levoleucovorin and Intestinal-Neoplasms

We report a case of a 59-year-old woman with metastatic carcinoma of the ileocecal region who received FOLFOX(oxaliplatin/leucovorin/5-fluorouracil) and bevacizumab therapy and exhibited a partial remission with minimal side effects. She developed a mild self-limited episode of immune-mediated hemolytic anemia during her 16th cycle of chemotherapy, which precluded her from receiving further oxaliplatin. We review the literature on oxaliplatin-induced immune-mediated hemolysis, including its mechanism, presenting symptoms, laboratory features, management, and implications for future therapy.

Topics: Anemia, Hemolytic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cecal Neoplasms; Drug Hypersensitivity; Female; Fluorouracil; Humans; Hypersensitivity, Delayed; Ileal Neoplasms; Intestinal Neoplasms; Leucovorin; Middle Aged; Organoplatinum Compounds; Oxaliplatin; 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

Several studies have suggested that chemotherapy prolonged survival in patients with metastatic or recurrent small bowel adenocarcinoma (SBA); however, there is still no standard chemotherapy regimen. Here, we evaluated the efficacy and safety of a 5-fluorouracil (5-FU)/L-leucovorin (l-LV)/oxaliplatin (mFOLFOX6) protocol as a first-line therapy for patients with SBA.. This was a multicenter, single-arm, open-label phase II study. Eligibility criteria included histologically confirmed adenocarcinoma, age 20-80 years, and an Eastern Cooperative Oncology Group performance status (PS) of 0-2. The primary endpoint was 1-year progression-free survival (PFS). The secondary endpoints included overall response rate (ORR), overall survival (OS), overall PFS, and safety.. Between April 2010 and November 2012, 24 patients were enrolled from 12 institutions. The median age of the patients was 63 years (range 31-79) and there was a male/female ratio of 18/6. The number of PS 0/1 patients was 17/7 and locally advanced/metastatic disease was seen in 2/22 patients, respectively. The primary tumor site was the duodenum in 14 patients (58%) and jejunum in 10 patients (42%). The median follow-up time was 14.7 months (3.7-40.3). The 1-year PFS was 23.3%. The ORR was 9/20 (45%). The median PFS and OS times were 5.9 months (95% confidence interval [CI] 3.0-10.2) and 17.3 months (95% CI 11.7-19.0), respectively. Major grade 3/4 toxicities were neutropenia (38%), anemia/peripheral neuropathy (25%), and stenosis (17%). There were no treatment-related deaths.. Although the primary endpoint was not met, mFOLFOX6 showed effective and good tolerance as a first-line treatment for SBA.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asian People; Disease-Free Survival; Female; Fluorouracil; Humans; Intestinal Neoplasms; Intestine, Small; Leucovorin; Male; Middle Aged; Neutropenia; Organoplatinum Compounds; Oxaliplatin; 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

Data about the use and effectiveness of targeted therapy in metastatic small bowel adenocarcinoma (SBA) are scarce.. The aim of this population-based study was to obtain insights into the use and effectiveness of targeted therapy in patients with synchronous metastases of SBA.. Data were retrieved from the Netherlands Cancer Registry. Patients treated with palliative chemotherapy and/or targeted therapy for synchronous metastatic SBA between 2007 and 2016 were included (n = 187). Differences in treatment and the subsequent effects on overall survival (OS) were evaluated.. In first-line treatment, 25 patients (13%) received additional targeted therapy, exclusively bevacizumab, and mostly in combination with CAPOX/FOLFOX (n = 24). A primary ileal tumour was predictive for receiving bevacizumab in first-line treatment (odds ratio 3.2, 95% confidence interval (CI) 1.06-9.93). Median OS for patients in whom bevacizumab was added to first-line chemotherapy was 9.3 months, compared to 9.1 months with chemotherapy only (p = 0.85). Median OS for patients receiving first-line treatment only was 8.5 months with and 6.4 months without the addition of bevacizumab, respectively (p = 0.54). In multivariable survival analyses, the addition of bevacizumab was no prognostic factor (hazard ratio 1.01, 95% CI 0.65-1.59).. Bevacizumab was the only prescribed targeted therapy in first-line treatment. Considering the limited number of patients receiving first-line bevacizumab and the unknown reasons to prescribe additional targeted therapy, the corresponding survival rates of patients treated with and without additional bevacizumab in first-line treatment might suggest a limited clinical effect of bevacizumab in addition to first-line palliative chemotherapy on OS. Future research should focus on identifying the subgroup of patients who might benefit from anti-VEGF therapy in metastatic SBA.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Female; Fluorouracil; Humans; Intestinal Neoplasms; Intestine, Small; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Netherlands; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Prognosis; Quinazolines; Registries; Retrospective Studies; Survival Rate

