxaliplatin (FIRINOX MB) was developed and its efficacy tested, together with the non-toxic folinic acid, in preclinical murine models of pancreatic and colorectal cancer. A significant improvement in tumour growth delay was observed in both models following ultrasound targeted microbubble destruction (UTMD) mediated FIRINOX treatment with pancreatic tumours 189% and colorectal tumours 82% smaller at the conclusion of the study when compared to animals treated with a standard dose of FOLFIRINOX. Survival prospects were also improved for animals in the UTMD mediated FIRINOX treatment group with an average survival of 22.17 ± 12.19 days (pancreatic) and 44.40 ± 3.85 days (colorectal) compared to standard FOLFIRINOX treatment (15.83 ± 4.17 days(pancreatic) and 37.50 ± 7.72 days (colon)). Notably, this improved efficacy was achieved using FIRINOX MB that contained 5-fluorouricil, irinotecan and oxaliplatin loadings that were 13.44-fold, 9.19-fold and 1.53-fold lower than used for the standard FOLFIRINOX treatment. These results suggest that UTMD enhances delivery of FIRINOX chemotherapy, making it significantly more effective at a substantially lower dose. In addition, the reduced systemic levels of 5-fluorouracil, irinotecan and oxaliplatin should also make the treatment more tolerable and reduce the adverse effects often associated with this treatment.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Mice; Microbubbles; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome; Uridine

We investigated whether organoids can be generated from resected tumors of patients who received eight cycles of neoadjuvant FOLFIRINOX chemotherapy before surgery, and evaluated the sensitivity/resistance of these surviving cancer cells to cancer therapy.. We generated a library of 10 pancreatic ductal adenocarcinoma (PDAC) organoid lines: five each from treatment-naïve and FOLFIRINOX-treated patients. We first assessed the histologic, genetic, and transcriptional characteristics of the organoids and their matched primary PDAC tissue. Next, the organoids' response to treatment with single agents-5-FU, irinotecan, and oxaliplatin-of the FOLFIRINOX regimen as well as combined regimen was evaluated. Finally, global mRNA-seq analyses were performed to identify FOLFIRINOX resistance pathways.. All 10 patient-derived PDAC organoids recapitulate histologic, genetic, and transcriptional characteristics of their primary tumor tissue. Neoadjuvant FOLFIRINOX-treated organoids display resistance to FOLFIRINOX (5/5), irinotecan (5/5), and oxaliplatin (4/5) when compared with treatment-naïve organoids (FOLFIRINOX: 1/5, irinotecan: 2/5, oxaliplatin: 0/5). 5-Fluorouracil treatment responses between naïve and treated organoids were similar. Comparative global transcriptome analysis of treatment-naïve and FOLFIRINOX samples-in both organoids and corresponding matched tumor tissues-uncovered modulated pathways mainly involved in genomic instability, energy metabolism, and innate immune system.. Resistance development in neoadjuvant FOLFIRINOX organoids, recapitulating their primary tumor resistance, suggests continuation of FOLFIRINOX therapy as an adjuvant treatment may not be advantageous for these patients. Gene-expression profiles of PDAC organoids identify targetable pathways involved in chemoresistance development upon neoadjuvant FOLFIRINOX treatment, thus opening up combination therapy possibilities.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Organoids; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

FOLFIRINOX has demonstrated promising results for patients with pancreatic ductal adenocarcinoma (PDAC). Chemotherapy-induced immunogenic cell death can prime antitumor immune responses. We therefore performed high-dimensional profiling of immune cell subsets in peripheral blood to evaluate the impact of FOLFIRINOX on the immune system.. Peripheral blood mononuclear cells (PBMC) were obtained from treatment-naïve (. Our study reveals that neoadjuvant chemotherapy with FOLFIRINOX enhances effector T cells and downregulates suppressor cells. These data indicate that FOLFIRINOX neoadjuvant therapy may improve immune therapy and clinical outcome in patients with PDAC.

Topics: Antineoplastic Combined Chemotherapy Protocols; CD8-Positive T-Lymphocytes; Fluorouracil; Humans; Irinotecan; Leucovorin; Leukocytes, Mononuclear; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms

In this study, we explored the predictive value of serum microRNA (miRNA) expression for early tumor progression during FOLFIRINOX chemotherapy and its association with overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). A total of 132 PDAC patients of all disease stages were included in this study, of whom 25% showed progressive disease during FOLFIRINOX according to the RECIST criteria. MiRNA expression was analyzed in serum collected before the start and after one cycle of chemotherapy. In the discovery cohort (

Topics: Adult; Aged; Aged, 80 and over; Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Disease Progression; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Leucovorin; Male; MicroRNAs; Middle Aged; Multivariate Analysis; Oxaliplatin; Pancreatic Neoplasms; Prospective Studies

According to the NAPOLI-1 trial, nanoliposomal irinotecan (nal-IRI) plus fluorouracil/folinic acid (5-FU/LV) showed improved overall survival compared to fluorouracil alone for patients with metastatic pancreatic cancer who were previously treated with gemcitabine-based therapy. In that trial, Asian patients had frequent dose modification due to haematological toxicity. There has been limited information on the clinical benefits and toxicity of this regimen in real-world settings. In this study, we assessed real-world experience of nal-IRI plus 5-FU/LV in patients with advanced pancreatic cancer after gemcitabine failure.. Fifty-one patients received nal-IRI plus 5-FU/LV between January 2015 and December 2020. The median age was 67 years, and males were 58.8%. A total of 40 (78.4%) and 11 (21.6%) patients had received one and two lines of prior chemotherapy before enrollment, respectively. Median progression-free survival was 2.8 months (95% CI 1.8-3.7) and median overall survival was 7.0 months (95% CI 6.0-7.9). Chemotherapy doses were reduced or delayed in 33 (64.7%) patients during the first 6 weeks and median relative dose intensity was 0.87. Thirty-six (70.6%) patients experienced grade 3 or 4 adverse events, most commonly neutropenia (58.8%). Most non-haematologic adverse events were under grade 2. Since the start of first-line chemotherapy, median overall survival was 16.3 months (95% CI 14.1-18.4).. Nal-IRI plus 5-FU/LV seems to be effective, with manageable toxicities, following gemcitabine-based treatment in patients with metastatic pancreatic ductal adenocarcinoma. Nal-IRI plus 5-FU/LV following gemcitabine with nab-paclitaxel is a feasible sequential treatment option in patients with metastatic pancreatic cancer.. Retrospectively registered.

Topics: Aged; Albumins; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Drug Administration Schedule; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liposomes; Male; Middle Aged; Nanoconjugates; Neutropenia; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival; Proportional Hazards Models; Retrospective Studies

Gemcitabine-nab-paclitaxel (GEMNAB) and fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) both improve survival of patients with advanced pancreatic cancer when compared with single-agent gemcitabine in clinical trials.. To describe changes in the survival of patients with advanced pancreatic cancer associated with sequential drug-funding approvals and to determine if there exist distinct patient populations for whom GEMNAB and FOLFIRINOX are associated with survival benefit.. This population-based, retrospective cohort study examined all incident cases of advanced pancreatic cancer treated with first-line chemotherapy in Ontario, Canada (2008-2018) that were identified from the Cancer Care Ontario (Ontario Health) New Drug Funding Program database. Statistical analysis was performed from October 2020 to January 2021.. First-line chemotherapy for advanced pancreatic cancer.. The main outcomes were the proportion of patients treated with each chemotherapy regimen over time and overall survival for each regimen. Cox proportional hazards regression models were used to compare overall survival between treatment regimens after adjustment for confounding variables, inverse probability of treatment weighting, and matching.. From 2008 to 2018, 5465 patients with advanced pancreatic cancer were treated with first-line chemotherapy in Ontario, Canada. The median (range) age of patients was 66.9 (27.8-93.4) years; 2447 (45%) were female; 878 (16%) had prior pancreatic resection, and 328 (6%) had prior adjuvant gemcitabine. During the time period when only gemcitabine and FOLFIRINOX were funded (2011-2015), 49% (929 of 1887) received FOLFIRINOX. When GEMNAB was subsequently funded (2015-2018), 9% (206 of 2347) received gemcitabine, 44% (1034 of 2347) received FOLFIRINOX, and 47% (1107 of 2347) received GEMNAB. The median overall survival increased from 5.6 months (95% CI, 5.1-6.0 months) in 2008 to 2011 to 6.9 months (95% CI, 6.5-7.4 months) in 2011 to 2015 to 7.6 months (95% CI, 7.1-8.0 months) in 2015 to 2018. Patients receiving FOLFIRINOX were younger and healthier than patients receiving GEMNAB. After adjustment and weighting, FOLFIRINOX was associated with better overall survival than GEMNAB (hazard ratio [HR], 0.75 [95% CI, 0.69-0.81]). In analyses comparing patients treated with GEMNAB and gemcitabine, GEMNAB was associated with better overall survival (HR, 0.86 [95% CI, 0.78-0.94]).. This cohort study of patients with advanced pancreatic cancer receiving first-line palliative chemotherapy within a universal health care system found that drug funding decisions were associated with increased uptake of new treatment options over time and improved survival. Both FOLFIRINOX and GEMNAB were associated with survival benefits in distinct patient populations.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Ontario; Oxaliplatin; Palliative Care; Pancreatic Neoplasms; Retrospective Studies; Survival Rate

Pancreatic cancer has a poor prognosis, and it is traditionally treated with chemotherapy. Fortunately, immunotherapy has rapidly changed the landscape of solid tumor treatment, and improving the survival of cancer patients. However, pancreatic cancer is non-immunogenic, and single agent immunotherapies are unfavorable to its prognosis.. Here, we report a case of stage IV pancreatic cancer in a patient with TSC2 and SMAD4 mutations treated with immunotherapy when the disease progressed after multi-line chemotherapy. Next generation sequencing (NGS) confirmed the presence of TSC2 and SMAD4 mutations and microsatellite stability (MSS). When the disease progressed after chemotherapy, a combination strategy was devised consisting of chemotherapy (S-1) and sintilimab. The patient had a partial response to therapy with this regimen, the lesions were significantly reduced and nearly disappeared. In metastatic pancreatic cancer, responses of this magnitude are rarely seen.. This outcome reveals that this combination can be effective in treating metastatic pancreatic cancer, especially in pancreatic cancer patients with SMAD4 and TSC2 mutations. This may help increase the use of this therapy in large-scale clinical research.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; DNA Mutational Analysis; Drug Combinations; Drug Resistance, Neoplasm; Fluorouracil; High-Throughput Nucleotide Sequencing; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Staging; Oxaliplatin; Oxonic Acid; Pancreatic Neoplasms; Prognosis; Programmed Cell Death 1 Receptor; Response Evaluation Criteria in Solid Tumors; Smad4 Protein; Tegafur; Tuberous Sclerosis Complex 2 Protein

The prognosis of pancreatic cancer (PC) has been improved by new chemotherapy regimens (combination of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel (GnP)). Unfortunately, chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event of these two regimens. The efficacy of pregabalin for CIPN has been reported in previous studies. However, the efficacy of mirogabalin for CIPN remains unknown. Thus, in this study, we aimed to clarify which drug (mirogabalin or pregabalin) was more valuable for improving CIPN.. A total of 163 PC patients who underwent FOLFIRINOX or GnP between May 2014 and January 2021 were enrolled. Among them, 34 patients were diagnosed with CIPN. Thirteen patients were treated with mirogabalin (mirogabalin group), and twenty-one patients were treated with pregabalin (pregabalin group). Treatment efficacy was compared between the two groups.. In both the mirogabalin group and the pregabalin group, the grade of patients with CIPN at 2, 4, and 6 weeks after the initiation of treatment showed significant improvement compared to the pretreatment grade. Notably, the rate of CIPN improvement was higher in the mirogabalin group than in the pregabalin group (2 weeks: 84.6% (11/13) vs 33.3% (7/21), P value = 0.005; 4 weeks, 6 weeks: 92.3% (12/13) vs 33.3% (7/21), P value = 0.001).. Although both mirogabalin and pregabalin were effective at improving CIPN, mirogabalin might be a suitable first choice for CIPN in PC patients.. Not applicable.

Topics: Aged; Analgesics; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Peripheral Nervous System Diseases; Pregabalin; Retrospective Studies; Treatment Outcome

A 70-year-old man with metastatic pancreatic ductal adenocarcinoma(cT4N1bM1, cStage Ⅳ)underwent chemotherapy with modified FOLFIRINOX without any severe adverse event to 20 cycles. In the middle of that, concurrent irradiation toward primary lesion(total dose, 43.2 Gy)was administered. Grade 1 adverse events include anemia, thrombocytopenia, hypoalbuminemia, hypokalemia, alkaline phosphatase increased, hypertension, peripheral sensory neuropathy, fatigue, anorexia and nausea. The relative dose intensities of oxaliplatin, irinotecan and fluorouracil at 6 months after beginning of treatment were 77.6, 84.0 and 88.3 percent, respectively. The total dose of administered oxaliplatin was 825 mg to the square meter. The primary lesion had been stable for the 20 cycles, although peritoneal dissemination had progressively increased in size. For 17 months, opioid was not necessary for the control of abdominal or back pain to the end of third-line treatment. Though safety or clinical benefits of modified FOLFIRINOX plus concurrent radiotherapy for metastatic pancreatic ductal adenocarcinoma have not been reported, in this case, such treatment might contribute to prolong prognosis or prevent developing abdominal or back pain.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Oxaliplatin; Pancreatic Neoplasms

There has been growing evidence on the utility of neoadjuvant FOLFIRINOX in borderline resectable (BR) or locally advanced (LA) pancreatic cancer. However, factors predicting survival in these patients remain to be identified, and we aimed to identify these prognostic factors.. Between January 2013 and April 2017, patients with BR or LA pancreatic cancer who received FOLFIRINOX as their initial treatment were identified. Demographic data and clinical outcomes, including the chemotherapy response, conversion to resection, and survival, were reviewed.. A total of 117 patients with BR (n=39) or LA (n=78) pancreatic cancer were included. Of these patients, 29 (24.8%) underwent curative surgery, and R0 resection was achieved in 21 patients (72.4%). The median progression-free survival and overall survival time of all patients were 11.6 and 19.0 months, respectively. In resected patients, the median relapse-free survival and overall survival times were 14.8 and 28.6 months, respectively. In the multivariate Cox model, the lowest level of serum carbohydrate antigen 19-9 (CA 19-9) and resection after FOLFIRINOX were independent factors for improved overall survival. In the subgroup analysis of patients with initial. In patients with BR or LA pancreatic cancer, FOLFIRINOX is a valuable neoadjuvant treatment that enables curative surgery in approximately one-quarter of patients and significantly improves overall survival. In these patients, the prognosis can be estimated using the lowest level of serum CA 19-9, operative status, and initial FDG-PET SUVmax.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Retrospective Studies

Patients with borderline resectable pancreatic cancer are at high risk of incomplete resection with upfront surgery. Currently, no standard induction chemotherapy regimen exists for these patients. Both FOLFIRINOX (5-FU, irinotecan, & oxaliplatin) and gemcitabine plus nab-paclitaxel (GnP) have shown better efficacy than gemcitabine alone in advanced pancreatic cancer. The current study aims to assess outcomes of real-world patients with borderline resectable pancreatic cancer who received induction FOLFIRINOX or GnP.. In this population-based multicenter retrospective cohort study, patients with biopsy-proven borderline resectable pancreatic cancer diagnosed from 2011 to 2017, in the province of Saskatchewan, Canada, who received FOLFIRINOX or GnP were assessed. Kaplan Meier methods and log rank tests were performed for survival analyses.. Of 161 patients with pancreatic cancer who received FOLFIRINOX or GnP during the study period, 20 eligible patients with borderline resectable pancreatic cancer were identified. Ten patients each received FOLFIRINOX or GnP. Eleven patients had partial response (5, FOLFIRINOX; 6, GnP); 3 progressed during treatment. Five patients (4, FOLFIRINOX; 1, GnP; p = NS) underwent curative surgery. The median progression-free survival was 17 months in FOLFIRINOX (95% CI, 5.3-28.6) vs. 9 months (95% CI, 3.0-15) in GnP groups (p = 0.27). Overall, 80% patients in GnP vs. 40% in FOLFIRINOX died from progressive disease. The median overall survival has not been reached in FOLFIRINOX group versus 16 months (95% CI, 9.3-22.7) in GnP group (p = 0.15).. The current study suggests that patients with borderline resectable pancreatic cancer who received FOLFIRINOX tend to have better outcomes. Future studies are warranted to establish a preferred systemic therapy for patients with borderline resectable pancreatic cancer.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies; Saskatchewan; Survival Analysis; Treatment Outcome

Resectability of pancreatic carcinoma (PC) is directly linked to vascular extension (Tempero MA et al. in J Natl Compr Canc Netw 15(8):1028-1061, 2017. https://doi.org/10.6004/jnccn.2017.0131 ; Isaji S et al. in Pancreatology 18(1):2-11, 2018. https://doi.org/10.1016/j.pan.2017.11.011 ). Involvement of the celiac axis (CA) is typically a contraindication to surgery. High postoperative morbidity and subsequent poor prognosis have been observed in this case, especially for contact > 180° requiring arterial resection (Tempero MA et al. 2017). Recent medical advances in PC treatment, such as FOLFIRINOX-based chemotherapy eventually followed by chemoradiation therapy, offer the potential to select tumour for surgery and to obtain a negative-margin resection even in case of unresectable PC at diagnosis (Suker M et al. in Lancet Oncol 17(6):801-10, 2016. https://doi.org/10.1016/s1470-2045(16)00172-8 ; Pietrasz D et al. in Ann Surg Oncol 26(1):109-117, 2019. https://doi.org/10.1245/s10434-018-6931-6 ). A major pathologic response has been observed in more than 20% of patients after this treatment and is associated with an improved survival (Suker M et al. 2016; Pietrasz D et al. 2019). This evolution allows aggressive surgical strategies with the possibility of long-term disease control for patients showing a good response to induction treatment.. This video presents the case of a 66-year-old man diagnosed with a locally advanced ductal adenocarcinoma of the pancreatic body with a 360° involvement of the CA and the hepatic artery. After eight courses of FOLFIRINOX chemotherapy and a capecitabin-based chemoradiation, a surgical exploration was planned for potential resection.. The key steps of the procedure are presented, i.e. surgical exposition, assessment of resectability with frozen sections of peri-arterial tissues, en bloc resection (Strasberg SM et al. in Surgery 133(5):521-527, 2003. https://doi.org/10.1067/msy.2003.146 ), and primary end-to-end arterial reconstruction.. A modified Appleby operation for locally advanced PC is a technically challenging but feasible procedure in experienced teams. It offers the possibility of en bloc R0 resection of a locally advanced PC with the potential of long-term disease local control. This video may help surgeons to perform this complex intervention.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms

To identify multiparametric MRI biomarkers to predict the tumor response to neoadjuvant FOLFIRINOX therapy in patients with borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC).. From May 2016 to March 2018, adult patients with BR or LA PDAC were prospectively enrolled in this study. They received eight cycles of FOLFIRINOX therapy and underwent multiparametric MRI twice (at baseline and after the second cycle). MRI evaluations included dynamic contrast-enhanced MRI, intravoxel incoherent motion diffusion-weighted imaging, and assessment of T2* relaxivity (R2*) and the change in T1 relaxivity (ΔR1, equilibrium phase R1 minus non-enhanced R1) of the tumors. Factors to predict the responders determined by the best overall response during FOLFIRINOX therapy and those to predict progression-free survival (PFS) and overall survival (OS) were evaluated using multivariable logistic regression and the Cox proportional hazard model.. Forty-one patients (mean age, 60.3 years ± 9.3; 24 men) were included. Among the clinical and MRI factors, the baseline ΔR1 (adjusted odds ratio, 31.07; p = 0.008) was the only independent predictor for tumor response. The baseline ΔR1 was also an independent predictor for PFS (adjusted hazard ratio, 0.40; p = 0.033) along with R0 resection. The use of a cutoff ΔR1 value of ≥ 1.31 s. The baseline tumor ΔR1 value may be useful to predict tumor response and survival in patients with BR or LA PDAC receiving FOLFIRINOX neoadjuvant therapy.. • Baseline ΔR1 was an independent predictor for tumor response (adjusted odds ratio, 31.07; p = 0.008) and progression-free survival (adjusted hazard ratio, 0.40; p = 0.033) in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma receiving neoadjuvant FOLFIRINOX therapy. • The criterion of baseline ΔR1 value ≥ 1.31 s

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Multiparametric Magnetic Resonance Imaging; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms

Although many studies have reported the promising effect of neoadjuvant treatment for borderline resectable pancreatic cancer (BRPC) to increase resectability, only a few studies have recommended the use of first-line chemotherapeutic agents as neoadjuvant treatment for BRPC. The current study compared clinical outcomes between gemcitabine and FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) in patients with BRPC.. In this single-center retrospective study, 100 BRPC patients treated with neoadjuvant chemotherapy and resection from 2008 to 2018 were reviewed. Clinical outcomes included overall survival, resectability, and recurrence patterns after gemcitabine or FOLFIRINOX treatment.. For neoadjuvant chemotherapy, gemcitabine was administered to 34 patients and FOLFIRINOX to 66. Neoadjuvant radiotherapy was administered to 27 patients (79.4%) treated with gemcitabine and 19 (28.8%) treated with FOLFIRINOX (p<0.001). The 2- and 5-year survival rates (YSRs) were significantly higher after FOLFIRINOX (2YSR, 72.2%; 5YSR, 46.0%) than after gemcitabine (2YSR, 58.4%; 5YSR, 19.1%; p=0.041). The margin negative rate was comparable (gemcitabine, 94.1%; FOLFIRINOX, 92.4%; p=0.753), and the tumor size change in percentage showed only a marginal difference (gemcitabine, 20.5%; FOLFIRINOX, 29.0%; p=0.069). Notably, the metastatic recurrence rate was significantly lower in the FOLFIRINOX group (n=20, 52.6%) than in the gemcitabine group (n=22, 78.6%; p=0.001). The rate of adverse events after chemotherapy was significantly higher with FOLFIRINOX than with gemcitabine (43.9%, 20.6%, respectively; p=0.037).. FOLFIRINOX provided more clinical and oncological benefit than gemcitabine, with significantly higher overall survival and lower cumulative recurrence rates in BRPC. However, since FOLFIRINOX causes more adverse effects, the regimen should be individualized based on patient's general condition and clinical status.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

We aimed to assess the ability of CT-determined resectability, as defined by a recent version of NCCN criteria, and associated CT findings to predict margin-negative (R0) resection in patients with PDAC after neoadjuvant FOLFIRINOX chemotherapy.. Sixty-four patients (36 men and 28 women; mean age, 58.8 years) with borderline resectable or unresectable PDAC who received neoadjuvant FOLFIRINOX were evaluated retrospectively. CT findings were independently assessed by two abdominal radiologists according to NCCN criteria (version 3. 2019). Tumor resectability was classified as resectable, borderline resectable, or unresectable, and change in resectability was classified as regression, stability, or progression. The associations of R0 resection rate with CT-determined resectability and change in resectability categories were evaluated, as were the sensitivity and specificity of NCCN criteria for R0 resection. Factors associated with R0 resection were identified by logistic regression analysis.. R0 resection rate did not differ significantly among the resectable, borderline resectable, or unresectable PDAC (67-73%, p = 0.95) or among PDAC with regression, stability, or progression (56-77%, p = 0.39). The sensitivity and specificity for R0 resection were 67% and 37%, respectively, for resectability (resectable/borderline vs. unresectable) and 80% and 21%, respectively, for changes in resectability (regression/stable vs. progression). Low-contrast enhancement of soft tissue contacting artery (≤ 46.4 HU) was independently associated with R0 resection (p = 0.01).. CT-determined resectability after neoadjuvant FOLFIRINOX chemotherapy was relatively insensitive and non-specific for predicting R0 resection. Low-contrast enhancement of soft tissue contacting artery may increase the ability of CT to predict R0 resection.. • Margin-negative resection rate of pancreatic cancer following FOLFIRINOX therapy did not differ among each resectability (67-73%, p = 0.95) based on NCCN criteria or changes in resectability categories (56-77%, p = 0.39). • The sensitivity and specificity for margin-negative resection were 67% and 37% for resectability (resectable/borderline vs. unresectable) and 80% and 21% for changes in resectability (regression/stable vs. progression). • Low-contrast enhancement of soft tissue contacting artery (≤ 46.4 HU) was independently associated with margin-negative resection (p = 0.01).

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Tomography, X-Ray Computed; Treatment Outcome

The incidence of pancreatic cancer is increasing in developed countries. The incorporation of new therapies, to the first-line treatment of patients with good performance status led to better survival in clinical trials. However, there is a wide variability in their use and some concerns about the treatment of elderly patients who were not included in the clinical trials.. This is a retrospective multicenter study. Data from consecutive patients diagnosed with metastatic pancreatic cancer (mPC) treated with FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (GnP) were analysed to evaluate efficacy (overall survival-OS) and toxicity.. A total of 119 patients were included. 49.6% were treated with FFX and 50.4% with GNP in first-line. The median OS was 12 months with no statistically significant differences between both regimens (12.7 m for FFX vs 10.2 m for GnP). Elevated Ca 19.9 levels and neutrophil-lymphocyte ratio (NLR) increased the risk of death. Patients who received both regimens in first/second line had a median OS longer than 15 months whichever the sequence. 32 patients (27%) were older than 70-y. 54% patients received a second-line treatment, 56% in the FFX group and 44% in the GnP group. The median OS for patients older than 70 was 9.5 m versus 12.3 m for patients younger than 70. Progression of the disease was the cause of death in 67.6% of the patients.. In our setting, the use of FFX and GnP for treating mPC is quite similar, but superiority could not be demonstrated for any of the schemes in the first line. OS was determined by basal levels of Ca 19.9 and NLR. Patients receiving both regimens in first/second line whichever the sequence, exhibited the best survival rates. In our series, elderly patients had poorer survival rates.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cause of Death; Deoxycytidine; Disease Progression; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies; Survival Rate

Sarcopenia, defined as decrease in skeletal muscle mass (SMM) and strength, might be associated with reduced survival. We investigated the impact of sarcopenia and decrease in SMM in patients with advanced pancreatic cancer during FOLFIRINOX (FX) therapy. Consecutive sixty-nine patients who received FX were evaluated. Skeletal muscle index (SMI) (cm2/m2) was used to evaluate SMM. The cut-off value of sarcopenia was defined as SMI <42 for males and <38 for females, based on the Asian Working Group for sarcopenia criteria. Sarcopenia was diagnosed in thirty-three (48 %) subjects. Comparison of baseline characteristics of the two groups (sarcopenia group: non-sarcopenia group) showed a significant difference in sex, tumour size and BMI. There was no significant difference in the incidence of adverse events with grades 3-5 and progression-free survival (PFS) during FX between the two groups (PFS 8·1 and 8·8 months; P = 0·88). On the multivariate analysis, progressive disease at the first follow-up computed tomography (hazard ratio (HR) 3·87, 95 % CI 1·53, 9·67), decreased SMI ≥ 7·9 % in 2 months (HR 4·02, 95 % CI 1·87, 8·97) and carcinoembryonic antigen ≥ 4·6 (HR 2·52, 95 % CI 1·10, 6·11) were significant risk factors associated with poor overall survival (OS), but sarcopenia at diagnosis was not. OS in patients with decreased SMI of ≥7·9 % and <7·9 % were 10·9 and 21·0 months (P < 0·01), respectively. In conclusion, decrease in SMM within 2 months after the initiation of chemotherapy had significantly shorter OS, although sarcopenia at diagnosis did not affect OS. Therefore, it might be important to maintain SMM during chemotherapy for a better prognosis.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Sarcopenia

Nab-paclitaxel (Abraxane®) plus gemcitabine (AG) and Fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX) have shown significant clinical benefit and been widely used as 1. Markov model was developed with a lifetime survival projection in Microsoft Excel® to simulate the progression of the mPC over time. The quality-adjusted life years (QALYs), resource consumption in the health care sector and incremental cost-effectiveness ratios (ICERs) were reported. Uncertainty was assessed by one-way and probabilistic sensitivity analyses.. AG regimen provided an effectiveness of 1.35 QALY at an average cost of USD 22,300 whereas FOLFIRINOX regimen brought 0.82 QALY at a cost of USD 22,980 in lifetime horizon. Therefore, AG regimen was dominant with an ICER of USD -1300 compared with FOLFIRINOX regimen. AG arm generated less drug cost, medical cost, hospitalization cost, and end-of-life cost than FOLFIRINOX arm did. Sensitivity analyses confirmed the robustness of base case findings.. AG is likely a cost-effective option for the 1

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; China; Cost-Benefit Analysis; Deoxycytidine; Disease Progression; Fluorouracil; Gemcitabine; Health Care Costs; Hospitalization; Humans; Irinotecan; Leucovorin; Markov Chains; Neoplasm Metastasis; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Quality-Adjusted Life Years; Survival Rate

To investigate the potential benefits of a hypofractionated radiotherapy boost (HRB) after chemotherapy (CT) and concomitant chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC) patients. Primary endpoints were early and late toxicity, local control (LC) and pain-free progression (PFP) assessment. Two-years overall survival (OS), metastasis-free survival (MFS) and disease-free survival (DFS) were secondary endpoints.. Patients (pts) affected by unresectable non-metastatic LAPC, previously treated with CT and CRT in upfront or sandwich setting, were selected for sequential HRB. Total prescribed dose was 30 Gy in 5 fractions (fr) to pancreatic primary lesion. Dose de-escalation was allowed in case of failure in respecting organs at risk constraints. Early and late toxicity were assessed according to CTCAE v.4.0 classification. The Kersh-Hazra scale was used for pain assessment. Local Control, PFP, MFS and DFS were calculated from the date of HRB to the date of relapse or the date of the last follow-up.. Thirty-one pts affected by unresectable, non-metastatic LAPC were consecutively enrolled from November 2004 to October 2019. All pts completed the planned HRB. Total delivered dose varied according to duodenal dose constraint: 20 Gy in 5 fr (N: 6; 19.4%), 20 Gy in 4 fr (N: 5; 16.2%), 25 Gy in 5 fr (N: 18; 58.0%) and 30 Gy in 6 fr (N: 2; 6.4%). Early and late toxicity were assessed in all pts: no Grade 3 or 4 acute gastrointestinal toxicity and no late gastrointestinal complications occurred. Median LC was 19 months (range 1-156) and 1- and 2-year PFP were 85% and 62.7%, respectively (median 28 months; range 2-139). According to the Kersh-Hazra scale, four pts had a Grade 3 and four pts had a Grade 1 abdominal pain before HRB. At the last follow-up only 3/31 pts had residual Grade 1 abdominal pain.Median MFS was 18 months (range 1-139). The 2-year OS after HRB was 57.4%, while 2-year OS from diagnosis was 77.3%.. Treatment intensification with hypofractionated radiotherapy boost is well tolerated in pts affected by unresectable LAPC previously treated with CT/CRT. Its rates of local and pain control are encouraging, supporting its introduction in clinical practice. Timing, schedule and dose of HRB need to be further investigated to personalize therapy and optimize clinical advantages.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemoradiotherapy; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Radiation Dose Hypofractionation; Retrospective Studies; Survival Rate

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Dose-Response Relationship, Drug; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liposomes; Longitudinal Studies; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies; Treatment Outcome

To evaluate somatic mutations, circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in patients with Pancreatic ductal adenocarcinoma (PDAC) with pathologic complete response (pCR) to neoadjuvant therapy (NAT) and find their associations with outcome.. Thirty-six patients with PDAC with pCR were identified from 2009 to 2017. Macrodissection was performed on resected specimens to isolate DNA from 332 regions of interest including fibrosis, normal duct, normal parenchyma, and undefined ductal cells (UDCs). Cell-free DNA and CTCs were also extracted. Next-generation sequencing was used to detect mutations of. This study first reports that somatic mutations, CTCs, and ctDNA existed even in patients with PDAC with pCR to NAT, which could possibly predict early recurrence and reduced survival. The current regression evaluation system of PDAC needs to be reassessed at a molecular level.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Circulating Tumor DNA; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liquid Biopsy; Male; Middle Aged; Mutation; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplastic Cells, Circulating; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Risk Assessment

To investigate important factors for recurrence-free survival (RFS) and overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDA) who underwent surgery after neoadjuvant FOLFIRINOX using CT and histopathological findings.. Sixty-nine patients with PDA who underwent surgery after neoadjuvant FOLFIRINOX were retrospectively included. All patients underwent baseline and first follow-up CT. Two reviewers assessed the CT findings and resectability based on the NCCN guideline. They graded extrapancreatic perineural invasion (EPNI) using a 3-point scale focused on 5 routes. Clinical and histopathological results, such as T- and N-stage, tumor regression grade (TRG) using the College of American Pathology (CAP) grading system, and resection status, were also investigated. Kaplan-Meier methods were used for RFS and OS. The Cox proportional hazard model and logistic regression model were used to identify significant predictive factors.. There were 57 patients (82.6%) without residual tumors (R0) and 12 patients (17.4%) with residual tumors (R1 or R2). The median RFS was 13 months (range 0~22 months). For RFS, EPNI on baseline CT (hazard ratio (HR) 2.53, 95% confidence interval (CI) 1.116-5.733, p = 0.026) and TRG (HR 1.76, 95% CI 1.000-3.076, p = 0.046) were important predictors of early recurrence. The mean OS was 48 months (range 11~35 months). For OS, TRG (HR 1.05, 95% CI 1.251-6.559, p = 0.013) was a significant factor. However, there were no independent predictors for residual tumors according to the CT findings.. EPNI on baseline CT and TRG were important prognostic factors for tumor recurrence. In addition, TRG was also an important prognostic factor for OS.. • CT and histopathological findings are helpful for predicting early recurrence and poor survival. • EPNI on baseline CT (HR 2.53, p = 0.026) is an important predictor of early recurrence. • The TRG is an important prognostic factor for early recurrence (HR 1.76, p = 0.046) and poor survival (HR 1.05, p = 0.013).

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Tomography, X-Ray Computed

Due to its late diagnosis and dismal prognosis, pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating solid malignancies, with only 9% of patients surviving after being diagnosed. A multidrug chemotherapeutic regimen FOL-F-IRIN-OX (combination of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) offers survival benefits superior to that of gemcitabine single agent, but the treatment-related side effects are also severe. To overcome this therapeutic barrier, we developed polymeric micelles bearing active formats of irinotecan and oxaliplatin, SN38 and 1,2-diaminocyclohexane‑platinum (II), DACHPt. Crosslinked micelles were prepared using amphiphilic PEG-b-poly(L-glutamic acid)/SN38 conjugates and subsequently loaded with DACHPt. The dual drug-loaded micelles exhibited improved colloidal stability, prolonged drug release and remarkable cytotoxicity in human pancreatic cancer cell lines and Kras

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Mice; Oxaliplatin; Pancreatic Neoplasms

5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) has activity in pancreatic neuroendocrine tumors (pNETs), but its use is limited, partly because of toxicities. pNETs can often become aggressive over time. We evaluated the efficacy of FOLFOX in patients with aggressive pNETs who had progressed after capecitabine plus temozolomide (cap/tem) among other treatments.. This was a retrospective study of all patients with well-differentiated metastatic pNETs, treated at an academic cancer center between January 2008 and June 2019, who received FOLFOX and had received cap/tem in the past. The primary endpoint was objective response rate.. Thirty-one patients met eligibility criteria. Twenty-five received FOLFOX, and six received FOLFOX with bevacizumab. Patients were heavily pretreated, having received a median of three prior lines of systemic therapy prior to FOLFOX (range, 1-8). Three (9.7%) patients had grade [G]1 tumors, 16 (51.6%) had G2, and 6 (19.4%) had G3, and grade was unspecified in 6 (19.4%) patients. Fourteen (45.2%) exhibited a best response of partial radiographic response per RECIST 1.1 criteria, 15 (48.4%) stable disease, and 2 (6.4%) progressive disease; overall response rate was 45.2% and disease control rate was 93.5%. Median progression-free survival was 6 months (95% confidence interval [CI], 5.0-7.0), and median overall survival was 16 months from onset of study treatment (95% CI, 11.3-20.7) and 67 months from date of diagnosis (95% CI, 49.8-84.2). Median duration of treatment was 3 months, and median duration of response was 2 months. Toxicity profile was consistent with known adverse events associated with this regimen.. FOLFOX is active in aggressive, heavily pretreated pNETs that have progressed on prior cap/tem chemotherapy; response durations are relatively short.. FOLFOX chemotherapy has robust activity in patients with rapidly progressive, heavily pretreated pancreatic neuroendocrine tumors (NETs), a setting in which few, if any, other options are likely to be effective. Durations of response, however, are relatively short, and new treatments are urgently needed for patients with aggressive transformation of pancreatic NETs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Fluorouracil; Humans; Leucovorin; Neuroendocrine Tumors; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Temozolomide; Treatment Outcome

Neoadjuvant therapy is increasingly utilized in the management of pancreatic adenocarcinoma. The type of neoadjuvant therapy and its effect on pathologic response remains understudied.. A retrospective review was performed on patients who underwent neoadjuvant therapy followed by pancreatectomy. Multivariable regressions were used to determine associations between neoadjuvant therapy regimens and pathologic response.. Seventy-five patients with pathologic responses available for review received FOLFIRINOX (61%) or gemcitabine with nab-paclitaxel (39%). Demographics, histologic differentiation, and utilization of chemoradiation were similar between the groups. Multivariable logistic regression demonstrated that chemoradiation was associated with an increased likelihood of a complete or near-complete pathologic response and a decreased rate of lymphovascular invasion and lymph node positivity. Neither chemotherapy regimen nor number of cycles administered were associated with pathologic response.. Neoadjuvant chemoradiation may be associated with complete or near-complete pathologic response regardless of chemotherapy regimen in pancreatic cancer patients.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Logistic Models; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Paclitaxel; Pancreatectomy; Pancreatic Neoplasms; Retrospective Studies; Treatment Outcome

Since current studies on locally advanced pancreatic cancer (LAPC) mainly report from single, high-volume centers, it is unclear if outcomes can be translated to daily clinical practice. This study provides treatment strategies and clinical outcomes within a multicenter cohort of unselected patients with LAPC.. Consecutive patients with LAPC according to Dutch Pancreatic Cancer Group criteria, were prospectively included in 14 centers from April 2015 until December 2017. A centralized expert panel reviewed response according to RECIST v1.1 and potential surgical resectability. Primary outcome was median overall survival (mOS), stratified for primary treatment strategy.. Overall, 422 patients were included, of whom 77% (n = 326) received chemotherapy. The majority started with FOLFIRINOX (77%, 252/326) with a median of six cycles (IQR 4-10). Gemcitabine monotherapy was given to 13% (41/326) of patients and nab-paclitaxel/gemcitabine to 10% (33/326), with a median of two (IQR 3-5) and three (IQR 3-5) cycles respectively. The mOS of the entire cohort was 10 months (95%CI 9-11). In patients treated with FOLFIRINOX, gemcitabine monotherapy, or nab-paclitaxel/gemcitabine, mOS was 14 (95%CI 13-15), 9 (95%CI 8-10), and 9 months (95%CI 8-10), respectively. A resection was performed in 13% (32/252) of patients after FOLFIRINOX, resulting in a mOS of 23 months (95%CI 12-34).. This multicenter unselected cohort of patients with LAPC resulted in a 14 month mOS and a 13% resection rate after FOLFIRINOX. These data put previous results in perspective, enable us to inform patients with more accurate survival numbers and will support decision-making in clinical practice.

Topics: Adenocarcinoma; Aged; Albumins; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Paclitaxel; Pancreatectomy; Pancreatic Neoplasms; Prospective Studies; Response Evaluation Criteria in Solid Tumors; Survival Rate

The purpose of this study was to compare efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) and gemcitabine-cisplatin as first-line therapy in patients with pancreatic cancer.. Pancreaticobiliary cancer patients who had Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating greater severity of illness) were evaluated to receive folfirinox or gemcitabine plus cisplatin. The primary endpoints were progression-free and overall survival time. Safety analysis was also evaluated as secondary measures.. There were 32 patients in the folfirinox group and 36 patients in the gemcitabine-cisplatin group. The median overall survival was 18.1 months (7.5–28.7) in the folfirinox group as compared with 9.7 months (6.5–13) in the gemcitabine-cisplatin group (p = 0.009). Median progression-free survival was 16.2 months (9–23.4) in the folfirinox group and 6.9 months (6.1–7.6) in the gemcitabine- cisplatin group (p = 0.001).. Folfirinox is an option for the first-line treatment of patients with pancreatic cancer and good performance status.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Deoxycytidine; Female; Fluorouracil; Gastrointestinal Neoplasms; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

Historically, a positive margin after pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) was associated with decreased survival. In an era when neoadjuvant chemotherapy (NAC) is being used frequently, the prognostic significance of margin status is unclear.. Patients with localized PDAC who received NAC and underwent pancreatectomy from 2011 to 2018 were identified from a single-institution database. Patients with fewer than 2 months of NAC, R2 resection, or fewer than 90 days of follow-up were excluded. A positive margin included tumors within 1 mm of the surgical margin.. Four hundred and sixty-eight patients met inclusion criteria. Median age was 65 years and 53% were female. Preoperative clinical staging demonstrated that most had locally advanced (n = 222 [47%]) or borderline resectable (n = 172 [37%]) disease. Median follow-up was 18.5 months (interquartile range 10.6 to 30.0 months). Median duration of NAC was 119 days (interquartile range 87 to 168 days). FOLFIRINOX was first-line therapy for 67%, and 73% received neoadjuvant radiotherapy. Most underwent pancreaticoduodenectomy (69%). Forty percent were node-positive and 80% had an R0 resection. Fifty-six percent received at least 1 cycle of adjuvant therapy. Median overall survival and recurrence-free survival were 22.0 months (95% CI, 19.4 to 25.1 months) and 11.0 months (95% CI, 10.0 to 12.1 months). On multivariate analysis, margin status was not a significant predictor of overall survival or recurrence-free survival. Factors associated with overall survival included clinical stage, duration of NAC, nodal status, histopathologic treatment response score, and receipt of adjuvant chemotherapy.. Microscopic margin positivity is not associated with recurrence and survival in localized PDAC patients resected after treatment with NAC. Aggressive surgical extirpation in high-volume centers should be considered in selected patients after extensive NAC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Margins of Excision; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Pancreaticoduodenectomy; Prospective Studies; Retrospective Studies

Microscopically positive margins (R1) negatively impact survival in pancreatic ductal adenocarcinoma (PDAC). For patients with close/positive margins, intraoperative radiotherapy (IORT) can improve local control. The prognostic impact of an R1 resection in patients who receive total neoadjuvant therapy (TNT; FOLFIRINOX with chemoradiation) and IORT is unknown.. Clinicopathologic data were retrospectively collected for borderline/locally advanced (BR/LA) PDAC patients who received TNT and underwent resection between 2011 and 2019. Disease-free (DFS) and overall survival (OS) measured from time of diagnosis were compared between groups.. Two hundred one patients received TNT and were resected, with a median DFS and OS of 24 months and 47 months, respectively. Eighty-eight patients (44%) received IORT; of these, 69 (78%) underwent an R0 and 19 (22%) an R1 resection. There was no significant difference in clinicopathologic factors between the IORT and no-IORT groups, except for resectability status (LA: IORT 69%, no-IORT 53%, p = 0.021) and surgeons' concern for a positive/close margin. R1 resection was associated with worse DFS and OS in the no-IORT population. However, among patients who received IORT, there was no difference in DFS (R0: 29 months, IQR 14-47 vs R1: 20 months, IQR 15-28; p = 0.114) or OS (R0: 48 months, IQR 25-not reached vs R1: 37 months, IQR 30-47; p = 0.307) between patients who underwent R0 vs R1 resection. In multivariate analysis, within the IORT group, R1 resection was not associated with DFS or OS.. IORT may mitigate the adverse effect of an R1 resection on DFS and OS in BR/LA PDAC patients receiving TNT.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Survival Rate

Modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine + nab-paclitaxel (GemNab) regimens represent a standard treatment in advanced pancreatic cancer (aPC). DPYD and UGT1A1 variants are relevant predictors of fluoropyrimidine and irinotecan-associated adverse events (AEs). Furthermore, data about the associations between polymorphisms in ABCB and CDA genes and GemNab-related toxicities are still controversial. The present study analyzes the association between DPYD, UGT, ABCB1, CDA variants, and AEs in aPC patients (pts) treated with mFOLFIRINOX or GemNab. Blood samples collected from 104 aPC pts treated with mFOLFIRINOX and 63 with GemNab were tested for DPYD c.1679T>G, IVS14+1G>A, c.2194G>A, c.2846A>T, UGT1A1*28, CDA c.79A>C, and ABCB1 c.1236C>T, c.2677G>T/A, c.3435C>T by real-time PCR and automatic sequencing. In mFOLFIRINOX cohort, DPYD IVS14+1GA genotype was associated with G4 hematological AEs, while the UGT1A1*28 significantly correlated with the risk of thrombocytopenia (p = 0.006). In the GemNab cohort, a significant association between CDA c.79CC and high-grade nausea was observed (p = 0.002). Moreover, the presence of at least a mutant allele in ABCB1 increased the risk of overall hematological AEs (p = 0.01), both further strengthened by the presence of CDA c.79CC (p = 0.0002). DPYD IVS14+1A allele is confirmed to be associated with fluoropyrimidine life-threatening toxicities, and UGT1A1*28 is related with a higher risk of hematologic AEs following irinotecan treatment. CDA c.79C and ABCB1 c.1236T, c.2677T/A, and c.3435T mutant alleles are predictive biomarkers of GemNab-related AEs. All these variants should be considered in aPC pts candidate to mFOLFIRINOX or GemNab treatments.

Topics: Adult; Aged; Albumins; Alleles; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B; Cytidine Deaminase; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Genotype; Glucuronosyltransferase; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms; Pharmacogenomic Testing; Polymorphism, Genetic

Experienced pancreatic surgeons, for whom complexity is not an issue, must decide at the end of neoadjuvant therapy whether to continue or discontinue surgery, when pancreatectomy with vascular resection is planned in patients with pancreatic ductal adenocarcinoma (PDAC).. Our study aimed to determine preoperative factors that can predict short postoperative survival in such situations.. Overall, 105 patients with borderline or locally advanced PDAC received neoadjuvant FOLFIRINOX (followed by chemoradiation in 22% of patients) and underwent pancreatectomy with segmental venous and/or arterial resection at two high-volume centers. The primary endpoint was overall survival (OS) of < 1 year after surgery for patients who did not die from the surgery.. Tumors were classified as borderline in 78% of cases and locally advanced in 22% of cases. Mean CA19-9 at diagnosis was 934 U/mL, which significantly decreased to 213 U/mL (p < 0.01) after a median of six cycles of FOLFIRINOX. Pancreaticoduodenectomy was performed most often (76%). The vast majority of patients underwent venous resection (92%), and a simultaneous arterial resection was performed in 16 patients (15%). The severe morbidity rate and 30- and 90-day mortality rates were 21%, 8.5%, and 10.4%, respectively. The median OS after surgery was 23 months. In the multivariate analysis, preoperative CA19-9 ≥ 450 U/mL was the only preoperative factor independently associated with OS of < 1 year (p = 0.044).. The preoperative CA19-9 value should be considered in the clinical decision-making process when complex vascular resection is required.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Retrospective Studies

Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2.. We interrogated whole genome sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status.. Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.

Topics: Aged; Alleles; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cisplatin; Deoxycytidine; DNA-Binding Proteins; Drug Resistance, Neoplasm; Fanconi Anemia Complementation Group N Protein; Female; Fluorouracil; Gemcitabine; Genes, BRCA1; Genes, BRCA2; Genomic Instability; Germ-Line Mutation; Homologous Recombination; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Prognosis; Recombinational DNA Repair; Sensitivity and Specificity; Survival Rate; Tumor Suppressor Protein p53; Whole Genome Sequencing

There is no clear consensus on the recommended second-line treatment for patients with metastatic pancreatic cancer who have disease progression following gemcitabine-based therapy. We retrospectively evaluated the clinical outcomes of liposomal irinotecan (nal-IRI) plus fluorouracil/leucovorin (FL) and FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) in patients who had failed on the first-line gemcitabine-based therapy.. From January 2015 to August 2019, 378 patients with MPC who had received nal-IRI/FL (n = 104) or FOLFIRINOX (n = 274) as second-line treatment across 11 institutions were included in this retrospective study.. There were no significant differences in baseline characteristics between groups, except age and first-line regimens. With a median follow-up of 6 months, the median progression-free survival (PFS) was 3.7 months with nal-IRI/FL versus 4.6 months with FOLFIRINOX (P = 0.44). Median overall survival (OS) was 7.7 months with nal-IRI/FL versus 9.7 months with FOLFRINOX (P = 0.13). There was no significant difference in PFS and OS between the two regimens in the univariate and multivariate analyses. The subgroup analysis revealed that younger age (<70 years) was associated with better OS with FOLFIRINOX. In contrast, older age (≥70 years) was associated with better survival outcomes with nal-IRI/FL. Adverse events were manageable with both regimens; however, the incidence of grade 3 or higher neutropenia and peripheral neuropathy was higher in patients treated with FOLFIRINOX than with nal-IRI/FL.. Second-line nal-IRI/FL and FOLFIRINOX showed similar effectiveness outcomes after progression following first-line gemcitabine-based therapy. Age could be the determining factor for choosing the appropriate second-line therapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Republic of Korea; Retrospective Studies

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Diet, Ketogenic; Fluorouracil; Gemcitabine; Humans; Hyperbaric Oxygenation; Hyperthermia; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms

Advanced pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor with an abysmal prognosis. Beyond the first-line setting, treatment for advanced PDAC is limited and suboptimal. Also, the efficacy of epidermal growth factor receptor (EGFR) targeted therapy alone in the chemo-refractory setting in PDAC tumors harboring druggable EGFR mutations is unclear. Here we describe the case of a patient with chemo-refractory advanced PDAC with an activating exon-19 EGFR mutation who had an exceptional response to erlotinib monotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Exons; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Mutation; Neoplasm Staging; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Treatment Outcome

Irinotecan (CPT-11) is metabolized to an active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterase (CES). SN-38 is then converted to the inactive metabolite SN-38 glucuronide (SN-38G) by glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphisms in UGT1A1 have been associated with altered SN-38 pharmacokinetics, which increase the risk of toxicity in patients. CPT-11 is also converted to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC) by cytochrome P450 3A (CYP3A), and this route also affects the plasma concentration of SN-38. We evaluated the activities of UGT1A1, CYP3A, and CES and the factors affecting the pharmacokinetics of plasma SN-38 in patients with UGT1A1 gene polymorphisms.. Three male patients aged 56, 65, and 49 years were recruited for the analysis. All patients had pancreatic cancer, received FOLFIRINOX, and had UGT1A1*6/*6 (patients 1 and 3) or *6/*28 (patient 2) genetic polymorphisms. The rate constants for evaluating the enzyme activity were determined from the measured plasma concentration of CPT-11 and its metabolites using a two-compartment model by WinNonlin.. The area under the plasma concentration-time curve (AUC) of SN-38 was patient 1 > patient 2 > patient 3. The rate constants obtained from the model analysis indicated the respective enzyme activities of UGT1A1 (k57), CYP3A (k13 + k19), and CES (k15). The order of values for UGT1A1 activity was patient 2 > patient 3 > patient 1. Since UGT1A1 activity was low in patient 1 with a high AUC of SN-38, it can be said that the increase in plasma concentration was due to a decrease in UGT1A1 activity. Conversely, the order of values for CYP3A and CES activities was patient 3 > patient 1 > patient 2 and patient 2 > patient 1 > patient 3, respectively. Patient 3 had the lowest AUC of SN-38, caused by a lower level of CES activity and increased CYP3A activity.. In this study, we indicated that the plasma AUC of SN-38 and AUC ratio of SN-38G/SN-38 may depend on changes in the activities of CYP3A, CES, and UGT1A1. Using pharmacokinetic analysis, it is possible to directly evaluate enzyme activity and consider what kind of enzyme variation causes the increase in the AUC of SN-38.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Camptothecin; Carboxylesterase; Cytochrome P-450 CYP3A; Fluorouracil; Glucuronides; Glucuronosyltransferase; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Models, Biological; Oxaliplatin; Pancreatic Neoplasms; Polymorphism, Genetic

Topics: Antineoplastic Combined Chemotherapy Protocols; Electroporation; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Tomography, X-Ray Computed

Pancreatic cancer (PC) and biliary tract cancer (BTC) are both aggressive and highly fatal malignancies. Nowadays we have a profound knowledge about the molecular landscape of these neoplasms and this has allowed new therapeutic options. Surgery is the only potentially curative therapy in both cancers, but disease recurrence is frequent. In PC, adjuvant treatment with mFOLFIRINOX has improved overall survival (OS) and in BTC adjuvant treatment with capecitabine seems to improve OS and relapse-free survival. Concomitant radio-chemotherapy could also be considered following R1 surgery in both neoplasms. Neoadjuvant treatment represents the best option for achieving an R0 resection in borderline PC. Upfront systemic chemotherapy is the treatment of choice in unresectable locally advanced PC and BTC; then locoregional therapy could be considered after an initial period of at least 3-4 months of systemic chemotherapy. In metastatic PC, FOLFIRINOX or Gemcitabine plus nab-paclitaxel have improved OS compared with gemcitabine alone. In metastatic BTC, cisplatin plus gemcitabine constitute the standard treatment. Progress in the knowledge of molecular biology has enabled the identification of new targets for therapy with encouraging results that could in the future improve the survival and quality of life of patients with PC and BTC.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Capecitabine; Chemoradiotherapy; Chemotherapy, Adjuvant; Cisplatin; Fluorouracil; Humans; Irinotecan; Leucovorin; Medical Oncology; Neoadjuvant Therapy; Neoplasm Staging; Oxaliplatin; Paclitaxel; Palliative Care; Pancreatic Neoplasms; Quality of Life; Societies, Medical; Spain

Ischemic complications are still prevalent after distal pancreatectomy with en bloc celiac axis resection (DP-CAR) despite the use of preoperative arterial embolization. We described our institutional experience with arterial reconstruction during DP-CAR.. We retrospectively reviewed short- and long-term outcomes of all DP-CAR performed for pancreatic adenocarcinoma between January 1, 1995 and March 30, 2020. Outcomes were compared according to the presence of arterial reconstruction.. Sixty consecutive DP-CARs were reviewed. Most patients underwent induction chemotherapy (85%) based on FOLFIRINOX protocol (80.3%). The hepatic artery was reconstructed in 50 patients (83.3%). The left gastric artery was reconstructed in 4 and preserved in 14 patients. A venous resection was associated during 44 DP-CARs (36 segmental venous resections/8 lateral venous resections). Ninety days mortality was 5.0% with 48.3% (n = 29) overall rate of morbidity. Postoperative outcomes in term of mortality, morbidity, and ischemic events between patients with and without arterial reconstruction were similar despite a higher rate of venous resection (81% vs. 40%; p = 0.005) and more complex cases (Mayo clinic DP-CARs class 1B, 2A, and 3A) in the reconstructed group.. Arterial reconstruction represents a safe surgical option during DP-CAR to lessen postoperative ischemic events. This technique, reserved to high volume centers expert in vascular resection during pancreatectomy, deserves further comparison with standard technique in a larger setting.

Topics: Antineoplastic Combined Chemotherapy Protocols; Celiac Artery; Cohort Studies; Female; Fluorouracil; Hepatic Artery; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Plastic Surgery Procedures; Retrospective Studies; Treatment Outcome; Vascular Surgical Procedures

Advanced, unresectable pancreatic cancer is often treated with either gemcitabine plus nab-paclitaxel (Gem/NabP) or FOLFIRINOX, although these regimens have never been compared in a head-to-head trial. In this study, we compared these two regimens using Veterans Administration (VA) data and evaluated the use of a novel tumor growth formula to predict outcomes.. We identified 670 Veterans from national VA data with unresected stage II-IV pancreatic adenocarcinoma diagnosed between 2003 and 2016 who were treated with either first-line Gem/NabP or FOLFIRINOX. We compared overall survival (OS) and adverse events by treatment using propensity scores (PS) to account for allocation bias. Using longitudinal CA19-9 biomarker information we then fit the data to a novel tumor growth equation, comparing growth with OS.. We found no difference in PS-adjusted (hazard ratio [HR] 1.00; 95% confidence interval [95% CI] 0.84-1.20) or PS-matched (HR: 0.93; 95% CI: 0.76-1.13) OS between the two treatment groups. Tumor growth analysis revealed similar growth parameter values for Gem/NabP and FOLFIRINOX (P = .074 for difference).. Gem/NabP appeared noninferior to FOLFIRINOX for survival outcomes for advanced pancreatic adenocarcinoma based on national VA data. Biomarker-based growth equations may be useful for monitoring treatment response and predicting prognosis for pancreatic cancer.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Veterans

Factors for overall survival after pancreatic ductal adenocarcinoma (PDAC) seem to be nodal status, chemotherapy administration, UICC staging, and resection margin. However, there is no consensus on the definition for tumor free resection margin. Therefore, univariate OS as well as multivariate long-term survival using cancer center data was analyzed with regards to two different resection margin definitions. Ninety-five patients met inclusion criteria (pancreatic head PDAC, R0/R1, no 30 days mortality). OS was analyzed in univariate analysis with respect to R-status, CRM (circumferential resection margin; positive: ≤1mm; negative: >1mm), nodal status, and chemotherapy administration. Long-term survival >36 months was modelled using multivariate logistic regression instead of Cox regression because the distribution function of the dependent data violated the requirements for the application of this test. Significant differences in OS were found regarding the R status (Median OS and 95%CI for R0: 29.8 months, 22.3-37.4; R1: 15.9 months, 9.2-22.7; p = 0.005), nodal status (pN0 = 34.7, 10.4-59.0; pN1 = 17.1, 11.5-22.8; p = 0.003), and chemotherapy (with CTx: 26.7, 20.4-33.0; without CTx: 9.7, 5.2-14.1; p < .001). OS according to CRM status differed on a clinically relevant level by about 12 months (CRM positive: 17.2 months, 11.5-23.0; CRM negative: 29.8 months, 18.6-41.1; p = 0.126). A multivariate model containing chemotherapy, nodal status, and CRM explained long-term survival (p = 0.008; correct prediction >70%). Chemotherapy, nodal status and resection margin according to UICC R status are univariate factors for OS after PDAC. In contrast, long-term survival seems to depend on wider resection margins than those used in UICC R classification. Therefore, standardized histopathological reporting (including resection margin size) should be agreed upon.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Margins of Excision; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Pancreaticoduodenectomy; Retrospective Studies; Risk Assessment; Time Factors; Treatment Outcome

ZFP91, an E3 ligase, has been reported to possess cancer-promoting functions. This study aimed to elucidate the exact role of ZFP91 in tumour progression of pancreatic cancer and underlying mechanisms.. We analysed the correlation between ZFP91 expression and pancreatic cancer through TCGA and GEO data sets. Growth curve, colony formation, wound healing and transwell invasion assays were conducted to evaluate proliferation, migration and invasion of lentivirus transfected pancreatic cancer cells. GSEA and Western blot analysis were performed to validate the regulatory effect of ZFP91 on β-catenin. Drug response curve and orthotopic implantation model reflected the sensitivity of chemotherapies.. ZFP91 overexpression is prevalent in pancreatic cancer and negatively correlated with overall survival. ZFP91 knock-down attenuated proliferation, migration and invasion of pancreatic cancer cells. β-catenin was a downstream gene of ZFP91, and its agonist could reverse the phenotype. ZFP91 promoted EMT and chemoresistance in pancreatic cancer.. We demonstrated that ZFP91 promoted pancreatic cancer proliferation, migration and invasion through activating β-catenin signalling. EMT and chemoresistance were also regulated by ZFP91. ZFP91 might be a potential therapeutic target for pancreatic cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; beta Catenin; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Fluorouracil; Humans; Imidazoles; Irinotecan; Isoxazoles; Kaplan-Meier Estimate; Leucovorin; Mice; Mice, Nude; Oxaliplatin; Pancreatic Neoplasms; RNA Interference; RNA, Small Interfering; Transplantation, Heterologous; Ubiquitin-Protein Ligases; Wnt Signaling Pathway

FOLFIRINOX has shown promising results in locally advanced (LAPA) or borderline resectable (BRPA) pancreatic adenocarcinoma. We report here a cohort of patients treated with this regimen from the AGEO group.. This is a retrospective multicentre study. We included all consecutive patients with non-pre-treated LAPA or BRPA treated with FOLFIRINOX.. We included 330 patients (57.9% male, 65.4% <65 years, 96.4% PS <2). Disease was classified as BRPA in 31.1% or LAPA in 68.9%. Objective response rate with FOLFIRINOX was 29.5% and stable disease 51%. Subsequent CRT was performed in 46.4% of patients and 23.9% had curative intent surgery. Resection rates were 42.1% for BRPA and 15.5% for LAPA. Main G3/4 toxicities were fatigue (15%), neutropenia (12%) and neuropathy (G2/3 35%). After a median follow-up of 26.7 months, median OS (mOS) and PFS were 21.4 and 12.4 months, respectively. For patients treated by FOLFIRINOX alone, or FOLFIRINOX followed by CRT, or FOLFIRINOX + /- CRT + surgery, mOS was 16.8 months, 21.8 months and not reached, respectively (p < 0.0001).. FOLFIRINOX for LAPA and BRPA seems to be effective with a manageable toxicity profile. These promising results in "real-life" patients now have to be confirmed in a Phase 3 randomised trial.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Cohort Studies; Combined Modality Therapy; Disease Progression; Female; Fluorouracil; France; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Survival Analysis; Treatment Outcome

The study aimed to evaluate the clinical outcomes of tailored adjuvant chemotherapy according to human equilibrative nucleoside transporter 1 (hENT1) expression in resected pancreatic ductal adenocarcinoma (PDA).. Patients who underwent pancreatectomy for PDA were enrolled prospectively. According to intra-tumoral hENT1 expression, the high hENT1 (≥50%) group received gemcitabine and the low hENT1 (<50%) group received 5-fluorouracil plus folinic acid (5-FU/FA). The propensity score-matched control consisted of patients who received hENT1-independent adjuvant chemotherapy. The primary outcome was recurrence free survival (RFS) and the secondary outcomes were overall survival (OS) and toxicities.. Between May 2015 and June 2017, we enrolled 44 patients with resected PDA. During a median follow-up period of 28.5 months, the intention-to-treat population showed much longer median RFS [22.9 (95% CI, 11.3-34.5) vs. 10.9 (95% CI, 6.9-14.9) months, P = 0.043] and median OS [36.2 (95% CI, 26.5-45.9) vs. 22.1 (95% CI, 17.7-26.6) months, P = 0.001] compared to the controls. Among 5 patients in the low hENT1 group who discontinued treatment, 2 patients receiving 5-FU/FA discontinued treatment due to drug toxicities (febrile neutropenia and toxic epidermal necrolysis).. Tailored adjuvant chemotherapy based on hENT1 staining provides excellent clinical outcomes among patients with resected PDA.. clinicaltrials.gov identifier: NCT02486497.

