levoleucovorin and Neuroendocrine-Tumors

A rare appendiceal malignancy is characterized by both glandular and neuroendocrine histology. It often presents with dissemination of the perforated tumor to peritoneal surfaces. Current treatments involve systemic chemotherapy, cytoreductive surgery and perioperative intraperitoneal chemotherapy.. The impact of clinical, histological and treatment-related characteristics on survival were evaluated and subjected to univariate statistical analyses. All patients had stage IV disease and were treated by a uniform treatment strategy. Survival was determined from onset of disease until death or most recent follow-up.. There were 47 patients available for study of whom 17 were male. Median age was 48 with a range of 27-65. None or a single symptom vs. 2 or more symptoms had a significant effect on survival. Median survival of the entire cohort was 45 months and 34.88% and 8.72% of patients survived 5 and 10 years, respectively. The use of neoadjuvant chemotherapy showed no impact on survival. Patients with a peritoneal cancer index (PCI) of 0-20 as compared to PCI > 20 survived longer (p = 0.012). The survival of patients able to have a complete resection as compared to an incomplete resection of disease was significant (p = 0.0087). The type of perioperative chemotherapy did not alter survival.. These data show that patients with a lesser extent of disease with a complete cytoreduction had an improved prognosis. No benefit from systemic or perioperative regional chemotherapy was apparent. With long-term follow-up, patients with the combined glandular and neuroendocrine histology exhibiting peritoneal metastases have a guarded prognosis.

Topics: Adenocarcinoma; Administration, Intravenous; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Appendiceal Neoplasms; Carcinoid Tumor; Cytoreduction Surgical Procedures; Doxorubicin; Female; Fluorouracil; Humans; Hyperthermic Intraperitoneal Chemotherapy; Infusions, Parenteral; Leucovorin; Male; Middle Aged; Mitomycin; Neoadjuvant Therapy; Neoplasm Staging; Neoplasm, Residual; Neoplasms, Complex and Mixed; Neuroendocrine Tumors; Perioperative Period; Peritoneal Neoplasms; Prognosis; Survival Rate; Symptom Assessment

Although the liver is the most common site of metastatic disease from a variety of tumor types, isolated hepatic metastases most commonly occur from colorectal cancer and, less frequently, from neuroendocrine tumors, gastrointestinal sarcoma, ocular melanoma, and others. Complete evaluation of the extent of metastatic disease, both intrahepatically and extrahepatically, is important before considering treatment options. Based on a preponderance of uncontrolled studies for hepatic metastatic colorectal carcinoma, surgical resection offers the only potential for cure of selected patients with completely resected disease, with 5-year survival rates of 25% to 46%. Systemic and hepatic arterial infusion chemotherapy may be useful treatment options in patients with unresectable disease and possibly as an adjuvant treatment after liver resection. Other techniques of local tumor ablation, including cryotherapy and radiofrequency ablation, although promising, remain unproved. Management of hepatic metastases from neuroendocrine tumors and other noncolorectal primary tumors should be individualized based on the patient's clinical course, extent of disease, and symptoms.

Topics: Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Colonic Neoplasms; Fluorouracil; Hepatectomy; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Neoplasm Recurrence, Local; Neuroendocrine Tumors; Rectal Neoplasms; Treatment Outcome

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

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

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

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

Chemotherapy of neuroendocrine tumors must be improved. The most widely used regimen, which combines streptozotocin with fluorouracil, commonly obtains poor results. The best response rate that has been reported for carcinoid tumors is 33%. From July 1991 through September 1994, 18 patients who had advanced neuroendocrine tumors-including nine carcinoid tumors, seven neuroendocrine tumors of unknown primary site, one insulinoma, and one paraganglioma-were treated with a regimen of dacarbazine, 400 mg/m2/day, plus fluorouracil, 1 g/m2/day, with leucovorin, 200 mg/m2/day, for 2 days every 21 days (DTIC-LVFU2 protocol). The results were assessed according to the World Health Organization criteria of toxicity and response. Toxicity was moderate. The most severe side effects were grade 3 vomiting in two patients, grade 3 leukopenia in three patients, and grade 3 mucositis in one patient. The overall response rate was 27%, with only one partial response for carcinoid tumors but one complete and three partial responses for the other tumor types. Efficacy was insufficient in patients who had carcinoid tumors but the combination of dacarbazine with fluorouracil and leucovorin could be an effective regimen for the treatment of neuroendocrine tumors of unknown primary site.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoid Tumor; Dacarbazine; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Male; Middle Aged; Nausea; Neoplasms, Unknown Primary; Neuroendocrine Tumors; Survival Rate

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neuroendocrine Tumors; Recombinant Proteins; Treatment Outcome