Small bowel adenocarcinoma (SBA) is a rare malignancy affecting approximately 3000 patients per year in the United States, and there is limited evidence prognosticating patients with resected SBA. We aimed to evaluate prognostic factors and the role of adjuvant therapy in patients with resected SBA.. Two hundred forty-one patients who had resected stage I-III SBA were retrospectively identified at a single tertiary referral institution. Overall survival (OS) analysis was performed by the Kaplan-Meier method, and Wilcoxon tests were used for statistical comparisons. Cox proportional hazards were performed to identify significant variables by univariate and multivariate analysis.. Median OS for the entire group was 54.5 months (95% confidence interval [CI], 37.2-81.2 months), with 5- and 10-year OS of 48% and 35%. Median follow-up was 113.7 months (95% CI, 97.9-126.6 months). For patients with stage III disease who received adjuvant therapy, the median OS was 33.8 months (95% CI, 27.8-78.8) compared to 24.7 months (95% CI, 11.5-37.8) for patients with no adjuvant therapy (P < .01). Male sex, advanced T stage, advanced N stage, increased positive lymph node ratio, lymphocyte-to-monocyte ratio < 1.56, presence of residual disease, and earlier date of diagnosis predicted worse survival on univariate analysis. Age > 60 years, lymphocyte-to-monocyte ratio < 1.56, and advanced T stage were identified as independent negative predictors of OS for all patients by multivariate analysis.. Advanced age, advanced T stage, and lymphocyte-to-monocyte ratio < 1.56 independently predicted survival in resected SBA. Adjuvant therapy is associated with improved survival in patients with resected stage III SBA.

Topics: Adenocarcinoma; Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Female; Fluorouracil; Follow-Up Studies; Humans; Intestinal Neoplasms; Intestine, Small; Kaplan-Meier Estimate; Leucovorin; Lymphocyte Count; Male; Margins of Excision; Middle Aged; Monocytes; Neoplasm Grading; Neoplasm Staging; Organoplatinum Compounds; Prognosis; Retrospective Studies; Risk Factors

A 56-year-old woman was diagnosed with rectal cancer and liver metastases(Stage IV), and underwent low anterior resection and laparoscopic partial hepatectomy. The patient received adjuvant chemotherapy(mFOLFOX6 for 24 weeks), but developed multiple lung metastases 11 months later. Before undergoing a pulmonary resection, the patient presented with acute small bowel obstruction. Abdominal computed tomography showed small bowel stenosis due to a tumor, and we suspected peritoneal metastases from the rectal tumor. We performed partial resection of the small intestine, and histopathological examination revealed a primary small bowel tumor. The patient was discharged to her home without complications, and later underwent pulmonary resections for bilateral lung metastases. We usually suspect that small bowel obstruction is due to peritoneal metastases in patients with advanced colorectal tumors, but must consider the rare possibility of a separate primary small bowel tumor, especially in patients with a solitary lesion. We report a rare primary small bowel tumor after FOLFOX treatment in a patient with Stage IV rectal cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Intestinal Neoplasms; Intestine, Small; Leucovorin; Liver Neoplasms; Lung Neoplasms; Middle Aged; Neoplasms, Multiple Primary; Organoplatinum Compounds; Rectal Neoplasms