Topics: Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Deoxycytidine; Equilibrative Nucleoside Transporter 1; Fluorouracil; Gemcitabine; Humans; Leucovorin; Pancreatic Neoplasms; Prospective Studies; Staining and Labeling

FOLFOX (5-Fluorouracile and oxaliplatin) exhibits promising activity in advanced well-differentiated neuroendocrine tumors (NETs). This retrospective study aimed to analyze the outcome of metastatic enteropancreatic NETs patients treated with FOLFOX.. We retrospectively identified patients treated with FOLFOX for NETs of enteropancreatic or unknown origin among those referred to our Regional Multidisciplinary Tumor Board.. Among 48 patients, most often pancreatic NETs (n=33, 68.8%), the median Ki67 index was 10%. The median number cycle of FOLFOX was 6 and median follow-up was 34.8 months. Disease control rate (DCR) was 83.3%. Median PFS and OS were 12.6 and 29.4 months respectively. Median chemotherapy break was 14.1 months. No significant difference was observed between PFS and the following criteria: Ki67 index, primary tumor site, alkaline phosphatase levels, primary tumor surgery and. FOLFOX exhibits a high DCR and a short duration of treatment with a relative long chemotherapy break in patients with metastatic enteropancreatic NETs.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; France; Humans; Intestinal Neoplasms; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neuroendocrine Tumors; Organoplatinum Compounds; Pancreatic Neoplasms; Retrospective Studies; Survival Analysis; Treatment Outcome; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Rectal Neoplasms

Second-line (2L) treatments for advanced pancreatic ductal adenocarcinoma (PDAC) achieve a modest benefit at the expense of potential toxicity. In the absence of predictive factors of response, the identification of prognostic factors could help in the therapeutic decisions-making. The purpose of this study was to assess the prognostic factors associated with shorter survival in patients with advanced PDAC who received 2L treatment.. We conducted a single institution retrospective study, which included all patients with advanced PDAC who received 2L treatment between September 2006 and February 2020 at La Paz University Hospital, Madrid (Spain). Significant variables in the logistic regression model were used to create a prognostic score.. We included 108 patients. The median overall survival (OS) was 5.10 months (95%CI 4.02-6.17). In the multivariate analysis, time to progression (TTP) shorter than 4 months after first-line treatment (OR 4.53 [95%CI 1.28-16.00] p = 0.01), neutrophil-to-lymphocyte ratio (NLR) greater than 3 at the beginning of 2L (OR 9.07 [95%CI 1.82-45.16] p = 0.01) and CA-19.9 level higher than the upper limit of normal at the beginning of 2L (OR 7.83 [95%CI 1.30-49.97] p = 0.02) were independently associated with OS shorter than 3 months. The prognostic score classified patients into three prognostic groups (good, intermediate and poor) with significant differences in OS (p < 0.001).. TTP shorter than 4 months after first-line treatment, NLR greater than 3 and CA-19.9 level higher than the upper limit of normal at the beginning of 2L were associated with shorter overall survival. We developed a prognostic score that classifies patients with advanced PDAC into three prognostic groups after progression to the first-line. This score could help in the decision-making for 2L treatment.

Topics: Adult; Aged; Aged, 80 and over; Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Carcinoma, Pancreatic Ductal; Clinical Decision-Making; Deoxycytidine; Disease Progression; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Logistic Models; Lymphocytes; Male; Middle Aged; Neutrophils; Oxaliplatin; Oxaloacetates; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Time Factors

This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC).. Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome.. Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively.. Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Deoxycytidine; Female; Fluorouracil; Forkhead Transcription Factors; Gemcitabine; Hepatitis A Virus Cellular Receptor 2; Humans; Immune Checkpoint Proteins; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Pilot Projects; Programmed Cell Death 1 Receptor; Progression-Free Survival; Prospective Studies; T-Lymphocytes, Regulatory

Endoscopic ultrasonography-guided tissue acquisition (EUS-TA) has become the norm for the diagnosis of pancreatic solid lesions. EUS-TA is relatively safe, but various complications can occur. Infected pancreatic necrosis (IPN) is a rare but serious complication. The latest guidelines suggest that all invasive interventions in patients with IPN should be delayed until walled-off necrosis appears.. A 73-year-old man was referred to our hospital with double primary cancers including gallbladder and pancreas. We performed EUS-TA on metastatic pancreatic tail cancer to confirm histologic diagnosis. Six days after the procedure, he developed abdominal pain and fever.. The patient's laboratory findings showed leukocytosis and C-reactive protein elevation. Fluid collection around pancreas tail and stomach was detected in computed tomography (CT) scan, and the patient was diagnosed with IPN.. EUS-guided endoscopic transmural drainage (EUS-TD) was performed for the treatment of IPN. Two days after the procedure with antibiotics, his CRP level decreased abruptly, and he received chemotherapy for the treatment of pancreatic ductal adenocarcinoma (PDAC) 5 days after the procedure. He was discharged from our hospital without complications 15 days after chemotherapy.. In selected patients with PDAC, early endoscopic drainage may be recommended as treatment for IPN resulting from complications of EUS-TA.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma, Pancreatic Ductal; Drainage; Endosonography; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Pancreatitis, Acute Necrotizing; Postoperative Complications; Stents; Treatment Outcome; Ultrasonography, Interventional

To compare the treatment outcomes of gemcitabine with nab-paclitaxel (GnP) and modified FOLFIRINOX (mFFX; a combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin) for metastatic pancreatic cancer.. We retrospectively analyzed consecutive patients with metastatic or recurrent pancreatic cancer treated with GnP or mFFX as the first-line chemotherapy between March 2014 and December 2019 in our hospital. Treatment outcomes were compared using propensity score matching to adjust for age, sex, performance status, carcinoembryonic antigen levels, carbohydrate antigen 19-9 levels, and disease status (metastatic or recurrent).. Five hundred sixty-eight patients were included (GnP/mFFX, 456/112). After propensity score matching, 218 patients were extracted. The median age was around 61 years, and the proportion of performance status 0 was approximately 90%. The median overall survival values were 14.6 and 15.5 months (P = 0.45), and the median progression-free survival was 7.4 months (P = 0.53) for GnP and mFFX, respectively. The disease control rates were higher in the GnP group (82.6% vs 67.9%, P = 0.02). In nonhematologic adverse events, grade 3/4 anorexia and diarrhea occurred significantly more frequently in the mFFX group.. Gemcitabine with nab-paclitaxel had a higher disease control rate and lower rates of severe anorexia and diarrhea in our propensity-matched population.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Anemia; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Nausea; Neoplasm Metastasis; Neoplasm Recurrence, Local; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival; Propensity Score; Retrospective Studies; Treatment Outcome

Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX are standard first-line treatment options for advanced pancreatic ductal adenocarcinoma (aPDAC), but currently no prospective randomised head-to-head comparison between these treatments has yet been performed.. We conducted a comparative propensity score (PS) analysis of overall (OS) and progression-free survival (PFS) in a tri-centre cohort of patients with aPDAC undergoing palliative first-line treatment with either GN or FOLFIRINOX.. In unadjusted analysis, OS and PFS were highly similar between patients treated with GN (n = 297) and FOLFIRINOX (n = 158). In detail, median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 11.2 months, 45% and 12% in the FOLFIRINOX group, respectively (log-rank p = 0.783). Accordingly, median (4.6 versus 4.8 months), 6-month (40% versus 43%) and 1-year (9% versus 9%) PFS estimates did not significantly differ (log-rank p = 0.717). However, patients treated with FOLFIRINOX were significantly younger, had fewer comorbidities, and a better Eastern Cooperative Oncology Group performance status. These imbalances were accounted for by weighting the data with the PS. In PS analysis of survival outcomes, OS and PFS remained comparable between the two treatment groups. In detail, PS-weighted median, 1- and 2-year OS estimates were 10.1 months, 42% and 18% in the GN group, as compared to 10.1 months, 40% and 13% in the FOLFIRINOX group (PS-weighted log-rank p = 0.449). PS-weighted PFS estimates again did not differ (PS-weighted log-rank p = 0.329).. This real-world comparative effectiveness study indicates that FOLFIRINOX and GN have similar effectiveness in the palliative first-line treatment of aPDAC.

Topics: Aged; Albumins; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Austria; Carcinoma, Pancreatic Ductal; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Paclitaxel; Palliative Care; Pancreatic Neoplasms; Progression-Free Survival; Propensity Score; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors

Pancreatic cancer is the 8th commonest cancer and the 5th commonest cause of cancer-related death in Australia, with a 9% average 5-year survival. This study aims to investigate the effects of neoadjuvant treatment on overall survival (OS) and recurrence-free survival (RFS) in borderline resectable (BRPC) and locally advanced (LAPC) pancreatic adenocarcinoma followed by curative resection.. Prospectively-collected demographic, medical, surgical and pathological data of patients with BRPC and LAPC treated with both neoadjuvant therapy (NAT) and surgery at a single tertiary referral centre in Australia were reviewed and analysed.. Between 2012 and 2018, 60 patients, 34 with BRPC and 26 with LAPC, were treated with NAT followed by curative resection. The commonest neoadjuvant chemotherapy regimens were Gemcitabine + Abraxane (51.7%) and FOLFIRINOX (35.0%), with 48.3% of patients additionally receiving neoadjuvant radiotherapy. Median RFS was 30 months and median OS was 35 months. On multivariable analysis, inferior OS was predicted by enlarged loco-regional lymph nodes on initial computed tomography (p = 0.032), larger tumour size post-NAT (p = 0.006) and Common Terminology Criteria for Adverse Events post-NAT toxicity greater than grade 2 (p = 0.015). LAPC patients received more neoadjuvant chemotherapy (p = 0.008) and radiotherapy (p = 0.021) than BRPC and achieved a superior pathological response (p = 0.010).. Patients who respond to NAT likely have a favourable disease biology and will progress well following resection. It is these patients who should be selected for more aggressive upfront management, and those with resistant disease should be spared from high-risk surgery.

Topics: Adenocarcinoma; Adult; Aged; Albumin-Bound Paclitaxel; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Lymph Nodes; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy; Radiotherapy, Adjuvant; Radiotherapy, Intensity-Modulated; Survival Rate; Tumor Burden

FOLFIRINOX (FFX) and Gemcitabine plus nab-paclitaxel (GnP) have been recommended as the first-line chemotherapy for metastatic pancreatic cancer (mPC). However, the evidence is lacking comparing not only two regimens, but also sequential treatment (FFX-GnP vs. GnP-FFX).. Data of 528 patients (FFX, n = 371; GnP, n = 157) with mPC were collected retrospectively. Propensity score matching was conducted to alleviate imbalance of the two groups. Overall survival (OS), progression free survival (PFS), and toxicity of patients were analyzed.. In the whole population, OS (12.5 months vs. 10.3 months, P = 0.05) and PFS (7.1 months vs. 5.8 months, P = 0.02) were longer in the FFX group before matching and after matching (OS: 11.8 months vs. 10.3 months, P = 0.02; PFS: 7.2 months vs. 5.8 months, P <  0.01). For sequential treatment, OS and PFS showed no significant difference. Interruptions of chemotherapy due to toxicities were more frequent (6.8 vs. 29.3%, P <  0.001) in the GnP group, and cessation of chemotherapy showed a significant association with mortality (z = - 1.94, P = 0.03).. FFX achieved a longer overall survival than GnP in mPC, but not in the comparison for sequential treatment. More frequent adverse events followed by treatment interruptions during GnP might lead to a poor survival outcome. Therefore, FFX would be a better first-line treatment option than GnP for mPC.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Propensity Score

Locally advanced pancreatic cancer (LAPC) is found in about 40% of patients with pancreatic cancer. Irreversible electroporation (IRE) is a nonthermal ablative technique that provides an alternative in patients with LAPC and can be safely combined with chemotherapy.. From 2015 until October of 2019, we performed laparotomic IRE in a total of 40 patients with stage III LAPC. The median age of these patients was 65.2 years (range: 46 to 81 y), and the median tumor size was 3.8 cm (range: 2 to 5.2 cm). 33 of 40 patients were treated preoperatively with FOLFIRINOX or nab-paclitaxel plus gemcitabine and in case of disease control, IRE was performed, whereas in 7 patients, IRE was performed without previous chemotherapy.. All patients were treated successfully with IRE as the tumor evaluation showed no disease progression after the completion of induction chemotherapy. No IRE-related deaths occurred. Two major grade III complications were reported: pancreatic fistula grade A in 8 patients and 3 patients diagnosed with delayed gastric emptying. Up to October 31, 2019, the median overall survival (OS) of all patients was 24.2 months (range: 6 to 36 mo), and the median progression-free survival was 10.3 months (range: 3 to 24 mo). After the completion of IRE, 30 patients (75%) continued with adjuvant chemotherapy. Fifteen patients (37%) have >24 months OS and 3 patients (8%) have reached 36 months OS and are still alive.. The combination of chemotherapy with IRE, which is a safe and effective procedure, may result in a survival benefit for patients with LAPC.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Electroporation; Female; Fluorouracil; Humans; Induction Chemotherapy; Irinotecan; Laparotomy; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Treatment Outcome

This study aimed to characterize chemotherapy-induced transient increase and surge of CA 19-9 level to treatment response in patients with advanced pancreatic ductal adenocarcinoma (PDAC). A retrospective case series was performed of advanced PDAC patients treated with first-line chemotherapy at City of Hope Comprehensive Cancer Center from Jan 2017 to May 2020. CA 19-9 surge was defined as an increase of >20% from baseline followed by a >20% drop in one or more subsequent CA 19-9 levels compared to baseline. Out of 106 advanced PDAC patients, 38 were evaluable for CA 19-9 surge. Fourteen (51.9%) patients treated with FOLFIRINOX and 3 (27.3%) patients treated with nab-P + Gem chemotherapy demonstrated an early transient rise in CA 19-9 level. A CA 19-9 surge was documented in 9 (23.7%) patients, all with duration of surge lasting < 16 weeks. Five out of 9 (55.6%) patients (4: FOLFIRINOX, 1: nab-P + Gem) with CA 19-9 surge demonstrated partial objective response rate on surveillance cross-sectional imaging. One patient (FOLFIRINOX) had stable disease, and 2 patients (1: FOLFIRINOX, 1: nab-P + Gem) were found to have disease progression after treatment interruption. The initial early rise of CA 19-9 levels during chemotherapy in patients with advanced PDAC may not indicate tumor progression. Rather, it may represent a chemotherapy-induced transient increase or surge phenomenon of the tumor marker in patients responding to treatment.

Topics: Adenocarcinoma; Aged; Albumins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

A 59-year-old woman presented with abdominal pain associated with nausea and night sweats. A large mass was found in the pancreatic tail and innumerable liver lesions were identified. Ultrasound-guided biopsy of a liver nodule confirmed moderately differentiated adenocarcinoma consistent with a pancreatobiliary primary. On FOLFIRINOX chemotherapy, subsequent CT scans showed shrinkage of the pancreatic mass and liver metastases. Her cancer antigen 19-9 (CA 19-9) normalised after 11 months. Oxaliplatin was discontinued due to peripheral neuropathy but she completed 37 cycles of FOLFIRI during which her pancreatic mass disappeared, liver lesions decreased in size and were subsequently deemed to be scar tissue by the radiologist. After 4 years of treatment, the patient agreed to a break from chemotherapy. Eighteen months afterwards, an MRI abdomen continues to demonstrate no visible pancreatic mass and the two remaining liver lesions, believed to be scar tissue, remain stable. Her CA 19-9 level remains normal. This appears to be a complete response to FOLFIRINOX/FOLFIRI chemotherapy in a patient with metastatic pancreatic cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Middle Aged; Oxaliplatin; Pancreatic Neoplasms

We aimed to evaluate the predictive factors of conversion surgery in pancreatic adenocarcinoma (PAC) after neoadjuvant or palliative FOLFIRINOX using baseline and follow-up CT.. We retrospectively included 189 patients who had undergone more than 4 cycles of FOLFIRINOX. We reviewed baseline CT (B-CT), 1st follow-up CT (1st-CT), and the preoperative or last follow-up CT (L-CT) and determined tumor size changes according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Extra-pancreatic perineural invasion (EPNI) and resectability using NCCN 2019 guideline were evaluated. Subgroup analysis by baseline resectability was performed.. B-CT included resectable (n = 25, 23.2%), borderline (n = 55, 29.1%), locally advanced (n = 44, 23.3%), and metastatic (n = 65, 34.4%) PAC. Seventy-four patients had undergone surgery (39.2%) with an 83.8% (62/74) R0 resection. For operability, resectable status at L-CT (hazard ratio (HR) 65.5; 95% confidence interval (CI) 5.0-865; P = 0.002), RECIST (partial response) at 1st-CT (HR 3.6; 95% CI 1.1-11.7; P = 0.032), and baseline borderline resectability (HR 8.6; 95% CI 1.6-46.4; P = 0.013) were important predictors. Based on a size reduction cut-off of 22.2%, the area under the receiver operating characteristic (ROC) curve (Az) was 0.761 (sensitivity = 70.3%, specificity = 74.8%). In subgroup analysis, RECIST (partial response) at 1st-CT was a significant predictor of locally advanced PAC (HR 32; 95% CI 4.5-227, P 0.001), and the optimal cut-off was 22.2% (Az = 0.914; sensitivity = 100%, specificity = 75%). Baseline tumor size ([Formula: see text] 4 cm) (HR 5.6, 95% CI 1.3-24.3, P = 0.022) and unresectable status at 1st-CT (HR 4.8, 95% CI 1.1-20.6, P = 0.035) were significantly associated with margin-positive resection.. Both baseline and follow-up CT findings are useful to predict conversion surgery for PAC after FOLFIRINOX.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Neoplasm Staging; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Tomography, X-Ray Computed

Patients with locally advanced pancreatic cancer (LAPC) are increasingly treated with FOLFIRINOX, resulting in improved survival and resection of tumors that were initially unresectable. It remains unclear, however, which specific patients benefit from FOLFIRINOX. Two nomograms were developed predicting overall survival (OS) and resection at the start of FOLFIRINOX for LAPC.. From our multicenter, prospective LAPC registry in 14 Dutch hospitals, LAPC patients starting first-line FOLFIRINOX (April 2015-December 2017) were included. Stepwise backward selection according to the Akaike Information Criterion was used to identify independent baseline predictors for OS and resection. Two prognostic nomograms were generated.. A total of 252 patients were included, with a median OS of 14 months. Thirty-two patients (13%) underwent resection, with a median OS of 23 months. Older age, female sex, Charlson Comorbidity Index ≤1, and CA 19.9 < 274 were independent factors predicting a better OS (c-index: 0.61). WHO ps >1, involvement of the superior mesenteric artery, celiac trunk, and superior mesenteric vein ≥ 270° were independent factors decreasing the probability of resection (c-index: 0.79).. Two nomograms were developed to predict OS and resection in patients with LAPC before starting treatment with FOLFIRINOX. These nomograms could be beneficial in the shared decision-making process and counseling of these patients.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Nomograms; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Prognosis; Prospective Studies; Survival Rate

The aim of the study was to evaluate gemcitabine plus nanoparticle albumin-bound paclitaxel (GnP) and FOLFIRINOX for recurrent pancreatic cancer (rPC) after resection.. Forty-four patients with rPC and 211 with de novo metastatic pancreatic cancer (mPC) who received GnP or FOLFIRINOX as first-line chemotherapy were retrospectively analyzed.. On crude analysis, the median overall survival (OS) was significantly longer in the rPC group than in the mPC group (14.0 vs. 10.6 months, respectively; p=0.02). However, the difference was not significant on adjusted analysis using the Cox proportional hazards model (adjusted p=0.90). Patients receiving FOLFIRINOX (n=10) and GnP (n=34) in the rPC group had comparable OS (medians, 12.2 vs. 14.4 months, respectively; p=0.82) even after adjusting for covariates using the Cox model (adjusted p=0.18).. The outcomes of patients in the rPC and mPC groups were comparable following chemotherapy. Both FOLFIRINOX and GnP may be reasonable options for treating rPC.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Nanoparticles; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

The study aimed to investigate the effect of body composition changes during chemotherapy on clinical outcomes in patients with pancreatic cancer.. In patients with locally advanced pancreatic cancer (LAPC), the cross-sectional area of skeletal muscle (SM) and adipose tissue (AT) at the level of third lumbar vertebra was measured. The SM and AT ratios indicated the changes during chemotherapy. The patients were classified into three groups based on these ratios: group 1, ≥ 1.00; group 2, 0.85-0.99; group 3, < 0.85. The overall survival (OS) and surgical resection rates were estimated. Fifty-eight patients with LAPC who received first-line FOLFIRINOX were analyzed. Fifteen (25.9%) patients who underwent resection showed maintained BMI, SM, and AT as compared to the patients who did not undergo resection. As the SM ratio decreased, the risk for death increased significantly. Further, the resection rate was significantly higher in patients with maintained SM compared to those with low SM ratio. On the contrary, the change in AT ratio was not associated with OS and resection rate; however, significant decrease in AT more than 15% showed poor clinical outcomes. Maintenance of SM during chemotherapy is a reliable prognostic factor indicating longer OS and higher resection rate.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Muscle, Skeletal; Oxaliplatin; Pancreatic Neoplasms; Prognosis

This study compared median OS after resection of LAPC after upfront FOLFIRINOX versus a propensity-score matched cohort of LAPC patients treated with FOLFIRINOX-only (ie, without resection).. Because the introduction of FOLFIRINOX chemotherapy, increased resection rates in LAPC patients have been reported, with improved OS. Some studies have also reported promising OS with FOLFIRINOX-only treatment in LAPC. Multicenter studies assessing the survival benefit associated with resection of LAPC versus patients treated with FOLFIRINOX-only are lacking.. Patients with non-progressive LAPC after 4 cycles of FOLFIRINOX treatment, both with and without resection, were included from a prospective multicenter cohort in 16 centers (April 2015-December 2019). Cox regression analysis identified predictors for OS. One-to-one propensity score matching (PSM) was used to obtain a matched cohort of patients with and without resection. These patients were compared for OS.. Overall, 293 patients with LAPC were included, of whom 89 underwent a resection. Resection was associated with improved OS (24 vs 15 months, P < 0.01), as compared to patients without resection. Before PSM, resection, Charlson Comorbidity Index, and Response Evaluation Criteria in Solid Tumors (RECIST) response were predictors for OS. After PSM, resection remained associated with improved OS [Hazard Ratio (HR) 0.344, 95% confidence interval (0.222-0.534), P < 0.01], with an OS of 24 versus 15 months, as compared to patients without resection. Resection of LAPC was associated with improved 3-year OS (31% vs 11%, P < 0.01).. Resection of LAPC after FOLFIRINOX was associated with increased OS and 3-year survival, as compared to propensity-score matched patients treated with FOLFIRINOX-only.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Staging; Netherlands; Oxaliplatin; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Propensity Score; Prospective Studies; Survival Rate

Optimal sequence of therapy for patients with metastatic pancreatic ductal adenocarcinoma is unknown. Combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and nab-paclitaxel + gemcitabine (nab-p/gem) are standard first-line (1L) therapies. They have never been prospectively compared. We retrospectively compared overall survival (OS) of patients treated with 1L nab-p/gem and second-line (2L) FOLFIRINOX with those treated with the reverse sequence.. Patients with metastatic pancreatic ductal adenocarcinoma treated with 1L FOLFIRINOX and 2L nab-p/gem or vice versa were identified using an electronic health record-derived real-world database. Using an intent-to-treat analysis, we compared OS from initiation of 1L therapy. A Cox model, stratified by deciles of propensity score, estimated the effect of treatment sequence on OS.. The study included 3027 patients. The median OS for 1L FOLFIRINOX versus nab-p/gem was 8.6 versus 6.1 months (hazard ratio, 0.77; 95% confidence interval, 0.70-0.84). The median OS for 1L FOLFIRINOX and 2L nab-p/gem versus 1L nab-p/gem and 2L FOLFIRINOX was 11.9 versus 11.5 months (hazard ratio, 0.97; 95% confidence interval, 0.79-1.18).. In this analysis of real-world data, 1L FOLFIRINOX was associated with increased OS in propensity analysis. For patients who received both FOLFIRINOX and nab-p/gem, median OS was similar regardless of sequence.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Drug Administration Schedule; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Outcome Assessment, Health Care; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Proportional Hazards Models; Retrospective Studies

The use of FOLFIRINOX (a combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin) is one of the therapeutic standards in pancreatic adenocarcinoma. We analyzed progression-free survival (PFS) and overall survival (OS) and their predictive factors in patients treated with FOLFIRINOX as first-line therapy in metastatic pancreatic cancer.. This multicenter retrospective analysis included patients treated with FOLFIRINOX between 2011 and 2015. The Kaplan-Meier method was used to estimate OS and PFS. The statistical comparison for survival was performed by the log-rank test. Predictive factors were estimated in multivariate analysis with the use of a Cox model.. One hundred and thirty-six patients were included (74 men, 62 women; median age, 62 years [range, 29-74 years]). The median PFS was 5.97 months (95% confidence interval, 4.4-6.63 months). The median OS was 8.93 months (95% confidence interval, 7.4-10.07 months). Prognostic factors in multivariate analysis were the use of granulocyte colony-stimulating factor, which appeared to be a good prognostic factor. Dose intensity of oxaliplatin (≥74.48%) and dose intensity of bolus of fluorouracil (>6.9%) appeared as pejorative factors.. In patients with metastatic pancreatic adenocarcinoma treated with FOLFIRINOX in first line, dose modifications at the onset of adverse effects and early use of granulocyte-colony stimulating factor seem to be associated with a better survival.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Multivariate Analysis; Nausea; Neoplasm Metastasis; Neutropenia; Outcome Assessment, Health Care; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Vomiting

FOLFIRINOX (FFX, a combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin) and gemcitabine plus nab-paclitaxel (GnP) have been used as standard, first-line treatments for advanced pancreatic cancer. However, no study has compared the efficacy of the 2 regimens. This study retrospectively compared the efficacy and safety of the 2 regimens in patients with locally advanced pancreatic cancer.. We reviewed the records of patients with locally advanced pancreatic cancer who started FFX or GnP as first-line chemotherapy as part of a multicenter retrospective study in patients with unresectable pancreatic cancer treated with FFX or GnP (NAPOLEON study).. Sixteen of the 63 patients were treated with FFX, and the other 47 patients were treated with GnP between December 2013 and March 2017. There were no significant differences in median overall survival rate between the GnP (15.5 months) and FFX (14.3 months, P = 0.60) groups or median progression-free survival rate between the GnP (8.8 months) and FFX (8.1 months, P = 0.51) groups. Both treatments were generally well tolerated, although anorexia was more severe in the FFX group than in the GnP group.. The effects of FFX and GnP were similar but resulted in different toxicities, which could guide agent choice.

Topics: Adult; Aged; Albumins; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Diarrhea; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neutropenia; Outcome Assessment, Health Care; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

The POLO (Pancreas Cancer Olaparib Ongoing) trial demonstrated improvement in progression-free survival (PFS) with olaparib maintenance in advanced pancreatic cancer (APC) patients with germline BRCA1/2 mutations who had disease control after 16 weeks of platinum-based first-line therapy. However, in the real-world, the first assessment is usually performed at 12 weeks. Therefore, this study aimed to identify the proportion of real-world patients with APC that have disease control at 12 weeks (DC12) after FOLFIRINOX, assess any associations of baseline variables with DC12, and to determine the effect of DC12 on PFS and overall survival (OS).. APC patients treated with first-line FOLFIRINOX from 2011 to 2018 in Alberta, Canada, were identified. We conducted an analysis of baseline characteristics to identify factors associated with DC12 and to compare the PFS and OS of patients with DC12 to those with earlier disease progression.. We identified 165 APC patients treated with FOLFIRINOX with unknown BRCA1/2 status, of which 56% were men, and the median age at diagnosis was 59 years (interquartile range, 38 to 75 y). Of these, 72 (44%) had DC12. Lower serum carbohydrate antigen 19.9 and normal serum albumin were associated with a higher likelihood of DC12. The PFS and OS of patients with DC12 was significantly higher than those with earlier progression (9.3 vs. 2.5 mo; hazard ratio, 0.22; 95% confidence interval, 0.15-0.32; P<0.001; 21.6 vs. 8.9 mo; hazard ratio, 0.35; 95% confidence interval, 0.25-0.49; P<0.0001).. Less than half of real-world patients treated with first-line FOLFIRINOX have DC12. Patients with APC who have higher carbohydrate antigen 19.9 and low albumin are less likely to have DC12. DC12 is significantly associated with longer PFS and OS.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Remission Induction; Retrospective Studies; Time Factors; Treatment Outcome

BACKGROUNDImmune checkpoint inhibitors (ICIs) fail to demonstrate efficacy in pancreatic cancer. Recently, genomic biomarkers have been associated with response to ICIs: microsatellite instability high (MSI-H) and tumor mutation burden (TMB) > 10 mutations/Mb. Alterations in Switch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling genes may predispose to improved outcomes with immunotherapy. The current study examined a possible role for SWI/SNF complex abnormalities in pancreatic cancer responsiveness to ICIs.METHODSA database of 6831 cancer patients that had undergone next-generation sequencing (NGS) was filtered for advanced pancreatic cancer, SWI/SNF alterations, and outcomes depending on immunotherapy treatment.RESULTSNine patients had metastatic pancreatic adenocarcinoma harboring SWI/SNF chromatin remodeling gene alterations and had received ICIs: 7 had an ARID1A alteration (77%); 2, ARID1B (22%); 3, SMARCA4 (33%); 1, SMARCB1 (11%); and 1, PBRM1 (11%). Three patients possessed more than 1 SWI/SNF complex alteration. Only 3 tumors were microsatellite unstable. Eight of 9 patients (89%) achieved an objective response, including a complete remission, with the 2 longest responses ongoing at 33+ and 36+ months. Median progression-free and overall survival was 9 and 15 months, respectively. Responses occurred even in the presence of microsatellite stability, low TMB, and/or low PD-L1 expression.CONCLUSIONA small subset of patients with pancreatic cancer have genomic alterations in SWI/SNF chromatin remodeling components and appear to be responsive to ICIs, suggesting the need for prospective trials.TRIAL REGISTRATIONClinicalTrials.gov, NCT02478931.FUNDINGJoan and Irwin Jacobs Fund, NIH P30 CA023100 (RK) and LRP KYGF9753 (GPB), the Gershenson, Duarte, and anonymous patient families (GPB).

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Biomarkers, Tumor; Databases, Genetic; DNA Helicases; DNA-Binding Proteins; Female; Fluorouracil; Humans; Immune Checkpoint Inhibitors; Irinotecan; Leucovorin; Male; Microsatellite Instability; Middle Aged; Nuclear Proteins; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Progression-Free Survival; Retreatment; SMARCB1 Protein; Survival Rate; Transcription Factors

Lay abstract Pegfilgrastim is used to prevent low white blood cell count in patients receiving chemotherapy. Comparable to a generic version of a drug, a biosimilar is a follow-on version of a biologic treatment. The authors calculated the savings from using biosimilar pegfilgrastim in a hypothetical group of 2500 patients with metastatic pancreatic cancer and then computed the number of additional doses of FOLFIRINOX chemotherapy that could be purchased with those savings. Using biosimilar pegfilgrastim for 12 cycles could save US$6,907.41 per patient. If all 2500 patients were treated with biosimilar pegfilgrastim, US$17.3 million could be saved. This could provide 72,273 additional FOLFIRINOX doses. Biosimilar pegfilgrastim can generate significant savings to purchase chemotherapy for additional patients cost-free.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biosimilar Pharmaceuticals; Computer Simulation; Cost Savings; Cost-Benefit Analysis; Drug Costs; Filgrastim; Fluorouracil; Health Services Accessibility; Humans; Irinotecan; Leucovorin; Middle Aged; Models, Economic; Oxaliplatin; Pancreatic Neoplasms; Polyethylene Glycols; SEER Program

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Oxaliplatin; Pancreatic Neoplasms

Cancers of the pancreas and biliary tree remain one of the most aggressive oncological malignancies, with most patients relying on systemic chemotherapy. However, effective biomarkers to predict the best therapy option for each patient are still lacking. In this context, an assay able to evaluate individual responses prior to treatment would be of great value for clinical decisions. Here we aimed to develop such a model using zebrafish xenografts to directly challenge pancreatic cancer cells to the available chemotherapies.. Zebrafish xenografts were generated from a Panc-1 cell line to optimize the pancreatic setting. Pancreatic surgical resected samples, without in vitro expansion, were used to establish zebrafish patient-derived xenografts (zAvatars). Upon chemotherapy exposure, zAvatars were analyzed by single-cell confocal microscopy.. We show that Panc-1 zebrafish xenografts are able to reveal tumor responses to both FOLFIRINOX and gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel in just 4 days. Moreover, we established pancreatic and ampullary zAvatars with patient-derived tumors representative of different histological types.. Altogether, we provide a short report showing the feasibility of generating and analyzing with single-cell resolution zAvatars from pancreatic and ampullary cancers, with potential use for future preclinical studies and personalized treatment.

Topics: Albumins; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Drug Therapy, Combination; Fluorouracil; Gemcitabine; Irinotecan; Leucovorin; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Zebrafish

Metastatic pancreatic ductal adenocarcinoma (PDAC) is characterized by a poor survival rate, which can be improved by systemic treatment. Consensus on the most optimal first- and second-line palliative systemic treatment is lacking. The aim of this study was to describe the use of first- and second-line systemic treatment, overall survival (OS), and time to failure (TTF) of first- and second-line treatment in metastatic PDAC in a real-world setting.. Patients with synchronous metastatic PDAC diagnosed between 2015 and 2018 who received systemic treatment were selected from the nationwide Netherlands Cancer Registry. OS and TTF were evaluated using Kaplan-Meier curves with log-rank test and multivariable Cox proportional hazard analyses.. The majority of 1,586 included patients received FOLFIRINOX (65%), followed by gemcitabine (18%), and gemcitabine + nab-paclitaxel (13%) in the first line. Median OS for first-line FOLFIRINOX, gemcitabine + nab-paclitaxel, and gemcitabine monotherapy was 6.6, 4.7, and 2.9 months, respectively. Compared to FOLFIRINOX, gemcitabine + nab-paclitaxel showed significantly inferior OS after adjustment for confounders (hazard ratio [HR], 1.20; 95% CI, 1.02-1.41), and gemcitabine monotherapy was independently associated with a shorter OS and TTF (HR, 1.98; 95% CI, 1.71-2.30 and HR, 2.31; 95% CI, 1.88-2.83, respectively). Of the 121 patients who received second-line systemic treatment, 33% received gemcitabine + nab-paclitaxel, followed by gemcitabine (31%) and FOLFIRINOX (10%).. Based on population-based data in patients with metastatic PDAC, treatment predominantly consists of FOLFIRINOX in the first line and gemcitabine with or without nab-paclitaxel in the second line. FOLFIRINOX in the first line shows superior OS compared with gemcitabine with or without nab-paclitaxel.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Paclitaxel; Palliative Care; Pancreatic Neoplasms; Treatment Outcome

Neoadjuvant therapy (NAT) has become part of the multimodality treatment for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC).. It is currently uncertain which are the preferable NAT regimens, who benefits from surgery, and whether more aggressive surgical strategy is motivated.. A retrospective cohort analysis was performed for all patients with BRPC/LAPC discussed and planned for NAT at multidisciplinary conference at Karolinska University Hospital from 2010 to 2017.. Of 233 patients eligible, 168 (72%) received NAT and were reevaluated for possibility of resection. A total of 156 (67%) patients (mean 64 yrs, 53% male) had pancreatic adenocarcinoma, comprising the study group for survival analysis. LAPC was diagnosed in 132 patients (85%), BRPC in 22 (14%), and resectable tumor in 2 (1.3%). Fifty patients (40.3%) received full-dose NAT. Only 54 (34.6%) had FOLFIRINOX. The overall survival among resected patients was similar for BRPC and LAPC (median survival 15.0 vs 14.5 mo, P = 0.4; and 31.9 vs 21.8 mo, P = 0.7, respectively). Resected patients had better survival than nonresected, irrespective of the type or whether full-dose NAT was given (median survival 22.4 vs 12.7 mo; 1-, 3-, and 5-yr survival: 86.4%, 38.9%, 26.9% vs 52.2%, 1.5%, 0%, respectively (P < 0001). For all preoperative values of Ca 19-9, surgical resection had positive impact on survival.. All patients with BRPC/LAPC who do not progress during NAT should be considered for surgical resection, irrespective of the type or dose of NAT given. Higher levels of Ca 19-9 should not be considered an absolute contraindication for resection.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Retrospective Studies; Survival Rate; Sweden

Despite introduction of new chemotherapeutic agents, outcomes of patients with metastatic pancreatic cancer are still poor. Metabolically supported chemotherapy (MSCT) is a novel approach targeting dysregulated energy mechanism of the tumor cell.. This study aimed to examine the efficacy of metabolically supported administration of chemotherapy combined with ketogenic diet, hyperthermia, and hyperbaric oxygen therapy (HBOT) in patients with metastatic pancreatic cancer.. This retrospective observational study included 25 patients with metastatic pancreatic ductal carcinoma (stage IV) who received MSCT (either gemcitabine-based or FOLFIRINOX regimen administered concomitantly with induced hypoglycemia) plus ketogenic diet, hyperthermia, and HBOT combination. Survival outcomes were evaluated.. During the mean follow-up duration of 25.4 ± 19.3 months, median overall survival and median progression-free survival were 15.8 months (95% CI, 10.5-21.1) and 12.9 months (95% CI, 11.2-14.6), respectively. Age and gender did not have any effect on overall survival (p > 0.05 for all).. MSCT administered together with ketogenic diet, hyperthermia, and HBOT appears to be a viable option with the potential to improve survival outcomes in patients diagnosed with metastatic pancreatic cancer. Further research, particularly with larger comparative clinical trials, is warranted.. Hintergrund: Trotz der Einführung neuer Chemotherapeutika sind die Verlaufsaussichten von Patienten mit metastasierendem Pankreaskarzinom weiterhin ungüns­tig. Die metabolisch unterstützte Chemotherapie (metabolically supported chemotherapy, MSCT) ist ein neuartiger Ansatz, der auf den entgleisten Energiehaushalt der Tumorzelle abzielt. Ziele: Ziel dieser Studie war die Untersuchung der Wirksamkeit einer MSCT in Kombination mit ketogener Ernährung, Hyperthermie und hyperbarer Sauerstofftherapie (HBOT) bei Patienten mit metastasierendem Pankreaskarzinom. Methoden: In dieser retrospek­tiven Beobachtungsstudie betrachteten wir 25 Patienten mit metastasierendem duktalem Pankreaskarzinom (Stadium IV), die mit einer Kombination aus MSCT (Gemcitabin-haltiges oder FOLFIRINOX-Schema, verabreicht unter induzierter Hypoglykämie) mit ketogener Ernährung, Hyperthermie und HBOT behandelt wurden. Verschiedene Überlebenskennzahlen wurden ausge­wertet. Ergebnisse: Während eines mittleren Nachbeobachtungszeitraums von 25,4 ± 19,3 Monaten betrug das mediane Gesamtüberleben 15,8 Monate (95%-KI: 10,5–21,1) und das mediane progressionsfreie Überleben 12,9 Monate (95%-KI: 11,2–14,6). Alter und Geschlecht hatten keinen Einfluss auf das Gesamtüberleben (p > 0,05 für alle). Schlussfolgerungen: MSCT in Kombination mit ketogener Ernährung, Hyperthermie und HBOT scheint bei Patienten mit metastasierendem Pankreaskarzinom eine praktikable Behandlungsoption mit Potenzial zur Verbesserung von Überlebens-Outcomes zu sein. Weitere Forschung hierzu ist gerechtfertigt, insbesondere in Form größerer vergleichender klinischer Studien.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Combined Modality Therapy; Deoxycytidine; Diet, Ketogenic; Female; Fluorouracil; Gemcitabine; Humans; Hyperbaric Oxygenation; Hyperthermia, Induced; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Survivors

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Neoplasm Staging; Oxaliplatin; Pancreatic Neoplasms

A combination of nab-paclitaxel plus gemcitabine (N+G) has recently become a standard first-line treatment in patients with metastatic pancreatic adenocarcinoma (MPA), but there are currently no published data concerning second-line treatment after N+G. The aim of this study was to evaluate the survival outcomes and tolerability of three usual fluoropyrimidine-based regimens FOLFOX, FOLFIRI and FOLFIRINOX after N+G failure in MPA patients.. Patients receiving N+G as first-line regimen were prospectively identified in 11 French centers between January 2014 and January 2017. After disease progression or unacceptable toxicity, patients eligible for second-line therapy were enrolled in the study. The primary endpoint was overall survival following the second-line regimen. Secondary endpoints were objective response, progression-free survival and safety.. Out of 137 patients treated with N+G as first-line regimen, 61 (44.5%) received second-line chemotherapy, including FOLFOX (39.4%), FOLFIRI (34.4%) or FOLFIRINOX (26.2%). Baseline characteristics were not different between the 3 groups. In particular, median age was 71.7 years, sex ratio was 1/1, and performance status (PS) was 0 in 11.5% of case. Main grade 3 toxicities were neutropenia (4.9%) and nausea (3.3%), without major differences between the groups. No toxic death was observed. Median second-line progression-free survival (PFS) and overall survival (OS) were 2.95 (95% CI: 2.3-5.4) and 5.97 months (95% CI: 4.0-8.0), respectively, with no difference between the 3 groups. Median OS from the start of first-line chemotherapy was 12.7 months (10.4-15.1) and was significantly better in patients receiving FOLFIRI after N+G failure, 18.4 months (95% CI: 11.7-24.1, P<0.05), as compared with FOLFOX or FOLFIRINOX (10.4 and 12.3 months, respectively).. This study suggests that second-line fluoropyrimidine-based regimens after N+G failure are feasible, have a manageable toxicity profile in selected patients with MPA, and are associated with promising clinical outcomes, in particular when combined with irinotecan. Randomized phase 3 trials are needed to confirm this trend.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Prospective Studies; Treatment Failure

Transforming growth factor-beta (TGF-β) is a multifunctional regulatory factor. Here we measured serum soluble TGF-β (sTGF-β) levels and evaluated its dynamics and prognostic capabilities during chemotherapy in unresectable pancreatic cancer patients.. We prospectively enrolled 60 patients treated with FOLFIRINOX as the first-line palliative chemotherapy. We collected blood samples at the time of diagnosis, first response assessment, and disease progression and measured serum sTGF-β using an enzyme-linked immunosorbent assay.. The patients' median overall survival (OS) and progression-free survival (PFS) were 10.3 (95% confidence interval [CI], 8.5-12.1) and 6.5 (95% CI, 4.9-8.1) months, respectively. Patients with low sTGF-β at diagnosis (<31.2 ng/mL) had better OS and PFS than patients with high sTGF-β, respectively, (OS, 13.7 vs 9.2 months; hazard ratio [HR], 2.602; P = .004; PFS, 9.0 vs 5.8 months; HR, 2.010; P = .034). At the time of disease progression, sTGF-β was increased compared with that of diagnosis (mean, 26.4 vs 23.9 ng/mL). In particular, sTGF-β was significantly increased at disease progression in patients with a partial response (mean, 25.7 vs 31.0 ng/mL; P = .049).. Pretreatment sTGF-β levels can serve as a prognostic indicator in unresectable pancreatic cancer patients treated with FOLFIRINOX chemotherapy. Likewise, the dynamics of sTGF-β during chemotherapy have prognostic value.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Disease Progression; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Oxaliplatin; Palliative Care; Pancreatic Neoplasms; Prognosis; Progression-Free Survival; Prospective Studies; Transforming Growth Factor beta

Folate-dependent one-carbon (C1) metabolism is compartmentalized in the mitochondria and cytosol and is a source of critical metabolites for proliferating tumors. Mitochondrial C1 metabolism including serine hydroxymethyltransferase 2 (SHMT2) generates glycine for de novo purine nucleotide and glutathione biosynthesis and is an important source of NADPH, ATP, and formate, which affords C1 units as 10-formyl-tetrahydrofolate and 5,10-methylene-tetrahydrofolate for nucleotide biosynthesis in the cytosol. We previously discovered novel first-in-class multitargeted pyrrolo[3,2-

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Membrane; Cytosol; Drug Screening Assays, Antitumor; Gene Knockout Techniques; Glutathione; Glycine Hydroxymethyltransferase; Humans; Leucovorin; Mitochondria; Pancreatic Neoplasms; Purine Nucleotides; Pyrimidines; Pyrroles; Reactive Oxygen Species; Serine; Tetrahydrofolates

In Ontario, FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GnP) have been publicly funded for first-line unresectable locally advanced pancreatic cancer (uLAPC) or metastatic pancreatic cancer (mPC) since April 2015. We examined the real-world effectiveness and safety of FFX vs GnP for advanced pancreatic cancer, and in uLAPC and mPC.. Patients receiving first-line FFX or GnP from April 2015 to March 2017 were identified in the New Drug Funding Program database. Baseline characteristics and outcomes were obtained through the Ontario Cancer Registry and other population-based databases. Overall survival (OS) was assessed using Kaplan-Meier and weighted Cox proportional hazard models, weighted by the inverse propensity score adjusting for baseline characteristics. Weighted odds ratio (OR) for hospitalization and emergency department visits (EDV) were estimated from weighted logistic regression models.. For 1130 patients (632 FFX, 498 GnP), crude median OS was 9.6 and 6.1 months for FFX and GnP, respectively. Weighted OS was improved for FFX vs GnP (HR = 0.77, 0.70-0.85). Less frequent EDV and hospitalization were observed in FFX (EDV: 67.8%; Hospitalization: 49.2%) than GnP (EDV: 77.7%; Hospitalization: 59.3%). More frequent febrile neutropenia-related hospitalization was observed in FFX (5.8%) than GnP (3.3%). Risk of EDV and hospitalization were significantly lower for FFX vs GnP (EDV: OR = 0.68, P = .0001; Hospitalization: OR = 0.76, P = .002), whereas the risk of febrile neutropenia-related hospitalization was significantly higher (OR = 2.12, P = .001). Outcomes for uLAPC and mPC were similar.. In the real world, FFX had longer OS, less frequent all-cause EDV and all-cause hospitalization, but more febrile neutropenia-related hospitalization compared to GnP.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy-Induced Febrile Neutropenia; Deoxycytidine; Emergency Service, Hospital; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Hospitalization; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Ontario; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Propensity Score; Treatment Outcome

To define short-term and long-term outcomes of IORT for the management of BR/LA PDAC in the era of modern neoadjuvant therapy (NAT).. In the era of neoadjuvant FOLFIRINOX, many patients with borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC) become candidates for surgical exploration with curative intent. IORT may be used to consolidate treatment for successfully resected patients with close or positive margins or administered in unresectable patients without distant metastases.. A retrospective review of 158 patients who received IORT in the setting of biopsy-proven BR/LA PDAC following NAT between 2008 and 2017 was performed. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS) of FOLFIRINOX treated patients.. Most patients (83%) received FOLFIRINOX, and 95% underwent consolidative chemoradiation therapy (50.4-58.8 Gy). Among FOLFIRINOX-treated patients, 86 underwent combined surgical resection with IORT (10 Gy) while 46 received IORT alone (15-20 Gy). The median PFS and OS were 21.5 and 46.7 months for patients who underwent resection with IORT and 14.7 and 23 months in the IORT alone group. Local progression occurred in 12.7% of patients after resection with IORT, and in 15% of patients who received IORT alone. Major complications occurred in 13% of patients following resection, and 5% of patients after IORT alone, including one death.. IORT combined with surgical resection appears to be associated with improved survival and minimal morbidity in patients with positive or close margins. IORT is also associated with improved survival in patients with unresectable, non-metastatic disease.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Chemoradiotherapy; Female; Fluorouracil; Humans; Intraoperative Care; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy; Progression-Free Survival; Radiotherapy; Retrospective Studies

FOLFIRINOX (FFX) or abraxane plus gemcitabine (AG)-based chemotherapy is used widely as firstline treatment for patients with pancreatic cancer. However, their use in the elderly is discouraged because of adverse events. More clinical data about the therapeutic response and tolerability to FFX or AG in elderly patents (over 70 years old) are required.. Patients with advanced pancreatic cancer (n = 203; 131 metastatic pancreatic cancer patients (MPC) and 72 locally advanced pancreatic cancer patients (LAPC)) were treated using modified-FFX (mFFX) or AG and mFFX sequentially. The patients were grouped according to their age, patients below 70 years old and patients above 70 years old. The objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), overall survival (OS) and adverse events were compared between the groups.. The ORRs in the elderly and in patients below 70 were similar (30.0% versus 32.3%). The median OS and PFS were also similar between the groups (mOS 13.3 m vs 12.7 m, p = 0.729, HR 0.874 (95% CI 0.5310 to 1.438); mPFS mPFS 10.6 m vs 10.3 m, p = 0.363, HR 0.800 (95% CI 0.4954 to 1.293)). However, the elderly patients suffered a higher incidence of severe adverse events (50% vs. 28.3%).. These data could provide guidance for chemotherapy use in elderly patients with advanced pancreatic cancer. Age did not affect treatment outcome; however, supportive treatment is very important for elderly patients receiving chemotherapy.

Topics: Aged; Aged, 80 and over; Albumin-Bound Paclitaxel; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms

Retrospective studies suggest a survival benefit when platinum-based chemotherapy is administered to patients with pancreatic cancer harbouring a germline mutation in BRCA1, BRCA2 or PALB2 (mut-positive PDAC). However, the objective response rate (ORR) and real-world progression free survival (rwPFS) achieved with such treatment remain ill-defined.. Twenty-six patients with advanced-stage mut-positive PDAC who had been treated with platinum-based therapy were matched by age, race and sex to 52 platinum-treated control PDAC patients. Responses to therapy were determined by RECIST v1.1, performed by blinded radiology review. Measured outcomes included ORR and rwPFS.. The ORR in mut-positive patients was 58% compared to 21% in the control group (p = 0.0022). There was no significant difference in ORR between platinum regimens in mut-positive patients (p = 0.814), whereas in control patients, the only observed responses were to FOLFIRINOX. rwPFS was 10.1 mo. for mut-positive patients and 6.9 mo. for controls (HR 0.43; 95% CI 0.25-0.74; 0.0068).. Mut-positive PDAC has a high ORR and prolonged rwPFS to platinum-based chemotherapy. These findings may have implications particularly in the neoadjuvant setting, and for future clinical trial design, and highlight the importance of early germline testing in patients with PDAC.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; BRCA2 Protein; Carcinoma, Pancreatic Ductal; Case-Control Studies; Cisplatin; Deoxycytidine; Fanconi Anemia Complementation Group N Protein; Female; Fluorouracil; Gemcitabine; Germ-Line Mutation; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Prognosis; Progression-Free Survival; Retrospective Studies

Pancreatic ductal adenocarcinoma (PDAC) has dismal 5-year survival (<9%). We hypothesize that exposure of tumors to conventional therapies may preferentially modulate immune biomarkers in the tumor microenvironment in PDAC. PDAC patients who underwent upfront surgical resection or who received neoadjuvant FOLFIRINOX with or without neoadjuvant radiotherapy followed by surgical resection were selected for study. Total expression of immunologically relevant transcripts and spatially resolved expression of immunologically relevant proteins was quantitated using multiplexed methods (NanoString nCounter and GeoMX platforms). This analysis identified numerous differentially expressed transcripts associated with the type of neoadjuvant therapy received. Moreover, we identified significant alterations in the expression and/or spatial distribution of immunologically relevant proteins in different regions (tumor cell rich, immune cell rich, stromal cell rich) of the tumor microenvironment. These data provide insight into the immunological effects of clinically relevant neoadjuvant therapy for resectable/borderline-resectable PDAC by describing significant differences in the expression of key immunologic biomarkers within the PDAC microenvironment that were associated with the type of treatment patients received prior to surgical resection. This represents a comprehensive analysis of numerous biomarkers conducted on the PDAC microenvironment. This work may guide strategic new combination therapies for pancreatic cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Combined Modality Therapy; Female; Fluorouracil; Gene Expression; Humans; Irinotecan; Keratins; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Radiotherapy; Transcriptome; Tumor Microenvironment

We evaluated the usefulness of the 2017 definition of borderline pancreatic ductal adenocarcinoma (BR-PDAC) in fit patients (performance status 0-1) based on anatomical (A) and biological dimensions (B).. From 2011 to 2018, 139 resected patients with BR-PDAC according to the 2017 definition were included: 18 patients underwent upfront pancreatectomy (CA 19-9 > 500 U/mL and/or regional lymph node metastasis; BR-B group), and 121 received FOLFIRINOX (FX) induction chemotherapy and were divided into BR-A (CA 19-9 < 500 U/mL, no regional lymph node metastasis; n = 68) and BR-AB (CA 19-9 > 500 U/mL and/or regional lymph node metastasis; n = 53) groups.. The 3 groups were comparable according to patient characteristics (except for back pain (P < .01) and CA 19-9 (P < .01)), intraoperative data, and postoperative courses. BR-AB patients required more venous resections (P < .01). The 3 groups were comparable on pathologic findings, except that BR-B patients had more lymph node invasions (P = .02). Median overall survival (OS) of the 121 patients was 45 months. In multivariate analysis, venous resection (P = .039) and R1 resection (P = .012) were poorly linked with OS, whereas BR-A classification (P < .01) independently favored OS. Median survival times of BR-A, BR-AB, and BR-B groups were undetermined, 27 months, and 20 months (P < .001), respectively.. The 2017 definition was relevant for sub-classifying patients with BR-PDAC. The anatomical dimension (BR-A) was a favorable prognostic factor, whereas the biological dimension (BR-AB and BR-B) poorly impacted survival.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Consensus; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Reference Standards; Survival Analysis; Treatment Outcome

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease that can be separated into distinct subtypes based on molecular signatures. Identifying PDAC subtype-specific therapeutic vulnerabilities is necessary to develop precision medicine approaches to treat PDAC.. A total of 56 PDAC liver metastases were obtained from the UNMC Rapid Autopsy Program and analyzed with quantitative proteomics. PDAC subtypes were identified by principal component analysis based on protein expression profiling. Proteomic subtypes were further characterized by the associated clinical information, including but not limited to survival analysis, drug treatment response, and smoking and drinking status.. Over 3,960 proteins were identified and used to delineate four distinct PDAC microenvironment subtypes: (i) metabolic; (ii) progenitor-like; (iii) proliferative; and (iv) inflammatory. PDAC risk factors of alcohol and tobacco consumption correlate with subtype classifications. Enhanced survival is observed in FOLFIRINOX treated metabolic and progenitor-like subtypes compared with the proliferative and inflammatory subtypes. In addition, TYMP, PDCD6IP, ERAP1, and STMN showed significant association with patient survival in a subtype-specific manner. Gemcitabine-induced alterations in the proteome identify proteins, such as serine hydroxymethyltransferase 1, associated with drug resistance.. These data demonstrate that proteomic analysis of clinical PDAC liver metastases can identify molecular signatures unique to disease subtypes and point to opportunities for therapeutic development to improve the treatment of PDAC.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Molecular Typing; Oxaliplatin; Pancreatic Neoplasms; Proteome; Proteomics; Survival Rate; Treatment Outcome

Several studies have suggested a survival benefit of neoadjuvant therapy (NAT) for pancreatic ductal adenocarcinoma (PDAC) in the pancreatic head. Data concerning NAT for PDAC located in pancreatic body or tail are lacking.. Post hoc analysis of an international multicenter retrospective cohort of distal pancreatectomy for PDAC in 34 centers from 11 countries (2007-2015). Patients who underwent resection after NAT were matched (1:1 ratio), using propensity scores based on baseline characteristics, to patients who underwent upfront resection. Median overall survival was compared using the stratified log-rank test.. Among 1236 patients, 136 (11.0%) received NAT, most frequently FOLFIRINOX (25.7%). In total, 94 patients receiving NAT were matched to 94 patients undergoing upfront resection. NAT was associated with less postoperative major morbidity (Clavien-Dindo ≥ 3a, 10.6% vs. 23.4%, P = 0.020) and pancreatic fistula grade B/C (9.6% vs. 21.3%, P = 0.026). NAT did not improve overall survival [27 (95% CI 14-39) versus 31 months (95% CI 19-42), P = 0.277], as compared with upfront resection. In a sensitivity analysis of 251 patients with radiographic tumor involvement of splenic vessels, NAT (n = 37, 14.7%) was associated with prolonged overall survival [36 (95% CI 18-53) versus 20 months (95% CI 15-24), P = 0.049], as compared with upfront resection.. In this international multicenter cohort study, NAT for resected PDAC in pancreatic body or tail was associated with less morbidity and pancreatic fistula but similar overall survival in comparison with upfront resection. Prospective studies should confirm a survival benefit of NAT in patients with PDAC and splenic vessel involvement.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Internationality; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreas; Pancreatectomy; Pancreatic Fistula; Pancreatic Neoplasms; Postoperative Complications; Propensity Score; Retrospective Studies; Survival Analysis

Although FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS), pts > 75 yrs old were excluded from this study. The purpose of this study was to assess the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) in this population.. We retrospectively analyzed unresectable PC pts, age ≥ 75, treated with mFOLFIRINOX at MD Anderson from 2011 to 2017. Primary outcome was rate of grade 3 or 4 hematologic toxicity (HT).. 24 pts were included. Grade 3 or 4 HT occurred in 11 pts 6 pts required hospitalization for any toxicity, and 10 stopped mFOLFIRINOX due to toxicity. The most frequently used starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m. In this single-center retrospective analysis of unresectable PC pts age 75 or older given mFOLFIRINOX, toxicities and survival outcomes were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar toxicity and efficacy when compared to younger pts.

Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Survival Analysis; Treatment Outcome

Pancreatic ductal adenocarcinoma (PC) is characterized by a highly fibrotic desmoplastic stroma. Subtypes of cancer-associated fibroblasts (CAFs) have been identified in chemotherapy-naïve PC (CTN-PC), but their precise functions are still unclear. Our knowledge regarding the properties of CAFs in the regressive stroma after neoadjuvant treatment (NAT) of PC (NAT-PC) is particularly limited. We aimed to examine the marker phenotypic properties of CAFs in the regressive stroma of PC. Surgical specimens from patients with CTN-PC (n=10) and NAT-PC (n=10) were included. Juxtatumoural, peripheral, lobular, septal, peripancreatic, and regressive stromal compartments were manually outlined using digital imaging analysis (DIA) for area quantification. The compartment-specific expression of CD271, cytoglobin, DOG-1, miR-21, osteonectin, PDGF-Rβ, and tenascin C was evaluated by immunohistochemistry or in situ hybridization, using manual scoring and automated DIA. The area fraction of the regressive stroma was significantly higher in NAT-PC than in CTN-PC (P=0.0002). CD271 (P<0.01), cytoglobin (P<0.05), DOG1 (P<0.05), miR-21 (P<0.05), and tenascin C (P<0.05) exhibited significant differences in their expression profiles between the juxtatumoural compared to the peripheral and regressive stroma. PDGF-Rβ expression was significantly higher in juxtatumoural than in peripheral CAFs (P<0.05). Our data provide further support of the concept of stromal heterogeneity and phenotypic different CAF subtypes in PC. CAFs in the regressive stroma of NAT-PC show a marker phenotype similar to some (namely, peripheral) and different from other (namely, juxtatumoural) previously defined CAF subtypes. It may be hypothesized that phenotypic CAF subtypes, at least in part, also may share functional properties. Studies examining the precise functional characteristics of CAF subtypes in PC are needed.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cancer-Associated Fibroblasts; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Phenotype

Liposomal irinotecan (nal-IRI) is a topoisomerase inhibitor proven to improve survival in metastatic pancreatic cancer (mPC). This study describes real-world characteristics of patients treated with nal-IRI for mPC.. Patients 18 years or older diagnosed with stage IV mPC and treated with nal-IRI were selected retrospectively from a deidentified electronic health record database of more than 2 million US cancer patients. Demographics, clinical and dosing characteristics, and treatment outcomes were collected.. Of 257 total patients, 145 (57%) received nal-IRI as first- or second-line therapy. Median nal-IRI treatment duration was 51 days, longer when nal-IRI was used as first/second versus as third-line therapy or later (62 vs 44.5 days). Seventy patients (27.2%) experienced dose modification. Median time to treatment discontinuation was 2.3 versus 1.6 months for first-/second- versus third-line therapy or later, respectively. Median overall survival from nal-IRI initiation was 5.6 versus 4.1 months for first-/second- versus third-line therapy or later, respectively. Prior irinotecan treatment, baseline serum albumin less than 40 g/L, and baseline neutrophil-to-lymphocyte ratio greater than 5 were associated with reduced overall survival.. This is the first large US study of real-world US mPC patients treated with nal-IRI. These results, comparable to the NAPOLI-1 trial, can help inform future studies and the efficacy of nal-IRI in mPC therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Neutropenia; Outcome Assessment, Health Care; Pancreatic Neoplasms; Retrospective Studies; United States

In the adjuvant setting, when compared to gemcitabine, patients with pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX (Folinic Acid, Fluorouracil, Irinotecan, and Oxaliplatin) show superior survival. In this study, we quantitatively assess the pathological tumour response to chemoradiation in pancreatectomy specimens and reassess guidelines for tumour regression grading.. We evaluated 92 patients with borderline resectable/locally advanced PDAC following pancreatectomy and neoadjuvant treatment with FOLFIRINOX and radiation. Demographic data, CAP tumour regression grade (TRG) and overall survival (OS) were recorded. A quantitative analysis of residual tumour was performed on the slide with the highest tumour burden to derive a tumour-to-tumour bed ratio. On univariate analysis, only lymph node status (P = 0.043) and CAP TRG (P = 0.038) correlated with OS. Sixteen per cent of patients showed a complete pathological response. The optimal tumour-to-tumour bed ratio cut-point was 11.6%, and on a multivariate model was the only pathological parameter that correlated with OS (P = 0.016) (hazard ratio = 2.27).. The high proportion of patients with PDAC showing complete and near-complete pathological responses supports the use of FOLFIRINOX and radiation in the neoadjuvant setting. Several traditional pathology parameters fail to predict OS in patients treated with chemoradiation, while a quantitative tumour-to-tumour bed ratio is a powerful predictor of OS. The data support a two-tiered approach to TRG based on tumour-to-tumour bed ratio, and quantitative analysis merits further consideration.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Chemoradiotherapy, Adjuvant; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

Topics: Adult; Aged; Aged, 80 and over; Albumins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Medical Staff, Hospital; Middle Aged; Netherlands; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Regression Analysis; Young Adult

The combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is more toxic than gemcitabine, but it is a safe regimen with manageable toxicities.. We report a case with steatohepatitis mimicking liver metastasis as toxicity that was not seen in study patient population.. The adverse events of drugs are important predictive factor for treatment management, as important as efficacy. Especially the new lesion and metastasis is the most important factor for changing treatment. The clinicians must be careful about adverse events of regimens.. FOLFIRINOX regimen is the most important combination in pancreas cancer adjuvant setting. This case shows us the different presentation of usual adverse event.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fatty Liver; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Middle Aged; Oxaliplatin; Pancreatic Neoplasms

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies. TGF-β is strongly expressed in both the epithelial and stromal compartments of PDAC, and dysregulation of TGF-β signalling is a frequent molecular disturbance in PDAC progression and metastasis. In this study, we investigated whether blockade of TGF-β signalling synergizes with nal-IRI/5-FU/LV, a chemotherapy regimen for malignant pancreatic cancer, in an orthotopic pancreatic tumour mouse model. Compared to nal-IRI/5-FU/LV treatment, combining nal-IRI/5-FU/LV with vactosertib, a TGF-β signalling inhibitor, significantly improved long-term survival rates and effectively suppressed invasion to surrounding tissues. Through RNA-sequencing analysis, we identified that the combination treatment results in robust abrogation of tumour-promoting gene signatures and positive enrichment of tumour-suppressing and apoptotic gene signatures. Particularly, the expression of tumour-suppressing gene Ccdc80 was induced by vactosertib and further induced by vactosertib in combination with nal-IRI/5-FU/LV. Ectopic expression of CCDC80 suppressed migration and colony formation concomitant with decreased expression of epithelial-to-mesenchymal transition (EMT) markers in pancreatic cancer cells. Collectively, these results indicate that combination treatment of vactosertib with nal-IRI/5-FU/LV improves overall survival rates in a mouse model of pancreatic cancer by suppressing invasion through CCDC80. Therefore, combination therapy of nal-IRI/5-FU/LV with vactosertib could provide clinical benefits to pancreatic cancer patients.

Topics: Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinogenesis; Cell Line, Tumor; Cell Movement; Disease Models, Animal; Drug Synergism; Epithelial-Mesenchymal Transition; Fluorouracil; Gene Expression Regulation, Neoplastic; Irinotecan; Leucovorin; Liposomes; Mice, Inbred C57BL; Nanoparticles; Neoplasm Invasiveness; Pancreatic Neoplasms; Signal Transduction; Survival Analysis; Transcriptome; Transforming Growth Factor beta; Triazoles; Tumor Stem Cell Assay; Up-Regulation

Nationwide register data on the effect of primary treatment on survival in an unselected population of patients with pancreatic cancer (PC) have not been reported before. The study aim was to investigate the overall survival (OS) related to initial treatment with resection, chemotherapy, or best supportive care (BSC) in all patients diagnosed with PC in Denmark from 2011 to 2016.. From 1 May 2011 to 30 April 2016, 4260 patients with PC were identified in the Danish Pancreatic Cancer Database. Ninety-seven patients (2%) were excluded, 56 because of treatment with preoperative chemotherapy, 39 because of incorrect registration of diagnosis or treatment, and 2 because of loss to follow-up; thus, 4163 patients were included.. The 718 patients (17%) receiving resection had a median overall survival (mOS) of 21.9 months (range 20.0-24.2). In the chemotherapy group of 1746 patients (42%), those treated with FOLFIRINOX had the longest mOS of 10.0 months (9.2-11.0), whereas those treated with gemcitabine had the shortest mOS of 5.1 months (4.8-5.6). The 1697 patients (41%) receiving BSC had a mOS of only 1.6 months (1.5-1.7).. The resected PC cohort had an OS comparable with that reported in randomised controlled trials (RCTs). The mOS of the chemotherapy-treated patients was slightly shorter compared with the results from RCTs and reflects the unselected population in this study. During the last decade, a larger fraction of patients received anticancer treatment, but the BSC group was still large and showed extremely poor OS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Denmark; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Palliative Care; Pancreatectomy; Pancreatic Neoplasms; Registries; Survival Analysis; Time Factors; Treatment Outcome; Young Adult

Locally advanced pancreatic cancer (LAPC) is a devastating disease and irreversible electroporation (IRE) is a non-thermal ablation method that is especially suitable for the treatment of LAPC. This study aimed to compare the long-term survival of LAPC patients after induction chemotherapy followed by IRE and chemotherapy alone.. From August 2015 to August 2017, a total of 132 patients with LAPC were identified. The oncological outcomes of these two treatments were analyzed by propensity score matching (PSM) analysis.. Before PSM analysis, patients with LAPC had better overall survival (OS) and progression-free survival (PFS) after induction chemotherapy followed by IRE than those who received chemotherapy alone (2-year OS rates, 57.9% vs 19.8%, P < 0.001; 2-year PFS rates, 31.4% vs 9.3%, P < 0.001). The baseline clinicopathological factors were balanced between the 2 groups through PSM analysis. Even after PSM, the OS and PFS rates of patients after induction chemotherapy followed by IRE treatment were superior to those of patients who received chemotherapy treatment alone (2-year OS rates, 57.9% vs 18.1%, P < 0.001; 2-year PFS rates, 31.4% vs 7.1%, P < 0.001). Multivariate Cox regression analysis indicated that chemotherapy plus IRE was a significant prognostic factor for both OS and PFS in patients of both the whole cohort and the matched cohort.. Induction chemotherapy followed by IRE provided better OS and PFS than chemotherapy alone for patients with LAPC. This combination method may be a more suitable treatment for patients with LAPC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Combined Modality Therapy; Electroporation; Female; Fluorouracil; Follow-Up Studies; Humans; Induction Chemotherapy; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Progression-Free Survival; Propensity Score; Survival Analysis

This study aimed to determine the impact of FOLFIRINOX neoadjuvant therapy on patients with non-metastatic borderline/locally advanced (BL/LA) pancreatic ductal adenocarcinoma (PDAC), in current practice.. From 2010 to 2017, 258 patients with BL/LA PDAC from a single high-volume institution received FOLFIRINOX neoadjuvant treatment.. The 258 patients received a median number of 6 cycles of FOLFIRINOX (range, 3-16); 98 (38%) patients underwent curative surgery, and 160 (62%) continued medical treatment. A venous resection was performed in 57 patients (58%), and an arterial resection in 12 (12%). The postoperative 30- and 90-day mortality rates were 6.1% and 8.2%, respectively. Adjuvant chemotherapy was performed in 57 patients (59%). The median overall survival (OS) in patients who did (n = 98) or did not (n = 160) undergo surgical resection were 39 months and 19 months, respectively (P < 0.001). In resected patients, the ASA 3 score (P < 0.01), venous resection (P < 0.01), hemorrhage (P < 0.01), and R1 margin status (P = 0.03) were found to negatively influence the OS. The median OS was significantly higher in patients who did not require a venous resection (not reached vs. 26.5 months, P < 0.001).. Neoadjuvant FOLFIRINOX provided a survival benefit in BL/LA PDAC patients, particularly in those who did not ultimately require venous resection.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Humans; Induction Chemotherapy; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms

To determine the impact of basal-like and classical subtypes in advanced pancreatic ductal adenocarcinoma (PDAC) and to explore GATA6 expression as a surrogate biomarker.. Within the COMPASS trial, patients proceeding to chemotherapy for advanced PDAC undergo tumor biopsy for RNA-sequencing (RNA-seq). Overall response rate (ORR) and overall survival (OS) were stratified by subtypes and according to chemotherapy received. Correlation of. Between December 2015 and May 2019, 195 patients (95%) had enough tissue for RNA-seq; 39 (20%) were classified as basal-like and 156 (80%) as classical. RECIST response data were available for 157 patients; 29 basal-like and 128 classical where the ORR was 10% versus 33%, respectively (. The basal-like subtype is chemoresistant and can be distinguished from classical PDAC by GATA6 expression.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Drug Resistance, Neoplasm; Female; Fluorouracil; GATA6 Transcription Factor; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Multicenter Studies as Topic; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Prospective Studies; Response Evaluation Criteria in Solid Tumors; RNA-Seq

The current study aimed to evaluate the outcomes of patients with unresectable non-metastatic locally advanced pancreatic adenocarcinoma (LAPA) who did not benefit from resection considering the treatment strategy in the clinical settings.. Between 2010 and 2017, a total of 234 patients underwent induction chemotherapy for LAPA that could not be treated with surgery. After oncologic restaging, continuous chemotherapy or chemoradiation (CRT) was decided for patients without metastatic disease. The Kaplan-Meier method was used to determine overall survival (OS), and the Wilcoxon test to compare survival curves. Multivariate analysis was performed using the stepwise logistic regression method.. FOLFIRINOX was the most common induction regimen (168 patients, 72%), with a median of 6 chemotherapy cycles and resulted in higher OS, compared to gemcitabine (19 vs. 16 months, hazard ratio (HR) = 1.2, 95% confidence interval: 0.86-1.6, P = .03). However, no difference was observed after adjusting for age (≤75 years) and performance status score (0-1). At restaging, 187 patients (80%) had non-metastatic disease: CRT was administered to 126 patients (67%) while chemotherapy was continued in 61 (33%). Patients who received CRT had characteristics comparable to those who continued with chemotherapy, with similar OS. They also had longer progression-free survival (median 13.3 vs. 9.6 months, HR = 1.38, 95% confidence interval: 1-1.9, P < .01) and limited short-term treatment-related toxicity.. The median survival of patients who could not undergo surgery was 19 months. Hence, CRT should not be eliminated as a treatment option and may be useful as a part of optimised sequential chemotherapy for both local and metastatic disease.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Pancreatic Neoplasms; Prospective Studies; Survival Analysis; Treatment Outcome

FOLFIRINOX is the standard therapy in patients with unresectable pancreatic cancer (PC). However, FOLFIRINOX frequently induces febrile neutropenia (FN) and neutropenia. The purpose of this study was to explore risk factors for FN and grade 4 neutropenia (NP G4) in patients receiving FOLFIRINOX for PC.. We collected data on 106 patients with PC treated with first-line FOLFIRINOX between 2015 and 2017 using the Pancreatic Cancer Cohort Registry of Severance Hospital in Seoul, Korea.. Multivariate logistic regression analysis showed that female (OR, 3.24; P = 0.023), Eastern Cooperative Oncology Group performance status (OR, 3.70; P = 0.024), overweight (OR, 4.25; P = 0.022), and initial biliary stent insertion (OR, 4.22; P = 0.008) were significantly related to a high risk of FN. Time-dependent bias was reduced using Cox regression analysis, which revealed that female (OR, 2.29; P = 0.041), overweight (OR, 2.67; P = 0.022), and initial biliary stent insertion (OR, 2.59; P = 0.016) were statistically significant predictors. Regarding NP G4, female sex (OR, 2.90; P = 0.016) and overweight (OR, 4.07; P = 0.033) were identified as risk factors in multivariate analysis; however, in Cox regression analysis, tumor in the head of the pancreas (OR, 1.96; P = 0.027) and hemoglobin (g/dL < 12) (OR, 1.87; P = 0.049) were also identified as risk factors.. Female sex, overweight, and initial biliary stent insertion were independent risk factors for the occurrence of FN in patients with unresectable PC treated with FOLFIRINOX.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Factor Analysis, Statistical; Febrile Neutropenia; Female; Fluorouracil; Follow-Up Studies; Humans; Incidence; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Republic of Korea; Retrospective Studies; Risk Factors; Survival Rate

Pancreatic cancer represents the third leading cause of US cancer deaths, with median survival <1 year. The goal of this study was to describe systemic treatments, healthcare utilization and costs, and overall survival among patients with unresectable/metastatic disease.. This study used healthcare claims for commercial and Medicare Advantage enrollees diagnosed with pancreatic adenocarcinoma (at index date) during January 01 2010 to 31 May 2017. Included patients were aged ≥18 years, with continuous 6-month preindex enrollment. Patients were excluded by resectable disease, another primary cancer, or pregnancy. Cohorts were based on first-line (LOT1) chemotherapy regimen.. Overall, 12 978 patients (mean age 70 years, 51% male) were included, among which 5610 (43%) received chemotherapy. Of those, 23% received gemcitabine monotherapy, 22% gemcitabine-nab paclitaxel, 22% FOLFIRINOX, 3% FOLFOX, and 29% received other regimens. Mean LOT1 duration was 112 days; 60% did not undergo subsequent lines of therapy. Moreover, 50% of patients had an emergency room visit and 45% were hospitalized during LOT1. Among treated and untreated patients, mean total 6-month costs were $52 101. We found that patients receiving FOLFIRINOX had the highest costs, whereas those who received gemcitabine monotherapy had the lowest. Median overall survival (mOS) was 335 days with any first-line treatment. FOLFIRINOX-treated patients had the highest mOS (492 days), whereas gemcitabine monotherapy-treated patients had the lowest (223 days).. A large proportion (57%) of patients with unresectable/metastatic pancreatic cancer did not receive chemotherapy. Healthcare costs were higher for fluorouracil-based regimens, while lower for gemcitabine-based regimens. Survival rates were within expectations for advanced pancreatic cancer.

Topics: Aged; Aged, 80 and over; Albumins; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Duration of Therapy; Emergency Service, Hospital; Female; Fluorouracil; Gemcitabine; Health Care Costs; Hospitalization; Humans; Insurance, Health; Irinotecan; Leucovorin; Male; Medicare Part C; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies; Survival Rate; Treatment Outcome; United States

Over 55,000 people in the United States are diagnosed with pancreatic ductal adenocarcinoma (PDAC) yearly, and fewer than 20% of these patients survive a year beyond diagnosis. Chemotherapies are considered or used in nearly every PDAC case, but there is limited understanding of the complex signaling responses underlying resistance to these common treatments. Here, we take an unbiased approach to study protein kinase network changes following chemotherapies in patient-derived xenograft (PDX) models of PDAC to facilitate design of rational drug combinations. Proteomics profiling following chemotherapy regimens reveals that activation of JNK-JUN signaling occurs after 5-fluorouracil plus leucovorin (5-FU + LEU) and FOLFOX (5-FU + LEU plus oxaliplatin [OX]), but not after OX alone or gemcitabine. Cell and tumor growth assays with the irreversible inhibitor JNK-IN-8 and genetic manipulations demonstrate that JNK and JUN each contribute to chemoresistance and cancer cell survival after FOLFOX. Active JNK1 and JUN are specifically implicated in these effects, and synergy with JNK-IN-8 is linked to FOLFOX-mediated JUN activation, cell cycle dysregulation, and DNA damage response. This study highlights the potential for JNK-IN-8 as a biological tool and potential combination therapy with FOLFOX in PDAC and reinforces the need to tailor treatment to functional characteristics of individual tumors.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Fluorouracil; Humans; Leucovorin; MAP Kinase Kinase 4; Mice; Mitogen-Activated Protein Kinase 8; Organoplatinum Compounds; Pancreatic Neoplasms; Xenograft Model Antitumor Assays

Enhanced glucose metabolism is one of the hallmarks of pancreatic cancer. MUC1, a transmembrane protein, is a global regulator of glucose metabolism and essential for progression of pancreatic cancer. To clarify the role of MUC1 in glucose metabolism, we knocked out MUC1 in Capan-1 and CFPAC-1 cells. MUC1 knockout (KO) cells uptook less glucose and secreted less lactate with a much lower proliferating rate. The mRNA level of key enzymes in glycolysis also decreased significantly in MUC1 KO cells. We also observed increased expression of breast cancer type 1 susceptibility protein (BRCA1) in MUC1 KO cells. Since BRCA1 has a strong inhibitory effect on glycolysis, we want to know whether the decreased glucose metabolism in MUC1 KO cells is due to increased BRCA1 expression. We treated wild type (WT) and MUC1 KO cells with BRCA1 inhibitor. BRCA1 inhibition significantly enhanced glucose uptake and lactate secretion in both WT and MUC1 KO cells. Expression of key enzymes in glycolysis also elevated after BRCA1 inhibition. Elevated glucose metabolism is known to facilitate cancer cells to gain chemoresistance. We treated MUC1 KO cells with gemcitabine and FOLFIRINOX in vitro and in vivo. The results showed that MUC1 KO sensitized pancreatic cancer cells to chemotherapy both in vitro and in vivo. In conclusion, we demonstrated that MUC1 promotes glycolysis through inhibiting BRCA1 expression. MUC1 may be a therapeutic target in pancreatic cancer treatment.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Fluorouracil; Gemcitabine; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Glucose; Glycolysis; Humans; Irinotecan; Lactic Acid; Leucovorin; Male; Mice, Nude; Mucin-1; Neoplasm Transplantation; Oxaliplatin; Pancreatic Neoplasms

The incidence and magnitude of indicators of radiographic response of pancreatic cancer to systemic chemotherapy and (chemo)radiation administered prior to anticipated pancreatectomy are unclear.. Sequential computed tomography scans of 226 patients with localized pancreatic cancer who received chemotherapy consisting of 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) or gemcitabine and nanoparticle albumin-bound paclitaxel (GA) with or without (chemo)radiation and who subsequently underwent surgery with curative intent from January 2010 to December 2018 at The University of Texas MD Anderson Cancer Center and Verona University Hospital were re-reviewed and compared.. Overall, 141 patients (62%) received FOLFIRINOX, 70 (31%) received GA, and 15 (7%) received both; 164 patients (73%) received preoperative (chemo)radiation following chemotherapy and prior to surgery; and 151 (67%), 70 (31%), and 5 (2%) patients had Response Evaluation Criteria in Solid Tumors (RECIST) stable disease, partial response, and progressive disease, respectively. The tumors of 29% of patients with borderline resectable or locally advanced cancer were downstaged after preoperative therapy. Radiographic downstaging was more common with chemotherapy than with (chemo)radiation (24% vs. 6%; p = 0.04), and the median tumor volume loss after chemotherapy was significantly greater than that after (chemo)radiation (28% vs. 17%; p < 0.01).. Less than one-third of patients treated with FOLFIRINOX or GA with or without (chemo)radiation experienced either RECIST partial response or radiographic downstaging prior to surgery. The incidence of tumor downstaging was higher and the magnitude of tumor volume loss was greater following chemotherapy than after (chemo)radiation.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Pancreatectomy; Pancreatic Neoplasms; Treatment Outcome

There is no standard chemotherapy for advanced pancreatic cancer (APC) after gemcitabine plus nab-paclitaxel (GP) failure. The aim of this study was to evaluate the efficacy and safety of FOLFIRINOX (5-Fluorouracil, leucovorin, irinotecan, and oxaliplatin) (5-Fluorouracil, leucovorin, irinotecan, and oxaliplatin) (FFX) and modified FFX (mFFX) for APC patients after GP failure.. We retrospectively evaluated the efficacy and safety of FFX in APC patients who were refractory or intolerant of GP.. Between July 2014 and October 2018, 23 patients received FFX after failure of GP. The overall response rate (RR) was 23%, and the disease control rate (DCR) was 68%. The median progression-free survival (PFS) was 5.3 months (95% confidence interval, 2.5-8.9), and the median overall survival (OS) was 12.1 months (95% confidence interval, 4.0-14.2). Twelve patients received FFX, and 11 patients received mFFX. In the FFX group, the RR was 9%, the DCR was 73%, the PFS was 5.3 months, and the OS was 6.9 months. In the mFFX group, the RR was 23%, the DCR was 64%, the PFS was 4.3 months, and the OS was 12.8 months. There was no significant difference between the groups.. FOLFIRINOX has potential activity for patients with APC in whom GP failed.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Drug Substitution; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival; Retrospective Studies; Salvage Therapy

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Combined Modality Therapy; Female; Fluorouracil; Gastric Bypass; Hepatic Artery; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Pancreaticoduodenectomy; Splenic Artery; Vascular Grafting

Unresectable pancreatic cancer (UR-PC) has a poor prognosis. Although conversion surgery has been considered a promising strategy for improving prognosis in UR-PC, the clinical benefit offered to patients with UR-PC remains controversial. This study aimed to investigate the clinical benefits of conversion surgery in patients with UR-PC.. We evaluated patients with UR-PC referred to our department for possible surgical resection between January 2008 and June 2017. Resectability was evaluated using multimodal imaging in patients who underwent chemotherapy for more than 6 months. Conversion surgery was performed only in patients who were judged eligible for R0 resection.. In total, 90 patients were evaluated. Among them, only 22 (24.4%) could actually undergo conversion surgery, and the R0 resection rate was 72.7% (16/22). Although Evans grade ≥ IIB was noted in six patients (27.3%), none achieved complete response (CR). The median survival time was significantly longer among patients who underwent conversion surgery than in the unresected patients who underwent chemotherapy (21.3 months vs. 12.6 months; p < 0.001). Multivariate and Kaplan-Meier analyses revealed microvascular invasion to have a significant adverse effect on recurrence-free survival (RFS: 7 months vs. not reached, p = 0.004) and overall survival (OS: 21 months vs. 85 months, p = 0.047).. After long-term chemotherapy, conversion surgery for UR-PC is associated with long-term survival. Microvascular invasion is predictive of poor prognosis in these patients; adjuvant protocols are therefore needed for patients with microvascular invasion.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Deoxycytidine; Drug Combinations; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Lymph Node Excision; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Oxaliplatin; Oxonic Acid; Paclitaxel; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy; Prognosis; Pyridines; Radiotherapy; Retrospective Studies; Tegafur; Time Factors

Neoadjuvant FOLFIRINOX is a standard-of-care treatment for BRPC patients. Patients with gBRCAm who have demonstrated improved response to platinum-based chemotherapy may have impaired homologous repair deficiency. This study aimed to describe the pathologic complete response rate and long-term survival for patients with germline BRCA1 or BRCA2 mutation (gBRCAm) and borderline resectable pancreatic cancer (BRPC) treated with neoadjuvant FOLFIRINOX.. A dual-center retrospective analysis was performed. Patients who had BRPC treated with neoadjuvant FOLFIRINOX followed by curative resection were identified from clinical databases. Pathologic complete response was defined as no viable tumor cells present in the specimen. Common founder Jewish germline BRCA1 or BRCA2 mutation was determined for available patients.. The 61 BRPC patients in this study underwent resection after neoadjuvant FOLFIRINOX. Analysis of BRCA mutation was performed for 39 patients, and 9 patients were found to be BRCA2 germline mutation carriers. The pathologic complete response rate was 44.4% for the gBRCAm patients and 10% for the BRCA non-carriers (p = 0.009). The median disease-free survival was not reached for the gBRCAm patients and was 7 months for the BRCA non-carriers (p = 0.03). The median overall survival was not reached for the gBRCAm patients and was 32 months for the BRCA non-carriers (p = 0.2). After a mean follow-up period of 33.7 months, all eight patients with pathologic complete response were disease-free.. The study showed that gBRCAm patients with BRPC have an increased chance for pathologic complete response and prolonged survival after neoadjuvant FOLFIRINOX. The results support the benefit of exposing gBRCAm patients to platinum-based chemotherapy early in the course of the disease. Neoadjuvant FOLFIRINOX should be considered for BRCA carriers who have resectable pancreatic cancer.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Mutation; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

The effect of treatment delay on survival in pancreatic ductal adenocarcinoma (PDAC) remains unclear.. This study aimed to assess the prognostic impact of time to diagnosis and chemotherapy in advanced PDAC and factors influencing the time intervals.. advanced PDAC patients receiving chemotherapy in five centers in the decade 2007-2016 were included. Key time points during care pathway from clinical presentation to beginning of chemotherapy were retrospectively collected. Multivariate Cox proportional hazard model was performed.. A total of 409 patients were included (mean age 66.1 ± 10.3 years; 250 metastatic (61%); 139 received FOLFIRINOX chemotherapy (34%). The median overall survival (OS) was 7.2 months. The median times from first symptoms and from first specialist visit to the beginning of chemotherapy were respectively 100 days and 47 days. None of time intervals was significantly associated with OS. Significant prognostic factors were FOLFIRINOX chemotherapy (HR 0.6 [0.5-0.8]; P < 0.001), metastasis (HR 1.6 [1.3-2.0]; P = 0.001), WHO PS ≥ 2 (HR 1.6 [1.2-2.1]; P < 0.001) and acute pancreatitis as first symptom (HR 2.9 [1.7-4.9]; P < 0.001). Jaundice shortened time to diagnosis (P < 0.001). Acute pancreatitis (P < 0.001) and diabetes (P = 0.01) increased time to treatment.. Wait times from clinical presentation to beginning of chemotherapy do not influence survival in advanced PDAC.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Diabetes Mellitus; Female; Fluorouracil; France; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Multivariate Analysis; Oxaliplatin; Pancreatic Neoplasms; Pancreatitis; Prognosis; Proportional Hazards Models; Retrospective Studies; Time-to-Treatment

To evaluate the incidence of pulmonary metastases on chest computed tomography (CT) in patients with locally advanced pancreatic cancer (LAPC).. All patients diagnosed with LAPC in a single tertiary center (Erasmus MC) between October 2011 and December 2017 were reviewed. The staging chest CT scan and follow-up chest CT scans were evaluated. Pulmonary nodules were divided into three categories: apparent benign, too small to characterize, and apparent malignant.. In 124 consecutive patients diagnosed with LAPC, 119 (96%) patients underwent a staging chest CT scan at the initial presentation. In 88 (74%) patients no pulmonary nodules were found; in 16 (13%) patients an apparent benign pulmonary nodule was found, and in 15 (13%) patients a pulmonary nodule too small to characterize was found. Follow-up chest CT scan(s) were performed in 111 (93%) patients. In one patient with either no pulmonary nodule or an apparent benign pulmonary nodule at initial staging, an apparent malignant pulmonary nodule was found on a follow-up chest CT scan. However, a biopsy of the nodule was inconclusive. Of 15 patients in whom a pulmonary nodule too small to characterize was found at staging, 12 (80%) patients underwent a follow-up CT scan; in 4 (33%) of these patients, an apparent malignant pulmonary nodule was found.. In patients with LAPC in whom at diagnosis a chest CT scan revealed either no pulmonary nodules or apparent benign pulmonary nodules, routine follow-up chest CT scans is not recommended. Patients with pulmonary nodules too small to characterize are at risk to develop apparent malignant pulmonary nodules during follow-up.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Lung Neoplasms; Male; Middle Aged; Multiple Pulmonary Nodules; Neoplasm Staging; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Radiosurgery; Retrospective Studies; Tomography, X-Ray Computed

Granulocyte colony-stimulating factor (G-CSF) is frequently prescribed to prevent chemotherapy-induced neutropenia, but the administration schedule remains empirical in case of bimonthly chemotherapy such as FOLFIRINOX regimen. This pharmacokinetic/pharmacodynamic (PK/PD) study was performed to determine the effect of different G-CSF regimens on the incidence and duration of neutropenia following FOLFIRINOX administration in order to propose an optimal G-CSF dosing schedule.. A population PK/PD model was developed to describe individual neutrophil time course from absolute neutrophil counts (ANC) obtained in 40 advanced cancer patients receiving FOLFIRINOX regimen. The structural model considered ANC dynamics, neutropenic effect of cytotoxics and the stimulating effect of G-CSF on neutrophils. Final model estimates were used to simulate different G-CSF dosing schedules for 1000 virtual subjects. The incidence and duration of neutropenia were then calculated for different G-CSF dosing schedules.. The final model successfully described the myelosuppressive effect induced by the 3 cytotoxics for all patients. Simulations showed that pegfilgrastim administration reduced the risk of severe neutropenia by 22.9% for subjects with low ANC at the start of chemotherapy. Median duration in this group was also shortened by 3.1 days when compared to absence of G-CSF. Delayed G-CSF administration was responsible for higher incidence and longer duration of neutropenia compared to absence of administration.. The PK/PD model well described our population's ANC data. Simulations showed that pegylated-G-CSF administration 24 hours after the end of chemotherapy seems to be the optimal schedule to reduce FOLFIRINOX-induced neutropenia. We also underline the potential negative effect of G-CSF maladministration.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neutropenia; Oxaliplatin; Pancreatic Neoplasms; Recombinant Proteins

Locally advanced pancreatic cancer (LAPC) remains a challenge for current treatments. Local destructive therapies, such as irreversible electroporation (IRE) and radiofrequency ablation (RFA), were used more and more frequently in the treatment of LAPC.. This study aimed to compare the efficacy of IRE with RFA in patients with LAPC.. From August 2015 to August 2017, 58 LAPC patients after IRE or RFA therapy, which was performed through open approach, were retrospectively reviewed. The survival outcomes after IRE (36 patients) and RFA (18 patients) were compared after propensity score matching (PSM) analysis.. Before PSM analysis, IRE after the induction chemotherapy resulted in significant higher overall survival (OS) rates and progression-free survival (PFS) rates to RFA (2-year OS, 53.5% vs 30.8%, P = .013; 2-year PFS, 28.4% vs 12.1%, P = .043). After PSM analysis, compared with RFA, the survival benefit of IRE was even more obvious, (2-year OS, 53.5% vs 27.0%, P = .010; 2-year PFS, 28.4% vs 6.4%, P = .018). For patients with tumor larger than 4 cm, IRE resulted in comparable OS and PFS between RFA and IRE while IRE also achieved better long-term OS to RFA for those with tumor smaller than 4 cm. Multivariate analysis illustrated that IRE was a favorable prognostic factor in terms of OS and PFS in patients with LAPC.. IRE after induction chemotherapy is superior to RFA after induction chemotherapy for treating LAPC patients while these two therapies have comparable efficacy for tumors which were larger than 4 cm.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Electroporation; Female; Fluorouracil; Humans; Induction Chemotherapy; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Multivariate Analysis; Oxaliplatin; Pancreatic Neoplasms; Progression-Free Survival; Propensity Score; Radiofrequency Ablation; Retrospective Studies; Tumor Burden

We conducted an institutional study to compare the clinical and pathological efficacy between the neoadjuvant therapy (NAT)-modified FOLFIRINOX (mFOLF) vs nanoparticle albumin-bound paclitaxel plus gemcitabine (nab-P/G) for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) patients who completed resection. The study retrospectively enrolled patients with pathologically confirmed BRPC or LAPC from 2010 to 2018 at our institution. The survival rates were determined by the Kaplan-Meier method and log-rank test was used to test differences. Cox's proportional hazard model was used to assess survival with respect to covariates. Seventy-two patients who completed at least two cycles of neoadjuvant chemotherapy and surgical resection were included, with 52 (72.2%) patients receiving mFOLF and 20 (27.8%) receiving nab-P/G. Patients treated with mFOLF had statistically higher rates of RECIST 1.1 partial or complete response (16/52 vs 1/20, P = .028). Additionally, mFOLF patients had greater pathological tumor size reduction, fewer positive lymph nodes, and higher treatment response grade compared to the nab-P/G patients (all P < .05). The median overall survival was 33.3 months vs 27.1 months (P = .105), and distant metastasis-free survival (DMFS) was 21.3 months vs 14.6 months (P = .042) in the mFOLF vs nab-P/G groups, respectively. On multivariate analysis, mFOLF (hazard ratio, 0.428; 95% confidence interval [CI], 0.186-0.987) and abnormal postoperative CA 19-9 (hazard ratio, 2.47; 95% CI, 1.06-5.76) were associated with DMFS. Among patients with BRPC and LAPC who complete surgical resection, neoadjuvant mFOLF was associated with improved pathological and clinical outcomes compared with nab-P/G.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Linear Models; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Proportional Hazards Models; Radiotherapy, Adjuvant; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Tumor Burden

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; CA-19-9 Antigen; Diagnosis, Differential; Fatal Outcome; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Pancreatic Neoplasms; Pruritus; Severity of Illness Index; Tomography, X-Ray Computed

At 9%, and 2% when diagnosed at advanced stage, the 5-year relative survival rate for pancreatic ductal adenocarcinoma (pdac) is the lowest of any cancer. The currently approved treatment options for metastatic pdac in the United States are folfirinox [irinotecan-fluorouracil (5fu)-leucovorin (lv)-oxaliplatin], gemcitabine-nab-paclitaxel, and liposomal irinotecan plus 5fu-lv. Liposomal irinotecan is a novel formulation of irinotecan encapsulated within a lipid bilayer, which favours local metabolic activation. The napoli-1 trial demonstrated the efficacy of liposomal irinotecan in combination with 5fu and lv for the treatment of advanced pdac after progression on gemcitabine-based chemotherapy. The 1-year survival in those patients was 25%; however, none had had irinotecan-refractory disease before treatment with liposomal irinotecan. Furthermore, the U.S. National Comprehensive Cancer Network guidelines recommend liposomal irinotecan plus 5fu-lv in patients who have received prior fluoropyrimidine-based therapy if no prior irinotecan therapy has been given. Here, we report a male patient with stage iv cancer of pancreas or bile duct (site unconfirmed) who experienced a prolonged (51 weeks) response to liposomal irinotecan plus 5fu-lv despite prior disease progression on irinotecan. Several factors have previously been associated with long-term survival in patients receiving liposomal irinotecan therapy: no prior irinotecan-based chemotherapy, high Karnofsky performance status score, age 65 years or less, serum carbohydrate antigen 19-9 less than 59 U/mL, neutrophil-to-lymphocyte ratio 5 or less, and absence of liver metastasis. The patient in the present report had none of those characteristics indicative of long-term survival, except his age at diagnosis-47 years.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Betacoronavirus; Capecitabine; Coronavirus Infections; COVID-19; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Pandemics; Pneumonia, Viral; Romania; SARS-CoV-2

Stent insertion for biliary decompression to relieve jaundice and subsequent biliary infection is necessary for patients with biliary obstruction caused by pancreatic cancer, and it is important to keep the stent patent as long as possible. However, few studies have compared stent patency in terms of chemotherapy in patients with pancreatic cancer. This study aimed to evaluate the differences in stent patency in terms of recently evolving chemotherapy.. Between January 2015 and May 2017, 161 patients with pancreatic cancer who had undergone biliary stent insertion with a metal stent were retrospectively analyzed. The relationship between chemotherapy and stent patency was assessed. Additionally, overall survival according to the treatment, risk factors for stent patency, and long-term adverse events were evaluated.. Median stent patency was 42 days for patients with the best supportive care and 217 days for patients with chemotherapy (conventional gemcitabine-based chemotherapy and folfirinox) (P < 0.001). Furthermore, the folfirinox group showed the longest median stent patency and overall survival, with 283 days and 466 days, respectively (P < 0.001) despite higher adverse events rate. Patients who underwent folfirinox chemotherapy after stent insertion had better stent patency in multivariate analysis (HR = 0.26; 95% CI: 0.12-0.60; P = 0.001).. Compared with patients who received best supportive care only, patients who underwent chemotherapy after stent insertion had better stent patency. More prolonged stent patency can be expected for patients with folfirinox than conventional gemcitabine-based chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cholangiopancreatography, Endoscopic Retrograde; Cholestasis; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Palliative Care; Pancreatic Neoplasms; Prosthesis Failure; Retrospective Studies; Risk Factors; Sphincterotomy, Endoscopic; Stents; Time Factors; Treatment Outcome

Pancreatic cancer is ranked 4th in Japan in terms of number of deaths so far in 2019, surpassing liver cancer. Unlike other types of cancer, the number of patients in Japan is epidemiologically showing an upward trend, and 70% of cases are unresectable at diagnosis. Therefore, development of chemotherapy that improves the prognosis and maintains and improves the quality of life of the patient is a critical issue. Against this backdrop, the efficacy of nanoliposomal irinotecan(nal-IRI)in combination with fluorouracil and folinic acid(FF)for progressive metastatic pancreatic cancer after previous gemcitabine therapy was confirmed in Europe in 2015 ahead of Japan. In NAPOLI-1, an overseas phase Ⅲ study of this therapy, a significant improvement in overallsurvivalwas shown as compared with patients who received FF alone(median: 6.1 months for nal-IRI plus FF vs 4.2 months for FF alone, p=0.012). Therefore, this study yielded important evidence for second-line treatment of pancreatic cancer around the world. In Japan, a phase Ⅱ study was conducted to confirm the efficacy and safety of this therapy, which found a significant prolongation of progression-free survival(as assessed by the investigator)with this therapy as compared with FF alone(median: 2.7 months for nal-IRI plus FF vs 1.5 months for FF alone, p=0.039). In the latest version of Clinical Practice Guidelines for Pancreatic Cancer published in Japan in July 2019, nal-IRI plus FF therapy was included in a statement as a treatment option after a gemcitabine-based regimen. This paper provides an overview of development of this new nal-IRI plus FF therapy and relevant information. Drug therapies for pancreatic cancer currently being developed in Japan, as well as the position of this therapy in pancreatic cancer therapy in Japan and what the expectations are in the clinical setting, are also discussed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Europe; Fluorouracil; Humans; Irinotecan; Japan; Leucovorin; Liposomes; Pancreatic Neoplasms; Quality of Life

To evaluate the prognostic value of posttreatment fibrosis in human PDAC patients, and to compare a type I collagen targeted MRI probe, CM-101, to the standard contrast agent, Gd-DOTA, for their abilities to identify FOLFIRINOX-induced fibrosis in a murine model of PDAC.. Ninety-three chemoradiation-treated human PDAC samples were stained for fibrosis and outcomes evaluated. For imaging, C57BL/6 and FVB mice were orthotopically implanted with PDAC cells and FOLFIRINOX was administered. Mice were imaged with Gd-DOTA and CM-101.. In humans, post-chemoradiation PDAC tumor fibrosis was associated with longer overall survival (OS) and disease-free survival (DFS) on multivariable analysis (OS. In humans, post-chemoradiation tumor fibrosis is associated with OS and DFS. In mice, our MR findings indicate that translation of collagen molecular MRI with CM-101 to humans might provide a novel imaging technique to monitor fibrotic response to therapy to assist with prognostication and disease management.

Topics: Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Chemoradiotherapy, Adjuvant; Collagen; Disease-Free Survival; Female; Fibrosis; Fluorouracil; Follow-Up Studies; Heterocyclic Compounds; Humans; Irinotecan; Leucovorin; Magnetic Resonance Imaging; Male; Mice; Middle Aged; Molecular Imaging; Molecular Probes; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Organometallic Compounds; Oxaliplatin; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Survival Analysis; Xenograft Model Antitumor Assays

FOLFIRINOX [fluorouracil (5-FU), irinotecan, oxaliplatin] and gemcitabine plus nab-paclitaxel are standard treatments for patients with pancreatic ductal adenocarcinoma (PDAC). Despite efficacy rates of less than 32%, evidence is lacking to guide the use of one drug over the other. Herein, we compared the sensitivity of patient-derived PDAC cell lines to each of these regimens.. Changes in the growth of 19 low-passage patient-derived PDAC cell lines were evaluated in response to treatment with FOLFIRINOX and gemcitabine plus paclitaxel (Gem-Pac).. Six cell lines exhibited optimal sensitivity (high E. Further characterization of cancer cells exhibiting preferential sensitivity to each of these regimens may allow the identification of biomarkers to guide the selection of appropriate chemotherapy for a given patient.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms

The aim of this monocentric study was to evaluate the efficacy and tolerability of a polychemotherapy regimen based on gemcitabine, docetaxel, capecitabine, cisplatin (PDGX) as second-line for advanced pancreatic cancer after FOLFIRINOX.. Patients received FOLFIRINOX as first-line regimen were retrospectively identified between January 2016 and January 2019. After disease progression or unacceptable toxicity, patients eligible for second-line therapy were treated in our center by PDGX.. During this period, 18 patients received PDGX regimen as second-line therapy. Main grade 3 toxicities were hematologic, which required dose adaptation in 14/18 patients. No toxic death was observed. Median second-line progression-free survival (PFS) and overall survival (OS) were 2,91 and 5,3 months, respectively. Total OS from the initiation of first-line was and 11,9 months.. Second-line PDGX regimen after FOLFIRINOX failure is feasible, with notable toxicity profile and is associated with poor clinical outcomes.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Cisplatin; Deoxycytidine; Docetaxel; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

The synchronous diagnosis of two or more primary malignancies in a patient is overall rare. This is a case report of a 70-year-old female with a history of skin squamous cell carcinoma presenting with occult hematochezia. Colonoscopy and biopsy results confirmed a microsatellite stable (MMS) adenocarcinoma in the ascending colon, and subsequent computed tomography (CT) scans identified a 3.2 cm right colonic mass and a 5.0 cm mass in the pancreatic body. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) confirmed the presence of pancreatic ductal adenocarcinoma (PDAC). The patient underwent neo-adjuvant FOLFIRINOX (folinic acid, fluorouracil, irinotecan and oxaliplatin) chemotherapy prior to the simultaneous distal pancreatectomy and right hemicolectomy for both pancreatic and colonic tumors. The pathology diagnoses included moderately differentiated pancreatic ductal carcinoma (PDAC) with histiocyte-like features (tumor stage: ypT3N1M0) and moderately differentiated colonic adenocarcinoma, intestinal type (tumor stage: ypT3N0M0). To the best of our knowledge, this is the first documented case of synchronous primary colonic adenocarcinoma and PDAC in the English literature.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Carcinoma, Squamous Cell; Colonic Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasms, Multiple Primary; Oxaliplatin; Pancreatic Neoplasms; Skin Neoplasms

A significant gap in pancreatic ductal adenocarcinoma (PDAC) patient's care is the lack of molecular parameters characterizing tumours and allowing a personalized treatment.. Patient-derived xenografts (PDX) were obtained from 76 consecutive PDAC and classified according to their histology into five groups. A PDAC molecular gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n = 598) of resected tumours; ii/ 60 advanced tumours obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumours.. A unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumours (e.g. 308 consecutive resected PDAC, uHR=0.321 95% CI [0.207-0.5] and 60 locally-advanced or metastatic PDAC, uHR=0.308 95% CI [0.113-0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumour response: -0.67, p-value < 0.001).. PAMG unify all PDAC pre-existing classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient.. Project funding was provided by INCa (Grants number 2018-078 and 2018-079, BACAP BCB INCa_6294), Canceropole PACA, DGOS (labellisation SIRIC), Amidex Foundation, Fondation de France, INSERM and Ligue Contre le Cancer.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cell Line, Tumor; Clinical Trials as Topic; Disease-Free Survival; Drug Resistance, Neoplasm; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Irinotecan; Leucovorin; Male; Mice; Middle Aged; Neoplasm Metastasis; Neoplasm Proteins; Oxaliplatin; Pancreatic Neoplasms; Precision Medicine; Prognosis; Transcriptome; Young Adult

Repurposing commonly prescribed noncancer medications for use in oncology has substantial advantages over de-novo development of anticancer drugs. Calcium signalling has been implicated in many of the hallmarks of cancer. Previous in-vitro and in-vivo studies have shown that calcium channel blockers (CCBs) are able to promote apoptosis, inhibit proliferation and prevent invasion and metastasis in a variety of cancer types. This retrospective cohort study aimed to translate this into the clinic by investigating the effect of CCBs on survival in pancreatic cancer. One hundred sixty-four patients with unresectable pancreatic ductal adenocarcinoma were included. Data were collected on CCB prescription, and for a range of other potentially important prognostic factors: ECOG performance status, AJCC cancer stage, chemotherapy regimen, radiotherapy, age, hypertension and sex. Participants prescribed CCB (n = 30) were more likely to be older (P = 0.004) and have hypertension (P < 0.0005); baseline demographics were otherwise similar between groups. On adjusted cox regression patients prescribed CCBs demonstrated significantly improved overall survival; hazard ratio -0.496 (0.297-0.827; P = 0.007). Performance status (P < 0.0005), tumour stage (P < 0.0005), chemotherapy regimen (P < 0.0005), radiotherapy (0.002) and age (P = 0.012) were also independent predictors of survival. The Kaplan-Meier estimated median survival was 15.3 months for patients prescribed CCBs versus 10.1 months for patients not prescribed CCBs (P = 0.131). This study supports previous work suggesting CCBs may be beneficial in pancreatic cancer. Further work on larger datasets will allow for subgroup analysis delineating the effects of specific CCBs in combination with different forms of chemotherapy, paving the way for future prospective studies.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Calcium Channel Blockers; Carcinoma, Pancreatic Ductal; Cohort Studies; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Proportional Hazards Models; Retrospective Studies; Survival Rate; United Kingdom

More than 70% of patients with localized pancreatic cancer treated with upfront surgery develop disease recurrence. Herein we describe the radiographic patterns and timing of disease recurrence after neoadjuvant therapy and surgery in patients with pancreatic cancer.. Radiographic patterns of first disease recurrence were examined in patients with localized pancreatic cancer who completed neoadjuvant therapy and surgery. Disease recurrence was classified as local (pancreas, resection bed, or peripancreatic vasculature); regional (peritoneum or abdominal wall); or distant (liver, lung, bone). Progression-free survival was calculated from the date of diagnosis to the date of recurrence.. Of 306 consecutive patients who completed neoadjuvant therapy and surgery, 149 (49%) had resectable pancreatic cancer and 157 (51%) had borderline resectable disease. Neoadjuvant therapy consisted of chemoradiation (32%), chemotherapy (14%), or both therapies (54%). Overall, primary therapy (including preoperative and postoperative therapy) consisted of chemoradiation alone in 29 (9%), chemotherapy alone in 14 (5%), and both therapies in 263 (86%) patients. At a median follow-up of 27 months, 186 (61%) of the 306 patients had recurrent pancreatic cancer. Sites of first recurrence were local-only in 29 (9%), regional-only in 19 (6%), distant-only in 87 (28%), and multisite in 51 (17%). The overall median progression-free survival for all patients was 24 months. Neoadjuvant chemoradiation reduced the odds of local-only recurrence (odds ratio: 0.21; 95% confidence interval: 0.06-0.77; P = .02).. After neoadjuvant therapy and surgery, 9% of patients were found to have local-only recurrence. Treatment sequencing that incorporates neoadjuvant chemoradiation may improve local disease control.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Chemoradiotherapy, Adjuvant; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Oxaliplatin; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Progression-Free Survival; Radiography; Retrospective Studies; Treatment Outcome

In the 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) era, the benefit of surgery versus definitive radiation for borderline resectable (BR) and locally advanced (LA) unresectable pancreatic ductal adenocarcinoma (PDAC) is not well defined. Our primary objective was to identify the survival impact of surgery for BR and LA unresectable PDAC treated with induction FOLFIRINOX.. We performed a single-center retrospective review of BR and LA PDAC treated with FOLFIRINOX from 2010 to 2018. The overall survival of surgery and consolidative radiotherapy was estimated in the Kaplan-Meier method and compared via the log-rank test. Subgroup analyses were conducted for BR and LA patients.. We identified 101 BR and LA PDAC patients treated with induction FOLFIRINOX (41 surgeries and 60 consolidative radiotherapies). Surgery patients were 68.3% (28/41) BR and 31.7% (13/41) LA, whereas consolidative radiotherapy patients were 30% (18/60) BR and 70% (42/60) LA. The R0 resection rate was 100%, and 46.3% (19/41) received preoperative radiation. Median overall survival of surgery versus consolidative radiotherapy was 42.3 versus 19.6 months, respectively (P < 0.001). On multivariate analysis, surgery associated with improved survival.. Surgery after induction FOLFIRINOX is feasible and has a clinically meaningful survival benefit in BR and LA PDAC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Combined Modality Therapy; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Logistic Models; Male; Middle Aged; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Radiotherapy; Retrospective Studies

The goal of this study was to compare outcomes of patients with borderline and resectable pancreatic cancer treated with neoadjuvant stereotactic body radiation therapy (SBRT) versus fractionated chemoradiation.. Patients with borderline or resectable pancreatic cancer treated with neoadjuvant intent between November 2011 and December 2017 were reviewed. The SBRT volume/dose was 33 Gy in 5 fractions to gross tumor plus abutting vessel with or without 25 Gy in 5 fractions to pancreatic head/body and celiac/superior mesenteric artery. Fractionated chemoradiation volume/dose was 50.4 Gy in 28 fractions to gross tumor, superior mesenteric/celiac arteries, and enlarged lymph nodes with concurrent bolus 5-FU, leucovorin, oxaliplatin, irinotecan or gemcitabine/nab-paclitaxel. Failure patterns, local recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival were assessed.. Forty-three patients were reviewed (18 SBRTs and 25 fractionated). Among patients who underwent resection, patients treated with fractionated chemoradiation had improved LRFS (12-month LRFS, 86% vs 62%, P = 0.003) and PFS (median PFS, 23 months vs 11 months, P = 0.006) compared with SBRT. There was no difference in overall survival.. Stereotactic body radiation therapy may result in inferior LRFS and PFS compared with fractionated chemoradiation, likely because of under coverage of high-risk vascular targets.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Deoxycytidine; Diagnostic Imaging; Dose Fractionation, Radiation; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Middle Aged; Neoadjuvant Therapy; Outcome Assessment, Health Care; Oxaliplatin; Paclitaxel; Pancreas; Pancreatic Neoplasms; Radiosurgery

BACKGROUND Pancreatic adenocarcinoma (PDA) is associated with an 8.6-fold increased risk in Lynch syndrome patients. Here, we report the case of a Lynch syndrome PDA patient with an exceptional response to a single cycle of pembrolizumab immunotherapy. CASE REPORT A 65-year-old male patient with Lynch syndrome mismatch repair (MMR) deficient PDA with metastatic liver disease, received 1 cycle of pembrolizumab (200 mg) after progressing on 2 standard lines of treatment. His initial computed tomography (CT) showed 3×2.5 cm PDA. At that time, the disease was considered borderline resectable, and the patient received 6 cycles of FOLFIRINOX followed by chemoradiotherapy with capecitabine. A follow-up CT scan showed multiple new liver lesions. The biopsy showed metastatic PDA and tumor tissue demonstrated high microsatellite instability with abnormal/lost expression of MLH1 and PMS2 proteins. The patient was started on pembrolizumab. Only 1 cycle was given due to the development of thromboembolic complications: pulmonary embolism and myocardial infarction. His thrombophilia workup was negative. Restaging CT scans at 3, 6, and 9 months after 1 cycle of pembrolizumab revealed an excellent response with shrinkage of liver lesions. Restaging at 11 months showed the eventual resolution of most liver lesions. No new metastatic disease developed. A repeat biopsy of the dominant liver lesion showed no morphological evidence of PDA. CONCLUSIONS Only 1 cycle of pembrolizumab resulted in clinical complete response and pathologic response in metastatic PDA. We emphasize the importance of testing for MMR status and treating with immunotherapy in metastatic PDA patients with MMR deficiency.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms, Hereditary Nonpolyposis; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Oxaliplatin; Pancreatic Neoplasms

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms

Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel (GA) are first-line chemotherapy regimens for pancreatic cancer. Their relative efficacy in the setting of localized disease is unknown.. To evaluate radiographic and serologic measures of responses associated with first-line chemotherapy with FOLFIRINOX or GA, and to determine the association between these drug regimens, putative measures of response, and survival.. This case series assessed 485 consecutive patients who were diagnosed as having previously untreated localized pancreatic ductal adenocarcinoma at The University of Texas MD Anderson Cancer Center between January 1, 2010, and December 31, 2017, and who received at least 3 cycles of first-line chemotherapy with FOLFIRINOX or GA. The median (range) follow-up duration was 33 (2-28) months.. Administration of FOLFIRINOX (285 patients [59%]) or GA (200 patients [41%]) as first-line chemotherapy.. Resection rate, radiographic metrics (Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1, and change in tumor volume or anatomic staging), a serologic metric (serum cancer antigen 19-9 level), and overall survival after administration of first-line chemotherapy.. In total, 485 patients (266 [55%] male) were included in the analysis. Patients treated with FOLFIRINOX were generally younger (median [range] age at diagnosis: 61 [30-81] vs 71 [36-89] years; P = .001) and had better performance status as indicated by the Eastern Cooperative Oncology Group scale (range 0-4, with lower numbers representing better performance) score of 2 or lower (274 patients [96%] vs 165 patients [82%] P = .001) but more invasive tumors than patients who received GA (91 [32%] vs 90 [45%] resectable tumors; P = .01). After propensity score matching to control for these biases, many objective serologic and radiographic metrics of response associated with administration of FOLFIRINOX or GA-including low rates of local tumor downstaging-did not differ. However, RECIST partial response was more common among patients treated with FOLFIRINOX (27 of 140 patients [19%]) than with GA (8 of 140 patients [6%]; P = .001). Moreover, (chemo)radiation (50% vs 34%; P = .001) was more commonly administered to and pancreatectomy (27% vs 16%; P = .01) was subsequently performed more frequently for patients initially treated with FOLFIRINOX. The overall survival duration of patients treated with either regimen was similar (hazard ratio, 1.48; 95% CI, 0.97-2.26; P = .07).. In this cohort of patients with localized pancreatic adenocarcinoma who received FOLFIRINOX or GA as their first line of therapy, FOLFIRINOX was associated with higher rates of RECIST partial response and subsequent pancreatectomy than GA, but the overall survival associated with these regimens was similar.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Carcinoma, Pancreatic Ductal; Cohort Studies; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Radiography; Survival Rate; Treatment Outcome

Metastatic pancreatic carcinoma is an aggressive disease with adverse prognosis. Despite slight advances in chemotherapy, complete remission of the disease is extremely rare.. In this article we present a case of a patient with initially metastatic pancreatic adenocarcinoma, associated with double heterozygous germline mutation in BRCA2 and CHEK2 genes, with the description of clinical, radiological and histomorphological characteristics of the disease as well as the dia-gnostic and therapeutic procedure.. The patient with initially metastatic pancreatic adenocarcinoma with multiple liver involvement achieved complete remission following first-line FOLFIRINOX chemotherapy. The treatment lasted for 12 months but due to increased neurotoxicity since the 9th cycle, oxaliplatin was excluded from the regimen. Given the family history of several malignancies (prostate cancer, seminoma), genetic testing was performed, which confirmed heterozygous germline mutations in BRCA2 and CHEK2 genes. Since the treatment has been completed, the patient remains in complete remission at 30 months.. Given the low incidence of complete remissions in patients with metastatic pancreatic cancer, the further therapeutic approach is not clearly established, an individual treatment is important. Universal genetic testing is recommended in patients with pancreatic cancer as it may affect the treatment strategy.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; BRCA2 Protein; Checkpoint Kinase 2; Female; Fluorouracil; Genes, BRCA2; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Pedigree

Neoadjuvant chemotherapy has become a powerful tool to convert borderline resectable (BRPC) and locally advanced pancreatic cancers (LAPC) into a resectable scenario. However, data analyzing the optimal type of therapy are scarce. In the present multicenter retrospective study, we evaluated the influence of FOLFIRINOX (FFX) and gemcitabine (GEM)-based neoadjuvant therapy on patient prognosis.. Data on 239 patients from 7 centers across Europe was gathered using an online database. Patients having received their first cycle of chemotherapy for BRPC/LAPC before 06/2017, with a minimum follow-up of 12 months, were included in the intention-to-treat analysis.. Patients treated with neoadjuvant FFX (n = 135) or gemcitabine + nab-paclitaxel (GNP) (n = 38) had significantly improved radiological response according to RECIST criteria as compared to single-agent GEM (n = 16), with a partial/complete response of 59.3%, 55.3% and 6.25% respectively (p = 0.001). Treatment with FFX (n = 135) and GNP (n = 38) resulted in higher resection rates compared to GEM (73.3%, 81.6% and 43.8%; p = 0.01 and p = 0.005). Regardless of regimen, patients who were resected had significantly prolonged overall survival compared to non-resected patients (p < 0.01). Complete pathological responses (ypT0 ypN0) were predominantly observed with FFX (p = 0.01). Adjuvant GNP in addition to successful neoadjuvant therapy and surgery resulted in a trend towards improved median survival as compared to postoperative observation (47.0 vs. 30.1 months, p = 0.06).. Representing one of the largest studies published so far, our results reveal that patients with BRPC/LAPC should be offered either FFX or GNP to improve chances of resection and with this also survival.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Combined Modality Therapy; Deoxycytidine; Europe; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Postoperative Complications; Prognosis; Retrospective Studies; Survival Analysis; Treatment Outcome

To compare survival after CT-guided percutaneous irreversible electroporation (IRE) and folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) chemotherapy versus FOLFIRINOX only in patients with locally advanced pancreatic cancer (LAPC).. A post hoc comparison was performed of data derived from a prospective IRE-FOLFIRINOX cohort and a retrospective FOLFIRINOX-only cohort. All patients received a minimum of 3 cycles of FOLFIRINOX for LAPC and were considered eligible for CT-guided percutaneous IRE. Endpoints included overall survival (OS), local and distant progression-free survival, and time to progression (TTP) and were compared using stratified Kaplan-Meier analysis. Patients who received > 8 cycles of FOLFIRINOX before IRE and who had tumors > 6 cm in the FOLFIRINOX-only group were excluded.. Of 103 patients with a diagnosis of LAPC, 52 were deemed eligible (n = 30 IRE-FOLFIRINOX and n = 22 FOLFIRINOX-only). Patients in the FOLFIRINOX-only arm had larger tumors (53 mm ± 19 vs 38 mm ± 7, P = .340), had more locoregional lymph node metastases (23% vs 7%, P = .622), and more often received radiotherapy (7 patients vs 2 patients, P = .027); all other baseline characteristics were comparable. Median OS was 17.0 months (range, 5-35 mo; SD = 6) for IRE-FOLFIRINOX versus 12.4 months (range, 3-22 mo; SD = 6) for FOLFIRINOX-only (P = .038). After sensitivity analyses, median OS was 17.2 months (range, 6-27 mo; SD = 6) versus 12.4 months (range, 7-32 mo; SD = 10) (P = .05). Median TTP was longer in the IRE-FOLFIRINOX group: 14.2 months (range, 5-25 mo; SD = 4) versus 5.2 months (range, 2-22; SD = 6) (P = .0001).. In patients with LAPC after FOLFIRINOX chemotherapy, CT-guided percutaneous IRE may improve OS and TTP. This study may facilitate the design of randomized controlled trials to compare survival after IRE-FOLRINOX versus FOLFIRINOX-only.