Twenty-nine patients with adenocarcinomas of gastrointestinal or unknown primary, and three with advanced neuroendocrine tumours, were entered into a study of bolus plus infusional 5-fluorouracil (FUra) modulated with high-dose leucovorin (LV) and recombinant interferon alpha 2a (IFN-alpha). Successive cohorts of > or = 4 patients received IFN-alpha at 1.5, 3, 4.5, 6 and 9 MU on alternate days throughout the treatment period. The FUra/LV regimen consisted of: LV 200 mg m-2 i.v. infusion over 2 h, FUra 400 mg m-2 i.v. bolus then FUra 400 mg m-2 i.v. infusion over 22 h, all repeated on day 2, on a 14-day cycle. FUra was given at 75% dose for the first course, increasing (in the absence of WHO grade > or = 2 toxicity) to 87.5% for the second and 100% for subsequent courses up to a maximum of 12. The maximum tolerated dose (MTD) of IFN-alpha was 6 MU on alternate days, with 7/8 patients at 9 MU requiring dose reductions. At 6 MU IFN-alpha, the MTD of FUra was not exceeded at 100% (i.e. 400 mg m-2 bolus and infusion, days 1 and 2), and FUra-related toxicities (mucosal, haematological, dermatological) were extremely mild. Twenty-nine patients were assessable for tumour response, among whom WHO criteria partial responses were seen in 7/14 with colorectal, 1/4 with gastric, 0/1 with pancreatic, 1/3 with neuroendocrine and 3/6 with unknown primaries. Median response duration was 51 weeks. Minor responses and stable disease were seen in a further six patients. Median survival of patients with advanced adenocarcinomas was 9 months, with 33% surviving beyond 18 months. This schedule offers a safe way of co-administering FUra, LV and IFN-alpha. The addition of IFN-alpha, while causing significant independent toxicity, does not significantly increase the dose-limiting mucosal toxicities of FUra/LV. Further investigation is required to determine the contribution of IFN-alpha to the anti-tumour activity of the combination.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Infusions, Intravenous; Injections, Intravenous; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasms, Unknown Primary; Neuroendocrine Tumors; Recombinant Proteins

Neuroendocrine tumors (NETs) are highly vascularized neoplasms. While FOLFOX chemotherapy has shown efficacy in patients with advanced NETs, its combination with antiangiogenics has been scarcely described. Here, we report the efficacy and tolerance of FOLFOX-bevacizumab in this setting. We retrospectively studied all consecutive patients with metastatic NET treated by FOLFOX-bevacizumab in two expert centers from 2013 to 2020. We assessed time to treatment failure (TTF), objective response rate (ORR) and toxicity. We explored factors associated with TTF and ORR using multivariate analyses. We included 57 patients (35.1% female, median age 61.7 years), with pancreatic (66.7%), small-intestine (14%) or lung (7%) NETs. Most patients (57.9%) had extra-hepatic metastases and G3 NETs accounted for 40.3% of cases. Patients received a median of 17 cycles of treatment, including a median of seven cycles of bevacizumab and/or 5-fluorouracile maintenance. Median TTF was 15.5 months (95% CI: 9.8-21.2) and was shorter in patients age > 60 years (HR 2.56, 95% CI: 1.16-5.64), p = .020) and >1 previous systemic treatment line (HR 4.15, 95% CI: 1.96-8.78), p < .001). The ORR was 42.9% and was higher in cases of performance status at 0 (OR 5.25, 95% CI: 1.13-24.35), p = .034) and G3 NET (OR 5.39, 95% CI: 1.23-23.52), p = .025). The FOLFOX-bevacizumab combination has promising efficacy in patients with progressive metastatic NETs and notably for G3 NETs, for which optimal treatment as yet remains ill-defined. Hence, it could be a relevant alternative to alkylating-based chemotherapy in this setting and should be further explored prospectively.

Topics: Bevacizumab; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neuroendocrine Tumors; Retrospective Studies

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

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

To assess and report the efficacy of and tolerance to bevacizumab-based chemotherapy in treatment outcome of metastatic poorly differentiated neuroendocrine tumors.. From 2007 to 2018, 11 consecutive patients with metastatic poorly differentiated neuroendocrine treated in first- or second-line with bevacizumab-based chemotherapies were included in this monocentric retrospective cohort. Tumor response was evaluated by computed tomographic scans.. Administered treatment included 5-fluorouracil and irinotecan (FOLFIRI) bevacizumab, 5-fluorouracil and oxaliplatin (FOLFOX) bevacizumab and 5-fluorouracil, oxaliplatin and irinotecan (FOLFIRINOX) bevacizumab for four, two and five patients, respectively. Three were treated in first-line and eight in second-line after cisplatin-etoposide regimen. Using Response Evaluation Criteria in Solid Tumors, partial response was observed for seven patients, and stable disease for one patient, giving a response rate of 63.6% (95% confidence interval=35.2-92.1%) and disease control rate of 72.7% (95% confidence interval=46.6-99.0%). All patients had died by the time of analysis, median progression-free survival was 14 months, and median overall survival was 15.3 months. Observed toxicity with such protocols was classical with 10 grade 3-4 toxic events, including three of hematological toxicity, three of infection, and three of digestive toxicity.. Bevacizumab-based chemotherapy gave surprising efficacy and safety in first-or second-line treatment for metastatic poorly differentiated neuroendocrine tumor in this retrospective cohort. Prospective randomized trials of such therapy are warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neuroendocrine Tumors; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Survival Rate; Treatment Outcome

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

A standardised, effective systemic therapy for metastatic neuroendocrine tumours (NETs) has not been established to date. We reviewed the management of 15 patients with inoperable, metastatic NET treated systematically with a combination chemotherapy regimen of infusional 5-fluorouracil, folinic acid and streptozocin. Overall objective response rate was 53% and tolerability was excellent.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Disease Progression; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neuroendocrine Tumors; Retrospective Studies; Streptozocin; Survival Analysis; Treatment Outcome