Standard therapy for advanced small bowel adenocarcinoma (SBA) has not yet been established. The present study assessed the efficacy and safety of chemotherapy (CT) in association with molecular targeting approaches for SBA.. The histories of 33 advanced SBA patients from six different institutions in Japan, who received CT from 2008 to 2016, were retrospectively examined for background, clinical course and outcome.. Median patient age was 65 years (range 39-83). Primary tumor was located in the duodenum in 21 patients (67%), the ampulla of Vater in three patients (9%), the jejunum in seven patients (21%) and the ileum in one patient (3%). Histologically, well-to-moderately and poorly differentiated adenocarcinoma were identified in 20 (61%) and nine (27%) patients, respectively. Thirteen patients received a single CT regimen, seven patients received two types of CT regimen, and 13 patients received three or more CT regimens. As first-line CT, modified FOLFOX6, capecitabine plus oxaliplatin, and S-1 plus cisplatin were employed in 13, 1, and 4 patients, respectively. The response rate (RR) and median progression-free survival (PFS) were 25% and 6.0 months, respectively. Median overall survival (OS) was 13.0 months. Nine out of the 33 patients received bevacizumab-containing CT and three received cetuximab-containing CT. Median OS of bevacizumab-containing CT patients was 21.9 months. No unexpected serious adverse events were observed.. The analysis indicates that combination CT for advanced SBA is associated with modest efficacy and safety, and bevacizumab-containing CT may contribute to favorable outcome in these patients.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Cisplatin; Disease-Free Survival; Drug Combinations; Female; Fluorouracil; Humans; Intestinal Neoplasms; Intestine, Small; Japan; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxonic Acid; Retrospective Studies; Survival Rate; Tegafur

Small bowel adenocarcinomas (SBAs) are rarely seen tumors. Data regarding the use of chemotherapy together with bevacizumab in patients with advanced SBA are lacking. The aim of this study was the evaluation of treatment with bevacizumab in advanced SBA.. Twenty-eight patients from 5 centers with a diagnosis of advanced SBA who received first-line treatments with modified FOLFOX6 (mFOLFOX6; oxaliplatin, leucovorin, and 5-fluorouracil) and FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan) chemotherapy regimens were involved in the study. All patients were divided into 2 groups; those who received bevacizumab together with these chemotherapy regimens (Chemo+Bev group) and those who did not receive bevacizumab (Chemo group).. The median progression-free survival (PFS) and overall survival (OS) times of all population were 8.7 months and 16.9 months, respectively. The overall response rate was 43.7% in the Chemo group and 58.3% in the Chemo+Bev group. The median PFSs in the Chemo and Chemo+Bev groups were found to be 7.7 months and 9.6 months, respectively, and the median OSs were 14.8 months and 18.5 months, respectively. There was not a significant difference between the groups in terms of overall response rate, PFS, and OS.. Although there was no significant difference in any of the outcomes, use of bevacizumab together with chemotherapy is a more effective treatment approach compared with chemotherapy alone, and it does not cause an excess of significant toxicity.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Female; Fluorouracil; Humans; Intestinal Neoplasms; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Survival Analysis

Differential diagnosis of liver lesion in the absence of proven primary tumor is still a challenge. We experienced a case of an asymptomatic 14 cm lesion of right hemiliver in a 67 year-old man submitted to right hepatectomy in December 2010. One year before the patient underwent to endoscopic removal of a tubular adenoma of the right colon. Preoperative diagnosis was supported by ultrasound, CT scan, PET and liver biopsy. The patient received 6 cycles of preoperative chemotherapy (FOLFOX) with down-staging of the lesion diameter. Immunohistochemistry on the surgical specimen showed positivity for cytokeratins 19 and 20, CEA, MUC-2, negativity for cytokeratin 7 and a-fetoprotein. Moreover, the neoplastic cells showed a focal positivity with lower intensity for MUC-1 and MUC-5AC. The immunohistochemical profile suggested the possibility of a metastatic tumour from the large bowel, without excluding a primitive mucinous cholangiocarcinoma with intestinal phenotype. At 6 months after intervention, the patient was submitted to chemotherapy (FOLFOX). At present he is in good condition, without radiological signs of recurrence. Oncologists must evaluate the possible benefits of further adjuvant treatments based on the differential diagnosis between a primitive or metastatic liver tumour. In conclusion, correct diagnosis of liver masses is mandatory and remains a challenge that can differentiate either follow-up or surgical and adjuvant treatment. Histology and immunohistochemistry must be related to clinical findings as they may not always be sufficient to reach a correct final diagnosis, and can even be confusing. At present, molecular biology cannot be considered a helpful for diagnosis in these cases.