Topics: Ablation Techniques; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Electroporation; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Prospective Studies; Radiography, Interventional; Retrospective Studies; Risk Factors; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

Our study describes the feasibility and efficacy of a first-line FOLFIRINOX (5-fluorouracil [5FU], folinic acid, irinotecan, and oxaliplatin) induction chemotherapy (CT) followed by de-escalation as a maintenance strategy for advanced pancreatic cancer.. This multicenter retrospective study was conducted from January 2011 to December 2018. FOLFIRINOX de-escalation was defined as stopping oxaliplatin and/or irinotecan after at least four cycles of FOLFIRINOX, without evidence of disease progression. Maintenance schedules were fluoropyrimidine monotherapy (intravenous or oral [capecitabine]), FOLFOX (5FU, oxaliplatin), or FOLFIRI (5FU, irinotecan). Primary endpoint was overall survival (OS). Secondary endpoints were first progression-free survival (PFS1), second progression-free survival (PFS2), and toxicity.. Among 321 patients treated with FOLFIRINOX, 147 (45.8%) were included. Median OS was 16.1 months (95% confidence interval [CI], 13.7-20.3) and median PFS1 was 9.4 months (95% CI, 8.5-10.4). The preferred maintenance regimen was FOLFIRI in 66 (45%) patients versus 5FU monotherapy in 52 (35%) and FOLFOX in 25 (17%) patients. Among 118 patients who received maintenance CT with FOLFIRI or 5FU, there was no difference in PFS1 (median, 9.0 vs. 10.1 months, respectively; p = .33) or OS (median, 16.6 vs. 18.7 months; p = .86) between the two maintenance regimens. Reintroduction of FOLFIRINOX was performed in 20.2% of patients, with a median PFS2 of 2.8 months (95% CI, 2.0-22.3). The rates of grade 3-4 toxicity were significantly higher with FOLFIRI maintenance CT than with 5FU (41% vs. 22%; p = .03), especially for neuropathy (73% vs. 9%).. 5FU monotherapy maintenance appeared to be as effective as FOLFIRI, in a FOLFIRINOX de-escalation strategy, which is largely used in France.. FOLFIRINOX de-escalation and maintenance is a feasible strategy in advanced pancreatic cancer that decreases chemotherapy toxicity to improve both survival and quality of life. Survivals in patients with maintenance therapy are clinically meaningful. Fluoropyrimidine monotherapy maintenance seems to be as efficient as FOLFIRI and should be a reference arm in future pancreatic cancer maintenance trials.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; France; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Quality of Life; Retrospective Studies

By using the Korean Pancreatic Cancer (K-PaC) registry, we compared the clinical outcomes of FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GNP) in patients with metastatic pancreatic cancer (MPC).. We constructed a web-based database of 3748 anonymized patients diagnosed with pancreatic ductal adenocarcinoma. MPC patients who received first-line FFX or GNP were enrolled. Overall survival (OS), progression-free survival, grade III to IV toxicity, and cross-over treatment were analyzed.. A total of 413 patients (232 vs. 181, FFX vs. GNP; all data are presented in this sequence) were eligible. Median age was 63 years (60 vs. 69 y) with 43% (39% vs. 47%) comprising female individuals. The major metastatic sites were the liver (64%), peritoneum (25%), and distant lymph nodes (18%). The median OS was 11.5 versus 12.7 months (hazard ratio [HR]=0.87, 95% confidence interval [CI]: 0.68-1.12, P=0.286), and median progression-free survival was 7.5 versus 8.1 months (HR=0.92, 95% CI: 0.70-1.20, P=0.517), respectively. The frequency of grade III to IV febrile neutropenia was higher in the FFX group (18% vs. 11%, P=0.040), and that of peripheral neuropathy was higher in the GNP group (8% vs. 14%, P=0.046). The chance to receive second-line chemotherapy was higher in the GNP group (45% vs. 56%, P=0.036). In the cross-over treatment, the median OS of the FFX-GNP group (n=43) and the GNP-FFX group (n=47) was 16.8 versus 17.7 months (HR=0.79, 95% CI: 0.44-1.41, P=0.425).. FFX and GNP showed similar efficacy and comparable toxicity in MPC patients. Although the GNP group had a higher chance to receive second-line chemotherapy, they did not have improved overall survival.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cross-Over Studies; Deoxycytidine; Febrile Neutropenia; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Peripheral Nervous System Diseases; Peritoneal Neoplasms; Progression-Free Survival; Registries; Republic of Korea; Survival Rate; Treatment Outcome

Topics: Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Aortic Valve Insufficiency; Diffusion Magnetic Resonance Imaging; Echocardiography, Transesophageal; Endocarditis; Fluorouracil; Humans; Irinotecan; Ischemic Stroke; Leucovorin; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Staging; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Positron Emission Tomography Computed Tomography; Practice Guidelines as Topic; United Kingdom

The benefit of adjuvant chemotherapy after resection of pancreatic cancer following neoadjuvant combination treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is unclear.. To assess the association of adjuvant chemotherapy with overall survival (OS) in patients after pancreatic cancer resection and neoadjuvant FOLFIRINOX treatment.. This international, multicenter, retrospective cohort study was conducted from January 1, 2012, to December 31, 2018. An existing cohort of patients undergoing resection of pancreatic cancer after FOLFIRINOX was updated and expanded for the purpose of this study. All consecutive patients who underwent pancreatic surgery after at least 2 cycles of neoadjuvant FOLFIRINOX chemotherapy for nonmetastatic pancreatic cancer were retrospectively identified from institutional databases. Patients with resectable pancreatic cancer, borderline resectable pancreatic cancer, and locally advanced pancreatic cancer were eligible for this study. Patients with in-hospital mortality or who died within 3 months after surgery were excluded.. The association of adjuvant chemotherapy with OS was evaluated in different subgroups including interaction terms for clinicopathological parameters with adjuvant treatment in a multivariable Cox model. Overall survival was defined as the time starting from surgery plus 3 months (moment eligible for adjuvant therapy), unless mentioned otherwise.. We included 520 patients (median [interquartile range] age, 61 [53-66] years; 279 [53.7%] men) from 31 centers in 19 countries. The median number of neoadjuvant cycles of FOLFIRINOX was 6 (interquartile range, 5-8). Overall, 343 patients (66.0%) received adjuvant chemotherapy, of whom 68 (19.8%) received FOLFIRINOX, 201 (58.6%) received gemcitabine-based chemotherapy, 14 (4.1%) received capecitabine, 45 (13.1%) received a combination or other agents, and 15 (4.4%) received an unknown type of adjuvant chemotherapy. Median OS was 38 months (95% CI, 36-46 months) after diagnosis and 31 months (95% CI, 29-37 months) after surgery. No survival difference was found for patients who received adjuvant chemotherapy vs those who did not (median OS, 29 vs 29 months, univariable hazard ratio [HR], 0.99; 95% CI, 0.77-1.28; P = .93). In multivariable analysis, only the interaction term for lymph node stage with adjuvant therapy was statistically significant: In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved survival (median OS, 26 vs 13 months; multivariable HR, 0.41 [95% CI, 0.22-0.75]; P = .004). In patients with node-negative disease, adjuvant chemotherapy was not associated with improved survival (median OS, 38 vs 54 months; multivariable HR, 0.85; 95% CI, 0.35-2.10; P = .73).. These results suggest that adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease. Future randomized studies should be conducted to confirm this finding.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

Personalized medicine in treating pancreatic ductal adenocarcinoma (PDAC) is still in its infancy, albeit PDAC-related deaths are projected to rise over the next decade. Only recently, maintenance therapy with the PARP inhibitor olaparib showed improved progression-free survival in germline

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Ataxia Telangiectasia Mutated Proteins; BRCA2 Protein; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Chromosomal Instability; DNA Damage; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Leucovorin; Maintenance Chemotherapy; Mice; Mice, Nude; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Survival Analysis; Ubiquitin-Protein Ligases; Xenograft Model Antitumor Assays

The number of people aged 60 and above will rise from 46 million in 2015 to 157 in 2050 million, exceeding 30% of the population in many western countries. Consequently, the demand for oncological therapy for elderly patients will increase within the next decades. Currently, sufficient data on neoadjuvant therapy (NTx) of pancreatic cancer in elderly patients are lacking.. Data of a multinational, retrospective database were screened for patients having received preoperative FOLFIRINOX (FFx) or Gemcitabine/nab-paclitaxel (GNP) for locally advanced and borderline resectable pancreatic cancer (LAPC/BRPC) before June 2017. Data were included in an intention-to-treat-analysis and outcomes were compared between non-aged and elderly patients using a cut-off age of 63 (comparison 1) and 70 years (comparison 2).. Of 165 patients receiving NTx, 76 and 33 were older than 63 and 70 years. Baseline characteristics revealed that elderly patients preferably undergo GNP (comparison 1: p = 0.063; comparison2: p = 0.005), with less cycles of NTx (comparison 1: p = 0.057). Whereas reductions of NTx dosage was more common in elderly patients in comparison 1 (p = 0.003), resection rates (p = 0.575; p = 1.000) and median survival (p = 0.406; p = 0.499) were not different. Whereas resected patients showed no differences in survival (p = 0.328; p = 0.132), patients aged >70 years showed a decreased progression-free survival (p = 0.019).. Elderly patients treated with NTx show encouragingly high resection rates. If comorbidities allow for FFx or GNP, elderly patients with LAPC/BRPC can offered NTx with the prospect of survival comparable to younger patients.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Italy; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies; Treatment Outcome

Objectives: Pancreatic cancer (PC) is a costly disease with a limited life-expectancy as it generally presents as an advanced, metastatic disease. Though current literature suggests cost varies by first line treatment, there is limited real-world knowledge about the economic burden of pancreatic cancer. This study describes the economic burden of pancreatic cancer patients overall and by observed first line treatments.. The IBM MarketScan databases were used to identify adult metastatic PC patients from January 1, 2010 through 3/31/2017. Those without other primary cancers, pregnancy, or prior PC treatment, and with 6 months of continuous enrollment prior to PC were included. Treatment patterns and healthcare utilization and expenditures were measured during the variable-length follow-up period. Continuous measures were presented as per patient per month (PPPM).. A total of 6,360 patients met all inclusion criteria. Almost half (46.8%) of patients were untreated. Gemcitabine alone (15.6%) and FOLFIRINOX (11.4%) were the most commonly observed first line regimens. Treated patients incurred $17,513 PPPM (Gemcitabine alone) to $27,889 PPPM (FOLFIRINOX) during follow-up. Untreated patients incurred the highest unadjusted ($30,777 PPPM) and adjusted ($20,392 PPPM) cost.. Metastatic PC patients incur a high economic burden driven by high utilization of healthcare resources, which varies by first line treatment. Also, the high proportion of untreated patients is alarming as these patients may be the most expensive of all patients. There is an unmet need in these patients for effective treatments that also reduce their economic burden.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cost of Illness; Costs and Cost Analysis; Databases, Factual; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Health Care Costs; Health Resources; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Needs Assessment; Neoplasm Metastasis; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

Data on FOLFIRINOX as a second-line chemotherapy for advanced pancreatic cancer are limited. In the JASPAC06 study-a nationwide, multicenter, observational study-FOLFIRINOX for patients with unresectable or recurrent pancreatic cancer as any line of treatment showed favorable efficacy and safety in Japanese clinical practice.. We performed exploratory analyses of patients with unresectable or recurrent pancreatic cancer who received FOLFIRINOX as the second-line chemotherapy in Japanese clinical settings.. Of the 399 evaluable patients, 44 were eligible for inclusion in the analysis. The patients' characteristics were as follows: median age, 62 years; men, 26 (59%); Eastern Cooperative Oncology Group-Performance status 0/1, 30 (68%)/14 (32%); disease status, recurrent/local/metastatic: 4 (9%)/8 (18%)/32 (73%). The initial dose was reduced in 28 (64%) patients. The median time to treatment failure and number of cycles were 4.5 (range, 0.2-19.1) months and 6 cycles (range, 1-13 or more), respectively. The major grade 3/4 adverse events were neutropenia in 29 (66%), leucopenia in 17 (39%), anorexia in 7 (16%), febrile neutropenia in 5 (11%), and anemia in 5 (11%) patients. The median overall survival, progression-free survival, and 1-year survival rates were 10.3 (95% confidence interval [CI], 7.2-13.3), 4.1 (95% CI, 2.6-5.5) months, and 30%, respectively.. Our findings suggest that FOLFIRINOX as a second-line chemotherapy for advanced pancreatic cancer was effective in patients with a good performance status. It displayed toxicity similar to that observed with its use as a first-line treatment.

Topics: Adult; Aged; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Glucuronosyltransferase; Humans; Irinotecan; Japan; Kaplan-Meier Estimate; Leucovorin; Leukopenia; Male; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Oxaliplatin; Pancreatic Neoplasms; Progression-Free Survival; Survival Analysis; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Fatal Outcome; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Middle Aged; Nanoparticles; Pancreatic Neoplasms; Progression-Free Survival; Time Factors; Tomography, X-Ray Computed

Neoadjuvant systemic treatment is increasingly being integrated in the standard treatment of pancreatic ductal adenocarcinoma (PDAC) patients to improve oncological outcomes. Current available imaging techniques remain unreliable in assessing response to therapies, as they cannot distinguish between (vital) tumor tissue and therapy induced fibrosis (TIF). Consequently, resections with tumor positive margins and subsequent early post-operative recurrences occur and patients eligible for potential radical resection could be missed. To optimize patient selection and monitor results of neoadjuvant treatment, PDAC-specific diagnostic and intraoperative molecular imaging methods are required. This study aims to evaluate molecular imaging targets for PDAC after neoadjuvant FOLFIRINOX treatment. Expression of integrin α

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Follow-Up Studies; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Intraoperative Care; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Retrospective Studies

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Disease Models, Animal; Electrochemotherapy; Electroporation; Fluorouracil; Humans; Irinotecan; Leucovorin; Mice; Oxaliplatin; Pancreatic Neoplasms

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

In pancreatic cancer, toxicities associated with current chemotherapeutic regimens remain concerning. A modified combination of gemcitabine, S-1, and leucovorin (GSL) was used as the first-line treatment for newly diagnosed locally advanced or metastatic pancreatic adenocarcinoma patients.. GSL was administered every 2 weeks-intravenous gemcitabine 800 mg/m2 at a fixed-dose rate of 10 mg/m2/min on day 1 and oral S-1 (80-120 mg/day) plus leucovorin 30 mg twice daily on days 1-7. We retrospectively analyzed the feasibility of GSL and patient outcomes in three medical centers in Taiwan.. Overall, 49 patients received GSL with a median follow-up of 24.9 months from May 2015 to March 2019. The median patient age was 68 years (range, 47-83 years), with a marginally higher number of females (57.1%). Among the 44 patients who underwent image evaluation, 13 demonstrated a partial response (29.5%) and 17 presented with stable disease (38.6%). The partial response rate and stable disease rate was 26.5% and 34.7%, respectively, in the intent-to-treat analysis. The median time-to-treatment failure was 5.79 months (95% C.I., 2.63-8.94), progression-free survival was 6.94 months (95% C.I., 5.55-8.33), and overall survival time was 11.53 months (95% C.I., 9.94-13.13). For GSL treatment, the most common grade 3 or worse toxicities were anemia (18.3%), neutropenia (6.1%), nausea (4.1%), and mucositis (4.1%). Treatment discontinuation was mostly due to disease progression (65.3%).. The modified GSL therapy can be a promising and affordable treatment for patients with advanced and metastatic pancreatic cancer in Taiwan. A prospective trial of modified GSL for elderly patients is currently ongoing in Taiwan.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease Progression; Drug Combinations; Feasibility Studies; Female; Follow-Up Studies; Gemcitabine; Humans; Intention to Treat Analysis; Leucovorin; Male; Middle Aged; Oxonic Acid; Pancreatic Neoplasms; Progression-Free Survival; Retrospective Studies; Taiwan; Tegafur; Treatment Failure

The aim of the study was to identify plasma microRNA (miRNA) biomarkers for stratifying and monitoring patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX, and to investigate their functional roles.. FOLFIRINOX has become a standard therapy for patients with advanced PDAC and can be used to potentially downstage disease. However, only a subset of patients respond, and biomarkers to guide decision-making are urgently needed.. We used microarray-based profiling to discover deregulated miRNAs in pre- and postchemotherapy plasma samples from patients based on their progression-free survival (PFS) after FOLFIRINOX. Nine candidate plasma miRNAs were validated in an independent cohort (n = 43). The most discriminative plasma miRNA was correlated with clinicopathological factors and survival, and also investigated in an additional cohort treated with gemcitabine plus nab-paclitaxel. Expression patterns were further evaluated in matched tumor tissues. In vitro studies explored its function, key downstream gene-targets, and interaction with 5-fluorouracil, irinotecan, and oxaliplatin.. Plasma miR-181a-5p was significantly downregulated in non-progressive patients after FOLFIRINOX. In multivariate analysis, this decline correlated with improved PFS and overall survival, especially when combined with CA19-9 decline [hazard ratio (HR) = 0.153, 95% confidence interval (CI), 0.067-0.347 and HR = 0.201, 95% CI, 0.070-0.576, respectively]. This combination did not correlate with survival in patients treated with gemcitabine plus nab-paclitaxel. Tissue expression of miR-181a-5p reflected plasma levels. Inhibition of miR-181a-5p coupled with oxaliplatin exposure in pancreatic cell lines decreased cell viability.. Plasma miR-181a-5p is a specific biomarker for monitoring FOLFIRINOX response. Decline in plasma miR-181a-5p and CA19-9 levels is associated with better prognosis after FOLFIRINOX and may be useful for guiding therapeutic choices and surgical exploration.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Down-Regulation; Female; Fluorouracil; Humans; Immunohistochemistry; Irinotecan; Leucovorin; Male; MicroRNAs; Middle Aged; Netherlands; Oxaliplatin; Pancreatic Neoplasms; Survival Rate

Neoadjuvant therapy is recommended for patients with borderline-resectable pancreatic cancer (BRPC). In this study, we compare survival outcomes of neoadjuvant therapy with upfront surgery.. From January 2011 to June 2016, 1415 patients underwent treatments for pancreatic cancer in Samsung Medical Center. Among them, 112 (7.9%) patients were categorized as BRPC by the NCCN 2016 guideline. They were classified by type of initial treatments into neoadjuvant group (NA, N.=26) and upfront surgery group (US, N.=86).. The median survival duration of all patients was 18.3 months. Patients in the NA group had more T4 disease than those in the US group (38.5% in NA versus 15.1% in the US group; P=0.010). Arterial involvement was more frequent in the NA group (42.3% versus 15.1%; P=0.003). In the NA group, ten (38.5%) patients underwent surgery, and seven of them had complete R0 resection. In the US group, 83 (96.5%) patients received radical surgery, and 42 (48.8%) had R0 resection. In survival analysis according to intent to treat, the overall two-year survival rate was 51.1% in the US group and 36.7% in the NA group (P=0.001). However, among patients who underwent surgery (N.=96), the two-year overall survival rate was not significantly different between the two groups (P=0.089). According to involved vessels, the survival rate was not different between patients with arterial or both arterial and venous involvement and in patients with only venous involvement (P=0.649).. It is necessary to demonstrate the efficacy of neoadjuvant therapy and to standardize the regimens through large-scale, multicenter, randomized controlled studies.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy; Radiotherapy Dosage; Radiotherapy, Adjuvant; Retrospective Studies; Selection Bias; Survival Analysis; Survival Rate; Treatment Outcome

Preoperative/Neoadjuvant treatment (NT) is increasingly used in unresectable pancreatic cancer (PDAC). However, ∼40% of patients cannot be resected after NT and reliable preoperative response evaluation is currently lacking. We investigated CA 19-9 levels and their dynamics during NT for prediction of resectability and survival.. We screened our institution's database for patients who underwent exploration or resection after NT with gemcitabine-based therapy (GEM) or FOLFIRINOX (FOL). Pre- and post-NT CA 19-9, resection rate and survival were analyzed.. Of 318 patients 165 (51.9%) were resected and 153 (48.1%) received exploration. In the FOL group (n = 103; 32.4%), a post-NT CA 19-9 cutoff at 91.8 U/ml had a sensitivity of 75.0% and a specificity of 76.9% for completing resection with an AUC of 0.783 in the ROC analysis (95% CI: 0.692-0.874; p < 0.001. PPV: 84.2%, NPV: 65.2%). Resected patients above the cutoff did not benefit from resection. Post-NT CA 19-9 <91.8 U/ml (OR 11.63, p < 0.001) and CA 19-9 ratio of <0.4 (OR 5.77, p = 0.001) were independent predictors for resectability in FOL patients.. CA 19-9 levels after neoadjuvant treatment with FOLFIRINOX predict resectability and survival of PDAC more accurately than dynamic values and should be incorporated into response evaluation and surgical decision-making.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Carcinoma, Pancreatic Ductal; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Induction Chemotherapy; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Predictive Value of Tests; Retrospective Studies; Survival Rate

The majority of pancreatic cancers are diagnosed at an advanced stage, when surgical options are limited and treatment relies on systemic chemotherapy. In the NAPOLI-1 trial, liposomal irinotecan in combination with fluorouracil (nal-iri/5FU) was shown to improve overall survival when compared to fluorouracil alone for metastatic pancreatic cancer. Other retrospective studies have shown the combination of fluorouracil and conventional irinotecan (FOLFIRI) to be a viable option, though no randomized trials have compared nal-iri/5FU to FOLFIRI. The purpose of this single-center, retrospective, cohort study was to determine if nal-iri/5FU and FOLFIRI are similarly effective for the treatment of advanced pancreatic cancer. Due to the potential for treatment bias, inverse probability of treatment weighting was utilized to correct for baseline differences between the groups. The primary outcome of progression-free survival was similar at 4.1 months for nal-iri/5FU and 3.1 months for FOLFIRI. Overall survival and adverse effect frequency were also similar. Pegfilgrastim was used in 16% and 15% of patients, respectively, and nal-iri/5FU patients required significantly less atropine during treatment (36 vs. 70%). A cost analysis was conducted and concluded that the treatment with nal-iri/5FU was nearly 30 times more expensive than FOLFIRI treatment. Together, these data suggest a potential role for FOLFIRI for the treatment of advanced pancreatic cancer in the absence of clear benefits in effectiveness, toxicity, or cost for nal-iri/5FU.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies

Claudin (CLDN) family comprises of protein that form a tight junction, and is involved in regulating polarity and differentiation of cells. Here, we aimed to investigate the effects of inhibiting CLDN4 in pancreatic ductal carcinomas (PDC). We first examined 91 cases of human PDC by immunohistochemistry and found that CLDN4 expression was correlated with tumor invasion, nodal metastasis, and distant metastasis. Anti-CLDN4 extracellular domain antibody, previously established by us (4D3), inhibited the proliferation of MIA-PaCa-2 PDC cells and increased intracellular 5-fluorouracil (5-FU) concentration with lowering transepithelial electrical resistance. Concurrent treatment of 5-FU and 4D3 resulted in synergistic inhibition of growth of MIA-PaCa-2 cells in nude mice. In addition, MIA-PaCa-2 cell tumors treated with full-dose folfirinox (FFX) decreased tumor diameters to 50%; however, 60% of mice were dead from adverse effects. In contrast, half-dose FFX concomitant with 4D3 treatment decreased tumors equivalent to full-dose FFX, but without the adverse effects. These findings suggest that targeting CLDN4 might increase the effectiveness and safety of anticancer drug therapy in PDC.

Topics: Animals; Antibodies; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Claudin-4; Drug Synergism; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Leucovorin; Male; Mice; Mice, Nude; Oxaliplatin; Pancreatic Neoplasms; Up-Regulation; Xenograft Model Antitumor Assays

To improve short- and long-term outcomes of locally advanced pancreatic body-tail cancer followed by major vessels invasion.. A case report of pure laparoscopic DP-CAR procedure with portal vein resection for locally advanced pancreatic body-tail cancer followed by severe abdominal pain in a 49-year-old patient is presented.. Liver or stomach ischemia was not observed. Portal wall resection wasn't associated with any complication and resulted R0-resection. Postoperative period was complicated by Grade B pancreatic fistula. Preoperative abdominal pain completely disappeared after surgery. Surgery time was 330 min, intraoperative blood loss - 300 ml. The patient is currently undergoing FOLFIRINOX adjuvant chemotherapy. CT in 90 days after surgery confirmed no progression of disease or liver/stomach blood supply congestion.. Modern technologies provide the opportunity to perform pure laparoscopic advanced surgical procedures with major vessels resection. Pure laparoscopic DP-CAR procedure with portal vein resection is effective and safe procedure that can be performed with all principles of open surgery and is associated with acceptable short- and long-term results.. Улучшить непосредственные и отдаленные результаты хирургического лечения больных местно-распространенным раком тела—хвоста поджелудочной железы с инвазией магистральных сосудов.. Представлен клинический случай полностью лапароскопической DP-CAR с резекций воротной вены больной 49 лет по поводу местно-распространенной протоковой аденокарциномы тела—хвоста поджелудочной железы с выраженным болевым синдромом.. В результате операции ишемии печени и желудка не отмечено. Резекция воротной вены не привела к развитию каких-либо осложнений и позволила добиться R0-резекции. Послеоперационный период осложнился образованием панкреатической фистулы, grade B (ISGPF, 2016). После операции болевой синдром полностью купирован. Время операции составило 330 мин, объем кровопотери — 300 мл. Больная проходит адъювантную химиотерапию по схеме FOLFIRINOX. По данным КТ, через 90 дней после операции данных за прогрессирование заболевания не получено, нарушения кровоснабжения печени и желудка не выявлено.. Развитие современных технологий позволяет проводить технически сложные онкологические операции, в том числе с резекцией магистральных сосудов, лапароскопическим доступом. Полностью лапароскопическая DP-CAR с резекцией воротной вены является эффективной и безопасной процедурой, которую возможно выполнять по принципам открытой хирургии с удовлетворительными непосредственными и отдаленными результатами.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Celiac Artery; Fluorouracil; Humans; Irinotecan; Laparoscopy; Leucovorin; Middle Aged; Neoplasm Invasiveness; Oxaliplatin; Pancreatectomy; Pancreatic Fistula; Pancreatic Neoplasms; Portal Vein

Peritoneal carcinomatosis (pcm) in metastatic pancreatic ductal adenocarcinomas (mpdac) is frequently encountered in day-to-day practice, but rarely addressed in the literature. The objective of the present study was to describe the management and outcome of patients diagnosed with pcm.. Data for all consecutive patients with mpdac treated in our centre between 1 January 2014 and 31 August 2015 were analyzed retrospectively. Computed tomography imaging was centrally reviewed by a dedicated radiologist to determine the date of pcm diagnosis.. The analysis included 48 patients. Median age in the group was 61 years, and 41 patients had an Eastern Cooperative Oncology Group performance status (ecog ps) of 0-1. All patients presented with pcm either synchronously (group 1) or metachronously (group 2). Those groups differed significantly by baseline ecog ps and neutrophil-to-lymphocyte ratio (nlr), with ecog ps being poorer and nlr being higher in group 1. In addition to pcm, the main sites of metastasis were liver (62.5%) and lungs (31.3%). First-line chemotherapy in 36 patients (75%) was folfirinox (fluorouracil-irinotecan-leucovorin-oxaliplatin). The median overall survival for the entire population was 10.81 months [95% confidence interval (ci): 7.16 months to 14.16 months]; it was 13.17 months (95% ci: 5.9 months to 15.4 months) for patients treated with folfirinox. Median overall survival was 7.13 months (95% ci: 4.24 months to 10.41 months) for patients in group 1 and 14.34 months (95% ci: 9.79 months to 19.91 months) for patients in group 2,. Compared with other metastatic sites, synchronous pcm seems to be a poor prognostic factor. It could be more frequently associated with a poor ecog ps and a nlr greater than 5 in this group of patients. In patients with mpdac and pcm, either synchronous or metachronous, folfirinox remains an efficient regimen.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Peritoneal Neoplasms; Prognosis; Retrospective Studies; Survival Analysis; Tomography, X-Ray Computed; Treatment Outcome

Primary systemic therapy in resectable pancreatic cancer is currently under investigation. FOLFIRINOX has been shown to be effective in both the adjuvant and metastatic settings and is increasingly being used on and off study in the neoadjuvant setting. The objective pathologic response elicited by this regimen in truly resectable disease has not as yet been widely reported.. This analysis focuses on 14 patients with resectable pancreatic cancer who were treated in a pilot study of primary systemic therapy, using 4 cycles of neoadjuvant FOLFIRINOX before surgery. A dedicated pancreatic pathologist reviewed all of the subsequent surgical specimens to assess the degree of tumor regression elicited by this approach, according to the scoring system proposed by Evans.. Four patients (28.6%) had Evans grade I, 4 (28.6%) Evans grade IIa, 2 (14.2%) Evans grade IIb, and 4 (28.6%) Evans grade III response to the primary systemic therapy. There were no Evans grade IV responses.. The results are intriguing with 28% of the specimens showing destruction of <10% of tumor cells, and only 28% achieving >90% destruction of tumor cells. The significant variation in response once again confirms the known heterogeneity in the biology of this cancer and clearly FOLFIRINOX is not equally effective in all patients. Future studies evaluating primary systemic therapy in pancreatic cancer should examine the optimal duration of therapy before surgery and should include a standardized pathologic grading scheme to better enable comparison of results.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Cause of Death; Chemotherapy, Adjuvant; Cohort Studies; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Hospitals, University; Humans; Immunohistochemistry; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Pilot Projects; Prognosis; Proportional Hazards Models; Retrospective Studies; Survival Analysis; Treatment Outcome

Development of a supervised machine-learning model capable of predicting clinically relevant molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) from diffusion-weighted-imaging-derived radiomic features.. The retrospective observational study assessed 55 surgical PDAC patients. Molecular subtypes were defined by immunohistochemical staining of KRT81. Tumors were manually segmented and 1606 radiomic features were extracted with PyRadiomics. A gradient-boosted-tree algorithm was trained on 70% of the patients (N = 28) and tested on 30% (N = 17) to predict KRT81+ vs. KRT81- tumor subtypes. A gradient-boosted survival regression model was fit to the disease-free and overall survival data. Chemotherapy response and survival were assessed stratified by subtype and radiomic signature. Radiomic feature importance was ranked.. The mean±STDEV sensitivity, specificity and ROC-AUC were 0.90±0.07, 0.92±0.11, and 0.93±0.07, respectively. The mean±STDEV concordance indices between the disease-free and overall survival predicted by the model based on the radiomic parameters and actual patient survival were 0.76±0.05 and 0.71±0.06, respectively. Patients with a KRT81+ subtype experienced significantly diminished median overall survival compared to KRT81- patients (7.0 vs. 22.6 months, HR 4.03, log-rank-test P = <0.001) and a significantly improved response to gemcitabine-based chemotherapy over FOLFIRINOX (10.14 vs. 3.8 months median overall survival, HR 2.33, P = 0.037) compared to KRT81- patients, who responded significantly better to FOLFIRINOX over gemcitabine-based treatment (30.8 vs. 13.4 months median overall survival, HR 2.41, P = 0.027). Entropy was ranked as the most important radiomic feature.. The machine-learning based analysis of radiomic features enables the prediction of subtypes of PDAC, which are highly relevant for disease-free and overall patient survival and response to chemotherapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Keratins, Hair-Specific; Keratins, Type II; Leucovorin; Machine Learning; Male; Middle Aged; Neoplasm Proteins; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Sensitivity and Specificity; Survival Rate

Germline BRCA1 and BRCA2 mutations are the most common gene mutations in familial pancreatic adenocarcinoma. Several reports have demonstrated the utility of platinum-based chemotherapy for treating cancer patients who harbour a BRCA mutation. Here we discuss a 47-year-old Japanese female with no relevant past history who presented with epigastralgia and fever in September 2016. A computed tomography scan revealed a low-density, low-enhanced tumour 15 mm in diameter in the head of the pancreas. The pathological diagnosis was a ductal pancreatic carcinoma. A 6 mm low-enhanced metastatic tumour was also detected in segment 4 of the liver. Because she had early onset of the disease and a family history-her mother died of pancreatic adenocarcinoma at age 48-we considered a diagnosis of familial pancreatic adenocarcinoma. She received modified FOLFIRINOX. Two months after starting chemotherapy, she was diagnosed with an invasive ductal carcinoma in the right breast. FOLFIRINOX was continued for 8 cycles (4 months); the primary pancreatic adenocarcinoma shrank and the liver metastatic foci disappeared, but the size of the breast tumour increased. Total right breast excision and sentinel lymph node dissection were performed. FOLFIRINOX was continued and after 12 cycles (6 months), both her pancreatic adenocarcinoma and liver metastasis were no longer visible using imaging. Pancreatoduodenectomy was performed and the primary tumour had shrunk to 2.5 mm. Genetic testing revealed a germline BRCA2 mutation. The FOLFIRINOX regimen showed dramatic effects on the collision pancreatic but not on the breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; BRCA2 Protein; Carcinoma, Ductal, Breast; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Genetic Testing; Germ Cells; Germ-Line Mutation; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymph Node Excision; Middle Aged; Mutation; Oxaliplatin; Pancreatic Neoplasms; Pancreaticoduodenectomy

Limited evidence exists for chemotherapy selection in advanced pancreatic cancer (APC) after first-line FOLFIRINOX. Second-line gemcitabine/nab-paclitaxel (GEMNAB) is publicly funded in the Canadian provinces of Alberta (AB) and Manitoba (MB), but not in British Columbia (BC). We compared population-based outcomes by region to examine the utility of second-line GEMNAB versus gemcitabine (GEM) alone.. We identified patients treated with first-line FOLFIRINOX between 2013 and 2015 across BC, AB, and MB. Baseline characteristics and treatment regimens were compared between AB/MB and BC. Survival outcomes were assessed by the Kaplan-Meier method and compared with log-rank test.. A total of 368 patients were treated with first-line FOLFIRINOX (143 AB/MB, 225 BC): median age 61 (interquartile range: 55 to 68) years, 42% comprising female individuals, and 67% with metastatic disease. Receipt of second-line therapy was 48% in AB/MB versus 44% in BC (P=0.35), and time from diagnosis to second-line therapy was 7.7 (AB/MB) versus 9.4 months (BC; P=0.1). Distribution of second-line GEM use: 73% GEMNAB, 23% GEM (AB/MB) versus 27% GEMNAB, 66% GEM (BC; P<0.001). Median overall survival (OS) from diagnosis was similar: 12.4 (AB/MB) versus 11.5 months (BC; P=0.91). On Cox regression analysis, region was not significant. Secondary survival analysis by second-line regimen demonstrated a median OS of 18.0 months with GEMNAB versus 14.3 months with GEM (P<0.01).. In this population-based comparison of APC patients treated with first-line FOLFIRINOX, survival outcomes were comparable regardless of funded access to second-line GEMNAB. OS by regimen favored second-line GEMNAB, but patient selection may be largely responsible for this difference.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Canada; Cohort Studies; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Multivariate Analysis; Neoplasm Invasiveness; Neoplasm Staging; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms; Proportional Hazards Models; Retreatment; Retrospective Studies; Risk Assessment; Survival Analysis; Tertiary Care Centers; Treatment Failure; Treatment Outcome

A 55-year-old patient with locally advanced pancreatic carcinoma will start Folfirinox. Should he get thromboprophylaxis?. Patients with malignant disease have increased risk of venous thromboembolism (VTE). Several types of malignancy, surgery, chemotherapy and metastasis lead to increased risk. VTE is an underdiagnosed phenomenon and the second cause of death in patients treated with chemotherapy. Therapeutic doses increase the risk of bleeding compared to prophylactic anticoagulant treatment. Even though they are less than perfect, several risk scores are able to identify patients with high risk of VTE. The AVERT and CASSINI trials showed that prophylactic doses of DOACs in cancer patients with high risk of VTE are able to significantly reduce this risk.. Even though there are many unresolved questions, it seems rational to start thromboprophylaxis in patients with aggressive types of cancer, preferably using DOACs, but low molecular weight heparins are possible as well. Risk scores may be helpful when selecting patients.

Topics: Anticoagulants; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemoprevention; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Risk Adjustment; Risk Assessment; Venous Thromboembolism

The aim of this study was to determine (1) whether preoperative factors can predict resectability of borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant FOLFIRINOX, (2) which patients might benefit from adjuvant therapy, and (3) survival differences between resected BR/LA patients who received neoadjuvant FOLFIRINOX and upfront resected patients.. Patients with BR/LA PDAC are often treated with FOLFIRINOX to obtain a margin-negative resection, yet selection of patients for resection remains challenging.. Clinicopathologic data of PDAC patients surgically explored between 04/2011-11/2016 in a single institution were retrospectively collected.. Following neoadjuvant FOLFIRINOX, 141 patients were surgically explored (BR: 49%, LA: 51%) and 110 (78%) were resected. Resected patients had lower preoperative CA 19-9 levels (21 vs 40 U/mL, P = 0.03) and smaller tumors on preoperative computed tomography (CT) scan (2.3 vs 3.0 cm, P = 0.03), but no predictors of resectability were identified. Median overall survival (OS) was 34.2 months from diagnosis for all FOLFIRINOX patients and 37.7 months for resected patients. Among resected patients, preoperative CA 19-9 >100 U/mL and >8 months between diagnosis and surgery predicted a shorter postoperative disease-free survival (DFS); Charlson comorbidity index >1, preoperative CA 19-9 >100 U/mL and tumor size (>3.0 cm on CT or >2.5 cm on pathology) predicted decreased OS. DFS and OS were significantly better for BR/LA PDAC patients treated with neoadjuvant FOLFIRINOX compared with upfront resected patients (DFS: 29.1 vs 13.7, P < 0.001; OS: 37.7 vs 25.1 months from diagnosis, P = 0.01).. BR/LA PDAC patients with no progression on neoadjuvant FOLFIRINOX should be offered surgical exploration. Except size, traditional pathological parameters fail to predict survival among resected FOLFIRINOX patients. Resected FOLFIRINOX patients have survival that appears to be superior than that of resectable patients who go directly to surgery.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Survival Rate

Survival appears to be poor in cases of pancreatic ductal adenocarcinoma (PDAC) with para-aortic lymph node involvement (PALN+). However, resection is still performed in these cases because the prognostic impact of PALN+remains controversial.. PALN+was intraoperatively found in 14 patients (4.8%) with resectable PDAC who consequently did not undergo pancreatectomy.. The median overall survival time after laparotomy was 21 months. The 1- and 3-year overall survival rates were 58.3% and 25%, respectively.. We support the advisability of reconsidering pancreatectomy in patients with intraoperatively detected PALN+because the reported survival of such patients who undergo pancreatectomy is poorer than the survival observed for patients in our series.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Contraindications, Procedure; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Laparotomy; Leucovorin; Lymph Nodes; Male; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Progression-Free Survival; Retrospective Studies; Survival Rate; Treatment Outcome; Withholding Treatment

Advanced pancreatic adenocarcinoma (PA) is an aggressive disease that has poor prognosis and frequently interferes with patient's quality of life. There has been progress in first-line regimens; however, there is no standard second-line regimen. The aim of this study is to analyze second-line gemcitabine after first-line fluorouracil (FU) + leucovorin (LV) + irinotecan + oxaliplatin (FOLFIRINOX) regimen.. This study included consecutive patients with advanced PA treated at Hospital Sirio-Libanês from 2011 to 2016. The patients received FOLFIRINOX as first-line treatment and upon progression, received gemcitabine alone. Survival analysis was performed using the Kaplan-Meier method.. A total of 54 patients were evaluated. Most patients were male (61.1%) and most had an ECOG performance status of 0 or 1 prior to the beginning of second-line treatment (66.6%). The mean number of gemcitabine cycles was 3.4. Most patients had disease progression as the best response to treatment (75.9%), 11.1% had stable disease, and 9.3% experienced a partial response. The median progression-free survival was 1.7 months, and the median overall survival was 6.8 months.. Gemcitabine alone did not show meaningful clinical benefit as second-line treatment after FOLFIRINOX.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Brazil; Deoxycytidine; Disease Progression; Drug Resistance, Neoplasm; Electronic Health Records; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Progression-Free Survival; Quality of Life; Retrospective Studies

We aimed to explore the application of circulating cell-free DNA (cfDNA) profiling in monitoring tumor burden in patients with pancreatic ductal adenocarcinoma (PDAC). Thirty-eight patients with advanced PDAC receiving first-line FOLFIRINOX chemotherapy were prospectively enrolled. Next-generation sequencing for a panel of 560 genes covering a wide range of cancer-related loci was performed to profile cfDNA. In total, 25 patients (65.8%) had at least one common driver gene alterations (

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Case-Control Studies; Circulating Tumor DNA; Female; Fluorouracil; High-Throughput Nucleotide Sequencing; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Mutation; Oxaliplatin; Pancreatic Neoplasms; Prospective Studies; Sequence Analysis, DNA; Treatment Outcome; Tumor Burden

Modification of FOLFIRINOX significantly improves safety and tolerability in Chinese patients with locally advanced pancreatic cancer.Patients with locally advanced pancreatic cancer benefit from neoadjuvant therapy and experience a much better survival than patients with upfront surgery.. The objective of this study was to evaluate the efficacy of modified-FOLFIRINOX (mFOLFIRINOX) regimens in Chinese patients with locally advanced pancreatic cancer (LAPC) and to compare outcomes between patients with LAPC treated with mFOLFIRINOX-based neoadjuvant therapy (LAPC-N) and patients with LAPC who underwent upfront surgery (LAPC-S).. Forty-one patients with LAPC-N were enrolled prospectively. Imaging features, chemotherapy response, adverse events, perioperative complications, histology, and survival were analyzed. Seventy-four patients with resectable pancreatic cancer (RPC) (from April 2012 to November 2017) and 19 patients with LAPC-S (from April 2012 to March 2014) were set as observational cohorts, and data were collected retrospectively. LAPC-N patients with adequate response underwent surgical treatment, whereas continuous chemotherapy was given to LAPC-N patients who were not deemed resectable after treatment, and the response was re-evaluated every 2 months.. Forty-one patients with LAPC received mFOLFIRINOX with a response rate of 37.1%. The most common severe adverse events were neutropenia and anemia. mFOLFIRINOX-based neoadjuvant therapy contributed to a remarkable decrease in CA19-9 level and tumor diameter. Fourteen LAPC-N patients underwent surgery (LAPC-N-S) after downstaging. Compared with LAPC-N-S cases, LAPC-S patients had longer operative time, more blood loss, and a higher risk of grade 5 complications. The median overall survival (OS) and progression-free survival (PFS) of LAPC-N-S patients were 27.7 months and 19.3 months, respectively, which were similar to those of patients with RPC (30.0 months and 23.0 months) and much longer than those of patients with LAPC-S (8.9 months and 7.6 months), respectively.. Neoadjuvant chemotherapy such as the mFOLFIRINOX regimen can be recommended for Chinese patients with LAPC after dose modification. Patients with LAPC-N who underwent surgery obtained significantly improved survival compared with patients in the observational LAPC-S cohort, who did not undergo neoadjuvant therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; China; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Progression-Free Survival; Prospective Studies; Survival Rate; Treatment Outcome

FOLFIRINOX is the reliable treatments for pancreatic cancer, but it has a relatively high toxicity and the selection of suitable patients for this regimen remains challenge. On the other hand, sarcopenia is one of the important prognostic factors of pancreatic cancer. The aim of this study was to investigate the effect of sarcopenia on overall survival (OS) and time to treatment failure (TTF) in patients with pancreatic cancer who received FOLFIRINOX.. Clinical data of consecutive patients treated with FOLFIRINOX at our institution from 2011 to 2017 was retrospectively reviewed. Skeletal muscle index (SMI) and adipose tissue index (ATI) at the third lumbar spine level was calculated from computed tomography (CT) images. The association between clinical factors (SMI and ATI), and OS and TTF were determined using univariate and multivariate analyses.. We assessed 82 patients. The median OS of sarcopenia and the non-sarcopenia patients were 11.3 and 17.0 months, respectively (hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.43-4.32; p = 0.001). Median TTF was 3.0 and 6.1 months in the sarcopenia and the non-sarcopenia patients, respectively (HR, 1.67; 95% CI, 1.03-2.71; p = 0.032). Multivariate analyses revealed that sarcopenia (HR, 1.37; 95% CI, 1.01-1.87; p = 0.045) was an independent prognostic factor of OS. High ATI (p = 0.022) and sarcopenic obesity (p = 0.008) were significantly associated with hematologic toxicity.. Sarcopenia is an independent indicator of poor prognosis in patients with pancreatic cancer who received FOLFIRINOX, while ATI and sarcopenic obesity predicted severe hematologic toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Muscle, Skeletal; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Sarcopenia

The effectiveness and cost-effectiveness of using neoadjuvant FOLFIRINOX (nFOLFIRINOX) for patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA PDAC) are unknown. Our objective was to determine whether nFOLFIRINOX is more effective or cost-effective for patients with BR/LA PDAC compared with upfront resection surgery and adjuvant gemcitabine plus capecitabine (GEM/CAPE) or gemcitabine monotherapy (GEM).. We performed a decision-analysis to assess the value of nFOLFIRINOX versus GEM/CAPE or GEM using a mathematical simulation model. Model transition probabilities were estimated using published and institutional clinical data. Model outcomes included overall and disease-free survival, quality-adjusted life-years (QALYs), cost in U.S. dollars, and cost-effectiveness expressed as an incremental cost-effectiveness ratio. Deterministic and probabilistic sensitivity analyses explored the uncertainty of model assumptions.. Model results found median overall survival (34.5/28.0/22.0 months) and disease-free survival (15.0/14.0/13.0 months) were better for nFOLFIRINOX compared with GEM/CAPE and GEM. nFOLFIRINOX was the optimal strategy on an efficiency frontier, resulting in an additional 0.35 life-years, or 0.30 QALYs, at a cost of $46,200/QALY gained compared with GEM/CAPE. Sensitivity analysis found that cancer recurrence and complete resection rates most affected model results, but were otherwise robust. Probabilistic sensitivity analyses found that nFOLFIRINOX was cost-effective 92.4% of the time at a willingness-to-pay threshold of $100,000/QALY.. Our modeling analysis suggests that nFOLFIRINOX is preferable to upfront surgery for patients with BR/LA PDAC from both an effectiveness and cost-effectiveness standpoint. Additional clinical data that further define the long-term effectiveness of nFOLFIRINOX are needed to confirm our results.. Increasingly, neoadjuvant FOLFIRINOX has been used for borderline resectable and locally advanced pancreatic cancer with the goal of rendering them resectable and decreasing risk of recurrence. Despite many efforts to show the benefits of neoadjuvant over adjuvant therapies, clinical evidence to guide this decision is largely lacking. Decision-analytic modeling can provide a methodologic platform that integrates the best available data to quantitatively explore clinical decisions by simulating a hypothetical clinical trial. This modeling analysis suggests that neoadjuvant FOLFIRINOX is preferable to upfront surgery and adjuvant therapies by various outcome metrics including quality-adjusted life years, overall survival, and incremental cost-effectiveness ratio.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Decision Support Techniques; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Models, Statistical; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Survival Rate

Locally advanced or metastatic adenocarcinoma of the pancreas remains - despite the implementation of new chemotherapy protocols - a disease with short overall survival (OS).. Eighty-three patients were treated with locally advanced or metastatic adenocarcinoma of the pancreas with either FOLFIRINOX or nab-Paclitxel and Gemcitabine (nabPGem) as first- or second line therapy. We analysed the outcome for OS and progression-free survival (PFS) in terms of treatment regimen and sequence.. The majority of patients presented in good performance status (PS) with a median age of 68 years. Fourty-two patients received FOLFIRINOX as first-line therapy, 41 patients were treated with nabPGem as first line therapy. Forty-eight patients received both treatments. The OS of all 83 patients was 12.6 months (95% CI: 10.7-14.6), resulting in a 1-year OS of 54%. Forty-eight patients received FOLFIRINOX followed by nabPGem or vice versa. There was no significant difference in OS or PFS for either of the two sequences (p = 0.9). The OS for FOLFIRINOX followed by nabPGem or nabPGem followed by FOLFIRINOX was 13.7 months (95% CI: 12.6-14.7) and 13.8 months (95% CI: 8.6-19), respectively.. The sequence FOLFIRINOX followed by nab-Paclitaxel and Gemcitabine or vice versa lead to an equal OS outcome.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Drug Combinations; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organometallic Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival; Retrospective Studies; Treatment Outcome

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Random Allocation; Survival Analysis; Treatment Outcome

The analysis was conducted to assess the effect of front-line combination chemotherapies on progression free survival (PFS).. The analysis was restricted to phase III randomized controlled trials (RCTs) in first-line therapy for advanced pancreatic cancer. The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) was applied to the above phase III RCTs. We have also calculated differences in PFS between the different arms of each trial and the pharmacological costs necessary to get the benefit in PFS, for each trial.. Our study evaluated 11 phase III randomized controlled trials (RCTs), including 4572 patients. Combining the costs of therapy with the measure of efficacy represented by the PFS, we have obtained 74.12 € per month of PFS gained for 5-FU, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX), 90.14 per month of PFS gained for gemcitabine and oxaliplatin (GEMOX) and 4708.70 € per month of PFS gained for the combination of gemcitabine plus nab-pacliatxel against gemcitabine alone.. Combining pharmacological costs with the measure of efficacy represented by PFS, FOLFIRINOX is a cost-effective first-line for advanced pancreatic cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Pancreatic Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Gemcitabine; Humans; Leucovorin; Pancreatic Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Pancreatic Neoplasms

Advanced pancreatic cancer (aPC) has a poor prognosis with limited survival benefit from current standard treatment.. A 59-year-old architect developed epigastric pain. A cystic lesion of the pancreas of 45-mm diameter was detected. In a follow-up magnetic resonance imaging, about one year later, multiple lesions were seen in the corpus and the tail of the pancreas; CA-19-9 was elevated to 58.5 U/mL. A distal pancreatectomy with splenectomy was performed, and a tumor of 7 cm × 5 cm × 3.5 cm was excised. Histologic investigation showed an intraductal papillary mucinous neoplasm-associated invasive adenocarcinoma with invasion of the lymph vessels, perineural invasion, and positive nodes (2/27); surgical margins showed tumor cells, and the tumor was classified as pT3 N1 M0 R1. The patient was treated with radiation of the tumor bed and capecitabine/oxaliplatin followed by gemcitabine and FOLFIRINOX. Seven months after surgery, a liver metastasis was detected and treatment with FOLFIRINOX was started. Four months after detection of the metastasis, the patient opted for additional treatment with VAE. Another month later, the metastasis was treated with radiofrequency ablation (RFA). Eight months later, the hepatic lesion recurred and was again treated with RFA. The continuous VAE treatment was increased in dose, and the patient stayed recurrence-free for the next 39 mo in good health and working full-time (as of the time this case report was written).. We present the case of a patient with aPC with R1-resection with development of liver metastasis during the course of treatment who showed an overall survival of 63 mo and a relapse-free survival of 39 mo under increasing VAE therapy. The possible synergistic effect on tumor control of RFA treatment and immune-stimulatory effects of VAE should be further investigated.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Magnetic Resonance Imaging; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Plant Extracts; Time Factors; Treatment Outcome; Viscum album

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Muscle, Skeletal; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Treatment Outcome

Effective chemotherapy protocols are currently changing the treatment options for metastasized pancreatic cancer. Survival benefits after synchronous metastasectomy have been reported for selected patients. We set out to assess predictive factors of resectability for synchronous metastases after FOLFIRINOX.. Consecutive patients with metastatic pancreatic cancer undergoing surgery after FOLFIRINOX between 2011 and 2017 were identified from a prospectively collected database. Surgery following chemotherapy was indicated in patients with no more than six metastatic lesions, no progression detected on CT, and technically resectable disease. Patients who received synchronous metastasectomy were compared with patients who received explorative laparotomy or palliative surgery in terms of predictors of resectability and overall survival. In patients undergoing resection, prognostic factors were examined.. Of 101 patients scheduled for surgery after FOLFIRINOX, synchronous metastasectomy was performed in 43 cases (43%) and non-resection surgery in 58 cases (57%). The shrinkage rate of the primary tumor on CT (P = 0.04) and the postchemotherapy serum CA19-9 concentration (P = 0.02) were associated with resectability. The median overall survival of the patients undergoing metastasectomy was longer than that of the patients without resection (21.9 months vs 16.4 months, P = 0.006). Postchemotherapy serum CA19-9 value (P = 0.04) and lymph node ratio (P = 0.01) were prognostic factors in the patients undergoing metastasectomy.. In selected patients who satisfied our surgical criteria, shrinkage rate of primary tumor and postchemotherapy serum CA19-9 level, which predict resectability of metastasized pancreatic cancer, should be considered in decision making to avoid unnecessary surgery.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; CA-19-9 Antigen; Carcinoma, Pancreatic Ductal; Cohort Studies; Databases, Factual; Disease-Free Survival; Female; Fluorouracil; Germany; Humans; Induction Chemotherapy; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Metastasectomy; Middle Aged; Multivariate Analysis; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Staging; Oxaliplatin; Pancreatic Neoplasms; Patient Selection; Prognosis; Proportional Hazards Models; Retrospective Studies; Survival Analysis; Tomography, X-Ray Computed

FOLFIRINOX is a highly effective anticancer treatment, even in advanced pancreatic cancer, which provides a potential cure in patients initially treated with a palliative strategy. A 47-year-old man was found to have an unresectable pancreatic cancer (4 cm in size) surrounding both the superior mesenteric artery and superior mesenteric vein. A simultaneous liver metastasis in Segment 8, with a diameter of 17 mm, was also detected. The pancreatic tumor markers CEA, CA19-9, and DUPAN-2 were significantly elevated to 21.7 ng/mL, 6224 ng/mL, and 1200U/mL, respectively. After 21 courses of FOLFIRINOX, the primary pancreatic tumor diminished in size (partial response) from 42 to 17 mm, and the liver mass almost disappeared. The tumor markers significantly decreased to almost normal levels. Fourteen months after the initial chemotherapy, conversion surgery was performed. Upon surgical resection, the pancreatic tumor was found to be Grade 1b, and a pathologically complete response was observed for the liver metastasis. The patient is still alive 32 months after initial treatment with no recurrence. This is an informative case of a locally advanced pancreatic cancer with a synchronous liver metastasis that had a significant response to FOLFIRINOX, allowing for subsequent curative resection.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

Neoadjuvant chemoradiotherapy, potentially relevant to increase resection rate in pancreatic cancer, is still debated.. To assess tolerance, resection rate and outcomes of patients with non-metastatic pancreatic ductal adenocarcinoma treated by concomitant chemoradiotherapy.. This monocentric study included all consecutive patients treated from 2010 to 2014 for non-metastatic pancreatic adenocarcinoma. Chemotherapy was followed by chemoradiotherapy in operable patients, surgical resectability being assessed by CT-scan.. Seventy-nine patients were included: 41 patients had borderline and 38 locally advanced tumours. All patients were treated by chemotherapy (FOLFIRINOX), followed by chemoradiotherapy (median dose: 59 Gy, range 45-66 Gy) for 94% of patients. Thirty-seven patients (47%) could subsequently benefit from surgery with a complete R0 resection in 94% of cases, with a postoperative mortality of 5%. Median overall survival was 21.5 months (median follow-up: 48.8 months). Local control, overall and disease-free survival were significantly higher for patients who underwent resection compared to others, with 89.2% vs 59.5% (p = 0.01), 49.7 vs 17.4 months (p < 0.01) and 25.5 vs 9.2 months (p < 0.01), respectively.. Neoadjuvant treatment consisting of FOLFIRINOX chemotherapy followed by chemoradiotherapy is an efficient strategy for patients with borderline and locally advanced pancreatic cancer, resulting in a 43% rate of secondary complete surgical resection associated with high local control, overall and disease-free survival.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Disease-Free Survival; Female; Fluorouracil; France; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Pilot Projects; Prospective Studies; Tertiary Care Centers; Treatment Outcome

FOLFIRINOX is one of the most effective reference regimens in the 1st line treatment of locally advanced (LA) and metastatic pancreatic cancer (mPC), despite its high toxicity. We evaluated our real-life experience with "patient-tailored intent to treat FOLFIRINOX" in patients with LA or mPC compared to other reports along with the pivotal phase III trial.We analyzed data from all consecutive patients with pancreatic ductal adenocarcinoma treated with dose-modified FOLFIRINOX in 2016 at Paul Brousse University Hospital. Irinotecan was administered whenever initial serum bilirubin was <1.5 × upper limit of normal. Oxaliplatin was stopped for severe sensory neuropathy. Initial dose reductions were made according to patient profile (eg, age, comorbidities) and later due to toxicity. The treatment was continued until surgery or disease progression. Endpoints were time to progression (TTP), overall survival (OS), objective response rate (ORR), and secondary complete resection (R0R1).Thirty-seven patients with unresectable LA or mPC received patient-tailored FOLFIRINOX as 1st line chemotherapy. There were 22 male (59%) and 15 female patients (41%) aged 44 to 81 years with LA (18 patients, 49%) and mPC (19 patients, 51%). They had World Health Organization-performance status of 0 (59%) or 1 (41%). A total of 384 cycles were administered. Median dose intensities (mg/m/w) were 28.9 for oxaliplatin, 56.8 for irinotecan, and 886.2 for 5-fluorouracil. Thirty-four patients were assessed for response; ORR and disease control rates were 47% and 85%, respectively. R0R1 rate was 30%. Median TTP and OS were 9.6 and 14.6 months. LA disease was associated with significantly longer TTP and OS (P < .001).FOLFIRINOX with patient-tailored dose adaptations seems to offer better results in patients with advanced PC. This approach in the neoadjuvant setting results in a macroscopic R0R1 in 61% of patients with initially unresectable disease. It deserves prospective evaluation to further improve outcomes in the management of advanced PC.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Patient-Centered Care; Retrospective Studies; Survival Analysis

Determining the resectability of locally advanced pancreatic cancer (LAPC) after FOLFIRINOX chemotherapy is challenging because CT-scans cannot reliably assess vascular involvement. This study evaluates the added value of intra-operative ultrasound (IOUS) in LAPC following FOLFIRINOX induction chemotherapy.. Prospective multicenter study in patients with LAPC who underwent explorative laparotomy with IOUS after FOLFIRINOX chemotherapy. Resectability was defined according to the National Comprehensive Cancer Network guidelines. IOUS findings were compared with preoperative CT-scans and pathology results.. CT-staging in 38 patients with LAPC after FOLFIRINOX chemotherapy defined 22 patients LAPC, 15 borderline resectable and one resectable. IOUS defined 19 patients LAPC, 13 borderline resectable and six resectable. In 12/38 patients, IOUS changed the resectability status including five patients from borderline resectable to resectable and five patients from LAPC to borderline resectable. Two patients were upstaged from borderline resectable to LAPC. Tumor diameters were significantly smaller upon IOUS (31.7 ± 9.5 mm versus 37.1 ± 10.0 mm, p = 0.001) and resectability varied significantly (p = 0.043). Ultimately, 20 patients underwent resection of whom 14 were evaluated as (borderline) resectable on CT-scan, and 17 on IOUS.. This prospective study demonstrates that IOUS may change the resectability status up to a third of patients with LAPC following FOLFIRINOX chemotherapy.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Female; Fluorouracil; Follow-Up Studies; Humans; Intraoperative Period; Irinotecan; Laparotomy; Leucovorin; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Prospective Studies; Reproducibility of Results; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography

Pancreatic ductal adenocarcinoma (PDAC) exhibits a variety of phenotypes with regard to disease progression and treatment response. This variability complicates clinical decision-making despite the improvement of survival due to the recent introduction of FOLFIRINOX (FFX) and nab-paclitaxel. Questions remain as to the timing and sequence of therapies and the role of radiotherapy for unresectable PDAC. Here we developed a computational analysis platform to investigate the dynamics of growth, metastasis and treatment response to FFX, gemcitabine (GEM), and GEM+nab-paclitaxel. Our approach was informed using data of 1,089 patients treated at the Massachusetts General Hospital and validated using an independent cohort from Osaka Medical College. Our framework establishes a logistic growth pattern of PDAC and defines the Local Advancement Index (LAI), which determines the eventual primary tumor size and predicts the number of metastases. We found that a smaller LAI leads to a larger metastatic burden. Furthermore, our analyses ascertain that i) radiotherapy after induction chemotherapy improves survival in cases receiving induction FFX or with larger LAI, ii) neoadjuvant chemotherapy improves survival in cases with resectable PDAC, and iii) temporary cessations of chemotherapies do not impact overall survival, which supports the feasibility of treatment holidays for patients with FFX-associated adverse effects. Our findings inform clinical decision-making for PDAC patients and allow for the rational design of clinical strategies using FFX, GEM, GEM+nab-paclitaxel, neoadjuvant chemotherapy, and radiation.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Chemoradiotherapy; Clinical Decision-Making; Computer Simulation; Deoxycytidine; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Feasibility Studies; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Models, Biological; Neoadjuvant Therapy; Oxaliplatin; Paclitaxel; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Remission Induction; Tumor Burden

Following publication of improved patients' outcome using first line FOLFIRINOX for metastatic pancreatic adenocarcinoma, many physicians now prescribe it as neo-adjuvant or induction treatment for borderline and locally advanced pancreatic cancer. A pathologic complete response, rarely seen with previous preoperative regimens, is sometimes observed in these patients. The aim of this study was to assess long-term outcomes of patients presenting pathologic complete response after preoperative FOLFIRINOX usually followed by chemo-radiation therapy for non-metastatic pancreatic adenocarcinoma.. We retrospectively identified all resected patients with pancreatic cancer presenting pathologic complete response after FOLFIRINOX in 9 French centers from the AGEO group between November 2010 and May 2017.. 29 patients were enrolled, 14 had borderline, 14 locally advanced and 1 oligo-metastatic pancreatic cancer. M/F ratio was 1.2 and the mean age was 57 years. All patients were treated with FOLFIRINOX (n = 29), de-escalated to gemcitabine (n = 1) and FOLFIRI (n = 2), and 24 (83 %) received radiation therapy after chemotherapy. Objective response rate to preoperative chemotherapy was 66% (RECIST V1.1). Only 8 patients received postoperative chemotherapy. After a median follow-up of 34 months from surgery, the median overall survival was not reached and the median disease free survival was 48 months. The 1-year and 2-year survival rates were 100% for OS and 96% and 72 % for DFS from surgery, 8 of the 9 observed recurrences were distant metastases.. The promising 1 and 2-year overall survival and disease free survival rates suggest that pathologic complete response is a major prognostic factor in resected pancreatic cancer following preoperative chemo-radiotherapy. A longer follow-up and prospective series are now necessary to confirm these encouraging results and to potentially validate pathologic complete response as a relevant surrogate marker of preoperative treatment efficacy.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Combined Modality Therapy; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Preoperative Period; Remission Induction; Retrospective Studies; Time Factors; Treatment Outcome

We report a case of metastatic pancreatic-head mucinous carcinoma (with multiple lymph node and bone metastases) and review the relevant literature. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was useful for diagnosis, and a satisfactory outcome was achieved after systemic chemotherapy with FOLFIRINOX followed by resection of the primary lesion as conversion surgery. The patient was a 55-year-old man. Hematological findings included elevated serum tumor marker levels: CEA 12.7 ng/mL, DUPAN-2 400 U/mL. Findings from several imaging modalities and EUS-FNA confirmed a clinicopathological diagnosis of metastatic pancreatic mucinous carcinoma with multiple bone and lymph node metastases. Five courses of modified FOIFIRINOX (m-FFX) were given as systemic chemotherapy, which had an antitumor effect. Subtotal stomach-preserving pancreaticoduodenectomy and extensive lymph-node dissection were thus performed. Histopathological analysis showed invasive ductal carcinoma, muc (pT3, pN1b, cM1). After surgery, the clinical course was notable for the absence of complications. Tegafur/gimeracil/oteracil (S-1) was started as maintenance adjuvant chemotherapy postoperatively, and no disease progression has been observed at 10 months after surgery.

