Metastatic colorectal carcinoma with signet-ring cells: Clinical, histological and molecular description from an Association des Gastro-Entérologues Oncologues (AGEO) French multicenter retrospective cohort.

BACKGROUND: Metastatic signet-ring cell colorectal carcinoma is rare. We analyzed its clinicopathological and molecular features, prognostic factors and chemosensitivity. METHODS: Retrospective study from 2003 to 2017 in 31 French centers, divided into three groups: curative care (G1), chemotherapy alone (G2), and best supportive care (G3). RESULTS: Tumors were most frequently in the proximal colon (46%), T4 (71%), and poorly differentiated (86%). The predominant metastatic site was peritoneum (69%). Microsatellite instability and BRAF mutation were found in 19% and 9% (mainly right-sided) of patients and RAS mutations in 23%. Median overall survival (mOS) of the patients (n = 204) was 10.1 months (95%CI: 7.9;12.8), 45.1 for G1 (n = 38), 10.9 for G2 (n = 112), and 1.8 months for G3 (n = 54). No difference in mOS was found when comparing tumor locations, percentage of signet-ring cell contingent and microsatellite status. In G1, relapse-free survival was 14 months (95%CI: 6.5-20.9). In G2, median progression-free survival (PFS) was 4.7 months (95%CI: 3.6;5.9]) with first-line treatment. Median PFS was higher with biological agents than without (5.0 vs 3.9 months, p = 0.016). CONCLUSIONS: mSRCC has a poor prognosis with specific location and molecular alterations resulting in low chemosensitivity. Routine microsatellite analysis should be performed because of frequent MSI-high tumors in this population.

Role of FOLFIRINOX and chemoradiotherapy in locally advanced and borderline resectable pancreatic adenocarcinoma: update of the AGEO cohort.

BACKGROUND: 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. METHODS: This is a retrospective multicentre study. We included all consecutive patients with non-pre-treated LAPA or BRPA treated with FOLFIRINOX. RESULTS: 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). CONCLUSIONS: 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.

5-Fluorouracil rechallenge after 5-fluorouracil-induced hyperammonemic encephalopathy.

For several decades, 5-Fluorouracil (5-FU) has been the backbone of many chemotherapy regimens for various tumor types. Its most common side effects are gastrointestinal disorders, mucositis, myelosuppression, hand-foot syndrome, and rarely cardiac toxicity. More rarely, 5-FU infusion can induce hyperammonemic encephalopathy. 5-FU toxicities can be worsened by complete or partial genetic and/or phenotypic dihydropyrimidine dehydrogenase deficiency. Here, we report the case of a patient who initially developed a 5-FU-induced hyperammonemic encephalopathy after receiving FOLFIRINOX (oxaliplatin, irinotecan, folinic acid, and 5-FU) chemotherapy with bevacizumab to treat a metastatic gastrointestinal cancer of unknown primary. Thereafter, the patient was rechallenged successfully by the same chemotherapy regimen (FOLFIRINOX) for more than 6 months with a protocol consisting in a free protein diet, and administration of ammonium chelators, and Krebs and urea cycle intermediates, to prevent further hyperammonemia. We also present a review of the literature on 5-FU rechallenge after 5-FU-induced hyperammonemic encephalopathy.

Trastuzumab in Combination with FOLFIRI in Patients with Advanced HER2-Positive Gastro-Esophageal Adenocarcinoma: A Retrospective Multicenter AGEO Study.

BACKGROUND: Trastuzumab with fluoropyrimidine and cisplatin is the standard first-line treatment in patients with HER2-positive advanced gastro-esophageal adenocarcinoma. However, there are no safety and efficacy data of trastuzumab with FOLFIRI. OBJECTIVE: To evaluate safety and efficacy of FOLFIRI plus trastuzumab in patients with HER2-positive advanced gastro-esophageal adenocarcinoma. PATIENTS AND METHODS: This retrospective multicenter study included all consecutive patients with HER2-positive advanced gastro-esophageal adenocarcinoma treated with FOLFIRI plus trastuzumab between 2012 and 2015. RESULTS: A total of 33 patients (median age, 60.3; performance status 0-1, 78.8%) with HER2-positive advanced gastro-esophageal adenocarcinoma treated with FOLFIRI plus trastuzumab in first (n = 3), second (n = 20) or third (n = 10) line of chemotherapy were included. There was one case of a severe non-hematological adverse event corresponding to a left ventricular systolic dysfunction. The most common hematological grade 3 or 4 adverse events were neutropenia (12.9%) and thrombocytopenia (6.4%). There was no febrile neutropenia. For patients treated with FOLFIRI plus trastuzumab in second-line chemotherapy, the median overall survival was 9.5 months. CONCLUSIONS: This is the first western population-based study of FOLFIRI plus trastuzumab reporting a satisfactory safety profile and a potential efficacy in advanced HER2-positive gastric cancer.

Trastuzumab beyond progression in patients with HER2-positive advanced gastric adenocarcinoma: a multicenter AGEO study.

INTRODUCTION: Trastuzumab in combination with platinum-based chemotherapy is the standard first-line regimen in HER2-positive advanced gastric cancer. However, there are very few data concerning efficacy of continuing trastuzumab beyond first-line progression. METHODS: This retrospective multicenter study included all consecutive patients with HER2-positive advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma who received a second-line of chemotherapy with or without trastuzumab after progression on platinum-based chemotherapy plus trastuzumab. Progression-free survival (PFS) and overall survival (OS) were estimated from the start of second-line chemotherapy using the Kaplan-Meier method and compared using log-rank test. The prognostic variables with P values ≤ 0.05 in univariate analysis were eligible for the Cox multivariable regression model. RESULTS: From May 2010 to December 2015, 104 patients were included (median age, 60.8 years; male, 78.8%; ECOG performance status [PS] 0-1, 71.2%). The continuation (n=39) versus discontinuation (n=65) of trastuzumab beyond progression was significantly associated with an improvement of median PFS (4.4 versus 2.3 months; P=0.002) and OS (12.6 versus 6.1 months; P=0.001. In the multivariate analysis including the ECOG PS, number of metastatic sites and measurable disease, the continuation of trastuzumab beyond progression remained significantly associated with longer PFS (HR, 0.56; 95% CI, 0.35-0.89; P=0.01) and OS (HR, 0.47; 95% CI, 0.28-0.79; P=0.004). CONCLUSION: This study suggests that continuation of trastuzumab beyond progression has clinical benefit in patients with HER2-positive advanced gastric cancer. These results deserve a prospective randomized validation.