Topics: Adenoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Cholangiocarcinoma; Diagnosis, Differential; Fluorouracil; Humans; Immunohistochemistry; Intestinal Neoplasms; Leucovorin; Male; Neoplasms, Second Primary; Neoplasms, Unknown Primary; Organoplatinum Compounds

Small bowel adenocarcinoma (SBA) is a rare tumor with poor prognosis. First-line platinum-based chemotherapy is active in patients with advanced SBA, but data regarding second-line chemotherapy are lacking. The aim of this study was to evaluate the efficacy and tolerability of fluorouracil, leucovorin, and irinotecan (FOLFIRI regimen) as second-line chemotherapy in patients with advanced SBA.. We analyzed all consecutive patients who received second-line chemotherapy with FOLFIRI among 93 patients with advanced SBA included from 1996 to 2008 in a previous retrospective multicenter study. Progression-free survival (PFS) and overall survival (OS) were estimated from the start of second-line chemotherapy using the Kaplan-Meier method. Cox models were applied for multivariate analyses.. Among 51 patients who received second-line chemotherapy, 28 patients (male, 57%; median age, 54 years; metastatic disease, 96%) were treated with FOLFIRI after progression (n = 24) or limiting toxicity (n = 4) to first-line FOLFOX (n = 19) or LV5FU2-cisplatin (n = 9). Grade 3-4 toxicity was observed in 48% of patients (grade 3-4 neutropenia, 37%). After a median follow-up of 21.5 months, all patients had tumor progression, and 22 patients died. Objective response rate was 20%, and disease control rate was 52%. Median PFS and OS were 3.2 and 10.5 months, respectively. No clinical, biological, or tumor characteristics were associated with PFS or OS by multivariate analysis.. Second-line chemotherapy with FOLFIRI produced disease control in half of patients with advanced SBA after failure with first-line platinum-based chemotherapy. Nevertheless, the short median PFS warrants the evaluation of other treatments including targeted therapies.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Humans; Intestinal Neoplasms; Intestine, Small; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Retreatment

Mutations in the DNA mismatch repair (MMR) gene MSH2 cause Lynch syndromes I and II and sporadic colorectal cancers. Msh2(null) mice predominantly develop lymphoma and do not accurately recapitulate the colorectal cancer phenotype.. We generated and examined mice with a conditional Msh2 disruption (Msh2(LoxP)), permitting tissue-specific gene inactivation. ECMsh2(LoxP/LoxP) mice carried an EIIa-Cre transgene, and VCMsh2(LoxP/LoxP) mice carried a Villin-Cre transgene. We combined the VCMsh2(LoxP) allele with either Msh2(Delta7null) (VCMsh2(LoxP/null)) or Msh2(G674D) mutations (VCMsh2(LoxP/G674D)) to create allelic phase mutants. These mice were given cisplatin or 5-fluorouracil/leucovorin and oxaliplatin (FOLFOX), and their tumors were measured by magnetic resonance imaging.. Embryonic fibroblasts from ECMsh2(LoxP/LoxP) mice do not express MSH2 and are MMR deficient. Reverse transcription, polymerase chain reaction, and immunohistochemistry from VCMsh2(LoxP/LoxP) mice demonstrated specific loss of Msh2 messenger RNA and protein from epithelial cells of the intestinal tract. Microsatellite instability was observed in all VCMsh2 strains and limited to the intestinal mucosa. Resulting adenomas and adenocarcinomas had somatic truncation mutations to the adenomatous polyposis coli (Apc) gene. VCMsh2(LoxP/LoxP) mice did not develop lymphoma. Comparison of allelic phase tumors revealed significant differences in multiplicity and size. When treated with cisplatin or FOLFOX, tumor size was reduced in VCMsh2(LoxP/G674D) but not VCMsh2(LoxP/null) tumors. The apoptotic response to FOLFOX was partially sustained in the intestinal mucosa of VCMsh2(LoxP/G674D) animals.. Msh2(LoxP/LoxP) mice in combination with appropriate Cre recombinase transgenes have excellent potential for preclinical modeling of Lynch syndrome, MMR-deficient tumors of other tissue types, and use in drug development.