Topics: Adenocarcinoma, Mucinous; Antineoplastic Combined Chemotherapy Protocols; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Fluorouracil; Humans; Irinotecan; Leucovorin; Lymph Nodes; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Tomography, X-Ray Computed

Spontaneous cancer regression is a rare event, scarcely reported among gastrointestinal malignancies. Pancreatic adenocarcinoma regression has been documented in five previous cases, none of which included liver metastases, and the mechanism by which this occurs is not known. A 56-year-old woman with history of discoid lupus, homocysteinemia and peripheral vascular disease was diagnosed with stage IV pancreatic ductal adenocarcinoma (PDA) metastatic to the liver. She received palliative chemotherapy with 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) for 6 months, complicated by mucositis, diarrhoea, vomiting and two

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lupus Erythematosus, Discoid; Middle Aged; Neoplasm Metastasis; Neoplasm Regression, Spontaneous; Oxaliplatin; Pancreatic Neoplasms

Treatment containing FOLFIRINOX was planned to be administered to a 51-year-old man with locally advanced pancreatic cancer as second-line chemotherapy and to a 66-year-old woman with recurrent pancreatic cancer as third-line chemotherapy in their treatments. Since both patients were revealed to harbor UGT1A1 polymorphisms, which were highly associated with irinotecan-induced toxicity(the former: UGT1A1 *6/*28, the latter: UGT1A1*6/*6), there was no alternative hopeful treatment other than FOLFIRINOX for them. Therefore, FOLFIRINOX was administered very carefully. Although both patients showed Grade 4 neutropenia during the initial course, it was controllable with G-CSF administration and following stepwise reduction of the irinotecan dose. Severe diarrhea and other adverse events were not observed in both cases. Since the determined regimen of FOLFIRINOX for patients with high-risk UGT1A1 polymorphisms has not been developed yet, it would be critical to accumulate and review an experience of FOLFIRINOX administration for these patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Glucuronosyltransferase; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Polymorphism, Genetic

Topics: Adenocarcinoma; Antihypertensive Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Drug Combinations; Fluorouracil; Humans; Irinotecan; Leucovorin; Losartan; Neoplasm Staging; Oxaliplatin; Pancreatic Neoplasms

The aim of this study was to compare the efficacy and safety of FOLFIRINOX (5-FU/leucovorin, irinotecan, and oxaliplatin) and gemcitabine/nab-paclitaxel (GnP) in patients with advanced pancreatic cancer.. Patients with newly diagnosed advanced pancreatic cancer in Saskatchewan, Canada, from 2011 to 2016, who received FOLFIRINOX or GnP were assessed. A Cox proportional multivariate analysis was performed to evaluate prognostic variables.. One hundred nineteen eligible patients with median age of 61 years and male/female ratio of 70:49 were identified. Seventy-seven percent had metastatic disease. Of 119 patients, 86 (72%) received FOLFIRINOX and 33 (28%) were treated with GnP. Median progression-free survival of the FOLFIRINOX group was 6.0 months [95% confidence interval (CI), 4.5-7.5] versus 4.0 months (95% CI, 2.9-5.1) with GnP (P = 0.39). The median overall survival of the FOLFIRINOX group was 9.0 months (95% CI, 7-11) compared with 9.0 months (95% CI, 4.2-13.8) with GnP (P = 0.88). On multivariate analysis, albumin [hazard ratio (HR), 0.63; 95% CI, 0.41-0.97], male sex (HR, 0.65; 95% CI, 0.43-0.97), and second-line therapy (HR, 0.50; 95% CI, 0.28-0.86) were correlated with survival.. Our results showed that real-world patients with advanced pancreatic cancer treated with FOLFIIRNOX or GnP had comparable survival with different safety profile.

Topics: Aged; Albumins; Anemia; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Community Health Planning; Deoxycytidine; Fatigue; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Nausea; Outcome Assessment, Health Care; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Proportional Hazards Models; Saskatchewan

Pancreatic cancers of the tail have an especially poor prognosis due to their late detection. An earlier diagnosis depends on a better understanding of the clinical course of the disease; however, much of the current literature focuses on pancreatic head adenocarcinomas owing to their higher incidence. Thus, we add our case report to the current literature of pancreatic tail cancers in the hope of aiding earlier detection. We present an interesting case of a patient who initially presented with innocuous abdominal pain and a single episode of vomiting who was subsequently diagnosed with metastatic pancreatic tail cancer.. A 56-year-old Hispanic man with a past medical history of alcohol and cocaine abuse was initially evaluated in our clinic after presenting to the emergency department with sudden onset of abdominal pain and one episode of emesis. On further questioning, he stated that he had been experiencing dull, intermittent left back pain for the past 2-3 years. Laboratory tests were performed, which showed that the patient had new-onset diabetes, and imaging revealed a pancreatic tail mass with metastases to the liver. Biopsy confirmed the diagnosis of stage IV metastatic pancreatic tail adenocarcinoma. During follow-up 1 month later, the patient reported that he had been largely asymptomatic since his hospital admission; however, his left back pain had increased in severity. He was then started on a FOLFIRINOX chemotherapy regimen (5-fluorouracil/leucovorin, irinotecan, and oxaliplatin).. There are many pitfalls in the diagnosis of pancreatic cancer, especially pancreatic tail cancer due to its vague symptoms. Thus, pancreatic cancer of the tail often presents late with a very poor prognosis. Because there is currently no widespread screening for pancreatic cancer, it is often difficult for practitioners to identify pancreatic tail cancers. Current research suggests that there is a strong association between new-onset diabetes after the age of 50 and pancreatic cancer, and tumors detected at the onset of diabetes are favorable to resection. Pancreatic cancer has also been shown to be associated with certain risk factors, such as smoking, high body mass index, chronic pancreatitis, and a family history of pancreatic cancer. Thus, when patients with presentations similar to our patient's with new-onset diabetes after the age of 50, along with vague symptoms such as back or abdominal pain as well as the presence of risk factors, we suggest that it is beneficial for practitioners to maintain a high index of suspicion for pancreatic cancer.

Topics: Abdominal Pain; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Diabetes Mellitus; Diagnosis, Differential; Early Detection of Cancer; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Risk Factors

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Pancreatic Neoplasms; Standard of Care

Microvascular invasion (MVI) has been proved to be poor prognostic factor in many cancers. To date, only one study published highlights the relationship between this factor and the natural history of pancreatic cancer. The aim of this study was to assess the impact of MVI, on disease-free survival (DFS) and overall survival (OS), after pancreatico-duodenectomy (PD) for pancreatic head adenocarcinoma. Secondarily, we aim to demonstrate that MVI is the most important factor to predict OS after surgery compared with resection margin (RM) and lymph node (LN) status.. Between January 2015 and December 2017, 158 PD were performed in two hepato-bilio-pancreatic (HBP) centers. Among these, only 79 patients fulfilled the inclusion criteria of the study. Clinical-pathological data and outcomes were retrospectively analyzed from a prospectively maintained database.. Of the 79 patients in the cohort, MVI was identified in 35 (44.3%). In univariate analysis, MVI (P = .012 and P < .0001), RM (P = .023 and P = .021), and LN status (P < .0001 and P = .0001) were significantly associated with DFS and OS. A less than 1 mm margin clearance did not influence relapse (P = .72) or long-term survival (P = .48). LN ratio > 0.226 had a negative impact on OS (P = .044). In multivariate analysis, MVI and RM persisted as independent prognostic factors of DFS (P = .0075 and P = .0098, respectively) and OS (P < .0001 and P = .0194, respectively). Using the likelihood ratio test, MVI was identified as the best fit to predict OS after PD for ductal adenocarcinomas compared with the margin status model (R0 vs R1) (P = .0014).. The MVI represents another major prognostic factor determining long-term outcomes.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Microvessels; Neovascularization, Pathologic; Oxaliplatin; Pancreatic Neoplasms; Pancreaticoduodenectomy; Prognosis; Retrospective Studies

Neoadjuvant therapy (NT) is used for advanced pancreatic ductal adenocarcinoma (PDAC). No clear guidelines exist for switching therapies when patients do not respond to initial NT. We sought to characterize patients who underwent early switch from FOLFIRINOX to gemcitabine/nab-paclitaxel (GA) as NT for PDAC.. We identified patients at a single institution switched from FOLFIRINOX to GA within the first 4 months of NT for PDAC during 2012-2017. We compared clinicopathologic data and oncologic outcomes.. Of 25 patients who met the criteria, 21 showed a serologic or radiographic response to GA; 11 (52%) reached resection. Responders had decreased carbohydrate antigen (CA) 19-9 levels from pretreatment to post-GA (P = 0.036). Resected responders had significantly decreased CA 19-9 comparing preswitch to post-GA (P = 0.048). The only predictor of GA response was prechemotherapy CA 19-9 of less than1000 U/mL (P = 0.021). Predictors of reaching resection were head/uncinate tumor (P = 0.010) and presenting stage lower than locally advanced (P = 0.041).. When patients do not respond to neoadjuvant FOLFIRINOX, early switch to GA should be considered. Future efforts should be directed toward identifying markers that will allow correct choice of initial therapy rather than attempting to rescue patients who respond poorly to first-line therapy.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Carcinoma, Pancreatic Ductal; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Outcome Assessment, Health Care; Oxaliplatin; Paclitaxel; Pancreatectomy; Pancreatic Neoplasms; Retrospective Studies; Treatment Failure

The introduction of FOLFIRINOX regimen greatly changed the treatment for advanced pancreatic cancers. However, detailed studies on the clinical effects and factors affecting the prognosis are insufficient. We performed this study to evaluate the effects of FOLFIRINOX and the surgical resection in advanced pancreatic cancer.. Three hundred and thirty-seven patients with advanced pancreatic cancer who initially received FOLFIRINOX, from January 2011 to December 2017, were retrospectively reviewed. Patients were evaluated according to the National Comprehensive Cancer Network guideline, responses after four to six cycles of FOLFIRINOX were re-evaluated according to the response evaluation criteria in solid tumors, and further treatment was decided in the multidisciplinary meeting.. Sixty-seven (19.9%) patients had borderline resectable pancreatic cancer, 135 (40.1%) locally advanced pancreatic cancer, and 135 (40.1%) metastatic pancreatic cancer. The median survival period was significantly longer in the surgical group than in the nonsurgical group in each clinical stage, even in metastatic pancreatic cancer (32 vs. 14, P = 0.012). In multivariate analysis, metastatic status at diagnosis, progressive disease after FOLFIRINOX, surgical resection, and declined CA19-9 after FOLFIRINOX were significant prognostic factors.. Surgical treatment greatly affects survival outcomes in advanced pancreatic cancer treated with FOLFIRINOX. Further studies on the optimal indication of operation and the protocol are needed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Disease Progression; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Survival Rate

To compare the survival outcomes associated with clinical and pathological response in pancreatic ductal adenocarcinoma (PDAC) patients receiving neoadjuvant chemotherapy (NAC) with FOLFIRINOX (FLX) or gemcitabine/nab-paclitaxel (GNP) followed by curative-intent pancreatectomy.. Newer multiagent NAC regimens have resulted in improved clinical and pathological responses in PDAC; however, the effects of these responses on survival outcomes remain unknown.. Clinicopathological and survival data of PDAC patients treated at 7 academic medical centers were analyzed. Primary outcomes were overall survival (OS), local recurrence-free survival (L-RFS), and metastasis-free survival (MFS) associated with biochemical (CA 19-9 decrease ≥50% vs <50%) and pathological response (complete, pCR; partial, pPR or limited, pLR) following NAC.. Of 274 included patients, 46.4% were borderline resectable, 25.5% locally advanced, and 83.2% had pancreatic head/neck tumors. Vein resection was performed in 34.7% and 30-day mortality was 2.2%. R0 and pCR rates were 82.5% and 6%, respectively. Median, 3-year, and 5-year OS were 32 months, 46.3%, and 30.3%, respectively. OS, L-RFS, and MFS were superior in patients with marked biochemical response (CA 19-9 decrease ≥50% vs <50%; OS: 42.3 vs 24.3 months, P < 0.001; L-RFS-27.3 vs 14.1 months, P = 0.042; MFS-29.3 vs 13 months, P = 0.047) and pathological response [pCR vs pPR vs pLR: OS- not reached (NR) vs 40.3 vs 26.1 months, P < 0.001; L-RFS-NR vs 24.5 vs 21.4 months, P = 0.044; MFS-NR vs 23.7 vs 20.2 months, P = 0.017]. There was no difference in L-RFS, MFS, or OS between patients who received FLX or GNP.. This large, multicenter study shows that improved biochemical, pathological, and clinical responses associated with NAC FLX or GNP result in improved OS, L-RFS, and MFS in PDAC. NAC with FLX or GNP has similar survival outcomes.

Topics: Academic Medical Centers; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cause of Death; Combined Modality Therapy; Databases, Factual; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Humans; Kaplan-Meier Estimate; Leucovorin; Logistic Models; Male; Middle Aged; Multivariate Analysis; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; Organoplatinum Compounds; Paclitaxel; Pancreatectomy; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Risk Assessment; Survival Analysis; Treatment Outcome

Chemotherapy is the recommended induction strategy in borderline resectable and locally advanced pancreatic ductal adenocarcinoma. However, the associated results on an intention-to-treat basis are poorly understood.. To investigate pragmatically the treatment compliance, conversion to surgery, and survival outcomes of patients with borderline resectable and locally advanced pancreatic ductal adenocarcinoma undergoing primary chemotherapy.. This prospective study took place in a national referral center for pancreatic diseases in Italy. Consecutive patients with borderline resectable and locally advanced pancreatic ductal adenocarcinoma were enrolled at the time of diagnosis (January 2013 through December 2015) and followed up to June 2018.. The chemotherapy regimen, assigned based on multidisciplinary evaluation, was delivered either at a hub center or at spoke centers. By convention, primary chemotherapy was considered completed after 6 months. After restaging, surgical candidates were selected based on radiologic and biochemical response. All surgeries were carried out at the hub center.. Rates of receipt and completion of chemotherapy, rates of conversion to surgery, and disease-specific survival.. Of 680 patients, 267 (39.3%) had borderline resectable and 413 (60.7%) had locally advanced pancreatic ductal adenocarcinoma. Overall, 66 patients (9.7%) were lost to follow-up. The rate of chemotherapy receipt was 92.9% (n = 570). The chemotherapeutic regimens most commonly used included FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) (260 [45.6%]) and gemcitabine plus nanoparticle albumin-bound-paclitaxel (123 [21.6%]). Nineteen patients (3.3%) receiving chemotherapy died within 6 months, mainly for disease progression. The treatment completion rate was 71.6% (408 of 570). The overall rate of resection was 15.1% (93 of 614) (borderline resectable, 60 of 249 [24.1%]; locally advanced, 33 of 365 [9%]; resection:exploration ratio, 63.3%). Independent predictors of resection were age, borderline resectable disease, chemotherapy completion, radiologic response, and biochemical response. The median survival for the whole cohort was 12.8 (95% CI, 11.7-13.9) months. Factors independently associated with survival were completion of chemotherapy, receipt of complementary radiation therapy, and resection. In patients who underwent resection, the median survival was 35.4 (95% CI, 27.0-43.7) months for initially borderline resectable and 41.8 (95% CI, 27.5-56.1) months for initially locally advanced disease. No pretreatment and posttreatment factors were associated with survival after pancreatectomy.. This pragmatic observational cohort study with an intention-to-treat design provides real-world evidence of outcomes associated with the most current primary chemotherapy regimens used for borderline resectable and locally advanced pancreatic ductal adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Logistic Models; Male; Middle Aged; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Prospective Studies; Survival Analysis

In pancreatic cancer, acquiring a sufficient amount of tumor tissue is an obstacle. The soluble form of PD-L1 (sPD-L1) may have immunosuppressive activity. Here, we evaluated the prognostic implications of sPD-L1 in unresectable pancreatic cancer. We prospectively enrolled 60 patients treated with first-line FOLFIRINOX chemotherapy. We collected blood samples at diagnosis, first response assessment and disease progression. Serum sPD-L1 levels were measured using enzyme-linked immunosorbent assays. The median sPD-L1 level was 1.7 ng/mL (range, 0.4-5.7 ng/mL). Patients with low sPD-L1 level (<4.6 ng/mL) at diagnosis showed better overall survival (OS) than those with high sPD-L1 level (P = 0.015). Multivariate analysis identified sPD-L1 and the neutrophil-to-lymphocyte ratio as independent prognostic factors for OS. During chemotherapy, more patients achieved complete response (CR)/partial response (PR) as their best response when sPD-L1 was decreased at the first response assessment (P = 0.038). In the patients who achieved CR/PR as their best response, sPD-L1 was significantly higher at the time of disease progression than at the first response assessment (P = 0.025). In conclusion, the sPD-L1 level at diagnosis exhibits a prognostic value in pancreatic cancer. Furthermore, sPD-L1 dynamics correlate with disease course and could be used to understand various changes in the tumor microenvironment during chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Biomarkers, Tumor; Disease Progression; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Prospective Studies; Tumor Microenvironment

Modern-era systemic therapy for locally advanced pancreatic adenocarcinoma (LAPC) offers improved survival relative to historical regimens but not necessarily improved radiographic downstaging to allow more patients to undergo resection. The aim of this study was to evaluate the survival, progression, and pathologic outcomes after resection of LAPC that did not regress from > 180 degrees arterial encasement after neoadjuvant therapy.. Sixty-one LAPC patients were brought to the operating room after neoadjuvant therapy for NCCN-defined unresectable pancreatic cancer between 2012 and 2017. Pts were explored with intent of pancreatectomy and irreversible electroporation for margin extension; 5 (8%) had metastatic lesions on exploratory laparoscopy and were excluded from analyses. Imaging was re-examined to confirm LAPC prior to surgery. Data were analyzed from a prospective pancreatic cancer database.. Patients had arterial involvement of the celiac axis (37.5%) and/or superior mesenteric artery (42.9%) and/or an extended length of the common hepatic (n = 44.6%) artery. Twenty-nine males and 27 females, median 65 years of age, received neoadjuvant gemcitabine-based (58.9%) or FOLFIRINOX (35.7%) chemotherapy and stereotactic body (42.9%) or intensity-modulated (51.8%) radiation therapy. Median months from initiation of neoadjuvant therapy to surgery was 7.5. Sixty-one percent underwent Whipple, 21% distal, and 18% modified Appleby procedures; 57% patients underwent venous reconstruction. Ninety-day mortality was 2%. An R0 margin was achieved in 80%, and 53% were N0. Median overall and progression-free survival was 18.5 (95%CI 12.27-32.33) and 8.5 months (95%CI 6.0-15.0), respectively. One- and 3-year survival from surgery was 68.5% (95%CI 53.0-79.7) and 39.0% (95%CI 23.7-53.8), respectively.. With modern-era neoadjuvant therapy, R0 resections can be achieved in a majority of non-metastatic patients with locally advanced, unresectable disease based on cross-sectional imaging.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Arteries; Celiac Artery; Chemoradiotherapy, Adjuvant; Deoxycytidine; Disease Progression; Drug Combinations; Female; Fluorouracil; Gemcitabine; Hepatic Artery; Humans; Irinotecan; Leucovorin; Male; Mesenteric Artery, Superior; Middle Aged; Neoadjuvant Therapy; Neoplasm, Residual; Neoplasms, Second Primary; Organometallic Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Progression-Free Survival; Radiosurgery; Radiotherapy, Intensity-Modulated; Survival Rate

Localized and unresectable pancreatic ductal adenocarcinoma (PDA) comprises one third of new diagnoses and includes borderline resectable (BR) and locally advanced (LA) unresectable disease. In a cohort of patients who were treated and followed at a single institution, we assessed clinical and radiographic predictors of outcome.. The study included 69 consecutive patients with BR or LA PDA. Serial imaging studies were reviewed by both a pancreatic surgeon and a radiologist for vascular abutment or encasement by cancer, and they were recorded.. The cohort included 25 patients with BR and 44 patients with LA PDA, with median overall survivals (OS) of 15 and 14 months, respectively (p = 0.802). Fifteen patients were resected (22%), with a median OS of 21 months from diagnosis (HR 2.50, p = 0.006) and 13 months from resection. Median OS from diagnosis was 33 months in patients without lymph node metastases at resection (n = 10), but just 17 months with lymph node metastases (n = 5, HR = 8.95, p = 0.011). There were 12 two-year survivors in the total cohort (17%), and seven of them never underwent resection. First-line treatments consisted of gemcitabine (n = 13), modern first-line combinations (FOLFIRNOX or gemcitabine/nab-paclitaxel, n = 24), or alternative multi-agent therapies (n = 32); there were no statistical differences between treatment subgroups (OS of 10, 13, and 16 months, respectively). Common hepatic artery (CHA) abutment or encasement at diagnosis was associated with poor survival (adjusted hazard ratio, CHA abutment = 2.47 (p = 0.015) and CHA encasement = 2.16 (p = 0.036)).. In this cohort, common hepatic arterial abutment or encasement and residual lymph node disease at resection portended a particularly poor outcome in patients with localized, unresectable PDA.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Contraindications, Procedure; Deoxycytidine; Drug Combinations; Female; Fluorouracil; Gemcitabine; Hepatic Artery; Humans; Irinotecan; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Organometallic Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Prognosis; Proportional Hazards Models; Survival Rate; Tomography, X-Ray Computed

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Neoadjuvant Therapy; Pancreatic Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Neoadjuvant Therapy; Pancreatic Neoplasms

To describe the survival outcome of patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA-PDAC) who have a pathologic complete response (pCR) following neoadjuvant chemoradiation.. Patients with BR/LA-PDAC are often treated with neoadjuvant chemoradiation in an attempt to downstage the tumor. Uncommonly, a pCR may result.. A retrospective review of a prospectively maintained database was performed at a single institution. pCR was defined as no viable tumor identified in the pancreas or lymph nodes by pathology. A near complete response (nCR) was defined as a primary tumor less than 1 cm, without nodal metastasis. Overall survival (OS) and disease-free survival (DFS) were reported.. One hundred eighty-six patients with BR/LA-PDAC underwent neoadjuvant chemoradiation and subsequent pancreatectomy. Nineteen patients (10%) had a pCR, 29 (16%) had an nCR, and the remaining 138 (74%) had a limited response. Median DFS was 26 months in patients with pCR, which was superior to nCR (12 months, P = 0.019) and limited response (12 months, P < 0.001). The median OS of nCR (27 months, P = 0.003) or limited response (26 months, P = 0.001) was less than that of pCR (more than 60 months). In multivariable analyses pCR was an independent prognostic factor for DFS (HR = 0.45; 0.22-0.93, P = 0.030) and OS (HR=0.41; 0.17-0.97, P = 0.044). Neoadjuvant FOLFIRINOX (HR=0.47; 0.26-0.87, P = 0.015) and negative lymph node status (HR=0.57; 0.36-0.90, P = 0.018) were also associated with improved survival.. Patients with BR/LA-PDAC who had a pCR after neoadjuvant chemoradiation had a significantly prolonged survival compared with those who had nCR or a limited response.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Chemoradiotherapy, Adjuvant; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Radiosurgery; Retrospective Studies; Survival Analysis

Pancreatic cancer (PC) has a very low average survival, but its prognosis is further reduced in the case of metastatic spread. Medical therapy in these cases is the only applicable methodology in the international guidelines. During anticancer treatments, common side effects are nausea, vomiting, arthralgia, neuropathy, and alopecia as well as a myelosuppressive effect. The toxicity of various drugs not only affects the quality of life of the patient, but often its severity requires a reduction in if not the termination of drug administration. Scientific studies have shown that a combined use of chemotherapy and certain natural substances, in the form of standardized extracts, can lead to an enhancement of the action of the chemotherapy. Here, we describe 2 cases of metastatic PC. The first case concerns the integrated treatment of a patient with cancer of the pancreas tail with metastatic involvement ab initio of peripancreatic lymph nodes and liver parenchyma, with numerous secondary lesions greater than 9.5 cm. The second case concerns the integrated treatment of a patient with cancer of the pancreatic body with metastatic involvement of the liver parenchyma, with a small secondary lesion. In both cases, an integrated cancer treatment approach, combining chemotherapy with natural remedies, extracts, and hyperthermia, induced a notable remission of primary and metastatic lesions.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Drug Combinations; Female; Fluorouracil; Humans; Hyperthermia, Induced; Integrative Oncology; Irinotecan; Leucovorin; Middle Aged; Mind-Body Therapies; Neoplasm Metastasis; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Phytotherapy; Remission Induction; Treatment Outcome

Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy.. DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA).. DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009).. DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Deoxycytidine; Dihydrouracil Dehydrogenase (NADP); Equilibrative Nucleoside Transporter 1; Female; Fluorouracil; Gemcitabine; Humans; Immunohistochemistry; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Prognosis; Randomized Controlled Trials as Topic; Survival Analysis; Tissue Array Analysis

Effective treatment of patients with locally advanced pancreatic cancer is a significant unmet clinical need. One major hurdle that exists is inadequate drug delivery due to the desmoplastic stroma and poor vascularization that is characteristic of pancreatic cancer. The local iontophoretic delivery of chemotherapies provides a novel way of improving treatment. With the growing practice of highly toxic combination therapies in the treatment of pancreatic cancer, the use of iontophoresis for local delivery can potentiate the anti-cancer effects of these therapies while sparing unwanted toxicity. The objective of this study was to investigate the impact of formulation on the electro-transport of the FOLFIRINOX regimen for the development of a new treatment for pancreatic cancer.. Three formulations of the FOLFIRINOX regimen (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) were generated at a fixed pH of 6.0 and were referred to as formulation A (single drug solution with all four drugs combined), formulation B (two drug solutions with two drugs per solution), and formulation C (four individual drug solutions). Anodic iontophoresis of the three different formulations was evaluated in orthotopic patient-derived xenografts of pancreatic cancer.. Iontophoretic transport of the FOLFIRINOX drugs was characterized according to organ exposure after a single device treatment in vivo. We report that the co-iontophoresis of two drug solutions, leucovorin + oxaliplatin and 5-fluorouracil + irinotecan, resulted in the highest levels of cytotoxic drugs in the tumor compared to drugs delivered individually or combined into one solution. There was no significant difference in plasma, pancreas, kidney, and liver exposure to the cytotoxic drugs delivered by the three different formulations. In addition, we found that reducing the duration of iontophoretic treatment from 10 to 5 min per solution resulted in a significant decrease in drug concentrations.. Underlying the difference in drug transport of the formulations was electrolyte concentrations, which includes both active and inactive components. Electrolyte concentrations can hinder or improve drug electro-transport. Overall, balancing electrolyte concentration is needed for optimal electro-transport.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Biological Transport; Drug Combinations; Drug Delivery Systems; Electrolytes; Fluorouracil; Humans; Iontophoresis; Irinotecan; Leucovorin; Mice; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Time Factors; Tissue Distribution; Treatment Outcome; Xenograft Model Antitumor Assays

Purpose nab-paclitaxel plus gemcitabine (AG) and FOLFIRINOX have been established as standard first-line treatment in metastatic pancreatic cancer (mPC). We performed retrospective analysis comparing the efficacies of AG and FOLFIRINOX in daily practice setting. Materials and Methods We analyzed 308 patients who presented initially as mPC and received AG (n = 149) or FOLFIRINOX (n = 159) as first-line treatment between 2013 and 2016. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Result There were no significant differences between the two groups in terms of baseline characteristics, except older age and higher Charlson Comorbidity Index (CCI) score in AG group. The response rates (34% vs 34%) and median PFS (6.8 vs 5.1 months) were comparable between two groups (p = 0.88 and p = 0.19, respectively), while median OS was significantly better with AG than FOLFIRINOX (11.4 vs 9.6 months; p = 0.002). Elevated baseline CA19-9 level and liver metastasis were independent adverse prognostic factors for PFS and OS. In subgroup analyses, PFS with AG was better in patients with age ≥ 65 years, peritoneal metastasis, and higher CCI than that with FOLFIRINOX. Conclusion Both AG and FOLFIRINOX showed comparable efficacy outcomes in daily practice setting. AG might be preferentially considered in patients with peritoneal metastasis, comorbid medical conditions or old age.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease-Free Survival; Drug Combinations; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Organometallic Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

Advanced pancreatic cancer (APC) has a poor prognosis. Current first-line chemotherapy options include FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin), NG (nab-paclitaxel, gemcitabine), and GEM (gemcitabine) alone. The optimal second-line regimen is unclear. For patients with disease progression with FOLFIRINOX who have a good performance status, NG might be a reasonable second-line option.. Patients in whom APC was diagnosed from 2012 to 2016 who underwent chemotherapy at CancerCare Manitoba were identified from the Manitoba Cancer Registry. Pharmacy records were used to identified those patients who had received first-line FOLFIRINOX, followed by second-line NG, GEM alone, or best supportive care. A retrospective analysis was performed to identify the patient and treatment characteristics, toxicity, radiologic response, and survival. Edmonton Symptom Assessment System, revised, scores were analyzed to assess symptom control.. A total of 146 patients had received first-line FOLFIRINOX. Of those with disease progression who were offered second-line therapy, 30 received NG, 8 GEM alone, and 22 best supportive care. NG was more toxic than GEM alone; however, the dose intensity was similar between the 2 groups. The median progression-free survival was 3.61 months in the NG group and 2.51 months in the GEM-alone group. The median overall survival was 5.69 months in the NG group and 3.82 months in the GEM-alone group. No significant differences were found in the Edmonton Symptom Assessment System, revised, scores when stratified by the treatment received.. For select patients with APC in whom first-line FOLFIRINOX fails, a role might exist for second-line NG. In our institution, second-line NG was associated with improvement in survival compared with second-line GEM alone, with a manageable toxicity profile.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Disease Progression; Drug Combinations; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Organometallic Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival; Retrospective Studies

To assess factors associated with radical resection (R0) of pancreatic ductal adenocarcinoma (PDAC) after induction treatment with FOLFIRINOX.. Patients with either locally advanced (LA) and borderline resectable (BR) PDAC undergoing surgical exploration after FOLFIRINOX were retrospectively enrolled. Two pancreatic radiologists reviewed the CT blinded to the final outcome and assessed chemotherapy response and resectability. Patients were then divided into R0 resected (group A) and not resected/R1 resected (group B), which were compared.. Of 59 patients included, 19 were defined as unresectable (32%), 33 borderline resectable (56%) and 7 resectable (12%) during the blind radiological evaluation after FOLFIRINOX. Once in a surgical setting, 27% were non-resectable, whereas 73% received surgical resection with a 70% R0 rate. Consequent sensitivity and specificity were 86% and 29%. At imaging review, significant decreases in longest tumour dimension were observed in both groups: from 32 mm (95% CI 15-55) to 21 (10-44) in group A and from 34 (18-70) to 26 (7-60) in group B, p < 0.05. However, a significant increase in tumour attenuation in all phases was only observed for R0 resected, from 52 HU (26-75) to 65 (35-92) in arterial phase (p < 0.001) and from 62 (36-96) to 78 (40-120) in the venous (p = 0.001).. After neoadjuvant FOLFIRINOX, CT predicted resectability with acceptable sensitivity but low specificity. The observation of increased tumour attenuation at CT scan after FOLFIRINOX treatment might represent a reliable predictor of R0 resection.. • CT drives the assessment of PDAC resectability after FOLFIRINOX • CT predicts resectability with acceptable sensitivity but low specificity • Significant increase in tumour attenuation was only observed for R0 resected PDAC • Tumour attenuation after FOLFIRINOX represents a reliable predictor of R0 resection.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Organometallic Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Retrospective Studies; Sensitivity and Specificity; Tomography, X-Ray Computed

New chemotherapies have become available for the treatment of advanced pancreatic cancer and have led to changes in its standard treatments. Since pancreatic cancer is becoming more common as a result of population aging, there is a need for diversification of chemotherapy.. Between March 2014 and April 2017, FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (G-nab) was used as first-line therapy to treat 27 patients with locally advanced and metastatic pancreatic cancer at our hospital. In this study, we retrospectively evaluated their clinical characteristics, survival outcomes and adverse events.. Twelve of the 27 patients were treated with FFX, and the other 15 patients were treated with G-nab. The disease control rate was 86.7% in the G-nab group and 75% in the FFX group. Median OS time was 8.9 months in the FFX group and 11.8 months in the G-nab group. The 1-year survival rate was 46.6% in the G-nab group and 16.6% in the FFX group. The second-line treatment rate was 40% in the G-nab group and 66.7% in the FFX group. The grade 3-4 neutropenia rate was 20% in the G-nab group and 25% in the FFX group. No patients developed febrile neutropenia, or severe nausea, diarrhea, or anorexia. The peripheral sensory neuropathy rate was 73.3% in the G-nab group and 75% in the FFX group.. Although G-nab and FFX are effective treatments for advanced pancreatic cancer, the G-nab group had a higher 1-year survival rate, and G-nab can be more safely administered to older patients.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies; Survival Rate

Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leucovorin; Neoadjuvant Therapy; Pancreatectomy; Pancreatic Neoplasms

Topics: Adenocarcinoma; Allografts; Animals; Antineoplastic Combined Chemotherapy Protocols; Autografts; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Combinations; Fluorouracil; Humans; Irinotecan; Kinetics; Leucovorin; Male; Mice, Inbred C57BL; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Phenotype; Transplantation, Heterotopic

Given the significant morbidity burden associated with advanced pancreatic cancer (APC), its management is complex and frequently requires multidisciplinary care. Because of potential geographical barriers to healthcare access, we aimed to determine the effect of rurality on management and outcomes of APC patients. Patients diagnosed with APC from 2008 to 2015 and received Gemcitabine (Gem), Gemcitabine plus nab-Paclitaxel (Gem/Nab), or FOLFIRINOX at any 1 of 6 British Columbia cancer centers across the province were reviewed. Using postal codes, the Google Maps Distance Matrix determined the distance from each patient's residence to the closest cancer center. Rural and urban status were defined as patients living ≥ 100 and < 100 km from the closest treatment site, respectively. Univariate and Cox regression analyses were applied to examine whether rurality resulted in variations in management and outcomes. In total, we identified 659 patients: median age 68 years, 54.3% men, and 76.6% metastatic disease. For treatment, 67.7, 9.2, and 23.0% received Gem, Gem/Nab, and FOLFIRINOX, respectively. However, there were no differences in baseline clinical characteristics between rural and urban patients (all p > 0.05). Also, there were no significant variations in treatment patterns. For example, time from diagnosis to oncology appointment and time from appointment to treatment were 31.5 and 29.5 days for rural patients and 28.6 and 40.1 days for urban patients, respectively (all p > 0.05). Use of Gem/Nab (10.1% vs 9.1%) and FOLFIRINOX (21.0% vs 23.5%) were similar regardless of rurality. In multivariate Cox regression, risk of death was similar between rural and urban groups (HR 0.864, 95% CI 0.619-1.206, p = 0.09). Our findings suggest that there is no correlation between rurality and outcomes in APC. The strategic and geographic allocation of cancer care delivery across the province of British Columbia may serve as a model for other jurisdictions that experience disparities in the outcomes of cancers that often require complex multidisciplinary care.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; British Columbia; Deoxycytidine; Drug Combinations; Female; Fluorouracil; Gemcitabine; Healthcare Disparities; Humans; Irinotecan; Leucovorin; Male; Organometallic Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Rural Health; Rural Population; Urban Health; Urban Population

By the traditional definition of unintended weight loss, cachexia develops in ~80% of patients with pancreatic ductal adenocarcinoma (PDAC). Here, we measure the longitudinal body composition changes in patients with advanced PDAC undergoing 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin therapy.. We performed a retrospective review of 53 patients with advanced PDAC on 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin as first line therapy at Indiana University Hospital from July 2010 to August 2015. Demographic, clinical, and survival data were collected. Body composition measurement by computed tomography (CT), trend, univariate, and multivariate analysis were performed.. Among all patients, three cachexia phenotypes were identified. The majority of patients, 64%, had Muscle and Fat Wasting (MFW), while 17% had Fat-Only Wasting (FW) and 19% had No Wasting (NW). NW had significantly improved overall median survival (OMS) of 22.6 months vs. 13.0 months for FW and 12.2 months for MFW (P = 0.02). FW (HR = 5.2; 95% confidence interval = 1.5-17.3) and MFW (HR = 1.8; 95% confidence interval = 1.1-2.9) were associated with an increased risk of mortality compared with NW. OMS and risk of mortality did not differ between FW and MFW. Progression of disease, sarcopenic obesity at diagnosis, and primary tail tumours were also associated with decreased OMS. On multivariate analysis, cachexia phenotype and chemotherapy response were independently associated with survival. Notably, CT-based body composition analysis detected tissue loss of >5% in 81% of patients, while the traditional definition of >5% body weight loss identified 56.6%.. Distinct cachexia phenotypes were observed in this homogeneous population of patients with equivalent stage, diagnosis, and first-line treatment. This suggests cellular, molecular, or genetic heterogeneity of host or tumour. Survival among patients with FW was as poor as for MFW, indicating adipose tissue plays a crucial role in cachexia and PDAC mortality. Adipose tissue should be studied for its mechanistic contributions to cachexia.

Topics: Adipose Tissue; Aged; Antineoplastic Combined Chemotherapy Protocols; Body Composition; Body Weights and Measures; Cachexia; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Phenotype; Prognosis; Retrospective Studies; Tomography, X-Ray Computed

Gemcitabine (GEM), oxaliplatin plus GEM (OX + GEM), cisplatin plus GEM (CIS + GEM), capecitabine plus GEM (CAP + GEM), FOLFIRINOX (FFX), and nab-paclitaxel plus GEM (NAB-P + GEM) are the most commonly used regimens as first-line treatment of metastatic pancreatic cancer (MPC) in the UK. Independent economic evaluation of these regimens simultaneously has not been conducted for the UK.. Using data from a network meta-analysis as efficacy measures, we estimated the cost effectiveness and cost utility of these regimens for the UK.. A three-state Markov model (progression-free, progressed-disease, and death) simulating the total costs and health outcomes (quality-adjusted life-years [QALYs] gained and life-years [LYs]) was developed to estimate the incremental cost-utility (ICUR) and incremental cost-effectiveness ratios (ICER) for patients with MPC, from the payer perspective. The model was specified to calculate total costs in 2017 British pounds (GBP, £). All values were discounted at 3.5% per year over a full lifetime horizon. One-way sensitivity and probabilistic sensitivity analyses were conducted to assess the impact of parameter uncertainty on the results.. FFX was the most effective regimen, NAB-P + GEM was the most costly regimen, and GEM was the least costly and least effective regimen. OX + GEM, CIS + GEM, and NAB-P + GEM were dominated by CAP + GEM and FFX. Compared with GEM, the ICUR for CAP + GEM and FFX was £28,066 and £33,020/QALY gained, respectively; compared with GEM, the ICER for CAP + GEM and FFX was £17,437 and £22,291/LY gained, respectively; and compared with CAP + GEM, the ICUR and ICER for FFX were £34,947/QALY gained and 24,414/LY gained, respectively.. At a threshold value of £30,000/QALY, CAP + GEM was found to be the only cost-effective regimen in the management of MPC in the UK.

Topics: Adult; Albumins; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Cisplatin; Cost-Benefit Analysis; Deoxycytidine; Disease Progression; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Markov Chains; Neoplasm Metastasis; Network Meta-Analysis; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Progression-Free Survival; Quality-Adjusted Life Years; United Kingdom

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Deoxycytidine; Drug Combinations; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Maintenance Chemotherapy; Organometallic Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Randomized Controlled Trials as Topic

At time of diagnosis, less than 10% of patients with pancreatic adenocarcinomas (PDAC) are considered to be immediately operable (i.e. resectable). Considering their poor overall survival (OS), only tumours without vascular invasion (NCCN 2017) should be considered for resection, i.e. those for which resection with disease-free margins (R0) is theoretically possible in absence of presurgery treatment. With regard to high R1 rates and undetectable locoregional and/or metastatic spreading prior to surgery explain (at least in part) the observed 1-year relapse and mortality rates of 50 and 25%, respectively. Today, upfront surgery followed by adjuvant chemotherapy is the reference treatment in Europe. The main limitation of the adjuvant approach is the low rate of completion of the full therapeutic sequence. Indeed, only 47 to 60% patients received any adjuvant therapy after resection compared to more than 75% for neoadjuvant therapy. No previous prospective study has compared this approach to a neoadjuvant FOLFIRINOX or FOLFOX chemotherapy for resectable PDAC.. PANACHE01-PRODIGE48 is a prospective multicentre controlled randomized non comparative Phase II trial, evaluating the safety and efficacy of two regimens of neo-adjuvant chemotherapy (4 cycles of mFOLFIRINOX or FOLFOX) relative to the current reference treatment (surgery and then adjuvant chemotherapy) in patients with resectable PDAC. The main co-primary endpoints are OS rate at 12 months and the rate of patients undergoing the full therapeutic sequence.. The "ideal" cancer treatment for resectable PDAC would have the following characteristics: administration to the highest possible proportion of patients, ability to identify fast-progressing patients (i.e. poor candidates for surgery), a low rate of R1 resections (through optimisation of local disease control), and an acceptable toxicity profile. The neoadjuvant approach may meet all these criteria. With respect to published data on the efficacy of FOLFOX and mFOLFIRINOX, these two regimens are potential candidates for neoadjuvant use in the aim to optimising oncological outcomes in resectable PDAC.. ClinicalTrials.gov , NCT02959879 . Trial registration date: November 9, 2016.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Drug Combinations; Fluorouracil; Humans; Irinotecan; Leucovorin; Multicenter Studies as Topic; Neoadjuvant Therapy; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Randomized Controlled Trials as Topic

Approximately 30% of all pancreatic cancer patients have locally advanced (AJCC stage 3) disease. A sub-group of these patients-where the cancer only involves the celiac axis-may benefit from distal pancreatectomy with celiac axis resection (DP-CAR). Previous studies have shown that DP-CAR offers a survival benefit to a selected group of patients with otherwise unresectable pancreatic cancer, when performed by experienced pancreatic cancer treatment teams at high-volume centers. This article proposes a standardized approach to DP-CAR, including routine neoadjuvant (FOLFIRINOX) chemotherapy. This approach to selecting patients and performing DP-CAR has the potential to improve short-term outcomes and overall survival in selected patients, but it should be reserved for high-volume centers.

Topics: Antineoplastic Combined Chemotherapy Protocols; Celiac Artery; Chemotherapy, Adjuvant; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Neoplasm Staging; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Patient Selection; Postoperative Complications; Retrospective Studies; Survival Rate

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with lack of predictive biomarkers. We conducted a study to assess DNA damage repair (DDR) gene mutations as a predictive biomarker in PDAC patients treated with FOLFIRINOX.. Indiana University Simon Cancer Center pancreatic cancer database was used to identify patients with metastatic PDAC, treated with FOLFIRINOX and had tissue available for DNA sequencing. Baseline demographic, clinical, and pathologic information was gathered. DNA isolation and targeted sequencing was performed using the Ion AmpliSeq protocol. Overall survival (OS) analysis was conducted using Kaplan-Meier, logistic regression and Cox proportional hazard methods. Multivariate models were adjusted for age, gender, margin status, CA 19-9, adjuvant chemotherapy, tumor and nodal stage.. Overall, 36 patients were sequenced. DDR gene mutations were found in 12 patients. Mutations were seen in BRCA1 (. In a single institution, retrospective study, we found that the presence of DDR gene mutations are associated with improved OS in PDAC patients treated with FOLFIRINOX.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; DNA Damage; DNA Repair; Female; Fluorouracil; Genes, BRCA1; Genes, BRCA2; Germ-Line Mutation; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Mutation; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Treatment Outcome

To assess clinical and pathologic efficacy of neoadjuvant FOLFIRINOX for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC).. Patients receiving neoadjuvant FOLFIRINOX for LAPC and BRPC treated between 2014 and 2017 were identified. Post-treatment patients achieving resectability were referred for surgery, whereas unresectable patients continued chemotherapy. Clinical and pathological data were retrospectively compared with control group consisting of 47 consecutive patients with BRPC undergoing pancreatic and portal vein resection between 2008 and 2017.. Thirty LAPC and 23 BRPC patients were identified. Reasons for unresectability included disease progression (70%), locally unresectable disease (18%), and poor performance status (11%). Three patients (10%) with LAPC, and 20 (87%) with BRPC underwent curative surgery. Compared with control group, perioperative complication rate (4.3% versus 28.9%, p = 0.016), and pancreatic fistula rate (0 versus 14.8%, p = 0.08) were lower. Peripancreatic fat invasion (52.2% vs 97.8%, p = 0.001), lymph node involvement (22% vs 54.3%, p = 0.01), and surgical margin involvement (0 vs 17.4%, p = 0.04) were higher in the control group. Median survival was 34.3 months in BRPC patients operated after FOLFIRINOX and 26.1 months in the control group (p = 0.07). Three patients (13%) with complete pathological response are disease-free after mean follow-up of 19 months.. Whereas neoadjuvant FOLFIRINOX rarely achieves resectability in patients with LAPC (10%), most BRPC undergo resection (87%). Neoadjuvant FOLFIRINOX leads to complete pathological response in 13% of cases, tumor downstaging, and a trend towards improved survival compared with patients undergoing up-front surgery.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Drug Combinations; Female; Fluorouracil; Humans; Intention to Treat Analysis; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; Organometallic Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Ducts; Pancreatic Neoplasms; Pancreaticoduodenectomy; Portal Vein; Postoperative Complications; Survival Rate

The report describes a patient who presented to our centre with abdominal pain and significant weight loss due to adenocarcinoma of the tail of the pancreas. The cancer was deemed as 'resectable disease associated with morbid surgical outcomes' due to the local involvement of the vessels and adjacent organs. Given the patient's excellent performance status, the patient underwent neoadjuvant chemotherapy with folinic acid, fluorouracil, irinotecan and oxaliplatin to downstage the tumour for less morbid surgical resection. The patient underwent 12 cycles of chemotherapy with serial imaging which demonstrated positive response to treatment and surgical resection was performed. Surgical pathology revealed no residual tumour and imaging was negative for any extrapancreatic tumour metastasis. This is an unusual case as pancreatic malignancy is usually lethal with poor survival outcomes.

Topics: Abdominal Pain; Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Diagnosis, Differential; Drug Combinations; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Tomography, X-Ray Computed; Weight Loss

nab-Paclitaxel plus gemcitabine (nab-P + G) and FOLFIRINOX (FFX) are among the most common first-line (1L) therapies for metastatic adenocarcinoma of the pancreas (MPAC), but real-world data on their comparative effectiveness are limited.. This retrospective cohort study compared the efficacy and safety of 1L nab-P + G versus FFX, overall and under specific treatment sequences. Medical records were reviewed by 215 US physicians who provided information on MPAC patients who initiated 1L therapy with nab-P + G or FFX between April 1, 2015 and December 31, 2015. Study outcomes were overall survival (OS) and tolerability. OS was compared using Kaplan-Meier curves and adjusted Cox proportional hazards models.. In total, 654 medical records were reviewed, including those of 337 and 317 patients initiated on nab-P + G and FFX as 1L MPAC therapy, respectively. nab-P + G-initiated patients were older, less likely to have ECOG ≤ 1, and had more comorbidities than FFX-initiated patients. Median OS (mOS) was 12.1 and 13.8 months for nab-P + G- and FFX-initiated patients, respectively (HR = 0.99, P = 0.96). Among patients with ECOG ≤ 1, mOS was 14.1 and 13.7 months, respectively (HR = 1.00, P = 0.99). Among patients with 1L nab-P + G and FFX, 36.1% and 41.3% received 2L therapy and experienced mOS of 16.3 and 16.6 months, respectively (HR = 1.04, P = 0.76). The rates of diarrhea, fatigue, mucositis, and nausea and vomiting were significantly higher in the FFX than nab-P + G cohort.. The real-world survival was similar between patients receiving 1L nab-P + G or FFX both overall and among patients who received active 2L treatments. In addition, nab-P + G was associated with significantly lower rates of common AEs compared with FFX.. Celgene.

Topics: Adenocarcinoma; Aged; Albumins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies; Survival Analysis; Treatment Outcome; United States

One-third of the patients with pancreatic cancer present with locally advanced unresectable pancreatic cancer (LAPC). Our aim was to determine survival outcomes and toxicity after FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) followed by radiotherapy (RT) in biopsy-proven patients with LAPC.. We analysed a cohort of biopsy-proven patients with LAPC, who were eligible for induction FOLFIRINOX (eight cycles) and subsequent RT (30 fractions, 60 Gy). Eligible patients underwent a staging laparoscopy to detect occult metastasis before the treatment. The primary outcome was overall survival (OS), and secondary outcomes were progression-free survival (PFS), treatment-related toxicity, and resection rate.. Forty-four patients were diagnosed with biopsy-proven LAPC. Twenty-five patients were eligible and all underwent staging laparoscopy before the treatment. In three (12%) patients occult metastases were found. Twenty-two patients started induction FOLFIRINOX, 17 (77%) completed all cycles. Seventeen (77%) patients were treated with subsequent RT, with 16 (94%) receiving the full dosage. Three (14%) patients underwent a radical resection after the treatment. Median OS was 15.4 months (95% confidence interval [CI], 10.0-20.7), median PFS was 11 months (95% CI, 7.7-14.4).. Median OS after FOLFIRINOX and RT was 15 months in patients with LAPC. Toxicity remains severe, however, most patients completed all eight scheduled cycles of FOLFIRINOX and RT.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Camptothecin; Chemoradiotherapy; Cohort Studies; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Survival Rate

Pancreatic acinar cell carcinoma (PACC) is a relatively rare malignancy of the exocrine pancreas. BRCA2, a cancer susceptibility gene, has been widely studied in breast and ovarian carcinomas as mutation carriers for this gene are at a high risk for cancer development. Olaparib, an oral poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, has been approved for the treatment of ovarian cancer with any BRCA 1/2 mutations. Herein, we report the first case of a germline BRCA2-mutated unresectable advanced PACC patient who responded well to olaparib treatment.. A 59-year-old male with a family history of cancer presented with a persistent epigastric dull pain for 3 months.. The patient was diagnosed with advanced PACC based on computed tomography (CT) scan, laparotomy, and pathology.. Exploratory laparotomy, intratumoral brachytherapy by radioiodine-125 seeds, modified FOLFIRINOX chemotherapy, and targeted therapy with olaparib were administered.. The patient responded well to olaparib until the occurrence of severe adverse drug reactions, he died as a result of multiple organ failure with an overall survival period of 12 months.. As a PARP inhibitor, olaparib has remarkable curative effect not only on breast and ovarian cancers, but also on other malignancies with BRCA mutations. Patients with advanced cancer could benefit from active targeted therapy with improvement in overall survival and quality of life.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; BRCA2 Protein; Carcinoma, Acinar Cell; Drug Combinations; Fatal Outcome; Fluorouracil; Humans; Irinotecan; Laparotomy; Leucovorin; Male; Middle Aged; Mutation; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Phthalazines; Piperazines; Tomography, X-Ray Computed

Despite modern chemotherapy regimens, survival of pancreatic cancer patients remains dismal. Toxicity is a major concern and it is a challenge to upfront identify patients with the highest benefit from aggressive polychemotherapy. We aimed to evaluate ORR and side effects of the FOLFIRINOX regimen, highlighting dose modification and to explore possible prognostic response factors as a clinical tool.. This retrospective study includes 123 patients with metastatic PC that were treated with FOLFIRINOX between the years 2007 to 2016 in a single academic institution. Survival rates were analysed using the Kaplan-Meier method. Prognostic models including laboratory and clinical parameters were calculated using Cox proportional models in univariate and multivariate analyses.. Median age at diagnosis was 64 years (47-78 years), 71 (57, 7%) were male and the majority had an ECOG performance status of 0 or 1 (63 patients; 83.7%). After a median follow up of 17.8 months, median progression free survival (PFS) and overall survival (OS) were 5.7 (4.55-6.84; 95%CI) and 11.8 months (9.35-14.24; 95%CI) respectively. Overall response rate with FOLFIRINOX was 34.9% and stable disease rate was 21.9%. Regarding Grade 3/4 side effects, 62 events, were reported in 37 patients. Looking at risk factors e.g. patient characteristics, tumor marker, inflammatory markers and body composition multivariate analyses proved CEA >4 elevation and BMI > 25 at the time point before palliative chemotherapy to be independent negative prognostic factors for OS. Grouping patients with no risk factor, one or two of these risk factors we analyzed a median OS of 17.4 moths, 9.6 months and 6.7 months (p<0.001) respectively. In addition we identified thrombocytosis and low BMI as predictors of early toxicity.. This study identifies two easily available factors influencing overall survival with FOLFIRINOX therapy. By combining these two factors to create a score for OS, we propose a prognostic tool for physicians to identify patients, who are unlikely to benefit more from FOLFIRINOX or likely to experience toxicity.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Survival Analysis

MMR-D pancreatic cancer have been reported to respond to checkpoint inhibitor therapy. Here, we report the first case of acquired resistance to immunotherapy in MMR-D pancreatic cancer.. A 45-year-old woman with unresectable MMR-D pancreatic cancer was initially treated with FOLFIRINOX, FOLFIRI, and stereotactic body radiation with stable disease burden. After 3 months, imaging showed progression of disease with an increase in CA19-9. She was subsequently enrolled in a clinical trial of an anti-PD-L1 antibody in combination with an IDO1 inhibitor. She demonstrated a partial response to therapy by RECIST 1.1 criteria with declining tumor markers. Twenty-two months after beginning immunotherapy, imaging revealed an increasing left ovarian cystic mass. There were no other sites of progressive disease. The patient underwent a total hysterectomy and bilateral salpingo-oophorectomy, appendectomy, omentectomy and pelvic lymphadenopathy. Pathology was consistent with a metastasis from the pancreas involving the endometrium and left ovary. Thereafter, the patient continued with PD-1 blockade therapy off protocol with no further progressive disease. Immune profiling showed high levels of CD8+ T cells and PD-1 positive immune cells infiltrating the tumor, with a moderate level of PD-L1 expression in both the immune cells and the tumor cells. Next generation sequencing found only the KRAS G12D and RNF43 G659Vfs*41 mutations were retained from the pre-treatment tumor in the treatment-resistant tumor.. This is the first report describing acquired resistance to immunotherapy in MMR-D pancreatic cancer with accompanying genomic and immune profiling. This case of oligoprogression in the setting of immunotherapy demonstrates the feasibility of localized treatment followed by continuation of immunotherapy to sustain ongoing response.

Topics: Adenocarcinoma; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Camptothecin; Drug Resistance, Neoplasm; Endometrial Neoplasms; Female; Fluorouracil; Humans; Immunotherapy; Indoleamine-Pyrrole 2,3,-Dioxygenase; Irinotecan; Leucovorin; Middle Aged; Ovarian Neoplasms; Oxaliplatin; Pancreatic Neoplasms

Systemic chemotherapy or chemoradiotherapy is the initial primary option for patients with locally advanced pancreatic cancer (LAPC). This study analyzed the effect of FOLFIRINOX and assessed the factors influencing conversion to surgical resectability for LAPC.Sixty-four patients with LAPC who received FOLFIRINOX as initial chemotherapy were enrolled retrospectively. Demographic characteristics, tumor status, interval/dosage/cumulative relative dose intensity (cRDI) of FOLFIRINOX, conversion to resection, and clinical outcomes were reviewed and factors associated with conversion to resectability after FOLFIRINOX were analyzed.After administration of FOLFIRINOX (median 9 cycles, 70% of cRDI), the median patient overall survival (OS) was 17.0 months. Fifteen of 64 patients underwent surgery and R0 resection was achieved in 11 patients. During a median follow-up time of 9.4 months after resection, cumulative recurrence rate was 28.5% at 18 months after resection. The estimated median OS was significantly longer for the resected group (>40 months vs 13 months). There were no statistical differences between the resected and non-resected groups in terms of baseline characteristics, tumor status and hematologic adverse effects. The patients who received standard dose of FOLFIRINOX had higher probability of subsequent resection compared with patients who received reduced dose, although cRDIs did not differ between groups.FOLFIRINOX is an active regimen in patients with LAPC, given acceptable resection rates and promising R0 resection rates. Additionally, our data demonstrate it is advantageous for obtaining resectability to administer FOLFIRINOX without dose reduction.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Republic of Korea; Survival Analysis; Treatment Outcome

To assess the impact of chronomodulated irinotecan fluorouracil-leucovorin and oxaliplatin (chronoIFLO4) delivered at home on the daily life of patients with cancer in real time using a home-based e-Health multifunction and multiuser platform. This involved multidimensional telemonitoring of circadian rest-activity rhythm (CircAct), sleep, patient-reported outcome measures, and body weight changes (BWCs).. Patients received chronoIFLO4 fortnightly at home. Patients completed the 19-item MD Anderson Symptom Inventory on an interactive electronic screen, weighed themselves on a dedicated scale, and continuously wore a wrist accelerometer for CircAct and sleep monitoring. Daily data were securely teletransmitted to a specific server accessible by the hospital team. The clinically relevant CircAct parameter dichotomy index I < O and sleep efficiency (SE) were calculated. The dynamic patterns over time of patient-reported outcome measures, BWC, I < O, and SE informed the oncology team on tolerance in real time.. The platform was installed in the home of 11 patients (48 to 72 years of age; 45% men; 27% with performance status = 0), who were instructed on its use on site. They received 26 cycles and provided 5,891 data points of 8,736 expected (67.4%). The most severe MD Anderson Symptom Inventory scores were: interference with work (mean: 5.1 of 10) or general activity (4.9), fatigue (4.9), distress (4.2), and appetite loss (3.6). Mean BWC was -0.9%, and mean SE remained > 82%. CircAct disruption (I < O ≤ 97.5%) was observed in four (15%) cycles before chronoIFLO4 start and in five (19%) cycles at day 14.. The patient-centered multidimensional telemonitoring solution implemented here was well accepted by patients receiving multidrug chemotherapy at home. Moreover, it demonstrated that chronoIFLO4 was a safe therapeutic option. Such integrated technology allows the design of innovative management approaches, ultimately improving patients' experience with chemotherapy, wellbeing, and outcomes.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Circadian Rhythm; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Patient Reported Outcome Measures; Patient-Centered Care; Pilot Projects; Sleep; Survival Analysis; Telemedicine; User-Computer Interface

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Neoplasm Metastasis; Oxaliplatin; Pancreatic Neoplasms; Randomized Controlled Trials as Topic; Topoisomerase Inhibitors

Topics: Antigens, Neoplasm; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Deoxycytidine; Drug Resistance, Neoplasm; Fluorouracil; Gemcitabine; Histone Acetyltransferases; Humans; Hyaluronoglucosaminidase; Irinotecan; Leucovorin; Neoplasm Metastasis; Oxaliplatin; Pancreas; Pancreatic Neoplasms

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Neoplasm Metastasis; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Topoisomerase Inhibitors

Topics: Adenocarcinoma; Albumins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Oxaliplatin; Paclitaxel; Pancreas; Pancreatic Neoplasms

Undifferentiated carcinoma of pancreas (pancreatic cancer - PC) is a rare subtype of malignant PC. It was thought to be a sarcoma of the pancreas due to its typical morphological pattern. There are three histomorphological variants: anaplastic, sarcomatoid, and carcinosarcoma. There is also a separate category: undifferentiated pancreatic carcinoma with osteoclast-like giant cells. In contrast to ductal adenocarcinoma of the pancreas, undifferentiated carcinoma of pancreas is characterized by more aggressive behavior, other predilection localization of tumor and different predilection for localization of tumor and metastasis, a larger primary tumor, and different symptomatology at the time of diagnosis.. We present the case of a patient who was diagnosed with undifferentiated PC and was treated at the National Cancer Institute in Bratislava. We provide information about the clinical, radiological, and histomorphological characteristics of the disease, along with the diagnostic and therapeutic approach and a brief review of the literature.. The patient was diagnosed with inoperable locally advanced disease and was treated with first line chemotherapy comprising gemcitabine and cisplatin, followed by second line treatment with FOLFIRINOX. No response was achieved; on the contrary, we observed progression of the disease and deterioration in the patients condition. Overall survival was 4.5 months from the time of diagnosis.. The only appropriate therapeutic approach to this highly malignant disease is most likely “en-bloc” resection, which is possible only at the early stage of the disease. At present, no curative chemotherapy or radiotherapy regimen exists. The dominant features of undifferentiated PC described in the literature are aggressive behavior, an unfavorable prognosis, and chemo-refractoriness. Key words: pancreatic cancer - prognosis - chemotherapy The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 4. 6. 2018 Accepted: 25. 10. 2018.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Deoxycytidine; Fatal Outcome; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms

FOLFIRINOX has increased efficacy but also toxicity. Despite various modified FOLFIRINOX regimens, how much reduction is acceptable remains unclear. This study aimed to find the optimal relative dose intensity (RDI, %) of FOLFIRINOX that preserves tumour responses in patients with advanced pancreatic cancer (PC).. We reviewed 201 patients with PC treated with first-line FOLFIRINOX during 2012-2015. We established a modified Hryniuk model (http://www.rdicalc.com) and defined cumulative RDI (cRDI, %). The optimal cRDI thresholds for response rate (RR) and disease control rate (DCR) were assessed using receiver operating characteristic (ROC) analysis. Relationships between cRDI and haematologic toxicities (neutropenia and febrile neutropenia [FN]) were also analysed according to use of granulocyte colony-stimulating factor (G-CSF).. Among 156 eligible patients, 133 (48 locally advanced PC and 85 metastatic PC) completed initial treatment plan prior to the first radiological evaluation (median 58 days; 71.8% cRDI). For optimal cRDI thresholds, ROC curves showed a 71.2% cRDI for RR (83.3% sensitivity, 64.7% specificity, and 0.746 area under the curve [AUC]) and a 55.3% cRDI for DCR (93.6% sensitivity, 62.5% specificity and 0.805 AUC). Among 96 patients who did not receive prophylactic G-CSF, cRDI ≥80.1% was a significant predictor for frequent FN (73.7% sensitivity, 72.7% specificity and 0.793 AUC). There was no correlation between cRDI and haematologic toxicities in patients receiving prophylactic G-CSF.. To preserve optimal RR and DCR in advanced PC, cRDI values for FOLFIRINOX >70% and >55%, respectively, are recommended. If cRDI is >80%, primary G-CSF prophylaxis is needed.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Chemotherapy-Induced Febrile Neutropenia; Dose-Response Relationship, Drug; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

To evaluate gemcitabine efficacy in advanced pancreatic cancer patients after the FOLFIRINOX regimen.Patients with locally-advanced or metastatic pancreatic adenocarcinoma from French and Canadian centers, who were treated with the first-line FOLFIRINOX regimen (FFX L1), followed by gemcitabine monotherapy as a second-line treatment (GEM L2), were retrospectively evaluated. Statistical analyses were performed on the demographic, toxicity, and response rate data. Overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method.Seventy-two patients were reviewed (median age of 63.5 years [range, 32-75 years], men [62%], predominantly pancreatic head tumor location [51%] and metastatic disease [64%] at the time of diagnosis). The objective response rate to GEM-L2 treatment was 8/72 (11%), and 32 patients (44%) experienced a clinical benefit from gemcitabine. Four patients had a partial response to GEM-L2, although they previously showed a progressive response following FFX-L1 treatment. The median OS for the entire cohort was 13.6 months (95% confidence interval [CI]: 2.0-35). The median PFS of the GEM-L2 group was 2.5 months (95% CI: 0.2-10.8) with no statistical differences between patients with controlled or progressive disease on FFX-L1 therapy.Gemcitabine as a second-line treatment for advanced pancreatic adenocarcinoma after FOLFIRINOX failure showed clinical benefits in some patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Canada; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Pancreatic Neoplasms; Retrospective Studies

Few population studies have examined patterns of systemic therapy administration in metastatic pancreatic cancer (MPC) or the predictors associated with specific treatment choices.. We assessed 4,011 consecutive MPC patients who received chemotherapy between January 2005 and December 2015 at academic, private, and community-based oncology practices subscribing to a U.S.-wide chemotherapy order entry system capturing disease, patient, provider, and treatment data. Multivariate analyses of these prospectively recorded characteristics identified significant predictors of specific therapeutic choices.. Overall, 100 different regimens were used in first-line treatment of MPC. First-line gemcitabine monotherapy usage fell steadily from 72% in 2006 to 16% in 2015. This steep decline mirrored increases in first-line usage of both 5 fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine + nab-paclitaxel. Younger male patients were more likely to receive FOLFIRINOX as first-line treatment, whereas patients treated at community practices and by oncologists with lower MPC patient volume were more likely to receive gemcitabine plus nab-paclitaxel (all. This population-based study provides insight into treatment patterns of MPC in the U.S. Usage patterns varied greatly according to patient and provider characteristics.. This study examined real world metastatic pancreatic cancer treatment patterns in the United States with the goals of understanding changes in chemotherapy treatment frequencies over time and determining the individual predictors that underlie the chemotherapy choices oncologists make for their patients. Our data set is unique in that it captured not only patient-level data, but also oncologist-level data. It also captured data from private and community practices as well as academic centers. To our knowledge, this is the only data set that can give this degree of insight into oncologist decision making practices.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Decision Making; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms; United States

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Recurrence, Local; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms; Standard of Care

Following induction chemotherapy, both resection or irreversible electroporation (IRE) may further improve survival in patients with locally advanced pancreatic cancer (LAPC). However, prospective studies combining these strategies are currently lacking, and available studies only report on subgroups that completed treatment. This study aimed to determine the applicability and outcomes of resection and IRE in patients with nonprogressive LAPC after induction chemotherapy.. This was a prospective, single-center cohort study in consecutive patients with LAPC (September 2013 to March 2015). All patients were offered 3 months of induction chemotherapy (FOLFIRINOX or gemcitabine depending on performance status), followed by exploratory laparotomy for resection or IRE in patients with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 nonprogressive, IRE-eligible tumors.. Of 132 patients with LAPC, 70% (n = 93) started with chemotherapy (46% [n = 61] FOLFIRINOX). After 3 months, 59 patients (64%) had nonprogressive disease, of whom 36 (27% of the entire cohort) underwent explorative laparotomy, resulting in 14 resections (11% of the entire cohort, 39% of the explored patients) and 15 IREs (11% of the entire cohort, 42% of the explored patients). After laparotomy, 44% (n = 16) of patients had Clavien-Dindo grade 3 or higher complications, and 90-day all-cause mortality was 11% (n = 4). With a median follow-up of 24 months, median overall survival after resection, IRE, and for all patients with nonprogressive disease without resection/IRE (n = 30) was 34, 16, and 15 months, respectively. The resection rate in 61 patients receiving FOLFIRINOX treatment was 20%.. Induction chemotherapy followed by IRE or resection in nonprogressive LAPC led to resection or IRE in 22% of all-comers, with promising survival rates after resection but no apparent benefit of IRE, despite considerable morbidity. Registered at Netherlands Trial Register (NTR4230).