Topics: Adenocarcinoma; Adenoma; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cisplatin; Colorectal Neoplasms, Hereditary Nonpolyposis; Disease Models, Animal; Drug Resistance, Neoplasm; Fluorouracil; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, APC; Genotype; Immunohistochemistry; Integrases; Intestinal Neoplasms; Leucovorin; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Microsatellite Instability; Mutation; MutS Homolog 2 Protein; Organoplatinum Compounds; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Tumor Burden

Free peritoneal tumor cells (FPTCs) are an independent prognostic factor in patients undergoing curative resection for gastric carcinoma. Whether neoadjuvant chemotherapy (NAC) can eliminate FPTCs in the peritoneal lavage remains unclear. The aim of the study was to determine the effect of NAC on FPTCs.. From 1994 to 2000, data from a total of 61 patients with resectable gastric cancer were analyzed. Peritoneal cytology was performed before NAC at laparoscopy and at tumor resection. A minimum of 6 weeks of NAC, consisting of cisplatin, folinic acid, and fluorouracil, was administered. FPTCs were detected immunohistochemically with Ber-EP4 antibody.. No FPTCs could be detected in 42 patients (69%), compared to 19 (31%) with FPTCs before NAC. During chemotherapy, 10 (24%) of 42 patients developed FPTCs, and 7 (37%) of 19 patients reverted from positive to negative. Patients who became FPTC negative (n = 7) showed an improved median survival (36.1 months) and a longer 2-year survival (71.4%) compared to FPTC-positive patients before and after NAC (n = 12), with a median survival of 9.2 months and a 2-year survival rate of 25%. In contrast, patients who reverted from FPTC negative to positive during NAC (n = 10) had a median survival of 18.5 months and a 2-year survival of only 20%. Multivariate analysis identified ypN category and FPTC change as independent prognostic factors.. NAC for patients with positive cytology could lead to FPTC negativity in a subset of patients and improve their prognosis. However, NAC might be a risky strategy for almost one-quarter of patients whose disease develops positive cytology.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Humans; Intestinal Neoplasms; Laparoscopy; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Neoplastic Cells, Circulating; Peritoneal Cavity; Peritoneal Lavage; Peritoneal Neoplasms; Prospective Studies; Retrospective Studies; Stomach Neoplasms; Survival Rate; Treatment Outcome

This is an account of a case of primary adenocarcinoma of the small intestine with peritoneal dissemination successfully treated with chemotherapy. A 64-year-old woman was admitted with a complaint of severe abdominal distension. Abdominal computerized tomography revealed a bowel obstruction with tumor and the remarkable small bowel dilation of oral side of tumor. The tumor was found at surgery to be at the ileum 15 cm proximal from the ileocecal region. Peritoneal dissemination was recognized around the ileocecal region, so ileum partial resection was performed for the primary cancer lesion and dissemination region. Pathological diagnosis of the resected specimen was adenocarcinoma with lymph nodes metastasis. The peritoneal dissemination consisted of metastatic adenocarcinoma from small intestine. After an operation, internal use of S-1 was performed as adjuvant chemotherapy. But a recurrent lesion at the ovarium was detected 6 months after surgery. The patient was subsequently treated with resection of the ovarium. For lung metastasis, the combination chemotherapy with mFOLFOX6 + bevacizumab was administered. Primary small intestinal adenocarcinoma is a rare disease, and it is often diagnosed as advanced cancer because of few characteristic symptoms. So carcinoma of the small intestine usually has a poor prognosis.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Combined Modality Therapy; Drug Combinations; Female; Fluorouracil; Humans; Ileal Neoplasms; Intestinal Neoplasms; Leucovorin; Lymphatic Metastasis; Middle Aged; Organoplatinum Compounds; Ovarian Neoplasms; Oxonic Acid; Tegafur

Small-bowel adenocarcinoma (SBA) is rare. No standard chemotherapy for this type of cancer has yet been established. At Cancer Institute Hospital (CIH), the chemotherapy regimen used for colorectal cancer is initially used for patients with SBA, followed by that used for gastric cancer.. Patients with advanced or recurrent SBA who had been treated with chemotherapy in CIH were retrospectively analyzed. The first-line treatments were fluoropyrimidines used alone or in combination with other drugs, such as 5-fluorouracil plus leucovorin (FL), UFT-E, or TS-1. The second-line treatment was irinotecan (CPT-11) monotherapy.. Fluoropyrimidine-based regimens, mainly FL, were used for 10 patients. Seven patients received the second-line CPT-11 regimen. Disease control was seen in five patients (50%) with the first-line chemotherapy and in three (43%) with the second-line. The median overall survival time was 12 months (range 3-39). The treatments were generally tolerated. Gastrointestinal symptoms were the most common adverse effects.. Fluoropyrimidines as the first-line and CPT-11 as the second-line chemotherapy yielded low response, although the adverse effects were mild. The FOLFOX and FOLFIRI regimens such as those used for metastatic colorectal cancer are potential alternative strategies. Extensive trials are needed to develop standard chemotherapy with new drugs.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Disease Progression; Female; Fluorouracil; Follow-Up Studies; Humans; Intestinal Neoplasms; Intestine, Small; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Retrospective Studies; Survival Rate; Tomography, X-Ray Computed; Vitamin B Complex

This is an account of a case of primary adenocarcinoma of the small intestine successfully treated with chemotherapy. A 46-year-old man was admitted with a complaint of severe abdominal distension. Abdominal computerized tomography revealed bowel obstruction, and this was found at surgery to be due to a tumor at the jejunum 100 cm distal from the Treitz ligament. Pathological diagnosis of the resected specimen was adenocarcinoma. Although adjuvant chemotherapy with doxifluridine 800 mg/day was given, a recurrent lesion at the abdominal wall was detected 19 months after surgery. Colonoscopy simultaneously revealed stenosis at the descending colon. The patient was subsequently treated with resection of the mass at the abdominal wall, and colostomy was made at the transverse colon to circumvent the stenosis due to peritoneal carcinomatosis. It was not long before another recurrence developed at the abdominal wall with a subsequent rise in tumor markers. mFOLFOX6 (oxaliplatin 85 mg/m2, levofolinate calcium 200 mg/m2, 5-FU 400/2,400 mg/m2) was given, and the patient responded. Primary small intestinal adenocarcinoma is a rare disease with a dismal prognosis. Due to rarity of the disease, clinical trials have not been performed, and little is known about the effect of chemotherapy. The current patient survived for 4 years and 5 months after the diagnosis, owing at least partially to the mFOLFOX6 which was found to be the only active regimen.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Fluorouracil; Humans; Intestinal Neoplasms; Intestine, Small; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Tomography, X-Ray Computed; Treatment Failure

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Fluorouracil; Humans; Intestinal Neoplasms; Intestine, Small; Irinotecan; Leucovorin; Leukemia, Myeloid, Acute; Male; Prognosis; Recurrence; Remission Induction

Topics: Adenocarcinoma; Aged; Carcinoma, Small Cell; Female; Humans; Intestinal Neoplasms; Leucovorin; Lung Neoplasms