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Deoxycytidine; Disease Progression; Electrochemotherapy; Female; Fluorouracil; Gemcitabine; Humans; Induction Chemotherapy; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Prospective Studies; Response Evaluation Criteria in Solid Tumors; Survival Rate

Stereotactic body radiation therapy (SBRT) is an emerging treatment option for unresectable pancreatic cancer, and is postulated to be more effective and less toxic than conventionally fractionated intensity modulated radiation therapy (IMRT).. We retrospectively reviewed unresectable stage I-III pancreatic adenocarcinoma treated from 2008 to 2016 at our institution with SBRT (five fractions, 30-33 Gy) or IMRT (25-28 fractions, 45-56 Gy with concurrent chemotherapy). Groups were compared with respect to overall survival (OS), local and distant failure, and toxicity. Log-rank test and Cox proportional hazards regression model, and competing risks methods were used for univariate and multivariate analysis.. SBRT patients (n = 44) were older than IMRT (n = 226) patients; otherwise there was no significant difference in baseline characteristics. There was no significant difference in OS or local or distant failure. There was no significant difference in rates of subsequent resection (IMRT =17%, SBRT =7%, p = .11). IMRT was associated with more acute grade 2+ gastrointestinal toxicity, grade 2+ fatigue, and grade 3+ hematologic toxicity (p = .008, p < .0001, p = .001, respectively).. In this analysis, SBRT achieves similar disease control outcomes as IMRT, with less acute toxicity. This suggests SBRT is an attractive technique for pancreatic radiotherapy because of improved convenience and tolerability with equivalent efficacy. However, the lack of observed advantages in disease control with this moderate-dose SBRT regimen may suggest a role for increasing SBRT dose, if this can be accomplished without significant increase in toxicity.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Chemoradiotherapy; Deoxycytidine; Diarrhea; Fatigue; Female; Fluorouracil; Gemcitabine; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Mucositis; Multivariate Analysis; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Proportional Hazards Models; Radiation Injuries; Radiosurgery; Radiotherapy, Intensity-Modulated; Retrospective Studies; Survival Rate; Thrombocytopenia

The economic burden of metastatic pancreatic cancer (mPC) is substantial while treatment options are limited. Little is known about the treatment patterns and healthcare costs among mPC patients who initiated first-line gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-P + G) and FOLFIRINOX.. The MarketScan® claims databases were used to identify adults with ≥2 claims for pancreatic cancer, 1 claim for a secondary malignancy, completed ≥1 cycle of nab-P + G or FOLFIRINOX during 4/1/2013 and 3/31/2015, and had continuous plan enrollment for ≥6 months pre- and 3 months after the first-line treatment. Duration of therapy, per patient per month (PPPM) costs of total healthcare, mPC-related treatment, and supportive care were measured during first-line therapy.. 550 mPC patients met selection criteria (nab-P + G, n = 294; FOLFIRINOX, n = 256). There was no difference in duration of therapy (p = 0.60) between nab-P + G and FOLFIRINOX. Compared with FOLFIRINOX, patients with nab-P + G had higher chemotherapy drug costs but lower treatment administration costs and supportive care costs (all p < 0.01).. Patients treated with nab-P + G (vs FOLFIRINOX) had similar treatment duration but lower costs of outpatient prescriptions, treatment administration and supportive care. Lower supportive care costs in the nab-P + G cohort were mainly driven by lower utilization of pegfilgrastim and anti-emetics.

Topics: Aged; Albumins; Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cohort Studies; Cost of Illness; Deoxycytidine; Drug Costs; Female; Filgrastim; Fluorouracil; Gemcitabine; Granulocyte Colony-Stimulating Factor; Health Care Costs; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms; Polyethylene Glycols; Recombinant Proteins; Retrospective Studies; Time Factors

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemoradiotherapy; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Radiosurgery; Tomography, X-Ray Computed; Tumor Burden

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Medical Oncology; Nanostructures; Neoplasm Metastasis; Pancreatic Neoplasms

To compare neoadjuvant to adjuvant chemoradiation in non-metastatic pancreatic cancer patients.. Single-institution data were obtained for patients with non-metastatic pancreatic cancer treated with concurrent chemoradiation from 2011 to 2014. Univariate analyses were performed to evaluate clinical and pathological outcomes.. Fifty-two well-matched patients were enrolled (21 underwent neoadjuvant chemoradiation, 11 with adjuvant chemoradiation and 20 in the definitive group). Median tumor size was 2.6 cm pretreatment and 2.5 cm after neoadjuvant chemoradiation but 3.2 cm on pathology, with a treatment effect in 95.2% of specimens. Clinical node positivity at diagnosis for neoadjuvant and adjuvant chemoradiation groups was similar (28.6% vs 27.3%, P = 0.12). Of the 36 neoadjuvant patients, 21 (58.3%) underwent complete resection. In the neoadjuvant vs adjuvant chemoradiation groups, positive margins were decreased (4.8% vs 63.6%, P < 0.001), as was pathological nodal positivity (23.8% vs 90.9%, P < 0.001). After a median follow-up of 13.3 months, locoregional control for neoadjuvant and adjuvant chemoradiation was 7.7 and 7.2 months, respectively (P = 0.12) and the definitive group was 1.2 months (P = 0.014 compared with the surgical cohort). One-year overall survival was better with neoadjuvant than with adjuvant chemoradiation but this was not significant (94% vs 82%, P = 0.20); 1-year survival for the definitive group was 59% (P = 0.03 compared with the surgical cohort).. Neoadjuvant chemoradiation remains a promising approach for non-metastatic pancreatic cancer for improving resectability and pathological and clinical findings. Computed tomography may not fully demonstrate the effectiveness of neoadjuvant treatment.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy, Adjuvant; Deoxycytidine; Dose Fractionation, Radiation; Drug Combinations; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Male; Margins of Excision; Middle Aged; Neoadjuvant Therapy; Neoplasm, Residual; Organometallic Compounds; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Radiotherapy, Intensity-Modulated; Retrospective Studies; Survival Rate; Tomography, X-Ray Computed; Tumor Burden

FOLFIRINOX is a first-line treatment option for patients with metastatic pancreatic cancer (MPC) and is associated with improved survival yet significantly more toxicities than standard gemcitabine. Our aim was to determine the proportion of patients with MPC who would be eligible for FOLFIRINOX based upon the pivotal ACCORD study criteria.. Patients with confirmed MPC at the time of referral to the BC Cancer Agency between 2004 and 2007 were identified from the Gastrointestinal Cancers Outcomes Unit Database (GICOU). Proportion of patients that met the ACCORD study eligibility criteria was determined by chart review. Criteria for FOLFIRINOX exclusion were assessed using descriptive statistics.. A total of 100 consecutive patients with complete chart records and MPC were identified. Fifty-two (52%) were male and the median age was 68 years (range, 42 to 98 y). The most common sites of metastases were liver (63%) and peritoneum (22%). Only 26 patients fulfilled the ACCORD study eligibility criteria. The most common reasons for FOLIFIRINOX exclusion per ACCORD were poor Eastern Cooperative Oncology Group score of ≥2 (64%), age of 76 years or greater (22%), elevated bilirubin (22%), and inadequate renal function (6%).. Despite the proven survival benefit of FOLFIRINOX, only approximately one quarter of patients in the real-world setting with MPC would have been considered eligible for such therapy based upon the ACCORD eligibility criteria. Careful patient selection and more tolerable therapies are required.

Topics: Activities of Daily Living; Adenocarcinoma; Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; British Columbia; Camptothecin; Eligibility Determination; Female; Fluorouracil; Humans; Hyperbilirubinemia; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Peritoneal Neoplasms; Renal Insufficiency; Retrospective Studies

To assess anatomic changes on computed tomography (CT) after neoadjuvant FOLFIRINOX (5-fluorouracil/leucovorin/irinotecan/oxaliplatin) chemotherapy for secondary resected borderline resectable (BR) and locally advanced (LA) pancreatic adenocarcinoma and their accuracy to predict resectability and pathological response.. Thirty-six patients with secondary resected BR/LA pancreatic adenocarcinoma after neoadjuvant FOLFIRINOX chemotherapy (± chemoradiotherapy) were retrospectively included. Two radiologists reviewed baseline and pre-surgical CTs in consensus. NCCN (National Comprehensive Cancer Network) classification, largest axis, product of the three axes (P3A), and arterial/venous involvement were studied and compared to pathological response and resection status and to disease-free survival (DFS).. Thirty-one patients had R0 resection, including only six exhibiting a downstaging according to the NCCN classification. After treatment, the largest axis and P3A decreased (P < 0.0001). The pre-surgical largest axis and P3A were smaller in case of R0 resection (P = 0.019/P = 0.021). The largest axis/P3A variations were higher in case of complete pathological response (P = 0.011/P = 0.016). A decrease of the arterial/venous involvement was not able to predict R0 or ypT0N0 (P > 0.05). Progression of the vascular involvement was seen in two (5 %) patients and led to a shorter DFS.. In BR/LA pancreatic adenocarcinoma after the neoadjuvant FOLFIRINOX regimen (± chemoradiotherapy), significant tumour size decreases were observed on CT. However, CT staging was not predictive of resectability and pathological response.. • Significant tumour size decreases were observed on CT after FOLFIRINOX (± chemoradiotherapy). • CT is not able to predict R0 resection accurately after FOLFIRINOX (± chemoradiotherapy). • CT is not able to predict complete response accurately after FOLFIRINOX (± chemoradiotherapy). • Even with a stable NCCN classification, BR/LA pancreatic adenocarcinoma could have R0 resection.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Immunosuppressive Agents; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Radiation-Sensitizing Agents; Retrospective Studies; Tomography, X-Ray Computed; Treatment Outcome; Vitamin B Complex

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 64-year-old woman with a history of hypertension and type 2 diabetes had been in her usual state of health until she developed symptoms of diarrhea, abdominal bloating, and discomfort in the midepigastrium. Evaluation with a contrast-enhanced abdominopelvic computed tomography (CT) scan demonstrated a mass in the pancreatic body that was approximately 3.1 cm × 2 cm × 2.1 cm in size with abutment of the portal vein-superior mesenteric vein confluence for less than 180°. The confluence was narrowed but without thrombosis. No tumor-vessel interface was noted at the superior mesenteric artery, celiac artery, or common hepatic artery. Several peripancreatic lymph nodes were observed that measured up to 11 mm × 5 mm. No evidence for distant spread of disease was identified. An upper endoscopy with endoscopic ultrasound was performed and fine-needle aspirates of the pancreas mass were positive for malignant cells that were consistent with adenocarcinoma. Chest CT scan without intravenous contrast demonstrated no evidence of metastatic disease. The patient came to the clinic to discuss management of her newly diagnosed malignancy.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Organoplatinum Compounds; Pancreatic Neoplasms; Practice Guidelines as Topic; Preoperative Period; Review Literature as Topic

In patients with borderline resectable pancreas cancers, clinicians frequently consider radiographic response as the primary driver of whether patients should be offered surgical intervention following neoadjuvant therapy (NT). We sought to determine any correlation between radiographic and pathologic response rates following NT.. Between 2005 and 2015, 38 patients at a tertiary care referral center underwent NT followed by pancreaticoduodenectomy for borderline resectable pancreas cancer. Radiographic response after the completion of NT and pathologic response after surgery were graded according to RECIST and Evans' criteria, respectively.. Preoperatively, 50% of patients underwent chemotherapy alone and 50% underwent chemotherapy and chemoradiation. Radiographically, one patient demonstrated a complete radiologic response, 68.4% (n = 26) of patients had stable disease (SD), 26.3% (n = 10) demonstrated a partial response, and one patient had progressive. Among patients without radiographic response, 77.7% (n = 21) achieved a R0 resection. Of patients with SD on imaging, 26.9% (n = 7) had Evans grade IIB or greater pathologic response.. Our data indicate that approximately one-fourth of patients who did not have a radiologic response had a grade IIB or greater pathologic response. In the absence of metastatic progression, lack of radiographic down-staging following NT should not preclude surgery.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Chemoradiotherapy, Adjuvant; Chemotherapy, Adjuvant; Deoxycytidine; Erlotinib Hydrochloride; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms; Pancreaticoduodenectomy; Retrospective Studies; Tertiary Care Centers

Topics: Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Oxaliplatin; Pancreatic Neoplasms

Metastatic pancreatic cancer (mPC) is associated with low survival, with less than 10% of patients surviving 5 years. Recent therapies improve survival outcomes where few alternative therapies exist, but few economic analyses measure the value of survival gains attributable to new therapies.. To estimate the value of survival gains in advanced or mPC attributable to the introduction of novel treatment regimens.. Multivariate Cox proportional hazards models were used to estimate real-world survival gains associated with the introduction of gemcitabine (GEM) for patients diagnosed with stage IV or unstaged mPC in the Surveillance, Epidemiology, and End Results Program cancer registries. Then, evidence from clinical trials was used to evaluate the survival gains associated with nab-paclitaxel + gemcitabine (nP +GEM) and FOLFIRINOX (FFX) relative to GEM. The survival estimates and clinical trial evidence were used to calibrate an economic model and assess the cumulative value of survival gains in mPC to patients. Costs of treatment were calculated based on published cost-effectiveness studies.. We estimated that the introduction of GEM in 1996 was associated with a hazard ratio of 0.920 (P < 0.05) and an increase in median survival from 3.1 to 4.5 months. Results suggested that the value of survival gains attributable to GEM equaled about $71,000 per patient, while the value attributable to nP + GEM was an additional $56,700. Estimates for the value of survival gains per patient, net of total incremental lifetime treatment costs (drugs, adverse events, and other costs), were $50,294 for GEM and an additional $31,900 for nP + GEM. Clinical trials and cost-effectiveness studies reported an overall survival gain from FFX that was larger than, but statistically similar to, nP + GEM and had greater risk of adverse events and total incremental costs. We estimated that the total value of survival gains to mPC patients, net of total costs, associated with GEM was up to $47.6 billion, and the additional values attributable to nP+GEM and FFX were up to $39.0 billion and $26.3 billion, respectively.. Historically, mPC patients have faced high disease burden and had few treatment options. Treatments introduced since 1996 have led to improved survival, with varying costs associated with treatment and adverse events. Accounting for total incremental costs, the majority of the value of survival gains from GEM and nP+GEM was retained by mPC patients, highlighting the value of innovation in settings where survival is low and few alternative therapies exist.. Support for this research was provided by Celgene. Precision Health Economics was compensated by Celgene for work on this study. MacEwan is an employee of, and Yin is a consultant to, Precision Health Economics. Kaura and Khan are employees of Celgene. Study concept and design were contributed primarily by Yin and MacEwan, along with Kaura and Khan. MacEwan collected the data, and data interpretation was performed primarily by MacEwan and Yin, along with Kaura and Khan. The manuscript was written and revised by MacEwan, Yin, Kaura, and Khan.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms; Survival Analysis

Topics: Adenocarcinoma; Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Drug Combinations; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organometallic Compounds; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies; Risk Factors; Treatment Failure; Treatment Outcome

We compared real-world treatment patterns, resource utilization, and cost of care for patients with metastatic pancreatic cancer treated with first-line nab-paclitaxel + gemcitabine or FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin).. This was a retrospective study of inpatient and hospital-based outpatient data in the United States. Primary endpoints included median time to treatment discontinuation (TTD) and total cost of care per patient per month. Secondary endpoints included supportive care costs and hospitalization rate and length.. Overall, 345 patients were included (nab-paclitaxel + gemcitabine, n = 182; FOLFIRINOX, n = 163). Median TTD was significantly longer with nab-paclitaxel + gemcitabine vs FOLFIRINOX (4.3 vs 2.8 months; P = .0009). Mean acquisition cost was higher with nab-paclitaxel + gemcitabine ($10,643 vs $6549; P = .0043), but mean total cost of care was lower ($16,628 vs $19,936; P = .1740). Supportive care cost was significantly lower with nab-paclitaxel + gemcitabine ($1995 vs $6456; P < .0001). Hospitalization rate and length were both significantly lower with nab-paclitaxel + gemcitabine.. Despite higher acquisition costs with nab-paclitaxel + gemcitabine, FOLFIRINOX-treated patients had higher total costs driven by supportive care. Toxicity-related costs and drug acquisition costs should be considered when evaluating total cost of care.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Delivery of Health Care; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Health Care Costs; Hospitalization; Humans; Length of Stay; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies; Time Factors

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Acinar Cell; Carcinoma, Islet Cell; Combined Modality Therapy; Fluorouracil; Humans; Irinotecan; Laparotomy; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Pancreaticoduodenectomy; Preoperative Period; Treatment Outcome

Advanced pancreatic cancer (APC), one of the most aggressive tunors, was considered to be resistant to chemotherapy for decades. FOLFIRINOX (5-FU, leucovorin, iNinotecah and oxaliplatin) regimen showed an improvement of quality of life and overall sUrvival.ir APb patients with good performance status (ECOG < 2).. Seven patients diagnosed with APO, during a six-month period, received FOLFIRINOX as first line treat- ment. Tumor measurement Was assesed every two months and CA 19-9, tHe specific tumor marker of pahcteatid can6er, was assessed every two wedks at every cycle.. Three patients ouf of seven receiving FOLFiRINOX dtpe- riented an early And transitory increase of CA 19-9 after th6 first two cybles resulting ih a considerable response with a median survival of 15 mnths and suggesting a fhdel of fdmor release syndrome.. This phenoMenon of early and transitory increase of CA 19-9 in APC could reflect the high efficacy of FOLFIRINOX and could predict better out- come in these patients.

Topics: Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Fluorouracil; Humans; Irinotecan; Leucovorin; Organometallic Compounds; Oxaliplatin; Pancreatic Neoplasms

To evaluate the outcomes and toxicity of concurrent full-dose gemcitabine and intensity-modulated radiation therapy (IMRT) for patients with borderline resectable and locally advanced pancreatic adenocarcinoma after induction chemotherapy.. From 2009 to 2012, 32 patients were treated with concurrent gemcitabine and IMRT for borderline resectable or locally advanced pancreatic adenocarcinoma. All patients received induction FOLFIRINOX or gemcitabine-based chemotherapy before chemoradiation. The radiotherapy volume was limited to the primary tumor, and the median dose was 55 Gy in 25 fractions. Gemcitabine was administered weekly during radiotherapy on days 1, 8, 22, and 29 at a median weekly dose of 800 mg/m².. Twenty-five patients had locally advanced disease and 7 had borderline resectable disease. The median follow-up time was 14.6 months. The median progression-free and overall survival were 13.9 and 23.1 months, with a trend toward improved overall survival for patients receiving induction FOLFIRINOX compared with gemcitabine-based therapy. A radiographic complete or partial response was achieved in 13 patients (41%), with 4 (13%) having complete radiographic responses. Surgical resection was performed in 10 patients (31%)--6 patients with locally advanced disease and 4 with borderline resectable disease. Grade 3/4 hematologic toxicity during and up to 6 weeks after chemoradiation occurred in 12 patients (38%); grade 3 nonhematologic toxicity occurred in 7 patients (22%), with no grade 4 or 5 toxicity. All patients completed their radiotherapy.. Concurrent full-dose gemcitabine and limited-field IMRT after induction chemotherapy for the treatment of borderline resectable and locally advanced pancreatic cancer is promising with acceptable toxicity rates.

Topics: Adenocarcinoma; Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Chemoradiotherapy; Cisplatin; Cohort Studies; Deoxycytidine; Disease Progression; Duodenal Ulcer; Erlotinib Hydrochloride; Female; Fluorouracil; Gastrointestinal Diseases; Gemcitabine; Humans; Induction Chemotherapy; Irinotecan; Leucovorin; Male; Middle Aged; Multivariate Analysis; Neoadjuvant Therapy; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Proportional Hazards Models; Radiotherapy, Intensity-Modulated; Retrospective Studies; Thrombocytopenia; Treatment Outcome

The role of carbohydrate antigen 19-9 (CA 19-9) for predicting treatment outcome in pancreatic ductal adenocarcinoma (PDAC) remains to be elucidated. This study was aimed to determine the correlation between early decrement in CA 19-9 concentration and prognosis of advanced PDAC after chemotherapy.. All patients confirmed with locally advanced or metastatic PDAC who received initial systemic chemotherapy for at least two cycles in our institution between January 2012 and December 2013 were included. Serum CA 19-9 concentrations at baseline and 8 weeks after the initiation of chemotherapy were obtained. Correlation between CA 19-9 decrement and survival outcomes (time to progression [TTP] and overall survival [OS]) were evaluated.. A total of 183 patients with initially elevated CA 19-9 were included. OS and TTP was significantly longer for patients whose serum CA 19-9 concentration decreased more than 10% from baseline (n = 103), than that for patients whose serum CA 19-9 was not decreased (n = 80) (423 vs 155 days, P < 0.001 for OS and 222 vs 75 days, P < 0.001 for TTP). In multivariate analysis, CA 19-9 decrement more than 10% from baseline was still a significant factor for longer OS (hazard ratio for progression 0.275 [0.184-0.412], P < 0.001) and TTP (0.322 [0.219-0.473], P < 0.001) in both stage III and IV.. The early decrement of CA 19-9 after the initiation of chemotherapy was an independent factor related with better survival outcomes in unresectable PDAC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; CA-19-9 Antigen; Camptothecin; Carcinoma, Pancreatic Ductal; Deoxycytidine; Disease Progression; Drosophila Proteins; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Multivariate Analysis; Nerve Tissue Proteins; Nuclear Proteins; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Predictive Value of Tests; Prognosis; Survival Rate; Transcription Factors; Treatment Outcome

hENT1 is a transmembrane protein which acts as a nucleoside transporter and is the main mediator of Gemcitabine (GEM) uptake into human cells. In this retrospective study we compared GEM versus FOLFIRINOX in patients with metastatic pancreatic cancer in which hENT1 evaluation was available.. 149 patients affected by unresectable metastatic pancreatic cancer, treated in our institution from 2009 to 2013, have been screened for inclusion in this retrospective study. Seventy patients, treated with GEM or FOLFIRINOX in first-line therapy, fulfilled clinical inclusion criteria for survival analysis. Thirty-one patients were available and contained sufficient quality/quantity RNA for evaluation of hENT1 expression by RT-PCR. The primary endpoint was OS and the secondary endpoint was PFS.. The survival analysis, carried out on 70 patients regardless of hENT1 expression, showed a statistically longer OS and PFS in the group treated with FOLFIRINOX compared to GEM. Within the exploratory analysis, which included 31 patients, no differences were found in hENT1 positive patients treated with FOLFIRINOX compared to GEM in terms of OS (8.5 vs 7 months, HR: 0.89; 95 % CI 0.3-2.5; p = 0.8) and PFS (5.5 vs 5 months, HR: 0.8, 95 % CI 0.2-2.2; p = 0.61). GEM-treated hENT1 positive patients showed a statistically significant improvement both of OS (8 vs 2 months; p = 0.0012) and PFS (5 vs 1 months; p = 0.0004) in comparison to GEM-treated hENT1 negative patients.. In our exploratory analysis GEM seems as effective as FOLFIRINOX in terms of survival with a better safety profile in hENT1 positive metastatic pancreatic cancer.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Deoxycytidine; Equilibrative Nucleoside Transporter 1; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Irinotecan; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Survival Rate

Poor delivery and systemic toxicity of many cytotoxic agents, such as the recent promising combination chemotherapy regimen of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), restrict their full utility in the treatment of pancreatic cancer. Local delivery of chemotherapies has become possible using iontophoretic devices that are implanted directly onto pancreatic tumors. We have fabricated implantable iontophoretic devices and tested the local iontophoretic delivery of FOLFIRINOX for the treatment of pancreatic cancer in an orthotopic patient-derived xenograft model. Iontophoretic delivery of FOLFIRINOX was found to increase tumor exposure by almost an order of magnitude compared with i.v. delivery with substantially lower plasma concentrations. Mice treated for 7 wk with device FOLFIRINOX experienced significantly greater tumor growth inhibition compared with i.v. FOLFIRINOX. A marker of cell proliferation, Ki-67, was stained, showing a significant reduction in tumor cell proliferation. These data capitalize on the unique ability of an implantable iontophoretic device to deliver much higher concentrations of drug to the tumor compared with i.v. delivery. Local iontophoretic delivery of cytotoxic agents should be considered for the treatment of patients with unresectable nonmetastatic disease and for patients with the need for palliation of local symptoms, and may be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Cell Proliferation; Fluorouracil; Humans; Infusion Pumps, Implantable; Iontophoresis; Leucovorin; Mice; Mice, Nude; Organoplatinum Compounds; Pancreatic Neoplasms; Xenograft Model Antitumor Assays

The two combination chemotherapy regimens FOLFIRINOX and gemcitabine plus nab-paclitaxel represent major breakthroughs in the management of metastatic pancreatic cancer. Both regimens showed unprecedented survival advantage in the setting of front-line therapy. However, their application for treatment of patients in the community is challenging because of significant toxicities, thus limiting potential benefits to a narrow population of patients. Modifications to the dose intensity or schedule of those regimens improve their tolerability, while likely retaining survival advantage over single-agent chemotherapy. Newer strategies to optimize these two active regimens in advanced pancreatic cancer are being explored that can help personalize treatment to individual patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Organoplatinum Compounds; Pancreatic Neoplasms

To explore efficacy and safety of modified FOLFIRINOX (mFOLFIRINOX) regimen by dose attenuation in locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer(MPC).. Between April 2014 and October 2015, 35 patients with LAPC (n=18) or MPC (n=17) were treated with mFOLFIRINOX regimen (irinotecan 135 mg/m(2), oxaliplatin 68 mg/m(2), 5-FU 2 400 mg/m(2), no bolus of 5-FU, leucovorin 400 mg/m(2)) in the Second Affiliated Hospital of Zhejiang University School of Medicine. The primary end point was progression free survival. The second end points were overall survival, objective response rate, adverse effects, surgical resection rate for LAPC.. Among 35 patients, 6 patients (17.1%) who dropped out and received less than 2 cycles were excluded for response analysis. Among the other 29 patients, 9 patients had grade 3 or 4 adverse effects. No patients ceased treatment due to adverse effects. The 29 patients received 5 (2-13) cycles were evaluated by efficacy and found partial remission in 16 cases, stable disease in 10 cases, progression disease in 3 cases. Response rate was 55.2%. Nine patients with LAPC accomplished surgery after neoadjuvant treatment without perioperative complication and death, and 6 patients accepted R0 resection.. The mFOLFIRINOX regimen used in the study is well-tolerated in Chinese population with high treatment efficacy on patients with LAPC and MPC. Further investigation of efficacy and adverse effects on more advanced pancreatic cancer patients is necessary.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Disease Progression; Disease-Free Survival; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Tertiary Care Centers; Treatment Outcome

FOLFIRINOX is a standard first-line treatment for advanced pancreatic cancer (aPC). The Gruppo Oncologico Nord Ovest (GONO) FOLFOXIRI regimen demonstrated efficacy in metastatic colorectal cancer. We aimed to evaluate activity and tolerability of FOLFOXIRI regimen in patients with aPC and to explore putative prognostic factors. One hundred thirty-seven consecutive aPC patients were treated with FOLFOXIRI in our institution between 2008 and 2014. Clinical, laboratory and pathological data were collected and their association with activity, progression free survival (PFS) and overall survival (OS) was investigated. After a median follow up of 30 months, median PFS and OS were 8.0 months (95% CI 6.19-9.81) and 12 months (95% CI 9.75-14.25), respectively. Response rate was 38.6%, while disease-control rate 72.2%. At multivariate analysis liver metastases (p = 0.019; Hazard Ratio, HR, 0.59, 95% Confidence Interval, CI, 0.380.96), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 (p = 0.001; HR 2.26, 95%CI 1.42-3.59) and neutrophil-lymphocyte ratio (NLR)> 4 (p= 0.002; HR: 2.42; 95% CI 1.38-4.25) were associated with poorer OS. We categorized 119 pts with complete available data as good-risk (0 factors, 38 pts), intermediate-risk (1 factor, 49 pts) and poor-risk (≥2 factors, 32 pts). Median OS for these three groups were 17.6, 11.1 and 7.4 months, respectively (p < 0.001). FOLFOXIRI is active and feasible in aPC. Prognosis of aPC pts treated with FOLFOXIRI is influenced by easily available factors: our analysis revealed ECOG PS, liver metastases and NLR as the most important predictors of survival. These factors could be helpful for treatment decision and clinical trial design.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cohort Studies; Female; Fluorouracil; Humans; Leucovorin; Leukocyte Count; Lymphocytes; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Neutrophils; Organoplatinum Compounds; Pancreatic Neoplasms; Prognosis; Survival Analysis; Treatment Outcome

Fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel (GEM-N) have shown a significant survival benefit for the treatment of metastatic pancreatic cancer. The objective of this study was to assess the cost-effectiveness of FOLFIRINOX versus GEM-N for treating metastatic pancreatic cancer based on the PRODIGE and MPACT trials.. A decision model was performed to compare FOLFIRINOX with GEM-N. Primary base case data were identified from PRODIGE and MPACT trials. Costs were estimated and incremental cost-effectiveness ratio (ICER) was calculated at West China Hospital, Sichuan University, China. Survival benefits were reported in quality-adjusted life-years (QALY). Finally, sensitive analysis was performed by varying potentially modifiable parameters in the model.. The base-case analysis showed that FOLFIRINOX cost $37,203.75 and yielded a survival of 0.67 QALY, and GEM-N cost $32,080.59 and yielded a survival of 0.51 QALY in the entire treatment. Thus, the ICER of FOLFIRINOX versus GEM-N was $32,019.75 per QALY gained.. The GEM-N regimen was more cost-effective compared with the FOLFIRINOX regimen for the treatment of metastatic pancreatic cancer from a Chinese perspective.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; China; Clinical Trials as Topic; Cost-Benefit Analysis; Decision Support Techniques; Deoxycytidine; Drug Costs; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Quality-Adjusted Life Years; Survival Analysis

Treating metastatic pancreatic cancer (MPC) remains a challenging issue. Maintenance therapy is a growing concept used in different types of cancer. Our retrospective analysis aims to evaluate the effectiveness and tolerability of early maintenance capecitabine administrated to patients with MPC treated with first-line FOLFIRINOX.. 103 patients treated for MPC between November 2009 and July 2014 were retrospectively identified in our institution. Among them, 30 patients initially treated with a minimum of 4 and no more than 8 cycles of FOLFIRINOX, without signs of progression (every 14 days), received maintenance therapy with capecitabine until progression. Upon first progression (first progression-free survival, PFS1), patients were retreated with FOLFIRINOX or another scheme until second progression (second progression-free survival, PFS2).. Median OS was 17 months. Survival rates were 73% at 1 year (95% CI 0.59-0.91) and 25% at 2 years (95% CI 0.13-0.50). Median PFS1 was 5 months. Twenty-nine patients experienced disease progression during capecitabine treatment (96.7%). After disease progression, median PFS2 was 10 months. Considering the interval between the starting date of FOLFIRINOX treatment and second disease progression, the median time to treatment failure is 17 months.. Maintenance with capecitabine seems effective without compromising FOLFIRINOX efficacy and allows obtaining very promising OS and PFS.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Maintenance Chemotherapy; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

No clinically useful predictive factor has been yet identified for treatment of metastatic pancreatic cancer (mPC). It is noteworthy that FOLFIRINOX, despite its high toxicity, is effective only in some patients. We retrospectively analyzed expression of excision repair cross-complementing group-1 (ERCC1) - involved in the repair of platinum induced damage - in patients affected by mPC treated with FOLFIRINOX in order to evaluate its predictive role.. FOLFIRINOX resulted more effective in patients with normal ERCC1 levels than in those with ERCC1 hyper-expression. Median progression free survival (PFS) was 11 vs. 4 months (HR 0.26; 95% CI 0.14-0.50; p<.0001), median overall survival (OS) 16 vs. 8 months (HR 0.23; 95% CI 0.12-0.46; p<.0001) and disease control rate (DCR) 93% vs. 50% (p=0.00006). The advantage was confirmed at univariate and multivariate analysis.. 71 patients with histologically proven mPC and treated with FOLFIRINOX as first-line therapy were considered eligible. mRNA ERCC1 expression was determined using RT-PCR analysis.. ERCC1 might be an effective predictor of response to FOLFIRINOX in mPC. Patients overexpressing ERCC1 should be excluded by this often toxic therapy and referred to an alternative treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Disease-Free Survival; DNA-Binding Proteins; Endonucleases; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Drug Compounding; Fluorouracil; Humans; Irinotecan; Leucovorin; Liposomes; Pancreatic Neoplasms; Treatment Outcome

No consensus exists regarding the optimal neoadjuvant treatment paradigm for patients with borderline resectable pancreatic cancer (BRPC), including the respective roles of chemotherapy and radiation.. We performed a retrospective analysis, including detailed pathologic and radiologic review, of pancreatic cancer patients undergoing FOLFIRINOX, with or without radiation therapy (RT), prior to surgical resection at a high-volume academic center over a 4-year period.. Of 26 patients meeting inclusion criteria, 22 (84.6%) received FOLFIRINOX alone without RT (median number of treatment cycles = 9). The majority of patients met formal radiographic criteria for BRPC, with the superior mesenteric vein representing the most common vessel involved. R0 resection rate was 90.9%, with 12 patients (54.5%) requiring vascular reconstruction. Treatment response was classified as moderate or marked in 16 patients (72.7%) according to the College of American Pathologists grading system. Estimated median disease-free and overall survival rates are 22.6 months and not reached (NR), respectively.. This is one of the largest series to describe the use of neoadjuvant FOLFIRINOX, without radiation therapy, in patients with BRPC undergoing surgical resection. Given the high R0 resection rates and favorable clinical outcomes with chemotherapy alone, this strategy should be further assessed in prospective study design. J. Surg. Oncol. 2016;114:587-596. © 2016 Wiley Periodicals, Inc.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemoradiotherapy, Adjuvant; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Pancreatectomy; Pancreatic Neoplasms; Patient Selection; Preoperative Care; Retrospective Studies; Treatment Outcome

FOLFIRINOX has been shown to significantly increase both overall survival (OS) and progression-free survival (PFS) in metastatic pancreas cancer. There is limited data regarding the treatment of locally advanced pancreatic cancer. We present a retrospective study of patients with both locally advanced and metastatic pancreas cancer using FOLFIRINOX as first-line therapy in our centre.. This is a retrospective review of patients treated with FOLFIRINOX for pancreatic cancer at Princess Margaret Cancer Centre, between December 2011 and July 2014. The primary objective was to evaluate the efficacy and safety of FOLFIRINOX when used with dose modifications.. One hundred two patients were identified; 66 metastatic and 36 locally advanced. Sixty-eight per cent of patients initiated treatment with a dose reduction. The median (95% CI) OS in the metastatic group was 13.1 (6.3-16.1) months with full dose and 12.9 (10.3-30.1) months with modified dose. The median (95% CI) OS in the locally advanced group was 11.1 (6.1-not reached) months with full dose and 23 (not reached-not reached) months with modified dose. The median (95% CI) PFS in the metastatic group was 6.2 (4.9-15.2) months with full dose and 8.7 (5.7-12.9) months with modified dose. The median (95% CI) PFS in the locally advanced group was 11.1 (3.1-not reached) months with full dose and 10.4 (6.8-not reached) months with modified dose. Grade 3/4 haematologic adverse events were observed in 43% of patients. Grade 3/4 non-haematologic adverse events were observed in 28% of patients. Patient well-being significantly improved from baseline to cycle 4 (P=0.002).. Efficacy was achievable with dose-modified FOLFIRINOX in daily setting. The safety of FOLFIRINOX remains a concern with a high rate of grades 3 and 4 neutropaenia despite dose reduction.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; CA-19-9 Antigen; Camptothecin; Carcinoma, Pancreatic Ductal; Cisplatin; Combined Modality Therapy; Deoxycytidine; Disease-Free Survival; Drug Substitution; Female; Fluorouracil; Gastrointestinal Diseases; Gemcitabine; Hematologic Diseases; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Ontario; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Quality of Life; Sepsis; Treatment Outcome

Acinar cell carcinoma (ACC) of the pancreas is a very rare cancer, constituting 1 % of all malignant non-endocrine pancreatic tumors. Only very limited data exist to guide treatment in patients with advanced ACC.. Between 2000 and 2015, 15 patients with ACC were diagnosed and/or treated at our high-volume comprehensive cancer center. Medical records and correlating serum levels of the potential serum tumor markers CA 19-9, CEA and lipase were analyzed retrospectively.. A substantial antitumor activity was observed for treatment regimens containing 5-FU and oxaliplatin with partial responses or prolonged disease stabilizations (>12 months) observed in 6 out of 7 patients (86 %). Activity was also observed for single-agent 5-FU and its oral prodrugs. Serum lipase levels were elevated in 7 of 12 patients with advanced disease (58 %), whereas CEA and CA 19-9 seemed to be of minor importance for ACC (elevated pre-treatment levels in 4/12 and 3/12 cases, respectively). In selected patients, repeated serum lipase measurements were available and accurately predicted response to chemotherapy and relapse after surgery.. 5-FU- and oxaliplatin-containing regimens are active in advanced ACC. Lipase kinetics may be a useful novel tool to monitor the course of disease as well as treatment effects in ACC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Acinar Cell; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prevalence; Prognosis; Rare Diseases; Retrospective Studies; Survival Analysis

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Germany; Hospitals, Community; Humans; Irinotecan; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prevalence; Retrospective Studies; Risk Factors; Survival Rate

Recently, FOLFIRINOX and gemcitabine + nab-paclitaxel have been introduced as a novel intensified chemotherapy regimen for patients with metastasized pancreatic cancer. This study aims to analyze the real-world clinical practice with FOLFIRINOX and gemcitabine + nab-paclitaxel across Europe.. Invitations to participate in an anonymous web-based questionnaire were sent via e-mail to 5,420 doctors in 19 European countries through the network of national gastroenterological, oncological, surgical and pancreatic societies as well as the European Pancreatic Club. The questionnaire consisted of 20 questions, 14 regarding the use of intensified chemotherapy, 4 regarding demographics of the participants, and 1 to verify the active involvement in the management of metastatic pancreatic cancer.. Two hundred and thirteen responses were received and 153 entries were valid for analysis. Of those, 63.4% came from an academic institution, 51% were oncologists, and 52% treated more than 25 cases per year. A majority of responses (71%) were from Italy (40%), Germany (23%), and Spain (8%). As first-line therapy, 11% used gemcitabine +/- erlotinib, 42% used FOLFIRINOX, and 47% used gemcitabine + nab-paclitaxel. Of the intensified regimens, both were applied to equal parts, but the likelihood of protocol deviation was higher when using FOLFIRINOX (p < 0.01). FOLFIRINOX was considered more toxic than gemcitabine + nab-paclitaxel (neutropenia 88 vs. 68%; polyneuropathy 42 vs. 41%; rapid deterioration 42 vs. 31%). FOLFIRINOX was rated to achieve longer survival with an acceptable quality of life (52 vs. 44%). Moreover, 57% of participants thought that gemcitabine + nab-paclitaxel should be the backbone for further clinical trials in pancreatic cancer.. Intensified chemotherapy is widely used in pancreatic cancer patients in Europe following its recent clinical approval. Interestingly, nab-paclitaxel and FOLFIRINOX were used at comparable frequency although the latter had to be de-escalated more often.

Topics: Albumins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Clinical Decision-Making; Deoxycytidine; Erlotinib Hydrochloride; Europe; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms; Quality of Life; Surveys and Questionnaires

First-line treatment with FOLFIRINOX significantly increases overall survival (OS) in patients with metastatic pancreatic adenocarcinoma (PA) compared with gemcitabine. The aim of this observational cohort was to evaluate the tolerability and efficacy of this regimen in unresectable locally advanced PA (LAPA).. From February 2010 to February 2012, all consecutive patients from 11 French centers treated by FOLFIRINOX for a histologically proven LAPA were prospectively enrolled. Unresectability was defined independently by each center's multidisciplinary staff at diagnosis. Absence of metastatic disease was confirmed by chest-abdomen-pelvis computed tomography scan. FOLFIRINOX was delivered every 2 weeks as previously reported until progressive disease, major toxicity, or consolidation treatment by radiotherapy and/or surgery.. Seventy-seven patients were enrolled. They received a median number of five cycles (1-30). Grade 3-4 toxicities were neutropenia (11 %), nausea (9 %), diarrhea (6 %), fatigue (6 %), and anemia (1 %). Grade 2-3 sensory neuropathy occurred in 25 % of patients. No toxic death was reported and only 6 % of patients had to stop treatment because of toxicity. Disease control rate was 84 with 28 % of objective response (Response Evaluation Criteria in Solid Tumors). Seventy-five percent of patients received a consolidation therapy: 70 % had radiotherapy and 36 % underwent a surgical resection, with a curative intent. Within the whole cohort, 1-year OS rate was 77 % (95 % CI 65-86) and 1-year progression-free survival rate was 59 % (95 % CI 46-70).. First-line FOLFIRINOX for LAPA seems to be effective and have a manageable toxicity profile. These promising results will have to be confirmed in a phase III randomized trial.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Pancreatic Neoplasms; Prognosis; Prospective Studies; Survival Rate

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemoradiotherapy; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

For patients with metastatic pancreatic cancer, FOLFIRINOX (fluorouracil [5-FU], leucovorin [LV], irinotecan [IRI], and oxaliplatin) has shown improved survival rates compared with gemcitabine but with significant toxicity, particularly in patients with a high tumor burden. Because of reported response rates exceeding 30 %, the authors began to use a modified (m) FOLFIRINOX regimen for patients with advanced nonmetastatic disease aimed at downstaging for resection. This report describes their experience with mFOLFIRINOX and aggressive surgical resection.. Between January 2011 and August of 2013, 43 patients with borderline resectable pancreatic cancer (BRPC, n = 18) or locally advanced pancreatic cancer (LAPC, n = 25) were treated with mFOLFIRINOX (no bolus 5-FU, no LV, and decreased IRI). Radiation was used based on response and intended surgery. Charts were retrospectively reviewed to assess response, toxicities, and extent of resection when possible.. The most common grade 3/4 toxicity was diarrhea in six patients (14 %) with no grade 3/4 neutropenia or thrombocytopenia. Resection was attempted in 31 cases (72 %) and accomplished in 22 cases (51.1 %) including 11 of 25 LAPC cases (44 %). Vascular resection was required in 4 cases (18 %), with R0 resection in 86.4 % of the resections. Complications occurred in 6 cases (27 %), with no perioperative deaths. The median progression-free survival period was 18 months if the resection was achieved compared with 8 months if no resection was performed (p < 0.001).. Neoadjuvant mFOLFIRINOX is an effective, well-tolerated regimen for patients with advanced nonmetastatic pancreatic cancer. When mFOLFIRINOX is coupled with aggressive surgery, high resection rates are possible even when the initial imaging shows locally advanced disease. Although data are still maturing, resection appears to offer at least a progression-free survival advantage.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Prospective Studies; Retrospective Studies; Survival Rate

In this case report we detail the treatment of a patient with pancreatic ductal adenocarcinoma and a solitary liver metastasis who received nine cycles of FOLFIRINOX therapy with favourable response. The patient subsequently underwent synchronous distal pancreatectomy and hepatectomy with an R0 resection followed by three further cycles of FOLFIRINOX. At the last follow-up, 2 years from operation and 28 months from the diagnosis of metastatic pancreatic adenocarcinoma the patient remains disease free.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Neoadjuvant Therapy; Organoplatinum Compounds; Pancreatectomy; Pancreatic Neoplasms

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

On the basis of the ACCORD trial, FOLFIRINOX is effective in metastatic pancreatic adenocarcinoma (PDAC), making it a rational choice for locally advanced PDAC (LA). Aims of this study are to evaluate the accuracy of imaging in determining the resectability of PDAC and to determine the surgical and clinicopathologic outcomes of pancreatic resections after neoadjuvant FOLFIRINOX therapy.. Clinicopathologic data were retrospectively collected for surgical PDAC patients receiving neoadjuvant FOLFIRINOX or no neoadjuvant therapy between April 2011 and February 2014. Americas Hepato-Pancreato-Biliary Association/Society of Surgical Oncology/Society for Surgery of the Alimentary Tract consensus guidelines defined LA and borderline. Imaging was reviewed by a blinded senior pancreatic surgeon.. Of 188 patients undergoing resection for PDAC, 40 LA/borderline received FOLFIRINOX and 87 received no neoadjuvant therapy. FOLFIRINOX resulted in a significant decrease in tumor size, yet 19 patients were still classified as LA and 9 as borderline. Despite post-FOLFIRINOX imaging suggesting continued unresectability, 92% had an R0 resection. When compared with no neoadjuvant therapy, FOLFIRINOX resulted in significantly longer operative times (393 vs 300 minutes) and blood loss (600 vs 400 mL), but significantly lower operative morbidity (36% vs 63%) and no postoperative pancreatic fistulas. Length of stay (6 vs 7 days), readmissions (20% vs 30%), and mortality were equivalent (1% vs 0%). On final pathology, the FOLFIRINOX group had a significant decrease in lymph node positivity (35% vs 79%) and perineural invasion (72% vs 95%). Median follow-up was 11 months with a significant increase in overall survival with FOLFIRINOX.. After neoadjuvant FOLFIRINOX imaging no longer predicts unresectability. Traditional pathologic predictors of survival are improved, and morbidity is decreased in comparison to patients with clearly resectable cancers at the time of presentation.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemoradiotherapy; Disease-Free Survival; Female; Fluorouracil; Humans; Imaging, Three-Dimensional; Irinotecan; Leucovorin; Magnetic Resonance Imaging; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy; Retrospective Studies; Spiral Cone-Beam Computed Tomography; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Neuroendocrine; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Humans; Leucovorin; Male; Neoadjuvant Therapy; Organoplatinum Compounds; Pancreatic Neoplasms

To report the outcomes of surgical resection of borderline resectable (BL) and locally advanced (LA) 'unresectable' pancreatic cancer after neoadjuvant chemotherapy.. A review of a prospectively maintained database for pancreatic resections was undertaken to identify patients undergoing resection for BL and LA pancreatic cancer after neoadjuvant chemotherapy between January 2007 and December 2012. Clinicopathological, surgical and survival outcomes were analyzed.. A total of 45 patients with LA (n = 34) or BL cancer (n = 11) underwent surgery after a mean (± SD) of 7 ± 4 preoperative chemotherapy cycles. Ninety-day mortality was 6.7%, and overall morbidity was 33.3%. An R0 resection was achieved in 34 patients, and 4 patients showed a complete pathological response. Overall median postoperative survival was 17 months (21 after the start of neoadjuvant treatment). Overall and disease-free survival was 74.9 and 43.6% at 1 year and 21.2 and 10.3% at 3 years, respectively. In BL cancer patients, the 3-year survival was significantly higher compared to that of LA cancer patients (p = 0.02).. Curative intent resection in BL and LA cancer patients after neoadjuvant chemotherapy can be achieved with reasonable mortality and morbidity and an encouraging 3-year survival. After neoadjuvant therapy, resection provides a better overall survival for BL compared to LA cancer patients.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Databases, Factual; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; Organoplatinum Compounds; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy; Prognosis; Retrospective Studies; Risk Factors; Splenectomy; Treatment Outcome

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials as Topic; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms

In Europe, pancreatic cancer (PC) accounts for approximately 2.6% of all new cancer cases and is the fourth leading cause of cancer-related death. Despite substantial morbidity and mortality, limited data are available describing real-world treatment patterns and health care resource use in any European country. We evaluated PC-related treatment patterns and associated health care resource use among patients with metastatic PC in the United Kingdom and France.. One hundred three oncology specialists (53 in France and 50 in the United Kingdom) abstracted data from medical records of 400 patients whom they treated for metastatic PC. Eligible patients had a diagnosis of metastatic PC at age 18 years or older between January 1, 2009, and December 31, 2012; had ≥3 months of follow-up time beginning at metastatic diagnosis; and received at least 1 cancer-directed therapy for metastatic disease. Information on patient demographics, Eastern Cooperative Oncology Group performance status, location of primary tumor, presence of comorbidities, adverse events, and complications were collected. Data on cancer-directed treatments and supportive care measures were evaluated. All analyses were descriptive.. Approximately two thirds of patients were men, and median age at metastatic disease diagnosis was 62.2 years. Nearly all patients (97.3%) received chemotherapy to treat metastatic disease, 9.3% received radiation therapy, and 7.8% received a targeted therapy. Overall, the most frequently administered first-line regimens for metastatic disease were gemcitabine alone (46.0%), a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX; 20.1%); gemcitabine/capecitabine (10.8%); and gemcitabine/oxaliplatin (9.5%). Approximately 40% of patients in France and 15% of patients in the United Kingdom received second-line systemic therapy, whereas 20% of patients in France and 3.4% of patients in the United Kingdom received third-line systemic therapy for metastatic disease. Overall, 52.5% of patients experienced at least one complication of PC. More than two thirds of patients had ≥1 office visit unrelated to chemotherapy administration, 54.0% had ≥1 inpatient hospitalization, 36.8% had ≥1 emergency department visit, and 25.3% had ≥1 pain management clinic visit. A total of 26.5% of patients in France and 42.5% in the United Kingdom entered hospice or long-term care.. This study provides new, detailed information for patients with metastatic PC in real-world settings in 2 European countries. A small proportion of patients received >1 line of systemic therapy for metastatic disease, which is likely due to the aggressiveness of this disease and the lack of effective therapeutic options.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Deoxycytidine; Female; Fluorouracil; France; Gemcitabine; Health Resources; Hospice Care; Humans; Irinotecan; Leucovorin; Long-Term Care; Male; Middle Aged; Molecular Targeted Therapy; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Practice Patterns, Physicians'; Retreatment; Retrospective Studies; United Kingdom

Patients with metastasized carcinoma of the pancreas have a very poor prognosis, and long-term survival cannot be expected. This case report describes two patients with an initial diagnosis of metastatic pancreatic cancer, both with hepatic metastases and one with an additional peritoneal carcinomatosis. Initially, both patients were treated intravenously with the FOLFIRINOX chemotherapy regimen, consisting of 5-FU, folinic acid, irinotecan and oxaliplatin. Surprisingly, the FOLFIRINOX treatment resulted in complete resolution of the hepatic metastases in both patients, with no lesions detectable by computed tomography scan. Furthermore, treatment response included decreased diameter of the primary tumor in the tail of the pancreas and disappearance of the additional peritoneal carcinomatosis. Both patients were discussed by our multidisciplinary tumor board, which recommended surgical resections of the carcinoma. The R0 resection of the primary tumor was successful in both cases and, interestingly, the resected tissues showed no evidence of the hepatic metastases intraoperatively. In the first case, the patient received a postoperative 6-mo course of adjuvant chemotherapy with gemcitabine. In the second case, the patient continued to receive the FOLFIRINOX regimen for an additional 6 mo postoperatively. At 12 mo after the operation, a nonresectable retroperitoneal lymph node metastasis was detected in the first patient, whereas the second patient remained in complete remission at the time of this report (5 mo after the adjuvant therapy was discontinued). This case report is the first of its kind to describe two cases of hepatic metastatic pancreatic carcinoma that were resectable following treatment with FOLFIRINOX. Further studies are required to examine the role of FOLFIRINOX as a neoadjuvant treatment option in subgroups of patients with initially metastasized pancreatic carcinoma.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Camptothecin; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Magnetic Resonance Imaging; Male; Middle Aged; Multimodal Imaging; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Positron-Emission Tomography; Remission Induction; Tomography, X-Ray Computed; Treatment Outcome; Tumor Burden

Though necessary for improved outcomes, surgical resection is often limited in patients with locally advanced pancreatic cancers (LAPCs). We evaluated the efficacy of the approach adopted by our institution of using modified FOLFIRINOX chemotherapy followed by radiation with concurrent gemcitabine or capecitabine for patients with LAPCs, in an effort to enhance resectability while improving the toxicity profile compared with similar treatment regimens.. We included 29 consecutive patients with LAPC treated at our institution with the above approach in this review. We evaluated rates of resection, locol control, and survival outcomes in this cohort.. The median follow up for this series of patients was 15.2 months. Approximately half the patients were unresectable at presentation. After neoadjuvant therapy, 41.3% of all patients were able to undergo resection of their tumors and 83% achieved an R0 resection. One-year local control for the entire cohort was 85%; one-year progression-free and overall were 49.2% and 65.5%, respectively. High rates of metastatic disease were seen regardless of resectability. There were minimal toxicities in this cohort.. Neoadjuvant therapy with induction modified FOLFIRINOX and chemoradiation presents a well-tolerated, promising treatment approach for patients with LAPC. High rates of metastatic disease highlight the need to optimize systemic and targeted agents for pancreatic adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Chemoradiotherapy; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Pancreatic Neoplasms; Survival Analysis

Data on gastroenteropancreatic neuroendocrine neoplasms (NEN) G3 (well-differentiated neuroendocrine tumors (NET G3) and neuroendocrine carcinoma (NEC)) are limited. We retrospectively study patients with NET G3 and NEC from eight European centers. Data examined included clinical and pathological characteristics at diagnosis, therapies and outcomes. Two hundred and four patients were analyzed (37 NET G3 and 167 NEC). Median age was 64 (21-89) years. Tumor origin included pancreas (32%) and colon-rectum (27%). The primary tumor was resected in 82 (40%) patients. Metastatic disease was evident at diagnosis in 88% (liver metastases: 67%). Median Ki-67 index was 70% (30% in NET G3 and 80% in NEC; P<0.001). Median overall survival (OS) for all patients was 23 (95% CI: 18-28) months and significantly higher in NET G3 (99 vs 17 months in NEC; HR=8.3; P<0.001). Platinum-etoposide first line chemotherapy was administered in 113 (68%) NEC and 12 (32%) NET G3 patients. Disease control rate and progression free survival (PFS) were significantly higher in NEC compared to NET G3 (P<0.05), whereas OS was significantly longer in NET G3 (P=0.003). Second- and third-line therapies (mainly FOLFIRI and FOLFOX) were given in 79 and 39 of NEC patients; median PFS and OS were 3.0 and 7.6 months respectively after second-line and 2.5 and 6.2 months after third-line chemotherapy. In conclusion, NET G3 and NEC are characterized by significant differences in Ki-67 index and outcomes. While platinum-based chemotherapy is effective in NEC, it seems to have limited value in NET G3.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Etoposide; Female; Fluorouracil; Humans; Ki-67 Antigen; Leucovorin; Male; Middle Aged; Neuroendocrine Tumors; Organoplatinum Compounds; Pancreatic Neoplasms; Prognosis; Survival Analysis; Young Adult

The aim of this retrospective study was to investigate the relationship between UGT1A1 polymorphisms and toxicities in Chinese patients with pancreatic or biliary tract cancer receiving irinotecan-containing regimens as the second- or third-line chemotherapy.. A total of 36 patients with unresectable pancreatic cancer and 12 patients with unresectable biliary tract cancer were included. Approximately 33 patients were treated with FOLFIRI regimen, a chemotherapy regimen, where FOL stands for folinic acid, F for fluorouracil, and IRI for irinotecan (irinotecan 180 mg/m(2) at day 1, CF 200 mg/m(2) at day 1-2, 5-FU 400 mg/m(2) at day 1-2, followed by continuous infusion of 5-FU 600 mg/m(2) for 22 hours at day 1-2, every 2 weeks). The other 15 patients were treated with irinotecan monotherapy (180 mg/m(2), every 2 weeks). UGT1A1*6/*28 polymorphisms were detected by direct sequencing.. The frequencies of GG, GA, AA genotypes for UGT1A1*6 were 70.8% (n=34), 25.0% (n=12), and 4.2% (n=2), respectively. And those of TA6/TA6, TA6/TA7, TA7/TA7 for UGT1A1*28 were 79.2% (n=38), 18.8% (n=9), and 2.0% (n=1), respectively. A total of 22 patients (45.8%) had grade III-IV neutropenia, and six patients (12.5%) experienced grade III-IV diarrhea. The incidence of grade III-IV neutropenia in patients with UGT1A1*6 GA or AA genotype was 71.4%, which was significantly higher than that with GG genotype (35.3%, P=0.022). No relationship was found between grade III-IV neutropenia and UGT1A1*28 polymorphism. The statistical analysis between grade III-IV diarrhea and UGT1A1*6/*28 polymorphisms was not conducted in view of the limited number of patients.. In Chinese patients with pancreatic or biliary tract cancer administered irinotecan-containing regimens, those with UGT1A1*6 variant may have a high risk of severe neutropenia.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asian People; Biliary Tract Neoplasms; Camptothecin; Female; Fluorouracil; Genotype; Glucuronosyltransferase; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neutropenia; Pancreatic Neoplasms; Polymorphism, Genetic; Retrospective Studies; Severity of Illness Index; Young Adult