To determine the effect of combined treatment with 7-ethyl-10-hydroxycamptothecin (SN-38, the active metabolite of irinotecan) and 5-fluorouracil/ folinic acid (5FU/FA) in vitro using HCT-8 human intestinal adenocarcinoma cells.. Cell survival was examined using colony forming assays. Cell cycle distribution before and after treatment was assessed by flow microfluorimetry. Levels of thymidylate synthase (TS) and topoisomerase I (topo I) in untreated and treated cells were determined by immunoblotting. Changes in deoxynucleotide pools were examined by high-performance liquid chromatography.. Clonogenic assays revealed that colony formation was decreased by 50% after a 24-h exposure to 8+/-2 nM SN-38 or 12+/-3 microM 5FU, the latter being assayed in the presence of 2 microM FA. When treatment with 5FU/FA was followed by SN-38, the cytotoxicity was similar to that observed with 5FU/FA alone. In contrast, when HCT-8 cells were exposed to both agents simultaneously or to SN-38 followed by 5FU/FA, the cytotoxicity was greater than that of SN-38 or 5FU/FA treatment alone. Investigation of the mechanistic basis for this sequence dependence revealed that SN-38 treatment was associated with a dose- and time-dependent decrease in conversion of [5-3H]-2'-deoxyuridine to [3H]-H2O and thymidylate in intact cells. Immunoblotting failed to reveal any decrease in TS protein that could account for the decreased activity. High-performance liquid chromatography revealed that SN-38 treatment was associated with increased levels of the deoxynucleotide dTTP and decreased levels of dUTP. Flow microfluorimetry revealed that a 24-h treatment wit 10 nM SN-38 resulted in accumulation of HCT-8 cells in late S and G2 phases of the cell cycle, with a further increase in the G2 fraction during the 24 h after SN-38 removal.. These observations are consistent with a model in which SN-38 sequentially induces diminished DNA synthesis, elevated dTTP pools, inhibition of dUMP synthesis and enhanced toxicity of 5FU/FA. Accordingly, sequencing of irinotecan and 5FU/FA might be important in combining these agents into an effective treatment for colorectal cancer.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cell Cycle; Cell Survival; Deoxyuracil Nucleotides; DNA Topoisomerases, Type I; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Fluorouracil; Humans; Intestinal Neoplasms; Irinotecan; Leucovorin; Thymidylate Synthase; Thymine Nucleotides; Topoisomerase I Inhibitors; Tumor Cells, Cultured

1843U89 is a potent inhibitor (Ki = 0.09 nM) of thymidylate synthase (TS; EC 2.1.1.45) that is in clinical trial for the treatment of solid tumors. Although it is an excellent substrate for the folate anabolizing enzyme folylpolyglutamate synthetase (FPGS), 1843U89 differs from other folate-based inhibitors of TS (e.g., CBC3717, D1694, and LY231514), in that the parent compound is as potent an enzyme inhibitor as its polyglutamated analogues. As reported (D.S. Duch et at., Cancer Res., 53:810-818, 1993), 1843U89 is 10-80-fold more cytotoxic than the close structural analogue 1031U89, which is an equipotent inhibitor of TS but is a less efficient substrate for FPGS. This correlation between substrate efficiency for FPGS and cytotoxicity suggests that polyglutamation of 1843U89 contributes to its cytotoxicity. In the current study, we measured intracellular levels of polyglutamated anabolites of 1031U89, 1843U89, and three other benzoquinazoline inhibitors of TS as well as anabolites of D1694 in HCT-8 ileocecal carcinoma cells. Each TS inhibitor was anabolized to polyglutamated analogues with one to five added glutamyl residues after exposure for 24 h to IC90 concentrations (those that inhibit growth by 90% after 72 h of constant exposure). D1694, which requires polyglutamation for potent enzyme inhibition as well as for cytotoxicity, was anabolized mostly to penta- and hexaglutamates, whereas approximately 80% of intracellular 1843U89 was the diglutamate analogue. The substrate efficiency of the benzoquinazolines for FPGS was predictive of the extent of intracellular anabolism. The diglutamate analogue of 1843U89 was only 1/100 as efficient a substrate for further glutamation as was 1843U89 itself. The efficient anabolism to the diglutamate analogue and the lack of dependence on further polyglutamation for enzyme inhibition or cytotoxicity provide a rationale for the reported 1843U89 sensitivity of cells with impaired FPGS activity. As part of an investigation of the effects of polyglutamation, we measured the retention of intracellular 1843U89 and D1694 anabolites after 24 h of exposure to 20 nM of each compound. After 48 h in drug-free medium, 7% of intracellular 1843U89 (mostly diglutamate analogue) and 36% of D1694 (mostly penta- and hexaglutamates) remained in the cells. Because prolonged retention (associated with tissue storage of polyglutamates) can contribute to clinical toxicities, 1843U89 may present fewer long-term toxicities than D1694.