In view of increased response rates and survivals in patients with metastatic pancreatic adenocarcinoma (PAC) with FOLFIRINOX, many centers proposed this regimen as induction chemotherapy for borderline (BR) or locally advanced (LA) PAC. The aim of this study was to assess surgical and oncological outcomes of patients who underwent resection after induction FOLFIRINOX therapy.. We prospectively identified surgical consecutive BR or LA PAC patients after induction FOLFIRINOX in 20 observational French centers between November 2010 and December 2013. Two independent experts retrospectively evaluated initial CT scan for central review.. Eighty patients were included, 47 had BR and 33 had LA PAC. Median number of FOLFIRINOX cycles was 6 (range 1-30) and 65 % of patients received chemoradiation. The 30-day-mortality, major complications, and symptomatic pancreatic fistula rates were 2.5, 22.5, and 4 %, respectively. R0 resection was achieved in 84 %. After a median follow-up of 38.2 months since diagnosis, disease-free survival (DFS) was 17.16 months. The overall survival rates at 12 and 24 months were 92 and 81 %, respectively. A 26 % (n = 21) pathologic major response (pMR) rate was reached. In univariate and multivariate analysis, pMR was a prognostic factor for DFS (hazard ratio 0.33; P = 0.01 and hazard ratio 0.38; P = 0.035).. Resection after induction FOLFIRINOX is safe and associated with similar or better outcomes as upfront surgery in patients with PAC. A pMR was observed in 26 % of cases and was prognostic of DFS. This therapeutic design should be investigated in prospective studies.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Chemoradiotherapy; Female; Fluorouracil; Follow-Up Studies; Humans; Induction Chemotherapy; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Prospective Studies; Retrospective Studies; Survival Rate

Pancreatic cancer is the fourth leading cause of cancer related death with median survival ranging from 3 to 6 months for metastatic disease. Palliative chemotherapy has been the backbone of treatment in advanced stage and has evolved over time. Data pertaining to the disease are scarce from our part of the world where treatment poses a significant challenge due to lack of resources.. A retrospective chart review was performed for all patients presenting with stage IV pancreatic carcinoma at a tertiary care hospital in Karachi, Pakistan between January 2008 and December 2012. Data were collected using a pre-designed, coded questionnaire looking at patient characteristics, treatment given and outcome.. 101 patients were found to be eligible. Mean age was 56.7 ± 12.8 years, the male to female ratio was 2:1 and most patients had a good performance status. More than half of the tumors were located in the head (57%, n=58) and almost all were adenocarcinomas (95%, n=96). Some 58% (n=59) received first line chemotherapy of which 49% (n=29) received gemcitabine-based regimens and 39% (n=23) received FOLFIRINOX. The median progression free survival for gemcitabine based treatment was 2.9 months (IQR=1.6-5.6) as opposed to 7.3 months (IQR=4.5-9.2) for FOLFIRINOX (P=0.02). Median overall survival was 4.9 months (IQR=2.3-9.5) for first line gemcitabine based treatment and 10.5 months (IQR=7.0-13.2) for first line FOLFIRINOX therapy (P=0.002). Patients on FOLFIRINOX had better survival across all subgroups. Inpatient admissions and dose reductions were more frequent with FOLFIRINOX but the difference between the two regimens was not statistically significant. FOLFIRINOX could be successfully administered as outpatient therapy to a number of patients.. FOLFIRINOX remains a suitable first line option in patients with metastatic pancreatic cancer with good performance status even in a resource-poor country where diagnostic and supportive care facilities may be less than optimal and cost is a limitation.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cross-Sectional Studies; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pakistan; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Survival Rate

FOLFIRINOX is an active but relatively toxic chemotherapeutic regimen for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). The increased frequency of responding tumors shift interest to neoadjuvant approaches. We report our institutional experience with FOLFIRINOX for therapy-naïve patients with locally advanced and initially unresectable PDAC.. All patients with unresectable locally advanced PDAC who underwent treatment with FOLFIRINOX at a single center between 2011 and 2014 were identified and evaluated retrospectively regarding chemotherapy response, toxicity, conversion to resectability, and survival. Resectability, response to chemotherapy, and postoperative complications were reported according to NCCN-guidelines, RECIST-criteria, and Clavien-Dindo-classification, respectively.. Overall, 14 patients received FOLFIRINOX as first-line therapy for locally advanced and unresectable PDAC. Fifty-seven percent of the patients had severe tumor-related comorbidities at the time of diagnosis, and in 86 %, dose reduction due to toxicity was necessary during a median of seven cycles. Nevertheless, only one patient had progressive disease during FOLFIRINOX, whereas the others experienced stable disease (n = 6) or partial remission (n = 6; no restaging in one patient). Oncological tumor resection was possible in 4 patients (29 % of all patients) with no postoperative mortality and only one grade 2 surgical complication. After a median follow-up of 10 months, 4 of the 14 patients were still in remission, 5 were alive with stable disease under ongoing systemic chemotherapy, and 5 died tumor-related.. FOLFIRINOX is a powerful first-line regimen that leads to resectability in a substantial portion of patients with initially unresectable pancreatic cancer.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Prognosis; Prospective Studies; Retrospective Studies; Survival Rate

The combination of 5-fluorouracil (5-FU), irinotecan and oxaliplatin (FOLFIRINOX) is considered the first-line chemotherapy for fit patients with advanced pancreatic ductal adenocarcinoma (PDAC) but carries an unfavourable adverse event (AE) profile. We retrospectively evaluated the tolerability and efficacy of a modified FOLFIRINOX (mFOLFIRINOX) regimen: intravenous oxaliplatin 85 mg/m2, irinotecan 135 mg/m2, folinic acid 400 mg/m2 and 5-FU infusion 2,400 mg/m2 over 46 h, with routine subcutaneous filgrastim on a 14-day cycle.. Records of 18 patients with advanced PDAC who received treatment with mFOLFIRINOX were reviewed. Imaging of measurable disease was assessed for response, and survival was measured from the date of commencing chemotherapy to disease progression and/or death.. Grade 3 or 4 AEs (n; %) included vomiting (5; 28), nausea (4; 22), diarrhoea (3; 17) and non-neutropaenic fever (3; 17). For patients with stage IV disease, 12/15 (80%) achieved at least stable disease as the best radiological response, with 7/15 (47%) objective responses. In this subgroup, median overall and progression-free survival were 9.3 months (95% CI 8.3-10.4) and 7.2 months (95% CI 4.7-9.6), respectively.. Compared to full-dose FOLFIRINOX, our modified regimen resulted in lower haematological but only marginally improved non-haematological toxicity rates, with comparable efficacy outcomes. Prospective studies are required to validate these findings.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies

Recent guidelines have adopted an incidence of febrile neutropenia (FN) threshold of 20% for the use of prophylactic granulocyte colony-stimulating factor (G-CSF). In a Japanese phase II study of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) for Japanese patients with advanced pancreatic cancer, the incidence of FN and severe neutropenia were 24.7% and 77.8%, respectively, without G-CSF prophylaxis. The aim of this retrospective study was to investigate the incidence of FN or severe neutropenia induced by full-dose FOLFIRINOX administration with G-CSF prophylaxis during the first cycle of treatment.. Patients with advanced pancreatic cancer who received FOLFIRINOX with G-CSF prophylaxis during the first cycle of treatment from January 2014 to August 2014 were investigated and the frequency of adverse events during the first cycle was measured.. Among seven patients who received FOLFIRINOX, six patients met the eligibility criteria. The patient characteristics were as follows: median age (range), 57 (50-66); men/women, 3/3; performance status 0/1, 2/4. Grade 3/4 hematological adverse events were as follows: leukopenia in 33% of the patients, neutropenia in 33% of the patients, thrombocytopenia in 33% of the patients and FN in 17% of the patients. One patient was heterozygous for the UGT1A1*6 and UGT1A1*28 polymorphisms and experienced FN. Grade3/4 non-hematological adverse events were as follows: anorexia in 33% of the cases and nausea in 50% of the cases.. Although the present study was retrospective and small, the simultaneous administration of G-CSF might be effective for the prevention of severe neutropenia and FN in patients treated with FOLFIRINOX.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Incidence; Leucovorin; Male; Middle Aged; Neutropenia; Pancreatic Neoplasms; Retrospective Studies

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Drug Combinations; Erlotinib Hydrochloride; Fluorouracil; Gemcitabine; Humans; Leucovorin; Organoplatinum Compounds; Oxonic Acid; Pancreatic Neoplasms; Tegafur

The SCAN pancreatic cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy for pancreatic adenocarcinoma in Singapore.. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting.. Five international guidelines were evaluated- those developed by the National Cancer Comprehensive Network (2014), the European Society of Medical Oncology (2012), Cancer Care Ontario (2013), the Japan Pancreas Society (2013) and the British Society of Gastroenterology, Pancreatic Society of Great Britain and Ireland, and the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (2005). Recommendations on the management of resected, borderline resectable, locally advanced and metastatic pancreatic adenocarcinoma were developed.. These adapted guidelines form the SCAN Guidelines for systemic therapy for pancreatic adenocarcinoma in Singapore.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma, Pancreatic Ductal; Cetuximab; Chemoradiotherapy, Adjuvant; Chemotherapy, Adjuvant; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Silicates; Singapore; Titanium

This report presents a unique case of oxaliplatin-induced neurotoxicity featuring acute, recurrent, self-limiting dysarthria following multiple subsequent infusions of oxaliplatin. A 65-year-old man started chemotherapy for metastatic pancreatic adenocarcinoma with oxaliplatin-irinotecan-leucovorin-5-fluorouracil (FOLFIRINOX). During the first and subsequent infusions of oxaliplatin, the patient developed episodes of dysarthria that lasted between 2 and 4 h after oxaliplatin infusions, followed by their complete and uneventful resolution. A thorough neurological examination showed no new neurologic deficits except for very fine tongue fasciculations. Recognizing this self-limiting toxic effect of oxaliplatin is important in order to avoid dose reductions that may affect clinical outcomes.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Drug Administration Schedule; Dysarthria; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Neurotoxicity Syndromes; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Recurrence; Time Factors

FOLFIRINOX is a highly active regimen for the treatment of patients with unresectable pancreatic cancer. However, treatment with FOLFIRINOX is associated with relevant toxicity and predictors for response to therapy are warranted. We retrospectively analyzed 49 patients with unresectable pancreatic cancer treated with FOLFIRINOX in order to evaluate a possible predictive role of clinical parameters and tumor characteristics for response to chemotherapy. Tumor samples were characterized histopathologically before treatment and expression of p53 and Ki67 was analyzed using automated immunohistochemistry. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. The overall objective response rate was 55.1%, the disease control rate was 70.6%. Female gender was associated with a significantly higher disease control rate of 91.7 compared to 48.0% in male patients (p=0.001) which reached 100% in female patients when primarily treated compared to treatment after surgical resection and relapse (77.8%, p=0.057). For all patients median PFS was 3.5 months (95% CI, 2.7-4.3 months) and median OS was 13 months (95% CI, 9.4-16.6 months). Female patients showed a tendency towards a longer median PFS (5.0 months, 95% CI, 3.6-6.4 months) compared to males (3.0 months, 95% CI, 2.4-3.6 months) (p=0.099). Serum levels of CA19.9 and CEA were significantly higher in female patients compared to male patients (p=0.037, p=0.05). Tumors of patients with response to FOLFIRINOX showed a higher expression level of p53 and Ki67 as well as higher serum levels of CA19.9 compared to non-responders, which was statistically not significant. Our study indicates that female gender is a positive predictor for therapy response to FOLFIRINOX in patients with unresectable pancreatic cancer. Female gender in turn was associated with increased levels of tumor markers CEA and CA19.9 and patients with higher serum levels of CA19.9 were more responsive to FOLFIRINOX.

Topics: Adult; Aged; Antigens, Tumor-Associated, Carbohydrate; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Sex Characteristics; Treatment Outcome

Development of a second primary malignancy after an index esophageal cancer is a rare event, primarily due to short survival of patients with esophageal cancer. However, the number of long-term esophageal cancer survivors has been increasing due to advances in early detection and therapy.. We report herein a case of pancreatic adenocarcinoma that developed three years after a successfully treated early-stage adenocarcinoma of the esophagus. A 70-year-old Caucasian male presented with vague complaints of nausea, vomiting and abdominal distention, with subsequent development of jaundice. A computed tomography scan of abdomen revealed a 2.9 cm soft tissue mass in the head of the pancreas and the patient underwent a Whipple's procedure, with pathology confirming the diagnosis of pancreatic adenocarcinoma. Three years previously, the patient was successfully treated for adenocarcinoma of the esophagus via minimally invasive esophagogastrectomy. Despite chemoradiotherapy for localized disease and subsequent systemic chemotherapy for metastatic pancreatic cancer, the patient eventually succumbed to his illness.. We discuss the association between esophageal cancer and subsequent second malignancies, along with implications for surveillance and therapy.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Cholangitis; Combined Modality Therapy; Esophageal Neoplasms; Esophagectomy; Fatal Outcome; Fluorouracil; Gastrectomy; Humans; Irinotecan; Leucovorin; Lymphatic Metastasis; Male; Neoplasms, Second Primary; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Pancreaticoduodenectomy; Sepsis

Pancreatic acinar cell carcinoma (ACC) is a rare, aggressive variant of pancreatic ductal adenocarcinoma. Surgery is the only curative treatment option and protocols for palliative chemotherapies in this context are not standardized yet. We reported a 63-year-old white male patient who had painless jaundice, weight loss, elevated bilirubin, and a mass of the pancreatic head as well as liver metastasis. Core biopsy revealed the diagnosis of ACC. Therapy with FOLFIRINOX resulted in a significant decrease of the primary tumor and regressiveness of a liver metastasis after chemotherapy. Our report suggests that pancreatic ACC treated by FOLFIRINOX is well tolerated and might be superior to other single chemotherapies in this rare tumor disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Acinar Cell; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

Folfirinox has shown a benefit in terms of survival and quality of life in first line treatment of metastatic pancreatic cancer. However, efficacy of second line chemotherapy after folfirinox is still limited. Gemcitabine plus Nab-paclitaxel have been recently validated as first line treatment with an increased overall survival compared to gemcitabine. This combination has never been studied as second-line after folfirinox.. A metastatic pancreatic cancer was diagnosed in a 60-year-old patient with a performance status of 0. After 10 cycles of folfirinox, and an initial objective response, we objectively noted progressive disease according to the RECIST 1.1 criteria together with an increased carbohydrate antigen 19-9. The multidisciplinary team decided to use gemcitabine plus Nab-paclitaxel as second line palliative chemotherapy. After 2 months, we obtained an objective response. After 6 months, this response was maintained with an acceptable tolerability.. Gemcitabine plus Nab-paclitaxel, as second line palliative chemotherapy, after failure of folfirinox, could be a good strategy for patients with a performance status of 0 and 1. Obviously, this data has to be confirmed in larger patients series and in future comparative clinical studies.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Camptothecin; Carcinoma, Pancreatic Ductal; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Palliative Care; Pancreatic Neoplasms; Treatment Failure

Borderline resectable pancreatic cancer is best treated by multimodality therapy. FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin) tripled the response rate and significantly increased median survival for patients with advanced pancreatic cancer and shows promise for neoadjuvant use. Toxicity concerns prompted a careful analysis of our initial FOLFIRINOX experience.. All patients diagnosed with borderline resectable, biopsy-proven pancreatic adenocarcinoma treated with neoadjuvant FOLFIRINOX between July 2010 and December 2012 were reviewed. Primary outcome was surgical resectability. Secondary outcomes were treatment-related toxicities and survival.. FOLFIRINOX followed by gemcitabine- or capecitabine-based chemoradiation was initiated in 18 patients. The most common grade 3 or 4 toxicities during chemotherapy were gastrointestinal, including nausea/emesis (n = 5), weight loss (n = 3) and diarrhea (n = 2), and hematologic (n = 2; neutropenia); five patients (36%) required a total of six admissions. Neoadjuvant therapy was completed in 15 of 18 patients (83%), and 12 (67%) underwent pancreatectomy (10 Whipple, 2 total pancreatectomy) including portal vein resection/reconstruction in 10 (83%). Disease progression precluded surgery in 6 of the 18 patients (33%). All 12 resected patients had negative (R0) margins. Only 2 of 12 (17%) were node positive (median node count: 26.5 [range: 15-39]). There were no in-hospital or 30-day mortalities and no clinical pancreatic leaks or reoperations. Of the 12 patients who completed all intended therapy, 7 (58.3%) are alive, including 5 who have no evidence of disease (median months from diagnosis: 22 months [range: 18-35 months). The six patients who did not complete all planned therapy are deceased (months from diagnosis: 6.9-17.5 months).. FOLFIRINOX followed by chemoradiation as neoadjuvant therapy for borderline resectable pancreatic adenocarcinoma is safe, and our initial experience suggests favorable resection rates compared with previous reports in this high-risk patient population.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

In the field of treatment of pancreatic cancer, there has been significant progress lately. After the ACCORD/PRODIGE-4 study, 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) became the standard combination for first-line chemotherapy. This led also to its use in the neoadjuvant setting in borderline resectable tumors, or locally advanced unresectable disease, improving the resectability and survival. The major disadvantage of this therapy is increased toxicity, limiting its use to young patients with no comorbidities. This arises the need to make dose reductions in clinical practice, with a possible drawback in effectiveness. The authors summarize three Abstracts (#256, #275, #305) presented at the 2014 ASCO Gastrointestinal Cancers Symposium which were focused in the use of modified forms of FOLFIRINOX, their toxicity profile and effectiveness. Reduced toxicity was observed, without affecting the effectiveness of the combination.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Dose-Response Relationship, Drug; Fluorouracil; Humans; Leucovorin; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Survival Rate; Treatment Outcome

Pancreatic adenocarcinoma is the 10th most common malignancy in the United States but is responsible for the 4th most cancer related deaths. This disease can only be potentially cured through early discovery and complete surgical resection. Unfortunately, nearly half of patients have metastatic spread at presentation. Combination chemotherapy with FOLFIRINOX or gemcitabine with nab-paclitaxel can prolong survival in selected patients, but at the cost of significant toxicity. In the 2014 ASCO Gastrointestinal Cancers Symposium, several studies were presented that focus on the management of metastatic pancreatic cancer. A phase II trial by Le et al. (Abstract #177) found that the addition of CRS-207, a strain of Listeria modified to stimulate an anti-tumor immune response, improves survival in patients being treated with GVAX. Goldstein et al. (Abstract #178) presented a post-hoc survival analysis for the phase III MPACT trial that shows the addition of nab-paclitaxel to gemcitabine produces a persistent survival benefit. Ramanathan et al. (Abstract #224) demonstrated that, with appropriate dose adjustments and delays, induction nab-paclitaxel and gemcitabine followed by mFOLFIRINOX consolidation is a feasible treatment option for metastatic pancreatic cancer. Despite these advances, it is imperative that we continue to work towards developing additional treatment options that are better tolerated and further prolong survival for these patients. This highlight article focuses on the first-line therapy of metastatic pancreatic adenocarcinoma.

Topics: Adenocarcinoma; Albumins; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Drug Therapy; Drug Therapy, Combination; Fluorouracil; Gemcitabine; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Treatment Outcome

Schwartz Center Rounds are monthly multidisciplinary meetings where caregivers reflect on important psychosocial issues that they, along with patients and their families, face and gain insight and support from fellow staff members, with the goal of advancing compassionate health care, supporting caregivers, and fostering the connection between a clinician and his or her patients. This Schwartz Round focused on boundaries and the particular privileges and pressures of caring for a member of the staff. The article explores the tension between professional courtesy and empathic engagement. Major transitions can include the intrinsic fear of abandonment. Being "connected" is an important aspect of the patient-caregiver relationship. Patient-centered care requires that we balance clinical acumen and medical technology with humanism throughout the different phases of a patient's experience with a life-threatening illness.

Topics: Camptothecin; Caregivers; Diphosphonates; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Nurses; Organoplatinum Compounds; Oxaliplatin; Pain; Pain Management; Pancreatic Neoplasms; Patient-Centered Care; Physician-Patient Relations

Worldwide, pancreatic cancer (PC) ranks 13th in cancer incidence, but eighth as a cause of cancer death. For more than a decade, the reference regimen for palliative treatment of PC has been gemcitabine. In 2011, a randomised trial published by the PRODRIGE Intergroup showed an increase in median overall survival from 6.8 to 11.1 months in patients treated with FOLFIRINOX as compared with gemcitabine.. A total of 16 patients treated with FOLFIRINOX as first-line therapy for inoperable PC were included for this retrospective study. FOLFIRINOX was administered unmodified according to the PRODRIGE trial, and up to 12 cycles were planned with a computed tomography (CT) for every fourth cycle.. Eleven patients completing at least four cycles of chemotherapy and therefore evaluable for response were assessed by review of CT. Partial response (PR) was shown after four cycles in four patients, whereas seven patients had stable disease, which resulted in an objective response rate of 36%. After eight cycles, one additional patient obtained a PR. No complete responders or patients with progressive disease were recorded. Toxicity was assessed by review of medical records with respect to toxic effects requiring interruption of therapy, admission of the patient or prolonged admission.. Toxicity was shown to be a problem only during the first five cycles, and no patients were admitted to hospital due to toxicity after having received more than five cycles. The six-month-survival was 81%.. not relevant.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Denmark; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Vitamin B Complex

FOLFOX second-line treatment seems to be a validated option for patients with pancreatic cancer (PC) progressing after gemcitabine chemotherapy. However, other therapeutics strategy has developed in first-line therapy, as the FIRGEM phase II study that evaluated gemcitabine alone versus FOLFIRI.3 alternating with gemcitabine every two months. The present study assessed the efficacy and safety of FOLFOX after failure of the first-line therapy used in the FIRGEM study.. In this prospective observational cohort study, we analysed all consecutive patients who received second-line chemotherapy with FOLFOX among 98 patients with metastatic PC included in the FIRGEM study. Progression-free survival (PFS) and overall survival (OS) were estimated from the start of second-line chemotherapy using the Kaplan-Meier method.. Among 46 patients who received second-line chemotherapy, 27 patients (male, 55%; median age, 61 years; performance status (PS) 0-1, 44%) were treated with FOLFOX after progression to first-line gemcitabine alone (n = 20) or FOLFIRI.3 alternating with gemcitabine (n = 7). Grade 3 toxicity was observed in 33% of patients (no grade 4 toxicity). At the end of follow-up, all patients had progressed and 25 had died. No objective response was observed, and disease control rate was 36%. Median PFS and OS were 1.7 and 4.3 months, respectively. In multivariate analysis, PS was the only independent prognostic factor. For patients PS 0-1 versus 2-3, median PFS was 3.0 versus 1.2 months (log rank, p = 0.002), and median OS was 5.9 versus 2.6 months (log rank, p = 0.001).. This study suggests that FOLFOX second-line therapy offered interesting efficacy results with an acceptable toxicity profile in metastatic PC patients with a good PS.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Pancreatic Neoplasms; Prognosis; Treatment Outcome

Inoperable pancreatic ductal adenocarcinoma is known to have an extremely poor prognosis. Although rare, there are some patients who have unexpected long-term survival, but the reason is not yet clear.. A total of 482 inoperable pancreatic ductal adenocarcinoma of 1602 patients diagnosed at Severance Hospital between 2002 and 2009 were evaluated, who were selected statistically with a retrospective cohort study. They were divided into locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC). Short-term survivors (SS group) were defined as patients who survived less than 9 months with LAPC and 6 months with MPC. Patients who survived 3 times longer than the SS group were classified as long-term survivors (LS group). Predictive factors of long-survival were identified by comparing the 2 groups, and effects of these factors on survival were investigated statistically.. In multivariate analysis, better performance status and lower CA19-9 were related to overall survival in LAPC. In MPC, younger age, better performance status, peritoneal metastasis, higher serum albumin, lower CA19-9, and CA19-9 variation were related to overall survival.. These parameters related to long-term survivors of advanced pancreatic cancer can be useful for the expectation of survival. In the near future, conjunction of these clinical factors and novel molecular biologic characteristics of individual patients can be used for the personalized therapy.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Carcinoma, Pancreatic Ductal; Chemoradiotherapy; Combined Modality Therapy; Deoxycytidine; Disease-Free Survival; Erlotinib Hydrochloride; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Pancreatic Neoplasms; Peritoneal Neoplasms; Prognosis; Proportional Hazards Models; Quinazolines; Republic of Korea; Retrospective Studies; Survivors; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Combined Modality Therapy; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Treatment Outcome

Although standard of care for treatment of pancreatic cancer is established in the first line setting, there is limited data to support standard for second line chemotherapy for advanced pancreatic cancer. This is starting to change, as new studies have shown positive effect on overall survival in the second line setting. At the recent ASCO Annual Meeting 2014, several new second-line chemotherapy regimens were presented, including ruxolitinib with capecitabine, oxaliplatin with 5-FU/leucovorin, metformin plus paclitaxel and gemcitabine plus nab-paclitaxel. These abstracts provide exciting new directions for the second line treatment of advanced pancreatic cancer that has been refractory to both gemcitabine-based regimens as well as non-gemcitabine based regimens.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Docetaxel; Drug Resistance, Neoplasm; Fluorouracil; Gemcitabine; Humans; Leucovorin; Metformin; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Survival Analysis; Taxoids; Treatment Outcome

Pancreatic ductal adenocarcinoma (PDAC) is the third most common tumor of the gastrointestinal tract. At the time of diagnosis, the majority of PDACs shows already metastasis and does not qualify for curative surgery. Therefore, palliative chemotherapy has a very high priority, but recommendations after failure of first-line chemotherapies are quite limited. The aim of our analysis was to evaluate the efficacy of different second-line treatments after pretreatment with gemcitabine (57.5%), gemcitabine + erlotinib (25%), and platinum-based chemotherapy (17.5%). We included all patients with advanced PDAC treated with second-line chemotherapy in our department between 2005 and 2012. A total of 22 patients were treated with XELOX, 8 patients with FOLFOX, 6 patients with gemcitabine (+/- erlotinib) and 4 patients with FOLFIRI. On average, the patients received 4.2 cycles (standard deviation [SD] SD: 3.5) over a period of 2.5 months (SD: 2.6). The median overall survival (OS) for all patients was 5.4 months, progression-free survival was 3.5 months, and a tumor control was achieved in 21% of all cases. Toxicity profile was acceptable between the second-line chemotherapies and there was no significant difference in the other investigated end points. Interestingly, there was also no effect of the first-line treatment and their duration for the OS of the second-line therapy. According to our findings, second-line chemotherapies in advanced PDAC are beneficial and should be offered to patients, but we did not detect any superiority of a specific drug combination. More prospective, randomized and larger studies are necessary to evaluate new strategies for second-line chemotherapies.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Carcinoma, Pancreatic Ductal; Deoxycytidine; Drug Administration Schedule; Erlotinib Hydrochloride; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaloacetates; Palliative Care; Pancreatic Neoplasms; Quinazolines; Retrospective Studies; Survival Analysis; Treatment Outcome

Pancreatic ductal adenocarcinoma (PDA) has a very poor prognosis. Treatment with FOLFIRINOX has been shown to improve outcomes, but can be associated with significant toxicity.. A retrospective review was performed of all patients with locally advanced or metastatic PDA treated with FOLFIRINOX at the Royal Marsden between November 2010 and November 2013. Efficacy, tolerability, and potential prognostic factors were evaluated.. Twenty-seven patients with metastatic PDA and 22 patients with locally advanced PDA were treated with FOLFIRINOX. Patients received a median of 9 cycles (range, 1-26) of FOLFIRINOX. The overall response rate was 41% (20 patients), and a further 17 patients (35%) had stable disease. Thirty-five patients (71%) received FOLFIRINOX in the first-line setting, with a median progression-free survival and overall survival, respectively, of 12.9 months and 18.4 months for patients with locally advanced disease; and 8.4 months and 12.2 months for patients with metastatic disease. The most frequently occurring Grade 3/4 toxicities were neutropenia (29%), fatigue (18%), febrile neutropenia (14%), thromboembolism (12%), and thrombocytopenia (10%). In a univariate analysis, reduction in CA 19-9 of >50% (P < .001), normalization of CA19-9 (P < .001), surgery after FOLFIRINOX (P = .004), and use of prophylactic pegfilgrastim (P = .005) were prognostic for overall survival.. The efficacy and tolerability of FOLFIRINOX for PDA at our institution is similar to that reported in clinical trials. Careful selection of patients and monitoring of response (according to CA19-9) and toxicities can help maximize advantage in this patient population.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Survival Rate

5-Fluorouracile, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) has not been extensively used in the neoadjuvant setting because of concerns with safety and toxicity. We evaluated our institutional experience with neoadjuvant FOLFIRINOX in borderline resectable pancreatic adenocarcinoma (BRPAC). The primary endpoints were completion of therapy to surgery and negative resection margin (R0) rate. Patients with BRPAC treated with neoadjuvant FOLFIRINOX were retrospectively analyzed. Between August 2011 and September 2013, 20 patients with BRPAC treated with neoadjuvant FOLFIRINOX were identified. Most patients (88.8%) completed FOLFIRINOX therapy and underwent resection. Abutment of venous structures was identified in 13 cases (72.2%), while short segment portal vein encasement in 3 cases (16.6%) with concomitant arterial involvement in 3 cases (16.6%). Isolated superior mesenteric artery abutment was identified in 2 cases (11.2%). Patients received a median of 4 cycles of FOLFIRINOX. There was 1 case of progression. Vascular resection was performed in 9 cases (52.9%). Preoperative radiation therapy was used in 8 patients (44%). All patients underwent margin negative resection (R0). Histopathologic treatment response was evident in 10 cases (58.8%). Neoadjuvant FOLFIRINOX was generally safe and the expected toxicity did not prevent surgery allowing for a high rate of R0 resection.

Topics: Adenocarcinoma; Aged; Female; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Pancreatic Neoplasms; Retrospective Studies; Treatment Outcome; Vitamin B Complex

To compare the efficacy of full-dose gemcitabine-based concurrent chemoradiotherapy (FG-CCRT) and conventional 5-fluorouracil CCRT (5FU-CCRT) for locally advanced pancreatic cancer (LAPC).. 109 LAPC cases treated with FG-CCRT (n = 89) or 5FU-CCRT (n = 20) were reviewed retrospectively. The FG-CCRT group was composed of a full-dose gemcitabine monotherapy (1,000 mg/m(2)) arm and a combination therapy with cisplatin (70 mg/m(2)) arm. The 5FU-CCRT group used a radiosensitizing dose of 5-FU (500 mg/m(2)) plus leucovorin (20 mg/m(2)). Concurrent radiotherapy was targeted at the tumor with a 5-mm margin without lymph node irradiation.. Objective response rate (ORR) and disease control rate (DCR) was significantly higher in the FG-CCRT group (ORR: 32.6 vs. 5%, p = 0.013; DCR: 79.8 vs. 50.0%, p = 0.006). FG-CCRT showed remarkable superiority to 5FU-CCRT for suppressing distant metastasis (18.0 vs. 45.0%, p = 0.017). Neutropenia (34.8 vs. 10%, p = 0.032) and thrombocytopenia (21.3 vs. 0.0%, p = 0.021) were more frequent in the FG-CCRT group as originally expected. When dividing the FG-CCRT group to gemcitabine monotherapy (GEM) and gemcitabine plus cisplatin, toxicities of the GEM subgroup were not different than those of the 5FU-CCRT group.. FG-CCRT, especially full-dose gemcitabine monotherapy-based CCRT was more effective for the initial control of LAPC than 5FU-CCRT, and also relatively safe.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Cisplatin; Combined Modality Therapy; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies

The purpose of the present study was to evaluate the efficacy and the tolerability of modified FOLFIRINOX (mFOLFIRINOX), administered as a second-line or beyond second-line chemotherapy drug in patients with locally advanced or metastatic pancreatic cancer (PC) after the failure of both gemcitabine (GEM) and S-1.. Treatment of mFOLFIRINOX consisted of oxaliplatin, leucovorin, irinotecan and fluorouracil; all the anticancer drugs were reduced to an 80% dose of the original regimen of FOLFIRINOX, repeated every three weeks. The primary end point was response rate (RR) and disease control rate (DCR). The secondary end points were overall survival (OS), progression-free survival (PFS), total survival time (TST), safety, and tolerability.. Between November 2011 and November 2013, 13 enrolled patients were treated with mFOLFIRINOX, with a median of 5 courses (range 1-33). The RR and DCR were 30.8% and 69.2%, respectively. The median OS, PFS, and TST were 176, 137, and 779 days, respectively. The 6-month and the 1-year OS was 46.1% and 23.1%, respectively. Major grade 3 or grade 4 adverse events included neutropenia (38.5%), and anorexia (25.0%).. mFOLFIRINOX was moderately effective in locally advanced or metastatic PC patients after the failure of both GEM and S-1.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Disease Progression; Disease-Free Survival; Drug Combinations; Drug Resistance, Neoplasm; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Japan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Pancreatic Neoplasms; Tegafur; Time Factors; Treatment Outcome

Pancreatic cancer still remains a significant, unresolved therapeutic challenge and is the most lethal type of gastrointestinal cancer with a 5-year survival rate of 5%. Adjuvant chemotherapy remains to be gemcitabine alone, though fluorouracil offers the same survival and role of radiation remains controversial. Nevertheless, only a few patients survive for at least 5 years after R0 resection and adjuvant therapy. Borderline resectable pancreatic cancer remains an area that requires multi-disciplinary approach. Neo-adjuvant therapy very likely plays a role to downstage to a resectable state in these subgroup patients. There are different treatment approaches to locally advanced pancreatic cancer management, including single or multi-agent chemotherapy, chemotherapy followed by chemoradiation, or immediate concurrent chemoradiation. Most patients need palliative treatment. Once pancreatic cancer becomes metastatic, it is uniformly fatal with an overall survival of generally 6 months from time of diagnosis. Gemcitabine has been the standard since 1997. FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, leucovorin) has already shown superiority over gemcitabine in both progression-free survival and overall survival, but this regimen is suitable only for selected patients in ECOG performance status 0-1. FOLFIRINOX has already trickled down to the clinic in various modifications and in different patient groups, both locally advanced and metastatic. Many targeted agents, including bevacizumab, cetuximab showed negative results, except mild benefit with addition of erlotinib with gemcitabine, which was not considered clinically significant. There is no consensus regarding treatment in the second-line setting. It will be true to say that there was a real medical breakthrough with regards to improving the prognosis of pancreatic cancer as of 2013 with the results of MPACT study. In this study, patients who received nab-paclitaxel plus gemcitabine lived a median of 8.5 months, compared with 6.7 months for those who received gemcitabine alone. At the end of one year, 35% of those getting nab-paclitaxel were alive, compared with 22% of those getting only gemcitabine. After two years, the figures were 9% for those getting nab-paclitaxel and 4% for those who received gemcitabine.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Models, Biological; Neoplasm Metastasis; Organoplatinum Compounds; Pancreatectomy; Pancreatic Neoplasms

The objective of our retrospective institutional experience is to report the overall response rate, R0 resection rate, progression-free survival, and safety/toxicity of neoadjuvant FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, irinotecan, and leucovorin) and chemoradiation in patients with locally advanced pancreatic cancer (LAPC). Patients with LAPC treated with FOLFIRINOX were identified via the Massachusetts General Hospital Cancer Center pharmacy database. Demographic information, clinical characteristics, and safety/tolerability data were compiled. Formal radiographic review was performed to determine overall response rates (ORRs). Twenty-two patients with LAPC began treatment with FOLFIRINOX between July 2010 and February 2012. The ORR was 27.3%, and the median progression-free survival was 11.7 months. Five of 22 patients were able to undergo R0 resections following neoadjuvant FOLFIRINOX and chemoradiation. Three of the five patients have experienced distant recurrence within 5 months. Thirty-two percent of patients required at least one emergency department visit or hospitalization while being treated with FOLFIRINOX. FOLFIRINOX possesses substantial activity in patients with LAPC. The use of FOLFIRINOX was associated with conversion to resectability in >20% of patients. However, the recurrences following R0 resection in three of five patients and the toxicities observed with the use of this regimen raise important questions about how to best treat patients with LAPC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Massachusetts; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

Anaplastic pancreatic carcinoma is a rare tumor with poor survival. Data on surgical and medical therapies are currently limited to case reports and case series with small numbers.. We describe a case of multifocal anaplastic pancreatic carcinoma treated with neoadjuvant FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil and leucovorin) and total pancreatectomy with subsequent patient disease-free survival currently at 12 months.. The goal for anaplastic pancreatic carcinoma treatment should continue to be complete surgical resection. Optimum chemotherapeutic options continue to be investigated.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Combined Modality Therapy; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Treatment Outcome

Topics: Camptothecin; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

Here we bioengineered a metastatic pancreatic tumor model with homogenous human CD133(+)CXCR4(+) cancer stem cells (CSC) and a polyglyconate/gelatin electrospun scaffold. The scaffold sported a highly porous microstructure with the majority of fibers possessing a diameter between 500μm and 1500μm. The scaffold supported the growth of tumor cells without provoking apoptosis. The homogeneous CD133(+)CXCR4(+) CSC was transplanted with the scaffold into the pancreas of nude mice to establish a metastatic pancreatic tumor. After 8 weeks, the tumor volume and weight in the scaffold model were 40.52% and 51.49% greater than the traditional model, respectively. The scaffold also increased the incidence of tumor formation and readily induced a hepatic metastasis. In this model we found that FOLFIRINOX possessed a superior capability of preventing the hepatic metastasis of pancreatic tumor cells than gemcitabine. A mechanistic study attributed this superiority to the fact that FOLFIRINOX could induce a greater apoptosis of CD133(+)CXCR4(+) CSC, thus depriving the driving force of hepatic metastasis. This metastatic tumor model showed an increased incidence of tumor formation, an accelerated tumorigenesis and a significant hepatic metastasis, therefore offering scientists a proven platform to study chemotherapeutic drugs.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bioengineering; Camptothecin; Cell Line, Tumor; Deoxycytidine; Disease Models, Animal; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Organoplatinum Compounds; Pancreatic Neoplasms; Tissue Scaffolds; Xenograft Model Antitumor Assays

Borderline resectable pancreatic adenocarcinoma represents a subset of localized cancers that are at high risk for a margin-positive resection and early treatment failure when resected de novo. Although several different anatomic definitions for this disease stage exist, there is agreement that some degree of reconstructible mesenteric vessel involvement by the tumor is the critical anatomic feature that positions borderline resectable between anatomically resectable and unresectable (locally advanced) tumors in the spectrum of localized disease. Consensus also exists that such cancers should be treated with neoadjuvant chemotherapy and/or chemoradiation before resection; although the optimal algorithm is unknown, systemic chemotherapy followed by chemoradiation is a rational approach. Although gemcitabine-based systemic chemotherapy with either 5-FU or gemcitabine-based chemoradiation regimens has been used to date, newer regimens, including FOLFIRINOX, should be evaluated on protocol. Delivery of neoadjuvant therapy necessitates durable biliary decompression for as many as 6 months in many patients with cancers of the pancreatic head. Patients with no evidence of metastatic disease following neoadjuvant therapy should be brought to the operating room for pancreatectomy, at which time resection of the superior mesenteric/portal vein and/or hepatic artery should be performed when necessary to achieve a margin-negative resection. Following completion of multimodality therapy, patients with borderline resectable pancreatic cancer can expect a duration of survival as favorable as that of patients who initially present with resectable tumors. Coordination among a multidisciplinary team of physicians is necessary to maximize these complex patients' short- and long-term oncologic outcomes.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Neoadjuvant Therapy; Neoplasm Staging; Pancreatectomy; Pancreatic Neoplasms; Treatment Outcome

Traditional post-surgical chemotherapy for pancreatic cancer is notorious for its devastating side effects due to the high dosage required. On the other hand, legitimate concerns have been raised about nanoparticle-mediated drug delivery because of its potential cytotoxicity. Therefore, we explored the local delivery of a reduced dosage of FOLFIRINOX, a four-drug regimen comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil, for pancreatic cancer using a biocompatible drug-eluting scaffold as a novel chemotherapy strategy after palliative surgery. In vitro assays showed that FOLFIRINOX in the scaffold caused massive apoptosis and thereby a decrease in the viability of pancreatic cancer cells, confirming the chemotherapeutic capability of the drug-eluting scaffold. In vivo studies in an orthotopic murine xenograft model demonstrated that the FOLFIRINOX in the scaffold had antitumorigenic and antimetastatic effects comparable with those achieved by intraperitoneal injection, despite the dose released by the scaffold being roughly two thirds lower. A mechanistic study attributed our results to the excellent ability of the FOLFIRINOX in the scaffold to destroy the CD133(+)CXCR4(+) cell population responsible for pancreatic tumorigenesis and metastasis. This clinically oriented study gives rise to a promising alternative strategy for postsurgical management of pancreatic cancer, featuring a local chemotherapeutic effect with considerable attenuation of side effects.

Topics: Analysis of Variance; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Camptothecin; Cell Survival; Drug Delivery Systems; Flow Cytometry; Fluorouracil; Humans; Irinotecan; Leucovorin; Nanofibers; Nanotechnology; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Tumor Cells, Cultured

Pancreatic and biliary tract carcinomas are very chemoresistant. After a first-line treatment with a gemcitabine-based regimen, no second-line scheme is consolidated in clinical practice. The aim of this study was to evaluate the toxicity and the activity of the FOLFIRI regimen as first-line or second-line chemotherapy in patients with pancreatic or biliary tract tumors. Fifty-four patients (30 with pancreatic tumor, nine with gallbladder tumor, and 15 with biliary tract tumor) were treated with FOLFIRI (irinotecan 180 mg/m², day 1; leucovorin 100 mg/m² intravenously, days 1 and 2; 5-fluorouracil 400 mg/m² intravenous bolus, days 1 and 2; and 600 mg/m² in 22 h intravenously, continuous infusion days 1 and 2; every 14 days). Toxicity was recorded at each cycle according to the NCI-CTC V3.0 criteria, the response rate was verified each four cycles according to the RECIST criteria, and the progression-free survival rates as well as the overall survival rates were calculated according to the Kaplan-Meier method. Overall, the toxicity was mild. Grade 3-4 neutropenia occurred in 42.6% of patients. Grade 3-4 gastrointestinal toxicity was rare. FOLFIRI as a first-line treatment produced a response rate of 25%. In the second-line group, 9/21 patients (42.9%) obtained a stable disease as best response. In the entire population, the median progression-free survival rates were 3.1 months [95% confidence interval (CI), 1.9-4.4] and 3.5 months (95% CI, 2.6-4.4), respectively, in the first-line and the second-line cohort of patients. The median overall survival rates were 14.5 months (95% CI, 7.0-22.1) and 6.2 months (95% CI, 5.4-7.0), respectively, in the first-line and the second-line cohort of patients. FOLFIRI is feasible and well tolerated in patients with pancreatic or biliary tract tumors; it has a good activity in first line and mostly in patients with pancreatic cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Camptothecin; Carcinoma; Cohort Studies; Drug Monitoring; Female; Fluorouracil; Gallbladder Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Neutropenia; Pancreatic Neoplasms; Secondary Prevention; Severity of Illness Index; Survival Analysis

In Belgium, combination chemotherapy of cisplatin and 5-fluorouracil + leucovorin (CFL) according to the modified de Gramont schedule is the treatment of choice in second line for metastatic pancreatic cancer. We retrospectively analyzed survival data in 2 Belgian centers in a nonselected population.. Between January 2004 and October 2011, 48 patients with histologically proven recurrent or unresectable pancreatic adenocarcinoma who had received CFL as second-line treatment were identified. We retrospectively analyzed the following parameters: progression-free survival (PFS1 and PFS2) for each line (after the start of first and second line), overall survival (OS), and growth modulation index.. The median PFS1 was 5.4 months (95% confidence interval [CI], 4.1-6.6). The median PFS2 was 3.6 months (95% CI, 2-5.2). The median OS was 12 months (95% CI, 9.3-14.7). Twenty-three percent of patients had a growth modulation index >1.33.. We show an OS of 12 months with gemcitabine in first-line and CFL in second-line therapy for pancreatic cancer. Sequential therapy with good OS and good quality of life may be preferred to strong upfront therapy in an incurable disease such as pancreatic cancer.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies

FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, and irinotecan) as compared with gemcitabine in pancreatic cancer (PC) has superior activity and increased toxicity. The bolus 5-FU contributes to the toxicity. We hypothesized that the elimination of bolus 5-FU and use of hematopoietic growth factor will improve the safety profile without compromising the activity of FOLFIRINOX.. Sixty patients with PC treated with modified FOLFIRINOX (no bolus 5-FU) were reviewed. Patients were divided into metastatic or nonmetastatic (locally advanced or borderline resectable) disease. Toxicity, response rate, progression-free survival, and overall survival were evaluated.. Nonmetastatic and metastatic disease were present in 24 (40%) and 36 (60%) patients, respectively. The incidence of grade 4 neutropenia, grade 3/4 diarrhea, and fatigue were 3%, 13%, and 13%, respectively. Response rate was 30%. The median progression-free survival for nonmetastatic disease was 13.7 months (95% confidence interval [CI], 9.6-24.6 months), and that for metastatic disease was 8.5 months (95% CI, 3.7-11.0 months), respectively. The median overall survival for nonmetastatic disease was 17.8 months (95% CI, 9.9 months to not estimable), and that for metastatic disease was and 9.0 months (95% CI, 7.1 months to not estimable), respectively.. Modified FOLFIRINOX has an improved safety profile with maintained efficacy in metastatic PC. Modified FOLFIRINOX has promising activity in nonmetastatic disease.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Camptothecin; Diarrhea; Disease-Free Survival; Dose-Response Relationship, Drug; Fatigue; Female; Filgrastim; Fluorouracil; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Polyethylene Glycols; Recombinant Proteins; Retrospective Studies; Treatment Outcome

Advanced pancreatic adenocarcinoma still remains associated with a desperate prognosis. Nevertheless, treatment options for patients with metastasized disease have improved considerably over the last few years. Recently, cytotoxic combination therapies such as the FOLFIRINOX regimen and combined nab-paclitaxel/gemcitabine have shown improved overall survival compared to gemcitabine alone. There is still no standard of care in second-line therapy for patients with disease progression.. We report the case of a 47-year-old patient who dramatically responded to second-line treatment with nab-paclitaxel and gemcitabine after primary progression to the FOLFIRINOX protocol.. Second-line treatment after FOLFIRINOX is feasible for patients with good performance status. Our case report supports preclinical findings that suggest that pancreatic cancer is a heterogeneous disease. Further studies that characterize possible subgroups and identify predictive molecular markers to guide therapy are warranted.

Topics: Adenocarcinoma; Albumins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Paclitaxel; Pancreatic Neoplasms; Treatment Failure; Treatment Outcome

There is no standard consensus on a strategy in the second-line setting for gemcitabine-refractory advanced pancreatic cancer. This study evaluated the activity and tolerability of oxaliplatin, irinotecan, 5-fluorouracil and leucovorin (FOLFIRINOX) as a second-line therapy in advanced pancreatic adenocarcinoma pretreated with a gemcitabine-based regimen.. A retrospective survey was carried out on 18 patients with advanced pancreatic cancer who had been on gemcitabine-based chemotherapy and were then treated with FOLFIRINOX as a second-line therapy.. One patient (5.6%) had a confirmed complete response, 4 (22.2%) had confirmed partial responses and 5 (27.8%) had stable disease, resulting in a rate of disease control of 55.6% (95% CI, 33.3-77.8%). The median progression-free survival and median survival were 2.8 months and 8.4 months, respectively. Seven patients (38.9%) experienced grade 3-4 neutropenia. Grade 3 or 4 nonhematologic adverse events included nausea (38.9%) and vomiting (16.7%).. These results suggest the modest clinical activity regarding efficacy and the acceptable toxicity profile with the FOLFIRINOX regimen as a second-line treatment.

Topics: Adolescent; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Staging; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Treatment Outcome; Young Adult

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Humans; Irinotecan; Leucovorin; Male; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

In the present retrospective analysis we analysed the therapeutic outcome of a set of patients, who were treated with chemoradiation (CRT) for recurrent pancreatic cancer (RPC) in a single institution.. Forty-one patients had a history of primary resection for pancreatic cancer. In case of an unresectable recurrency patients were treated with CRT at our institution between 2002 and 2010 with a median dose of 48.4 Gy (range 39.6-54 Gy). Concurrent chemotherapy regimes included Gemcitabine (GEM) in 37/41 patients (90%) and Fluorouracil (FU) or Capecitabine (CAP) in 4/41 patients (10%). Patients were re-evaluated after CRT with computed tomography and/or explorative laparotomy. During re-resection or laparotomy 15 patients received an additional intraoperative radiotherapy (IORT) with a median dose of 15 Gy (range 12-15 Gy). Median age was 65 years (range 39-76 years) and there were 26 male and 15 female patients.. The median overall survival (mOS), local control (LC) and progression-free survival (PFS) were 16.1, 13.8 and 6.9 months respectively for all patients after the first day of CRT. Re-resection was possible in five patients (12%) and a complete remission (CR) as defined by tumor-free biopsy was seen in 6 patients (15%). When re-resection could be achieved after CRT mOS was improved to 28.3 months (n = 5 patients, 95%-CI 10.2 - 46.3 months). Patients receiving IORT had a significantly improved mOS compared to no IORT (p = 0.034). Fifteen patients (37%) experienced a local tumour progression and main site of distant metastasis was the liver (11 patients, 27%).Overall treatment-related toxicity was mild, grade III hematologic toxicity was observed in 11 patients (27%).. In summary we observed a good therapeutic response with mild to moderate toxicity levels for CRT in RPC. Overall survival and PFS were clearly improved in case of induction of a complete remission (tumor-free biopsies) or after achieving a re-resection, thus providing a curative intended therapy even in case of disease recurrence.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Combined Modality Therapy; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasm Staging; Pancreatic Neoplasms; Prognosis; Radiotherapy Dosage; Survival Rate

Patients with resected pancreatic cancer (PC) have a poor prognosis. In 2004, European Study Group for Pancreatic Cancer 1 (ESPAC1) showed that the use of adjuvant therapy (AT) with 5-fluorouracil (5-FU) improves overall survival (OS). Subsequently, the British Columbia Cancer Agency (BCCA) introduced guidelines to offer AT as the standard of care for patients with resected PC. This study reviews the OS and disease-free survival (DFS) in a pre-AT era (2000 to 2004) to the AT era (2005 to 2008) at the BCCA.. Using pathology records, all PC resections at Vancouver General Hospital from 2000 to 2008 were identified. Patients referred to the BCCA and their treatment records were obtained from the Cancer Agency Information System and BCCA pharmacy database. Charts were reviewed to abstract patient and tumor characteristics, DFS, and OS. Outcomes were compared by log-rank comparison.. In the pre-AT era, 53 resections were recorded, with 64% referred to the BCCA. Median age was 65 years; poorly differentiated 59% and margin positive 38%. About 24% of patients received AT: all 5-FU. In the AT era, 64 resections were recorded, with 86% referred. Median age was 65 years, poorly differentiated 34% and margin positive 34%. 69% of patients received AT: 61% 5FU and 39% gemcitabine. Major reasons for no AT: delayed referral or metastases at time of referral 45% and poor performance status 35%. Pre-AT DFS 13 months versus 15 months AT era (P=0.55). Pre-AT OS 19 months versus 18 months AT era (P=0.59).. Since the guideline for AT, there was an increase in the proportion of patients referred and treated, however, over 30% still do not receive or complete AT. In this single-institution series, there was no difference in survival outcomes between the pre-AT and AT eras. Strategies to improve rate and timeliness of referral should be explored.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; British Columbia; Canada; Chemotherapy, Adjuvant; Combined Modality Therapy; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Pancreatectomy; Pancreatic Neoplasms; Practice Guidelines as Topic; Prognosis; Retrospective Studies; Survival Rate

Patients with locally unresectable pancreatic cancer (AJCC stage III) have a median survival of 10-14 months. The objective of this study was to evaluate outcome of initially unresectable patients who respond to multimodality therapy and undergo resection.. Using a prospectively collected database, patients were identified who were initially unresectable because of vascular invasion and had sufficient response to nonoperative treatment to undergo resection. Overall survival (OS) was compared with a matched group of patients who were initially resectable. Case matching was performed using a previously validated pancreatic cancer nomogram.. A total of 36 patients with initial stage III disease were identified who underwent resection after treatment with either systemic therapy or chemoradiation. Initial unresectability was determined by operative exploration (n = 15, 42%) or by cross-sectional imaging (n = 21, 58%). Resection consisted of pancreaticoduodenectomy (n = 31, 86%), distal pancreatectomy (n = 4, 11%), and total pancreatectomy (n = 1, 3%). Pathology revealed T3 lesions in 26 patients (73%), node positivity in 6 patients (16%), and a negative margin in 30 patients (83%). The median OS in this series was 25 months from resection and 30 months since treatment initiation. There was no difference in OS from time of resection between the initial stage III patients and those who presented with resectable disease (P = .35).. In this study, patients who were able to undergo resection following treatment of initial stage III pancreatic cancer experienced survival similar to those who were initially resectable. Resection is indicated in this highly select group of patients.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Case-Control Studies; Chemoradiotherapy; Cisplatin; Cohort Studies; Combined Modality Therapy; Deoxycytidine; Docetaxel; Erlotinib Hydrochloride; Female; Fluorouracil; Gemcitabine; Humans; Length of Stay; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Pancreaticoduodenectomy; Quinazolines; Survival Rate; Taxoids

Controversies regarding the optimal therapy for patients with locally advanced pancreatic cancer (LAPC) exist. Although the prognosis as a whole remains dismal, subgroups are known to benefit from intensive therapy, including chemoradiotherapy (CRT). We describe the results in 178 patients treated from 2001 to 2010 and have developed a prognostic model for both survival and the possibility of a subsequent resection in these patients.. From 2001 until 2010, 178 consecutive patients with LAPC were treated and included in the present study, with CRT consisting of 50 Gy in 27 fractions combined with tegafur-uracil(UFT)/folinic acid(FA).. The median survival from diagnosis was 11.5 months. Adverse events of Grade 3 or above were seen in 36% of the patients. Ninety-three percent of the patients completed all fractions. A Cox regression model for survival demonstrated resection (hazard ratio [HR] 0.12; 95% confidence interval [CI], 0.1-0.3) and pre-CRT gemcitabine-based therapy (HR 0.57; 95% CI, 0.4-0.9) as being associated with a favorable outcome, increasing gross tumor volume (HR 1.14; 95% CI, 1.0-1.3) was associated with shorter survival. A logistic regression model showed Stage III disease (odds ratio [OR] 0.16; 95% CI, 0.0-1.1) and abnormal hemoglobin (OR 0.26; 95% CI, 0.0-1.2) as being associated with lower odds of resection.. This study confirms the favorable prognosis for patients receiving gemcitabine therapy before CRT and the poor prognosis associated with increasing tumor volume. In addition, CRT in patients with abnormal hemoglobin and Stage III disease rarely induced tumor shrinkage allowing subsequent resection.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Chemoradiotherapy; Deoxycytidine; Dose Fractionation, Radiation; Female; Gemcitabine; Humans; Leucovorin; Logistic Models; Male; Middle Aged; Pancreatic Neoplasms; Prognosis; Retrospective Studies; Tegafur; Tumor Burden; Uracil

The vast majority of patients with pancreatic cancer present with locally advanced unresectable or metastatic disease, and in this setting only a palliative treatment can be offered. Single-agent gemcitabine has been considered the standard chemotherapy for patients with advanced pancreatic cancer since the results of a pivotal phase III trial showing superior clinical benefit compared to bolus 5-fluorouracil were published in 1997. In recent years, many randomized trials have attempted to improve results obtained with gemcitabine exploring a different schedule (fixed dose rate) of its administration, or testing the addition of one or more drugs to gemcitabine. Unfortunately, none of these trials produced a statistically significant and clinically relevant improvement in overall survival compared to the standard. A randomized phase III trial has recently shown a survival advantage using a combination of more drugs (FOLFIRINOX: irinotecan, oxaliplatin, folinic acid and 5-fluorouracil) compared to single-agent gemcitabine, suggesting that regimens without gemcitabine can be successfully used in patients with advanced pancreatic cancer. FOLFIRINOX was associated with worse toxicity than gemcitabine, and the available data suggest that this regimen may be considered for patients with metastatic pancreatic cancer who are fit enough to withstand potential side effects. The best option for these patients remains the enrolment in prospective clinical trials. Improvements in the treatment of the advanced disease will possibly derive from new combinations or from new drugs, but certainly from a better knowledge of the multiple molecular pathways implicated in pancreatic carcinogenesis and in invasion and metastasis.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase III as Topic; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) is superior to gemcitabine in patients with metastatic pancreatic cancer who have a good performance status. We investigated this combination as neoadjuvant therapy for locally advanced pancreatic cancer (LAPC).. In this retrospective series, we included patients with unresectable LAPC who received neoadjuvant FOLFIRINOX with growth factor support. The primary analysis endpoint was R0 resection rate.. Eighteen treatment-naïve patients with unresectable or borderline resectable LAPC were treated with neoadjuvant FOLFIRINOX. The median age was 57.5 years and all had ECOG PS of 0 or 1. Eleven (61 %) had tumors in the head of the pancreas and 9 (50 %) had biliary stents placed prior to chemotherapy. A total of 146 cycles were administered with a median of 8 cycles (range 3-17) per patient. At maximum response or tolerability, 7 (39 %) were converted to resectability by radiological criteria; 5 had R0 resections, 1 had an R1 resection, and 1 had unresectable disease. Among the 11 patients who remained unresectable after FOLFIRINOX, 3 went on to have R0 resections after combined chemoradiotherapy, giving an overall R0 resection rate of 44 % (95 % CI 22-69 %). After a median follow-up of 13.4 months, the 1-year progression-free survival was 83 % (95 % CI 59-96 %) and the 1-year overall survival was 100 % (95 % CI 85-100 %). Grade 3/4 chemotherapy-related toxicities were neutropenia (22 %), neutropenic fever (17 %), thrombocytopenia (11 %), fatigue (11 %), and diarrhea (11 %). Common grade 1/2 toxicities were neutropenia (33 %), anemia (72 %), thrombocytopenia (44 %), fatigue (78 %), nausea (50 %), diarrhea (33 %) and neuropathy (33 %).. FOLFIRINOX followed by chemoradiotherapy is feasible as neoadjuvant therapy in patients with unresectable LAPC. The R0 resection rate of 44 % in this population is promising. Further studies are warranted.

Topics: Adult; Aged; Algorithms; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Treatment Outcome

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase III as Topic; Evidence-Based Medicine; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome

Despite the enormous advances in clinical research in oncology, the prognosis of pancreatic carcinoma remains poor. The therapeutic options in this type of cancer are very limited, with modest results at present. In the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, four interesting trials on the second line treatment of pancreatic cancer were presented. The first study (Abstract #4017) with a phase II design suggested that maintenance therapy with sunitinib, after a complete course of standard first line treatment, was feasible and effective while the second phase I/II study (Abstract #4034) evaluated the role of trabedersen, an agent that inhibits TGF-β2 expression. Finally, the efficacy and toxicity of lapatinib combined with either FOLFOX (Abstract #e14533) or capecitabine (Abstract #e14569) were examined in the second line setting of pancreatic cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Clinical Trials as Topic; Deoxycytidine; Fluorouracil; Humans; Lapatinib; Leucovorin; Oligodeoxyribonucleotides; Organoplatinum Compounds; Pancreatic Neoplasms; Quinazolines; Thionucleotides

Patients with neuroendocrine carcinomas (NECs) grade 3 have a poor prognosis. Etoposide-platinum combination is the standard chemotherapy but the role of a second-line therapy remains unknown. Irinotecan alone or in combination has shown some efficacy in patients treated for small cell lung cancer which had pathological similarities with neuroendocine tumors. The aim of this study is to determine safety and efficacy of the FOLFIRI regimen in patients with NECs grade 3 after failure of etoposide-platinum combination. This study was retrospective, including patients with NECs grade 3 and treated with the FOLFIRI regimen after progression or toxicity of etoposide-platinum combination in first-line. Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≥3 and/or serum alkaline phosphatase ≥5×upper limit of normal value (ULN) and/or bilirubin ≥1.5×ULN were excluded. Among 39 patients who failed etoposide-platinum combination, 19 (49%; 12 women, median age 53 (29-78) years) received the FOLFIRI regimen with a median number of 6 (1-16) courses. Six patients (31%) had at least one episode of grades 3-4 toxicity (neutropenia, n=3; diarrhea, n=3) without toxic death. Six patients (31%) had objective response, 6 (31%) stable disease, and 7 (38%) tumor progression. Median progression-free survival under FOLFIRI was 4 months. Overall survival was 18 vs 6.8 months in noneligible patients. FOLFIRI regimen is a safe and potentially efficient chemotherapy given as second-line in patients with NECs grade 3 who remain in good condition and with correct liver tests after failure of etoposide-platinum combination. These results should be confirmed in a future prospective study.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Anus Neoplasms; Camptothecin; Carcinoma, Neuroendocrine; Disease-Free Survival; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Grading; Pancreatic Neoplasms; Pelvic Neoplasms; Platinum; Treatment Outcome

To evaluate the efficacy and safety of the FOLFIRI regimen in patients with metastatic pancreatic adenocarcinoma (PAC) after the failure of gemcitabine and platinum salts.. All consecutive patients with histologically confirmed, metastatic PAC and World Health Organization performance status (PS) ≤ 2 received FOLFIRI-1 [irinotecan 180 mg/m(2) on day 1 and leucovorin 400 mg/m(2) followed by 5-fluorouracil (5-FU) 400 mg/m(2) bolus, then 5-FU 2400 mg/m(2) as a 46-h infusion, biweekly] or FOLFIRI-3 (irinotecan 100 mg/m(2) on day 1 and leucovorin 400 mg/m(2), then 5-FU 2400 mg/m(2) as a 46-h infusion and irinotecan 100 mg/m(2) repeated on day 3, biweekly) after failure of gemcitabine and platinum-based chemotherapies as a systematic policy in two institutions between January 2005 and May 2010. Tumor response, time to progression (TTP), overall survival rate (OS) and grade 3-4 toxicities were retrospectively studied. Subgroup analyses were performed to search for prognostic factors.. Sixty-three patients (52.4% male, median age 59 years) were analyzed. Among them, 42.9% were PS 0, 38.1% were PS 1 and 19.0% were PS 2. Fifty one patients (81.0%) had liver metastases. Before the FOLFIRI regimen, patients had received 1 line (n = 19), 2 lines (n = 39) or 3 lines (n = 5) of chemotherapy. Median TTP obtained with the line before FOLFIRI was 3.9 mo (95% CI: 3.4-5.3 mo). A total of 480 cycles was completed (median: 6 cycles, range: 1-51 cycles). The main reason for discontinuing FOLFIRI was tumor progression (90.3%). Tumor control was achieved in 25 patients (39.7%) (partial response: n = 5, stable disease: n = 20) with FOLFIRI. Median TTP was 3.0 mo (95% CI: 2.1-3.9 mo) and median OS was 6.6 mo (95% CI: 5.3-8.1 mo). Dose adaptation was required in 36 patients (57.1%). Fifteen patients (23.8%) had grade 3-4 toxicities, mainly hematological (n = 11) or digestive (n = 4). Febrile neutropenia occurred in 3 patients. There was no toxic death. PS 2 was significantly associated with poor TTP [hazard ratio (HR): 16.036, P < 0.0001] and OS (HR: 4.003, P = 0.004).. The FOLFIRI regimen had an acceptable toxicity and an interesting efficacy in our study, limited to patients in good condition (PS 0-1).

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Disease Progression; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Platinum; Retrospective Studies; Survival Rate; Treatment Failure; Treatment Outcome

Metastatic pancreatic carcinoma is an incurable disease and gemcitabine remains the standard of care in first-line chemotherapy. Recently, fluorouracil/leucovorin combined with irinotecan and oxaliplatin (FOLFIRINOX) demonstrated their superiority in first-line therapy. The objective of this study was to determine the efficacy of FOLFIRINOX in either first- and second-line treatment and to compare its efficacy in regard to the location of the primary tumor.. We performed a retrospective analysis of clinical factors associated with patients' survival using a cohort of 42 patients treated by FOLFIRINOX in either first- or second-line (2006-2011) and a control cohort of 42 patients matched on sex and age without FOLFIRINOX treatment was obtained from a previous period of time (2001-2005).. The median follow-up was 10 months. The median overall survival was 10 months for the whole cohort and 10 and 12 months for patients treated at first- and second-line, respectively (p<0.05). In this cohort using a multivariate model, among classical prognosis factors, only primary location in the head was associated with poor outcome. The median overall survival was 8 months for patients with primary location in the head and 14 months for patients with primary location in the corpse or tail (p=0.02). In the gemcitabine cohort, the median follow-up was 8 months. Using a multivariate model, only performance status was associated with outcome. The median overall survival was 9 versus 6.5 months for patients with tumor, of the head versus tail or corpse tumor respectively (p<0.05).. This retrospective study suggests the same efficacy of FOLFIRINOX used either in first- or second- line therapy for pancreatic cancer. Importantly, FOLFIRINOX compared favorably to gemcitabine only for patients with tumor of the corpse or tail. Further prospective trials are warranted to evaluate the efficacy of FOLFIRINOX in patients with tumor of the head of the pancreas.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Case-Control Studies; Cohort Studies; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Survival Rate; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Deoxycytidine; Equilibrative Nucleoside Transporter 1; Gemcitabine; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

In patients with pancreatic cancer treated with curative resection, we evaluated the effect of clinicopathologic parameters on early distant metastasis within 6 months (DM6m) to identify patients who might benefit from surgery.. The study involved 84 patients with pancreatic cancer who had undergone curative resection between August 2001 and April 2009. The parameters of gender, age, tumor size, histologic differentiation, T classification, N classification, pre- and postoperative carbohydrate antigen (CA) 19-9 level, resection margin, and adjuvant chemoradiotherapy were analyzed to identify the risk factors associated with DM6m.. Of the 84 patients, locoregional recurrence developed in 35 (41.7%) and distant metastasis in 58 (69%). Of the 58 patients with distant metastasis, DM6m had developed in 27 (46.6%). Multivariate analysis showed that preoperative CA 19-9 level was significantly associated with DM6m (p<.05). Of all 84 patients, DM6m was observed in 9.1%, 50%, and 80% of those with a preoperative CA 19-9 level of ≤100 U/mL, 101-400 U/mL, and >400 U/mL, respectively (p<.001).. The preoperative CA 19-9 level might be a useful predictor of DM6m and to identify those who would benefit from surgical resection.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Capecitabine; Chemoradiotherapy; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Radiotherapy Dosage; Retrospective Studies

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

There is no consensus on what constitutes "standard" adjuvant therapy for pancreatic cancer. This controversy derives from several studies, each fraught with its own limitations. Standards of care also vary somewhat on the geography as chemo-radiotherapy followed by chemotherapy or vice versa is considered the optimal therapy in North America (GITSG, RTOG) while chemotherapy alone is the current standard in Europe (ESPAC-1, CONKO, ESPAC-3). The high rate of locoregional failure following surgical resection for adenocarcinoma of the pancreas has made it clear that some form of adjuvant therapy should be considered in these patients. A phase II study was presented at the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium to assess the effect of the addition of algenpantucel-L immunotherapy to standard adjuvant therapy on survival in patients with resected pancreas cancer (Abstract #236). The author reviews the abstract in the context of our previous knowledge.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Chemotherapy, Adjuvant; Clinical Trials as Topic; Combined Modality Therapy; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Immunotherapy; Leucovorin; Pancreatic Neoplasms; Radiotherapy, Adjuvant; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Fluorodeoxyglucose F18; Humans; Leucovorin; Pancreatic Neoplasms; Positron-Emission Tomography; Radiopharmaceuticals; Tegafur; Tomography, X-Ray Computed; Uracil

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

To evaluate the efficacy and toxicity of irinotecan and oxaliplatin plus 5-fluorouracil (FU) and leucovorin (FOLFIRINOX) as second-line therapy in metastatic pancreatic adenocarcinoma (MPA).. We retrospectively analyzed the medical records of 27 patients with MPA treated with FOLFIRINOX as second-line therapy between January 2003 and November 2009 in our hospital. The recommended schedule was oxaliplatin 85 mg/m(2) on day 1 + irinotecan 180 mg/m(2) on day 1 + leucovorin 400 mg/m(2) on day 1 followed by FU 400 mg/m(2) as a bolus on day 1 and 2,400 mg/m(2) as 46-hour continuous infusion biweekly.. The median age of the 27 patients (13 males and 14 females) was 63 years (45-83). All patients had progressive disease after first-line chemotherapy by gemcitabine. A total of 167 cycles were administered, with a median number of 6 cycles (1-29) per patient. One toxic death occurred (sepsis). Tolerance of treatment was acceptable, and the relative dose density delivered per patient was 92.8% for oxaliplatin, 89.1% for irinotecan and 96.4% for FU. Grade 3-4 neutropenia occurred in 55.6% of the patients, including 1 febrile neutropenia. The other toxicities were manageable. Regarding efficacy, 22 of the 27 patients were evaluable (WHO and RECIST criteria). Five patients had partial responses and 12 stable disease, resulting in an overall disease control rate of 63%. Median time to progression was 5.4 months (0.7-25.48), and median event-free survival was 3 months (0.5-24.9). Median overall survival was 8.5 months (0-26). A clinical benefit was reported for 55% of the patients.. These results confirmed the good safety profile and the efficacy of the FOLFIRINOX regimen as second-line treatment of MPA.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Deoxycytidine; Disease Progression; Drug Administration Schedule; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Medical Records; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Retrospective Studies; Treatment Failure; Treatment Outcome

The development of novel therapeutic strategies for pancreatic adenocarcinoma (PAC) has traditionally been considered particularly challenging for clinical and laboratory investigators due to its aggressive underlying biology and inherent resistance to currently available therapies. More recently, however, advances have been made in the identification of promising therapeutic targets for intervention, along with several key insights into the complex sequence of genetic alterations involved in the evolution of PAC from premalignant precursor lesion to malignant cells with metastatic potential. FOLFIRINOX (5-fluorouracil/leucovorin/irinotecan/oxaliplatin) has recently been identified as a combination cytotoxic therapy associated with a significant survival benefit over single-agent gemcitabine in good performance status patients with advanced disease; it is hoped that a similar benefit will be seen in planned trials of FOLFIRINOX as perioperative therapy. The success of immune therapy with the anti-cytotoxic T-lymphocyte antigen-4 antibody ipilimumab in advanced melanoma has spurred interest in the development of vaccines and immune therapies for other solid tumors. Certainly, the concept of harnessing the power of the immune system for cancer treatment is an attractive concept to patients and clinicians alike. Herein we discuss recent advances in the development of novel therapeutic approaches to PAC, focusing in particular on recent developments in immune and vaccine therapy.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cancer Vaccines; Combined Modality Therapy; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Immunotherapy; Ipilimumab; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms

We present the case of a 57-year-old patient who initially presented with a constellation of symptoms including intense pruritis, flushing and diarrhoea. Following several months clinical deterioration, the patient was investigated radiologically, where multiple hepatic tumours were identified. Liver biopsy confirmed the presence of a well-differentiated metastatic gastroenteropancreatic endocrine carcinoma with biochemical evidence of serotonin secretion. Over a period of six months, the clinical course of the patient's disease progressed whereby severe hypoglycaemia became the major manifestation. Subsequent biochemical investigations confirmed the diagnosis of an insulinoma. Extensive radiological investigation revealed a solitary primary pancreatic tumour, indicating the presence of a metastatic pancreatic endocrine tumour (PET) secreting both insulin and serotonin. The patient was treated with a chemotherapy regimen consisting of 12 cycles of 5-fluorouracil/oxaliplatin, responding clinically - improved World Health Organization performance score from 3 to 1, biochemically - significantly reduced plasma chromogranin A and cancer antigen 19-9 concentrations and improved liver function tests, and radiologically - reduced pancreatic and hepatic tumour size. This is the first report of a primary PET secreting insulin and serotonin. Due to the association of serotonin-secreting gastroenteropancreatic endocrine tumours (GEP-ETs) with multiple endocrine neoplasia type-1 (MEN1) and biochemical evidence of an insulinoma, MEN1 should also be considered in such cases. The case provides further evidence for the biological heterogeneity of GEP-ETs and the myriad secretory humoral products and resultant clinical syndromes arising from such tumours.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma; Fluorouracil; Humans; Hyperinsulinism; Hypoglycemia; Leucovorin; Liver Neoplasms; Malignant Carcinoid Syndrome; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Vitamin B Complex

Patients with advanced pancreatic cancer failing gemcitabine-based first-line chemotherapy are still in relatively good clinical conditions and may still require second-line chemotherapy, which is frequently administered in daily clinical practice given to without solid scientific support.. A retrospective survey was carried out including 40 patients with stage III or IV gemcitabine-refractory pancreatic carcinoma. Patients received standard FOLFIRI regimen biweekly until progression or unacceptable toxicity. Response evaluation criteria in solid tumors and National Cancer Institute common toxicity criteria were employed respectively for response and toxicity assessment.. Six partial responses (15%) and 14 stabilizations of disease (35%) were recorded for a tumor growth control rate of 50%. The median time to progression was 3.7 (range, 1-6.5 months), and median overall survival was 6 months (range, 2-8.2 months). A stabilization of performance status and a subjective improvement of cancer-related symptoms were recorded in 21 patients (52.5%). No correlation has been found between length of time to progression during first-line chemotherapy and length of that reported in the second-line setting or objective response. Grade 3-4 diarrhea and mucositis was observed in 15% and 10% of cases, respectively.. Data presented in this article demonstrate that the second-line FOLFIRI regimen are able to induce an objective response in a relatively small fraction of patients with gemcitabine-refractory adenocarcinoma of the pancreas. The use of second-line chemotherapy should be carefully proposed to patients with good performance status or those who had a good response to first-line therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies; Survival Analysis

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Pain; Palliative Care; Pancreatic Neoplasms; Radiotherapy, Adjuvant; Treatment Outcome

More than half of patients with pancreatic adenocarcinoma (PA) are candidates for further treatment when they experience upfront treatment failure.. Patients with gemcitabine-resistant PA, age <76 years and Karnofski performance status (KPS) >50 were treated with a XELIRI or FOLFIRI regimen until progressive disease or a maximum of six months. As this was an observational study, no statistical design was performed.. Between July 2007 and December 2009, 34 patients (median age 60 years; median KPS 90) were treated with XELIRI (26) or FOLFIRI (8) regimen. Grade >2 toxicity consisted of neutropenia in 9% of patients, anemia and fatigue in 3% and hand-foot syndrome in 12%. Median progression-free survival was two months (range 1-4). Maximum response was stable disease in four patients (12%). Median survival was 4.2 (range 1-15) months.. Fluoropyrimidine and irinotecan combination does not seem to have any role in the treatment of gemcitabine-resistant PA.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Salvage Therapy; Survival Rate; Treatment Outcome; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemotherapy, Adjuvant; Deoxycytidine; Disease-Free Survival; Erlotinib Hydrochloride; Fluorouracil; Gemcitabine; Humans; Leucovorin; Pancreatic Neoplasms; Quality of Life; Quinazolines; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Failure

Acinar cell carcinoma of the pancreas is rare tumour with a generally poor prognosis. There are very few reports of tumour regression following chemotherapy. In this case report, a patient with metastatic acinar cell carcinoma in the liver developed progressive disease after cisplatin/etoposide and then had progressive disease after weekly paclitaxel chemotherapy. However, his tumour then responded to gemcitibine/5-flourouracil/leucovorin chemotherapy. Herein, previously described chemotherapy regimens used for this rare tumour are reviewed. This case represents the first reported metastatic acinar cell carcinoma responding to this regimen.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Acinar Cell; Deoxycytidine; Drug Resistance, Neoplasm; Fluorouracil; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Treatment Outcome; Vitamin B Complex

Majority of the patients with pancreatic cancer present with advanced disease that is lethal and notoriously difficult to treat. Survival has not improved dramatically despite routine use of chemotherapy and radiotherapy; this situation signifies an urgent need for novel therapeutic approaches. The treatment of advanced disease with gemcitabine has only a modest activity on survival with a favorable impact on quality of life. So far, the current targeted agents that have been used in combination with gemcitabine have failed to improve clinical outcomes. This failure may stem from the heterogeneous molecular pathogenesis of pancreatic cancers, which involves several oncogenic pathways and defined genetic mutations. However, recent data support the evidence that the combination of gemcitabine with erlotinib, capecitabine or platinum compounds could be more active than gemcitabine alone in advanced pancreatic cancer. New therapeutic strategies, particularly using molecular target agents, are under evaluation. A number of molecular mechanisms responsible of transformation and progression of pancreatic cancer have been identified, opening the possibility to identify also possible pharmacological targets. Pancreatic cancer remains the 4th leading cause of cancer death in the U.S.A.. How to treat a non-resectable pancreatic cancer has been a challenging topic for all medical oncologists. Historical 5-fluorouracil has been replaced by single agent gemcitabine since 1997. Numerous combinations using gemcitabine as a backbone have been tested in clinical trials; unfortunately, none of the combinations including the ones with biological agents was proved to be significantly superior to gemcitabine alone. This year, more combinations were investigated and the results were presented on the meeting. In first-line setting, two large phase III trials (Abstracts #4504 and #4601) failed to prove any additional benefit of a second cytotoxic agent or a vaccine. Folinic acid plus 5-FU plus oxaliplatin (FOLFOX) and 5-fluorouracil plus leucovorin plus irinotecan (FOLFIRI) could be considered in the second-line setting after failure of gemcitabine therapy (Abstract #4618). Novel agents (Abstracts #4501, #4625, #4626, #4617) provide some hope; however, in general, all combinations are still significantly relying on the backbone of gemcitabine. Thinking beyond the gemcitabine box and exploring novel agents are very crucial now.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Clinical Trials as Topic; Deoxycytidine; Erlotinib Hydrochloride; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Platinum; Quinazolines; Treatment Outcome

We undertook this study to analyze clinical features and surgical outcome of en bloc resections of the right side colon cancer directly invading duodenum and/or pancreatic head.. The records of all patients who underwent en bloc resection of duodenum and/or pancreas for right colon cancers were analyzed retrospectively. From September 1994 to September 2006, 1,016 patients underwent curative right hemicolectomy. Nine patients (0.9%) had en bloc resection of a right side colon cancer with duodenum or pancreatic head invasion.. The median operative time was 320 minutes (range, 200-420) and the median blood loss was 700 mL (range, 100-2,000). The mean size of tumor was 6.6 cm (range, 3.2-10.7). The mean preoperative carcinoembryonic antigen (CEA) was 10.6 ng/mL (range, 0.2-50.8). There was no 30 day perioperative mortality. The median disease-free survival was 23.5 months [95% confidence interval (CI) 5.2-41.8] and the median overall survival was 28.1 months (95% CI 9.7-46.5).. In patients with locally advanced right side colon cancer that directly invades the duodenum or pancreas can be safely resected with curative potential with minimum morbidity and mortality. Long term disease free survival can occur in a significant number of patients undergoing curative en bloc resection in this particular subset of patients.

Topics: Adult; Aged; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Duodenal Neoplasms; Duodenum; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Retrospective Studies; Treatment Outcome

Radiotherapy and chemotherapy are major therapies for locally advanced pancreatic cancer. This study was to evaluate the efficacy of three-dimensional conformal gamma-knife radiotherapy combined with thermochemotherapy on locally advanced pancreatic cancer.. From December 2001 to January 2006, 75 patients with locally advanced pancreatic cancer were divided into radiotherapy group (37 patients) and combination group (38 patients). All patients received gamma-knife radiotherapy using Stereotactic Radiotherapy Gamma Rays System, with iso-dose curves of 50%-60%, tumor encircling dose of 3.0-4.5 Gy per fraction, 8-11 fractions. The patients in combination group received simultaneous thermotherapy at 41.5-43.5 celsius (1 h/fraction, twice a week for 6 times), and chemotherapy with venous administration of tegafur (0.5-1.0 g) and calcium folinate (CF, 0.2 g) for 4-6 times, or venous administration of gemcitabine (0.6-1.0 g/m2) on Days 1 and 8 and cisplatin (DDP) (20-30 mg/m2) on Days 1-3, repeated every 28 days for 3-6 cycles.. At 3 months after treatment, the total response (complete remission and partial remission) rate was 70.7% (53/75); the response rate was 73.7% in combination group and 67.5% in radiotherapy group. The 1-year survival rate was 48.3%, and the 2-year survival rate was 22.1%. The 1-and 2-year survival rates were 51.2% and 26.5% in combination group, and 45.2% and 17.6% in radiotherapy group. No serious complications, such as perforation, bleeding and high fever, were seen during treatment and follow-up.. 3-D conformal gamma-knife radiotherapy combined with thermochemotherapy is well tolerated and is relatively effective for most patients with locally advanced pancreatic cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Deoxycytidine; Female; Gemcitabine; Humans; Hyperthermia, Induced; Leucovorin; Male; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Radiosurgery; Remission Induction; Survival Rate; Tegafur

In daily clinical practice second-line chemotherapy (SLCT) is frequently given to patients with advanced pancreatic cancer failing gemcitabine-based first-line chemotherapy without solid scientific support.. A retrospective survey was carried out including 42 patients. Patients received standard FOLFOX4 regimen biweekly until progression or unacceptable toxicity.. Six partial responses (14%) and 16 stabilizations (38%) were recorded for a tumor growth control rate of 57%. The median time to progression (TtP) was 4 months (range 1-7 months), and median overall survival (OS) was 6.7 months (range 2-9 months). A stabilization of performance status (PS) and a subjective improvement of cancer-related symptoms were recorded in 27 patients.. Data presented in this paper support the use of FOLFOX4 regimen in the second-line treatment of adenocarcinoma of the pancreas patients. The use of SLCT, however, should be carefully proposed to patients with good PS or those who had a good response to first-line therapy.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Pancreatic Neoplasms; Retrospective Studies

Patients with advanced pancreatic carcinoma benefit from chemotherapy with gemcitabine or 5-FU based regimens. Promising new combinations schedules with e.g. oxaliplatin, docetaxel, or erlotinib are under development. A survival benefit of adjuvant chemotherapy--after complete surgical resection of the primary tumor--has been demonstrated in some studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Combined Modality Therapy; Deoxycytidine; Docetaxel; Erlotinib Hydrochloride; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Pancreatic Neoplasms; Quinazolines; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Survival Rate; Taxoids

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Fluorouracil; Gemcitabine; Heart Neoplasms; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Remission Induction

The patient is a 66-year-old male who underwent gastrojejunostomy at another hospital with the diagnosis of type 3 unresectable gastric cancer. He was admitted to our hospital for adjuvant chemotherapy. A CT scan revealed both peritoneal dissemination and a large tumor directly invading the pancreas and liver. After 7 courses of combined chemotherapy with 5-FU, Leucovorin, cis-platinum and methotrexate, an effective response, tumor reduction and the disappearance of peritoneal dissemination, was verified by CT scan. Pancreatoduodenectomy with transverse colectomy was carried out and the pathological diagnosis was also curative (pT3, pN1, pP0, HO: stage III A). Although he unfortunately died from peritoneal recurrence after 9 months, he maintained good quality of life after re-operation. We think this case shows the possibility of NAC for patients with far advanced gastric cancer with peritoneal dissemination to improve their prognosis or QOL.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Fluorouracil; Gastrectomy; Humans; Jejunostomy; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Methotrexate; Neoadjuvant Therapy; Neoplasm Invasiveness; Pancreatic Neoplasms; Peritoneal Neoplasms; Quality of Life; Stomach Neoplasms

Folinic acid-modulated 5-FU regimens are standard elements in several chemotherapy combinations like FOLFIRI, FOLFOX or AIO-regimen in the palliative treatment of patients with gastrointestinal cancer. When the simultaneous mixed infusion of 5-FU and calcium-folinic acid (Leucovorin) was authorized by the BfArM in 2002, we introduced this application regimen in the treatment of our cancer patients. 19 patients (AIO-regimen [5], FOLFIRI [12] and FOLFOX [2]) received a simultaneously mixed infusion of calcium-folinic acid and 5-FU over 24 hours with a total of 110 applications. 5-FU doses varied between 2000 and 2600 mg/m2, calcium-folinic acid was given with 500 mg/m2, infusion rate was 10 ml/hour using a 24 h pump. Central venous catheters employed included single Barth-Port in 18 cases, 1 patient had a Viggon-Port. In 3 out of the 19 patients catheter occlusion was noticed after 8-10 weekly applications of the mixed infusion. Heparine and subsequently urokinase were not successful in reversing the obstruction. All three catheters had to be explanted. Catheter tips in all cases showed a yellow cristalline precipitation. The crystallographic analysis exhibited calcium carbonate (CaCO3) in its polymorphic form (calcite). Thus, we confirmed calcite formation causing catheter occlusion as a frequent complication during a continuous 24 h-infusion of mixed high dose 5-FU and calcium-folinic acid. This reaction could not be avoided by increasing infusion volume and the application flow rate. As a result of our findings, recommending using calcium-folinic acid mixed with 5-FU has been withdrawn in the meantime.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Calcium Carbonate; Catheterization, Central Venous; Catheters, Indwelling; Chemical Precipitation; Colorectal Neoplasms; Crystallization; Device Removal; Equipment Failure Analysis; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Palliative Care; Pancreatic Neoplasms; Stomach Neoplasms; Surface Properties

The combination of 5-fluorouracil (5-FU) modulated by folinic acid (FA) and cisplatin is commonly used in advanced digestive non-colon cancers (ADNCC). In order to simplify treatment administration by avoiding cisplatin-related hydration, we investigated a weekly regimen of 5-FU/FA/cisplatin. Patients with ADNCC were treated with 5-FU 2.0 g/m2, FA 500 mg/m2 and cisplatin 25 mg/m2 day 1, for 6 weeks with a 2-week rest, and were assessed for toxicity, tumor response and disease-free survival. Forty-three patients with measurable ADNCC were treated with this weekly regimen. Primary tumor sites were mainly esophagus (n = 17), stomach (n = 12) and pancreas (n = 9). Results were as follows. Toxicity was mostly hematological, with 16% grade 3/4 neutropenia (seven of 43) and 4% febrile neutropenia (two of 43). Objective response (OR) was observed in 19 of 43 (44%) patients including four complete responses (9%) and 15 partial responses (35%). Another 18 patients (42%) experienced stable disease. Time to progression was 6.5 months. The median response and stable disease durations were 4.3 (range 3-34) and 5 (range 2-16) months, respectively. We conclude that weekly administration of 5-FU/FA/cisplatin is an active and well-tolerated regimen. Toxicity is manageable and allows chemotherapy on an outpatient basis without hydration program as required when cisplatin is used at the dose of 50 mg/m2.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Cisplatin; Digestive System Neoplasms; Disease Progression; Drug Administration Schedule; Esophageal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Invasiveness; Pancreatic Neoplasms; Stomach Neoplasms

The use of neoadjuvant chemotherapy for pancreatic cancer has been advocated for its potential ability to optimize patient selection for surgical resection and to downstage locally advanced tumors, especially for patients with Stage IV b (Japan criteria). We report our experience with a six-drug chemotherapeutic regimen that resulted in sufficient downstaging of the tumor in some patients to justify surgical resection. From Jan. 2001 through December 2003, 6 patients received 5-FU as a continuous infusion (200 mg/m2/day), calcium leucovorin weekly by intravenous bolus injection (30 mg/m2), mitomycin-C every 6 weeks (10 mg/m2 intravenously), and dipyridamole daily orally (75 mg), according to the UCLA regimen and gemcitabine weekly (600 mg/m2) and heparin as a continuous infusion (0-3,000 U/day) for locally advanced unresected pancreatic cancer. All of these patients were evaluable for response and survival. There were 5 partial responses (83% response rate) and 1 no response. Four of 5 responding patients had sufficient tumor regression to meet clinical criteria for resectability, three of whom underwent a curative resection. All patients who underwent downstage operation were still alive for the follow-up period (4-23 months).

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Deoxycytidine; Dipyridamole; Drug Administration Schedule; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Neoplasm Staging; Pancreatic Neoplasms

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Pancreatic Neoplasms; Survival Analysis

Advanced pancreatic cancer is mainly treated by chemotherapy with poor prognosis. This study was designed to evaluate clinical efficacy and application of selective continuous transarterial infusion chemotherapy in treating patients with advanced pancreatic cancer.. Twenty patients with advanced pancreatic cancer were treated by selective continuous transarterial infusion chemotherapy. The interventional treatment was performed with Seldinger technique,12 patients received percutaneous femoral artery cannulization and catheter retention, 8 received percutaneous left subclavian artery port-catheter system implantation. Chemotheraputic drugs were continuously infused when the catheter was selectively placed in turner feeding artery. Nine patients were treated with pirarubicin (THP)/adriamycin (ADM) plus hydroxycamptothecin (HCPT),and 5-fluorouracil (5-FU)/calcium folinate (CF) regimen,and 11 were treated with gemcitabine (GEM) plus carboplatin (CBP),and 5-FU/CF regimen. Treatment regimens were repeated every 4-6 weeks with each cycle of 4 days. Tumor response rate,clinical benefit response (CBR),and survival time were observed.. Objective response rate was 10% with 1 case of complete remission (CR), and 1 case of partial remission (PR), CBR was 70% (14/20), 6-,and 9-month survival rates were 58.8%,and 39.2%. Median survival time for all patients was 8.8 months. No complication related to cannulization was found.. Selective continuous transarterial infusion chemotherapy is safe,and has good efficacy in treating patients with advanced pancreatic cancer, it may prolong survival time of patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carboplatin; Deoxycytidine; Doxorubicin; Female; Fluorouracil; Gemcitabine; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Remission Induction; Survival Rate

Topics: Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Combined Modality Therapy; Deoxycytidine; Diagnosis, Differential; Fluorouracil; Gemcitabine; Humans; Leucovorin; Neoadjuvant Therapy; Palliative Care; Pancreatectomy; Pancreatic Neoplasms; Prognosis; Risk Factors

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Pancreatic Neoplasms; Patient Selection; Randomized Controlled Trials as Topic; Time Factors

A 48-year-old male patient was admitted to our institution with left hypochondralgia. Preoperative serum CEA was 504 ng/ml. Under a radiological diagnosis of simultaneous double cancer of the pancreas and lung, resection was performed. Pathological study revealed primary pancreatic cancer with lung metastasis. After the operation, serum CEA fell to 55 ng/ml. Seventeen months later, bowel obstruction occurred and serum CEA was 140 ng/ml. One course of systemic chemotherapy, using the combination of CDDP, 5-FU and Leucovorin, was successful. After another three months, however, the same clinical symptoms occurred. With no response to the prior chemotherapy regimen, surgery was undertaken and a mass at the mesentery was removed. Fifty-nine months have passed since the initial operation and the patient is free of disease, though his serum CEA is around 50 ng/ml. In conclusion, there are cases of pancreatic cancer in which tumor dormancy can be achieved by postoperative 5-FU based chemotherapy.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoembryonic Antigen; Cisplatin; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Pneumonectomy

To explore the feasibility of intraperitoneal (IP) 5-fluorouracil (5-FU) and (IV) leucovorin for patients with advanced pancreatic carcinoma.. Thirty patients (11 men), median age 65 (range 36-74 years), with a non-resectable pancreatic carcinoma in stage III (n=2) and IV (n=28) were treated with IP 5-FU 750-1000 mg/m(2)and leucovorin IV 100 mg/m(2)for 2 days every 3rd week. Tumour effect was analysed with repeated computed tomography (CT) scans, performance status was estimated with Karnofsky's index (KI) and morphine consumption, and toxicity assessed using World Health Organization (WHO) criteria.. Median survival time was 7 months (range 0-21). There was no difference in survival between patients with different grading, staging or tumour size. Regional and systemic toxicity: The treatment was well tolerated, with no grade III or IV complications or side-effects. The median KI showed a minor reduction during treatment. The median morphine consumption per 24 hours increased from 0 mg (range 0-250) at inclusion, to 70 mg (range 0-540) at exclusion. The median nadir (WBC) was 7.2x10(3)/mm(3)(range 5.2-18.8). All patients had abdominal discomfort and distension during IP installation.. Intraperitoneal administration of 5-FU is feasible for patients with nonresectable pancreatic carcinoma. The treatment can induce a temporary stabilization of tumour growth and eventually prolong survival without adverse effects.

Topics: Adult; Aged; Analysis of Variance; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Parenteral; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

Single agents have only modest activity as treatment for metastatic pancreatic cancer with response rates of less than 10% and median survivals of less than 6 months. Evaluations of single-agent gemcitabine and rubitecan as second-line treatment for relapsed pancreatic cancer have reported good patient tolerability and median survivals of 3.85 months and 4.7 months, respectively. Regimens incorporating two drugs have demonstrated encouraging activity and clinical impact compared with single-agent therapy. G-FLIP is a regimen designed to incorporate four active single agents into a tolerable and active combination. This analysis is a retrospective evaluation of the efficacy and safety of the G-FLIP regimen as second-line chemotherapy in a series of consecutively treated patients with metastatic pancreatic cancer.. G-FLIP was administered over 48 hours and repeated every 2 weeks. Day 1 treatment consisted of sequentially administered gemcitabine 500 mg/m(2), irinotecan 80 mg/m(2), leucovorin 300 mg, 5-fluorouracil (5-FU) 400 mg/m(2) bolus followed by infusional 5-FU 600 mg/m(2) over 8 hours. Day 2 treatment consisted of leucovorin 300 mg and 5-FU 400 mg/m(2) bolus, followed by cisplatin 50 to 75 mg/m(2), and then infusional 5-FU 600 mg/m(2) over 8 hours.. Thirty-four patients with histologically confirmed metastatic pancreatic cancer were consecutively treated. The median patient age was 64.5 years (range 41-82 years) and all patients had objective disease progression on prior therapy: 32 patients had disease progression with gemcitabine and 31 had disease progression with a gemcitabine/5-fluorouracil/cisplatin combination. Grade 3-4 hematological toxicities included anemia (23%), thrombocytopenia (53%), and neutropenia (38%). There were no grade 3-4 neutropenic fevers, treatment-related mortalities, or withdrawals. Nonhematological grade 3-4 toxicities were rare: nausea/vomiting (3%), neurotoxicity (3%), nephrotoxicity (6%), and diarrhea (3%). Based on RECIST criteria a partial response (PR) was attained in eight patients (24%) and seven patients had stable disease (SD). Seven and six patients who attained a PR or SD, respectively, had disease progression with prior gemcitabine-based therapy. The median time to disease progression for all 34 patients was 3.9 months and 5.9 months for the eight patients who attained a PR. Median overall survival for all 34 patients was 10.3 months.. Adding a single new drug such as irinotecan to the same first-line chemotherapy combination upon disease progression may be an important alternative to switching to different drug classes for treatment of relapsed/resistant cancer. The promising clinical outcomes and moderate toxicity associated with G-FLIP in this heavily pretreated group warrant development of this novel regimen including tests as first-line therapy in patients with diseases likely to be responsive to the drugs contained in this combination.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Retrospective Studies; Survival Analysis

Most nonendocrine pancreatic neoplasms are adenocarcinomas of ductal cell or acinar origin. Primary carcinomas of the pancreas with squamous differentiation are rare enough to warrant a search for other primary tumors. In the past few decades, well-documented individual reports and large series reviews support the view that these squamous neoplasms are indeed of pancreatic origin and not uncommonly exhibit cystic degeneration. Late manifestation and unfavorable prognosis seem to be uniform features. We report a case with many of these features.

Topics: Abdominal Pain; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma, Squamous Cell; Cholangiopancreatography, Endoscopic Retrograde; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Jaundice; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pancreatic Cyst; Pancreatic Neoplasms; Tomography, X-Ray Computed

(1) To determine the toxicity of an intensified postoperative adjuvant regimen for periampullary adenocarcinoma (pancreatic and nonpancreatic) utilizing concurrent 5-fluorouracil (5-FU), leucovorin (LV), dipyridamole (DPM), and mitomycin-C (MMC) combined with split-course locoregional external beam radiotherapy (EBRT) to 50 Gy. This was followed by 4 cycles of the same chemotherapy as adjuvant therapy. (2) To determine preliminary estimates of the overall and disease-free survival associated with the use of this regimen. (3) To compare the toxicities and early survival results of patients treated with the current regimen to those of patients who completed our prior trial of concurrent chemoradiation infusion with 5-FU/LV chemotherapy and regional nodal and prophylactic hepatic irradiation.. Postpancreaticoduodenectomy, patients received every 4 weeks bolus administration of 5-FU, (400 mg/m(2)), and LV, (20 mg/m(2), Days l-3), DPM (75 mg p.o., 4 times per day, Days 0-3, and every 8 weeks), MMC, (10 mg/m(2); maximum of 20 mg, Day l during EBRT). This was followed by 4 months of the same chemotherapy, beginning 1 month following the completion of EBRT. EBRT consisted of split-course 5000 cGy/20 fractions with a 2-week planned rest after the first 10 fractions (2500 cGy).. From 4/96 to 6/99, 45 patients were enrolled and treated. Their experience constitutes the basis of this analysis. There were 29 patients with pancreatic cancer and 16 with nonpancreatic periampullary cancer. Seventeen patients had tumors of 3 cm or more, and 39 patients had at least 1 histologically involved lymph node. Thirteen patients had a histologically positive margin of resection. The mean time to start of treatment was 63 days following surgery. During chemoradiation therapy there were no Grade 3 or worse nonhematologic toxicities and 47% Grade 3 or Grade 4 hematologic toxicities of short duration. Following chemoradiation, during chemotherapy treatment only, there was one Grade 3 hepatic and one Grade 3 pulmonary toxicity which was nondebilitating (2% each case) and 42% Grade 3 or 4 hematologic toxicity. There were 2 episodes of neutropenic fever requiring admission and no treatment-related mortalities. One patient developed a mild case of HUS, which responded to standard management. One patient developed persistent shortness of breath (nondebilitating), and another patient had occasional dyspnea on exertion, both occurring after all therapy. The majority of patients complained of increased fatigue (Grade 1-2), greatest during the combined therapy and improving post all treatment. As of 6/23/99, 20 of 45 patients have relapsed, 13 in the liver. Twelve patients have died. Median follow-up for surviving patients is 14.3 months. Disease-free survival at 12 months following surgery is 66% (as compared to 25% in our prior study), and the median disease-free survival is 17 months (as compared to 8. 3 months in our prior study). Median survival has not yet been reached, but will be greater than 17 months.. With a 14.3-month median follow-up, acute toxicity has been acceptable and manageable. Observed relapses were seen 9-13 months following surgical resection. Early survival analysis suggests a trend toward increased median disease-free survival (8.3 vs. 17 months), especially for patients with nonpancreatic periampullary adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Dipyridamole; Disease-Free Survival; Duodenal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Neoplasm Recurrence, Local; Pancreatic Neoplasms; Pancreaticoduodenectomy; Radiotherapy Dosage; Radiotherapy, Adjuvant; Time Factors

A 55-year-old man had a metastasis in segment 3 of the liver 5 months after surgery for non-functioning islet cell carcinoma of the pancreas. The metastatic lesion increased in size in a short period, and other liver micro-metastases that could not be detected by imaging may exist, so hepatic arterial infusion chemotherapy was scheduled for 3 months. The patient underwent hepatic arterial infusion chemotherapy of 5-fluorouracil (250 mg/day/body for 5 days/week) and adriamycin (10 mg/day/body for 2 days/week) and cisplatin (10 mg/day/body for 5 days/week) and he was put on Leucovorin 30 mg/day as a biochemical modulator of 5-FU and tamoxifen 40 mg/day as a biochemical modulator of ADM. A total 6,000 mg of 5-FU, 100 mg of ADM and 240 mg of CDDP had been administered, until hepatic arterial infusion chemotherapy was discontinued because of complicated gastric ulcer. Three months later, the size of the metastatic liver tumor was reduced remarkably and no other metastasis was detected on CT scan, so he underwent partial hepatectomy of the metastatic lesion. No recurrence was found and he has survived in good physical condition during the follow-up period of 5 months after the second operation.

Topics: Administration, Oral; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Islet Cell; Cisplatin; Doxorubicin; Drug Administration Schedule; Hepatic Artery; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Tamoxifen

The effectiveness of different regimens of chemotherapy for advanced pancreatic cancer was compared in 74 cases (1995-1999). 5-fluorouracil (5FU), adriamycin and mitomycin C (FAM) were given to 12 patients, 5FU alone--23, 5FU plus leukovorin--29, and gemcitabine alone--10. Metastases to the liver were detected in 42 (57%) patients. Partial response (40) was registered in: FAM--1 (8%); 5FU--1 (4%); 5FU + leukovorin--3 (10%); gemcitabine--3 (30%). Mean duration (40) was 5.4; 4; 6.1 and 9 months, respectively. Stabilization was recorded in 17 (23%), mean duration--4.4 months; tumor progression--49 (66%). Toxic side-effects of all the regimens were insignificant. Mean survival rates following FAM, 5FU, 5FU + leukovorin were 4.4; 4.2 and 5.6 months, respectively, while that for gemcitabine varied 3-24 months (on average--7.9 months). Survival in patients responsive to chemotherapy was 9.8; remaining patients--4.7 (p (0.05). Chemotherapy for advanced pancreatic carcinoma is a measure of palliation; its use was followed by a 20% increase in survival. Gemcitabine treatment appeared most effective.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Doxorubicin; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Palliative Care; Pancreatic Neoplasms; Retrospective Studies; Survival Analysis; Treatment Outcome

The combination of radiotherapy and fluorouracil (5-FU) in patients with locally unresectable pancreatic carcinoma has led to a significant increase in survival in comparison with radiotherapy alone. Doxifluridine (5-DFUR) is an orally active fluoropyrimidine, and its cytotoxic metabolite (5-FU) may concentrate in areas of high tumor vascularization. This trial was carried out with the aims of improving locoregional control and making lesions resectable in patients with unresectable pancreatic cancer.. 5-DFUR was given at a dose of 500 mg/m2 b.i.d. by way of mouth for 4 days every other week for a total of four courses, with leucovorin 25 mg b.i.d. orally being given 2 hours before each 5-DFUR administration. External beam RT was administered at a dose of 1000 cGy per week for 3 weeks, followed by a 2-week break and then by 1000 cGy per week for a further 2 weeks (a total dose of 5000 cGy). The patients were restaged 4 weeks after the end of treatment and explored for resection in cases of partial response (PR).. A total of 32 patients were treated between 1992 and 1997. Ab initio unresectability was shown by laparotomy (16 cases) or computed tomography (16 cases), and was due to vascular invasion in 27 patients, massive regional nodal metastases in nine, and both in four. The median age was 63 years (range 36-71); performance status (PS) (ECOG): 0-1 = 28 and PS 2 = 4. All the patients had measurable disease and were evaluable for response. There were seven PR (22%), 10 SD (31%), and 15 PD (47%). All of the responders underwent surgical exploration, and radical resection was possible in 5. Three of these patients are still disease-free with a follow-up of 18, 27, and 65 months; the other two cases relapsed 11 and 14 months after surgery. The median survival time was 9 months for the entire group, and 1-year survival rate was 31%. The treatment was never stopped because of toxicity. There were no CTC-NCI grade 3 or 4 toxic events; grade 1-2 diarrhea was observed in 10 cases.. This preoperative regimen was feasible and led to a successful surgical resection in 16% of otherwise inoperable cases. The median survival was comparable with the results obtained after 5-FU infusion plus radiotherapy. The resectability rate, and the benefit in terms of survival in the resected patients, make these results worthy of confirmation by larger studies.

Topics: Adult; Aged; Antidotes; Antineoplastic Agents; Combined Modality Therapy; Disease Progression; Feasibility Studies; Female; Floxuridine; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Pancreatectomy; Pancreatic Neoplasms; Survival Rate

Local irresectable carcinoma of the pancreas was diagnosed by explorative laparotomy of a 62-years old patient. At this stage (T3 N1 M0), a curative surgical therapy was not possible. The prognosis in these cases is bad. Medium survival time is less than half a year. In order to improve prognosis a combined radiochemotherapy has been applied. The total tumor dose of 44.8 Gy was applied in 2 daily fractions of 1.6 Gy. On the first 3 days of radiotherapy 600 mg/m2 5-FU and 300 mg/m2 folinic acid were given i.v.. Chemotherapy was repeated each 28 days. After 45 months of observation and application of 20 courses chemotherapy no local or systemical progress can be proven in this patient. His health status is good. A combined radio-chemotherapy improves prognosis in locally irresectable carcinoma of the pancreas. In particular cases survival time is surprisingly long.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Cholangiopancreatography, Endoscopic Retrograde; Dose Fractionation, Radiation; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Particle Accelerators; Prognosis; Radiotherapy Planning, Computer-Assisted

Clinical experiences in interstitial 192-iridium HDR brachytherapy for the treatment of unresectable pancreatic carcinoma are presented. Brachytherapy has been used as boost irradiation in a multimodality treatment concept together with external radiotherapy and simultaneous chemotherapy. Practicability during clinical routine, tolerability and toxicity of treatment are investigated.. Nineteen patients (9 female, 10 male, median age 67 years) with unresectable carcinoma of the pancreas have been treated with interstitial brachytherapy. Distribution according to UICC stages showed 4, 10 and 5 patients in stage II to IV respectively. In all cases afterloading technique with 192-iridium in HDR-modus was used. A total dose of 10 to 34 Gy to the reference isodose was delivered (single dose 1.88 to 5 Gy, median 2.5 Gy). Brachytherapy was followed by external radiotherapy, delivering an additional dose of 40 to 58 Gy. Nine patients received simultaneous chemotherapy (5-fluorouracil, leucovorin). Treatment planning was performed based on CT scans, allowing spatial correlation of isodose curves to the patient's anatomy.. Median survival time was 6 months. A trend of lower survival rates with advanced stage of disease (median survival stage IV 4 months, stage II and III 6.5 months) was seen. Local control rate was 70%. Brachytherapy treatment was well tolerated, severe acute side effects were not observed. One patient developed pancreatic fistulae 4 months and 1 patient a gastric ulcer 7 months after treatment. Pain release was achieved in all patients.. 192-iridium HDR-brachytherapy is an effective tool in the treatment of unresectable pancreatic carcinoma with a high rate of local control and a low rate of side effects and is comparable IORT or seed implantation.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antidotes; Antimetabolites, Antineoplastic; Brachytherapy; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Time Factors; Tomography, X-Ray Computed

A 33 years old woman presented with cramp-like abdominal pain. Ultrasound examination revealed multiple lesions in the liver of hyper- and hypoechoic echogenicity which in accordance to subsequently performed computed tomography and dynamic hepatobiliary scintigraphy were considered to be a focal nodular hyperplasia (FNH). A severe increase of the serum lipase concentration, suspected to be an acute pancreatitis, was treated conservatively and led to a short improvement of symptoms. Some months later, a severe progression of the pain symptoms occurred, along with a measurable expansion of the abdominal circumference and palpable tumors of the liver. The dynamic hepatobiliary imaging and the static liver scan showed a decreased perfusion and function of the nodes as well as a reduced RES activity, respectively. A subsequently performed Positron Emission Tomography (PET) with F-18-Fluorodeoxyglucose (FDG) showed a massively increased glucose metabolism of the liver tumors. The histologic result of several biopsies of the tumors revealed metastases of an acinus cell carcinoma of the pancreas. Under systemic and local chemotherapy, a temporary remission could be obtained that was clearly detectable in a second FDG-PET. Nevertheless, during the further course of the disease, a progression occurred being detectable in an additional control PET-study by an increase in tumor size as well as in tumor glucose metabolism. The patient died in liver coma 15 months after the histologic diagnosis was obtained.

Topics: Adult; Antimetabolites, Antineoplastic; Carcinoma, Acinar Cell; Fatal Outcome; Female; Fluorodeoxyglucose F18; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Pancreatic Neoplasms; Radiopharmaceuticals; Time Factors; Tomography, Emission-Computed; Ultrasonography

The purpose of this study was to develop a satisfactorily tolerated regimen of radiation therapy, continuous infusion 5-fluorouracil, and leucovorin in patients with locally advanced upper-abdominal gastrointestinal cancer.. Patients with locally advanced or locally recurrent gastric, pancreatic, or extrapelvic colon cancer were eligible for this study. Radiation therapy consisted of 45 Gy in 25 fractions to the tumor and regional lymph nodes, followed by 5.4-9 Gy in three to five fractions to the tumor. Treatment with leucovorin, 10 mg orally daily, and continuous infusion 5-fluorouracil was initiated on the first day of radiation therapy. 5-Fluorouracil was administered at an initial daily dose of 125 mg/m2, with dose escalation planned in 25-mg increments, depending on patient tolerance.. Twenty-one evaluable patients participated in this study. Six were treated at the initial daily 5-fluorouracil dose of 125 mg/m2. One patient experienced Grade 4 anorexia and nausea. No other Grade > or = 3 toxicity was observed at this dose. Fifteen evaluable patients were entered at a planned 5-fluorouracil dose of 150 mg/m2 daily; 6 of them experienced Grade 3 toxicity, and none experienced Grade > or = 4 toxicity. Grade 3 toxicities and the number of patients who developed each were: vomiting (three patients); nausea (two patients); diarrhea (two patients); and skin toxicity, hand-foot syndrome, catheter-related infection, and stomatitis in one patient each. Four of the six patients who experienced Grade 3 toxicity developed more than one type of Grade 3 toxicity.. In patients with upper-abdominal gastrointestinal cancer, continuous infusion 5-fluorouracil (150 mg/m2 daily), leucovorin (10 mg orally daily), and radiation therapy (50-54 Gy) resulted in a 40% rate of severe toxicity but no life-threatening toxicity. This clinical trial excludes, with 90% confidence, a 20% risk of Grade 4 toxicity with this combination. The 40% rate of severe toxicity suggests that this combination of agents is near the maximal tolerated dose.

Topics: Antidotes; Antimetabolites, Antineoplastic; Colonic Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm, Residual; Pancreatic Neoplasms; Pilot Projects; Stomach Neoplasms

To study the outcome achieved with three-drug chemotherapy and split-course external-beam radiotherapy as a treatment for unresectable stage II and III pancreatic carcinoma.. Radiotherapy was given in three cycles of 2 Gy/d on days 1 to 5 and 8 to 12 (total dose, 54 Gy) concurrently with fluorouracil (FU) 1,000 mg/m2/d by continuous infusion for 4.5 days, streptozocin (STZ) 300 mg/m2 on days 1, 2, and 3 and cisplatin (P) 100 mg/m2 on day 3 of each every-28-day cycle. Subsequent treatment consisted of leucovorin (LV) 200 mg/m2 and FU 600 to 1,000 mg/m2 every 14 days.. The median survival time for the 35 patients was 15 months and 26% of patients were alive at 24 months. Fifteen patients (42.8%) had objective responses to therapy. Six (17%) had a complete response (CR). Three of nine patients with partial responses (PRs) achieved a radiographic CR within the next 3 months. Nine patients underwent attempts at surgical resection: five were resected (median survival time, 31 months; range, 12.8 to 44.7+), two had no residual disease found at complete resection, and three others also had a complete resection. Of four others who could not be resected, three underwent intraoperative radiotherapy and one had occult metastatic disease. Of primary tumors, 91% did not produce either back pain or local gastrointestinal complications for 2 years. The rates of severe side effects were stomatitis 15%, anemia 14%, granulocytopenia 6%, and thrombocytopenia 6%.. Palliation and survival compare favorably with other series, including many surgical series. The response findings encourage studies of both unresectable and (as neoadjuvant therapy) resectable tumors.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Palliative Care; Pancreatic Neoplasms; Radiotherapy Dosage; Streptozocin; Survival Rate

Recent studies have revealed decreased pancreatic cancer cell growth upon administration of peptide YY (PYY). We examined whether adjuvant treatment with PYY or its synthetic analog, BIM-43004, would decrease human pancreatic adenocarcinoma growth.. Human pancreatic ductal adenocarcinomas, MiaPaCa-2 and BxPC-3, were cultured and assessed for growth by MTT assay. Pancreatic cancer cells received 500 pmol of PYY or BIM-43004 for 24 hours prior to 5-fluorouracil (5-FU; 10 micrograms/mL) and leucovorin (40 micrograms/mL) administration. Cell membrane epidermal growth factor (EGF) receptors were analyzed by Western blotting after exposure to peptides and chemotherapy.. Cancer cell growth was reduced in all groups receiving hormonal pretreatment (23% PYY/5-FU/leucovorin versus control; 27% BIM-43004/5-FU/leucovorin versus control) as compared with groups receiving 5-FU and leucovorin only (16% versus control). The EGF receptor expression was reduced by 30% in cells treated with PYY/5-FU/leucovorin and by 45% in cells treated with BIM/5-FU/leucovorin as compared with control cells without treatment.. Human pancreatic cancer cell growth is further decreased when pretreated with PYY or its synthetic analog prior to chemotherapy.

Topics: Carcinoma, Ductal, Breast; ErbB Receptors; Fluorouracil; Gastrointestinal Hormones; Humans; Leucovorin; Pancreatic Neoplasms; Peptide YY; Peptides; Tumor Cells, Cultured

Systemic chemotherapy in patients who underwent resection of pancreatic carcinoma has not been significantly improved median survival times. We investigated whether regional chemotherapy administered via celiac trunc infusion increases survival rates in patients with locally advanced pancreatic carcinoma after resection of the primary. From 12/1992 to 2/1995 we treated 18 patients with regional chemotherapy consisting of mitoxantrone (d1), 5-FU + folinic acid (d2-4) and CDDP (d5) on five consecutive days. This cycle was repeated up to 6 times. Besides non-symptomatic GI-ulcerations (3/18) no severe side effects were observed. The median survival is actually 17.8 months (regression analysis). Compared to a historical control of our department survival times are significantly prolonged (17.8 vs. 9.3 months, p < 0,0003). In conclusion we state that adjuvant regional chemotherapy in patients with advanced pancreatic cancer is well tolerated and prolongs survival significantly.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intra-Arterial; Leucovorin; Male; Middle Aged; Mitoxantrone; Neoplasm Staging; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy; Survival Rate

The patient was a 44-year-old male with gastric cancer accompanied by pancreatic invasion and metastasis to the periaortic lymph nodes. Combination chemotherapy with 5-FU, leucovorin (LCV) and CDDP (FLP therapy) was preoperatively given. Pancreaticoduodenectomy was carried out as absolutely noncurative resection. FLP therapy was continued postoperatively, and resulted in disappearance of the metastases in the periaortic lymph nodes on CT. As there were no findings of recurrence, the patient was regarded as being in complete response. In addition, the performance status improved from Grade 2 to Grade 0. Since the three-drug combination therapy induced only slight adverse reactions (Grades 1-2), it could be safely carried out at the outpatient department. Thus, combination therapy with 5-FU, LCV and CDDP is thought to be effective against gastric cancer.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Neoplasm Invasiveness; Pancreatic Neoplasms; Remission Induction; Stomach Neoplasms

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Pilot Projects

This Phase I study was designed to build on the Gastrointestinal Tumor Study Group's experience with combined modality therapy in patients with pancreatic cancer. Thirteen patients with adenocarcinoma of the pancreas received weekly 5-fluorouracil by rapid intravenous infusion midway through a 2-h infusion of high dose leucovorin during external beam radiation therapy. Twelve patients received 100% of planned external beam radiation; treatment delays occurred in only three. Four patients received 100% of planned chemotherapy doses. Leukopenia and thrombocytopenia caused reduction of the number of chemotherapy doses given during radiation in six patients; diarrhea, severe nausea and vomiting, and wound abscess caused reduction in three patients. Ten patients were evaluable for response; two had complete responses, one had a partial response, and two had minor responses. In this small series baseline and post-treatment CA 19-9 levels predicted and correlated with response. We conclude that radiation and 5-FU modulated by leucovorin is a tolerable treatment regimen for carcinoma of the pancreas, with preliminary suggestion of activity, that warrants further Phase II testing.

Topics: Adenocarcinoma; Adult; Aged; Antigens, Tumor-Associated, Carbohydrate; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Remission Induction; Survival Analysis; Treatment Outcome

From September 1989 until March 1992 nine patients with unresectable, though localized carcinoma of the pancreas were treated by a multimodality therapy consisting of palliative surgery, interstitial conformal brachytherapy in high-dose rate mode (HDRBT) with iridium-192 up to 30 Gy and external-beam radiation therapy (EBRT) of about 52 Gy. Four patients simultaneously received two cycles of chemotherapy consisting of 5-FU and Leucovorin. Since high radiation doses are applied which are not tolerated in adjacent healthy tissues, doses to tumor and critical areas need to be known precisely and are to be adjusted before treatment. A three-dimensional imaging system is required. A self developed method combines the data of simulation radiographs and those of CT scans. The prescribed minimum target absorbed dose in HDRBT is adjusted to the target volume sparing organs at risk. The specialized quality assurance is adapted to this method. Differences between measured and calculated doses do not exceed 5%. The addition of isodoses of HDRBT and EBRT on CT scans is demonstrated. Due to patients' selection the treatment concept did not reveal any positive effects on survival. However, excellent palliative results were obtained without severe side-effects.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Chemotherapy, Adjuvant; Combined Modality Therapy; Fluorouracil; Humans; Iridium Radioisotopes; Leucovorin; Palliative Care; Pancreatic Neoplasms; Radiotherapy Dosage; Radiotherapy, High-Energy; Time Factors; Tomography, X-Ray Computed

This is a retrospective study to evaluate arterial infusion chemotherapy and radiotherapy for non-resectable pancreatic cancer without liver metastasis. Intra-arterial chemotherapy of the pancreas was performed for 17 patients, and 5 additionally received irradiation therapy. Five patients received radiation therapy alone. Both pain relief and tumor-reduction were more successful compared to the systemic chemotherapy group. In the locoregional treatment group, the patient survival rate was 50% at 1 year and 16% at 2 years. These rates were significantly higher than in the systemic chemotherapy group (p less than 0.01). Among the locoregional treatment groups, the median survival period was 7 months in radiation alone, 12 months in intra-arterial chemotherapy group, and 11 months in intra-arterial chemotherapy plus radiation group. These results suggested that locoregional treatment for pancreatic tumor is effective in increasing survival period and improving the quality of life.

Topics: Angiotensin II; Antineoplastic Combined Chemotherapy Protocols; Catheters, Indwelling; Combined Modality Therapy; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Methotrexate; Pancreatic Neoplasms; Radiotherapy, High-Energy; Retrospective Studies; Survival Rate

Leucovorin and interferon are capable of modulating the cytotoxicity of fluorouracil (5-FU). Preclinical studies demonstrate that d,l-leucovorin is rapidly metabolized in human breast and colon cells into the various one-carbon substituted folate pools and to the polyglutamated state. While increases in intracellular folate pools are proportional to the exposure concentration of leucovorin, relatively large increases in leucovorin concentrations (50- to 100-fold) are required to produce small intracellular changes (twofold). Polyglutamation is favored by prolonged exposures to leucovorin. Polyglutamate forms have a prolonged intracellular retention and a higher affinity for the target enzyme, thymidylate synthase. Ratios of up to 20:1 inactive to active leucovorin stereo-isomers had essentially no effect on the intracellular metabolism of the active isomer. Interferon gamma interacts with 5-FU in H630 colon cancer cells at the level of thymidylate synthase and enhances cytotoxicity of 5-FU by eliminating the 5-FU-induced acute overexpression of the target enzyme. No alterations in the intracellular metabolism or nucleic acid incorporation of 5-FU could be demonstrated with the addition of interferon gamma. A clinical trial combining interferon-alfa-2a (IFN-alpha-2a) (subcutaneous days 1 to 7) with 5-FU and leucovorin (given IV days 2 to 6) demonstrated that these agents could be combined with acceptable toxicity. While the addition of interferon did not allow dose escalation of 5-FU, it resulted in a significant increase in drug exposure (1.5-fold) compared with matched cycles of 5-FU plus leucovorin without interferon. The overall response rate in this pilot study of 13 untreated patients with gastrointestinal adenocarcinoma was 46%, including two complete responses. There were no responses in eight patients who had previously failed therapy with 5-FU.

Topics: Colonic Neoplasms; Colorectal Neoplasms; Drug Administration Schedule; Drug Interactions; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Interferon-gamma; Leucovorin; Neoplasms, Unknown Primary; Pancreatic Neoplasms; Recombinant Proteins; Stomach Neoplasms; Tetrahydrofolates; Tumor Cells, Cultured

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Male; Pancreatic Neoplasms

Leucovorin potentiates the cytotoxicity of fluorouracil (5-FU) in experimental tumor systems and appears to enhance the effectiveness of 5-FU in patients with colon cancer. Twenty-two eligible patients (18 previously untreated) with advanced pancreatic adenocarcinoma were treated in a phase II trial of leucovorin 500 mg/m2/d for 6 days by continuous intravenous infusion with 5-FU 370 mg/m2/d by rapid intravenous injection on 5 consecutive days, beginning 24 hours after initiation of leucovorin infusion. Among the 20 assessable patients, there were no complete or partial regressions, although there was one minor response lasting 4 months. Three patients had stable disease for 5, 20, and 21 months, respectively. Median survival was 10 weeks. Toxicity was predominantly mucosal; stomatitis grade 2 or worse was seen in five patients, and diarrhea grade 2 or worse was seen in four. Hospitalization for toxicity was necessary in four previously untreated patients and three previously treated patients. The median WBC nadir was 4.6 (range, 1.4 to 9.6) x 10(3)/microL, and the median platelet nadir was 147.0 (range, 69.0 to 240.0) x 10(3)/microL. This combination of leucovorin and 5-FU did not demonstrate meaningful therapeutic activity in patients with adenocarcinoma of the pancreas and was associated with moderate to severe toxicity. It should not be considered a standard treatment for patients with this disease.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Pancreatic Neoplasms; Prospective Studies

This study seeks to evaluate arterial infusion chemotherapy and radiotherapy for non-resectable pancreatic cancer with liver metastases. Arterial infusion to the liver was performed in 24 patients, 15 of whom received arterial infusion to the pancreas and 9 of whom underwent irradiation for pancreas tumor (40-50 Gy). However, arterial infusion to the liver alone did not prolong survival, but loco-lesional therapy for the pancreas tumor improved quality of life and resulted in good local control. The survival of the two treatment groups (arterial infusion to the liver combined with loco-regional treatment to the pancreas versus systemic chemotherapy) was statistically different (median 7 months versus 3 months, p less than 0.01). Arterial infusion to the pancreas decreased liver metastases as the first site of failure. These results suggested that arterial infusion to both liver and pancreas combined with irradiation for the pancreas tumor are effective in increasing survival time and improving the quality of life.

Topics: Administration, Oral; Angiotensin II; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Methotrexate; Pancreatic Neoplasms; Radiotherapy, High-Energy

This is a study which evaluates intra-arterial chemotherapy for non-resectable carcinoma of the pancreas without liver metastasis (locally advanced). Twenty-one patients received ia-chemotherapy (MA-CP: Methotrexate + Angiotensin II----Citrovorum factor + Prostaglandin E1). They showed a 39% 1-year survival rate and 92% of 1-year cumulative rate of survival without liver metastasis. These incidences were significantly higher than those of (13%, 50%) 52 patients who underwent systemic chemotherapy (control). As the reason for such significant differences, we suspected that a high dose of chemotherapeutic view after MTX had been infused into the pancreatic-supplying arteries. This speculation was confirmed by the serial determination of the MTX concentration in the portal blood.

Topics: Alprostadil; Angiotensin II; Antineoplastic Combined Chemotherapy Protocols; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Methotrexate; Middle Aged; Mitomycin; Mitomycins; Pancreatic Neoplasms; Portal Vein

Topics: Adenocarcinoma; Animals; Bone Marrow; Colonic Neoplasms; Deoxyuracil Nucleotides; Fluorodeoxyuridylate; Fluorouracil; Humans; Intestinal Mucosa; Leucovorin; Liver; Pancreatic Neoplasms; Rats; Rats, Inbred Strains; Rectal Neoplasms; Stomach Neoplasms; Thymidylate Synthase

Topics: Agranulocytosis; Antineoplastic Agents; Breast Neoplasms; Female; Hemangiosarcoma; Hodgkin Disease; Humans; Kidney Neoplasms; Leucovorin; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Lung Neoplasms; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Male; Melanoma; Methotrexate; Osteosarcoma; Pancreatic Neoplasms; Radiography; Rectal Neoplasms; Rhabdomyosarcoma; Testicular Neoplasms; Thrombocytopenia