Topics: Animals; Carcinoma; Enzyme Inhibitors; Folic Acid; Folic Acid Antagonists; Humans; Indoles; Intestinal Neoplasms; Isoindoles; Leucovorin; Liver; Metabolic Clearance Rate; Peptide Synthases; Polyglutamic Acid; Quinazolines; Swine; Thymidylate Synthase; Tumor Cells, Cultured

The cytotoxicity and molecular effects of antifolate thymidylate synthase inhibitor, ICI-D1694, against human ileocecal carcinoma, were evaluated. The drug concentration for 50% inhibition of cell growth by ICI-D1694 is 73 nM and 3 nM following 2 hr and 72 hr exposure, respectively. The drug induces high level of DNA single strand breaks in a time dependent manner, but subsequent to maximum inhibition of thymidylate synthase. Drug effects can be reversed by thymidine and leucovorin at > 1 microM concentrations. Leucovorin action is primarily at the cell membrane level, competing with the transport and activation of ICI-D1694. Thymidine, however, exerts its competitive effect primarily at the level of thymidylate synthase.

Topics: Antimetabolites, Antineoplastic; Carcinoma; Dose-Response Relationship, Drug; Drug Interactions; Evaluation Studies as Topic; Humans; Intestinal Neoplasms; Leucovorin; Quinazolines; Thiophenes; Thymidine; Thymidylate Synthase; Tumor Cells, Cultured

Topics: Adenocarcinoma; Angina Pectoris; Electrocardiography; Female; Fluorouracil; Heart; Heart Diseases; Humans; Hypotension; Intestinal Neoplasms; Intestine, Small; Leucovorin; Middle Aged; Syndrome; Tachycardia; Ventricular Function, Left

Twelve patients with primary small intestinal lymphoma were followed prospectively for 3 years. Endoscopic abnormalities were diagnostic of lymphoma in all cases where the duodenum was involved (83%). In three cases (25%) the disease extended to the stomach. One patient (8%) had diffuse small cell cleaved and 11 (92%) diffuse large cell lymphoma stages I (8%), II (25%), III (58%) and IV (8%). Nine of them were unresectable and primarily treated with combination chemotherapy; 67% achieved complete remission, 22% partial response and 11% no response. Only one patient relapsed and achieved a second remission. All complete remission patients are currently alive and free of disease at a median follow-up of 36 months. Overall survival for all patients is 58%, and disease-free survival is 50%. No instance of chemotherapy-related bleeding or perforation was seen. Tetracycline was necessary for the treatment of IPSID-associated diarrhea and malabsorption in spite of cytotoxic chemotherapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Follow-Up Studies; Humans; Intestinal Neoplasms; Intestine, Small; Leucovorin; Lymphoma; Male; Methotrexate; Middle Aged; Prednisone; Prospective Studies; Saudi Arabia; Vincristine

High-dose methotrexate was given to 28 patients with advanced malignant melanoma who had previously failed to respond to two chemotherapy protocols. There were five instances of serious, but not fatal, toxicity. One patient has had an objective response and seven patients have had stabilization of disease with an average duration of 4 months.

Topics: Adult; Aged; Female; Humans; Intestinal Neoplasms; Leucovorin; Leukopenia; Male; Melanoma; Methotrexate; Middle Aged; Skin Neoplasms

Topics: Adenocarcinoma; Blood Cell Count; Blood Chemical Analysis; Bone Marrow Examination; Carcinoma; Carcinoma, Papillary; Carcinoma, Squamous Cell; Drug Therapy; Facial Neoplasms; Hematopoiesis; Hemoglobinometry; Infusions, Intra-Arterial; Injections, Intra-Arterial; Injections, Intramuscular; Intestinal Neoplasms; Leucovorin; Methotrexate; Mouth Neoplasms; Myxosarcoma; Toxicology; Urine; Urogenital Neoplasms