Relative dose intensity of first-line triplet chemotherapy in metastatic colorectal cancer.

PURPOSE: Relative dose intensity (RDI) is a measurement of chemotherapy (CT) dose defined as the actual dose received divided by the standard calculated dose during a set period. The study objective was to assess the impact of a RDI ≥ 80% on response and survival of patients treated in first line CT by FOLFOXIRI or FOLFIRINOX ± Bevacizumab (BV) for an unresectable metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: It was a retrospective, non-interventional, multicenter study calculating RDI from the first cycles of CT to the first CT-scan evaluation (CT-scan1). Objective response and disease control rates (ORR and DCR), progression-free survival (PFS) and overall survival (OS) were compared between patients with RDI ≥ 80% and <80% and results were adjusted for age, gender, ECOG, tumor location, number of metastatic sites, RAS and BRAF status, the CT regimen, the use of BV, the delay from C1 to CT scan1. RESULTS: Among 152 screened patients, 100 met inclusion criteria, with a mean (± standard deviation) age at 59.0 (± 10.7) years. The ECOG performance status was 0-1 in 96 (96%) patients; metastases were synchronous in 95 (95%), RAS and BRAF were mutated in 60 (60%) and 22 (22%), respectively. ORR was observed in 51 (51%) at CT-scan1 with median PFS and OS of 10.5 and 21.9 months, respectively. A RDI ≥ 80% was observed in 44 (44%) patients without impact on ORR (ORa: 1.04, 95% CI: 0.37 to 2.89, p = 0.94) but was significantly associated to improved PFS and OS with HRa 0.50 (95%CI: 0.29 to 0.87, p = 0.013) and 0.52 (95% CI: 0.29 to 0.91, p = 0.023), respectively. CONCLUSION: Our results suggest a low level of FOLFOXIRI or FOLFIRINOX +/- BV exposure in first-line mCRC is associated with a significant trend on PFS and OS.

[Re-visiting the Pronopall score ten years later: A multicenter retrospective study]. / Réévaluation du score Pronopall : une étude rétrospective multicentrique.

INTRODUCTION: The Pronopall score, which distinguishes 3 prognostic groups in patients with advanced cancer, was initially proposed in 2008 and validated in a study published in 2018 but including patients between 2009 and 2010. Since the last decade, cancer management and therapeutic options have progressed. The objective of this study was to confirm the value of this score in patients with digestive and thoracic cancer. METHODS: From July 2019 to November 2020, this retrospective multi-center study included patients with digestive or thoracic cancers who fulfilled the same inclusion criteria as those used in the initial study, and in whom the Pronopall score could be calculated using its four variables (albumin serum level, LDH level, ECOG score, number of metastatic sites). Survival curves were analyzed using the Kaplan-Meier method. RESULTS: One hundred patients were included. According to the Pronopall score, patients were separated into group A (score 8-10, 7 patients), group B (score 4-7, 41 patients) and group C (score 0-3, 52 patients). Median overall survival was 73 days, CI [17-129], 228 days, CI [128-328] and 575 days, CI [432-718] for groups A, B and C, respectively. Survival at 2 months was 28 % for population A, 61 % for population B, and 94 % for population C. CONCLUSION: This study confirms that the Pronopall score still allows clinically relevant discrimination of patients, score C being associated with a good prognosis compared to scores A and B.

Prognostic factors associated with upper gastrointestinal bleeding based on the French multicenter SANGHRIA trial.

Background and study aims Prognostic and risk factors for upper gastrointestinal bleeding (UGIB) might have changed overtime because of the increased use of direct oral anticoagulants and improved gastroenterological care. This study was undertaken to assess the outcomes of UGIB in light of these new determinants by establishing a new national, multicenter cohort 10 years after the first. Methods Consecutive outpatients and inpatients with UGIB symptoms consulting at 46 French general hospitals were prospectively included between November 2017 and October 2018. They were followed for at least for 6 weeks to assess 6-week rebleeding and mortality rates and factors associated with each event. Results Among the 2498 enrolled patients (mean age 68.5 [16.3] years, 67.1 % men), 74.5 % were outpatients and 21 % had cirrhosis. Median Charlson score was 2 (IQR 1-4) and Rockall score was 5 (IQR 3-6). Within 24 hours, 83.4 % of the patients underwent endoscopy. The main causes of bleeding were peptic ulcers (44.9 %) and portal hypertension (18.9 %). The early in-hospital rebleeding rate was 10.5 %. The 6-week mortality rate was 12.5 %. Predictors significantly associated with 6-week mortality were initial transfusion (OR 1.54; 95 %CI 1.04-2.28), Charlson score > 4 (OR 1.80; 95 %CI 1.31-2.48), Rockall score > 5 (OR 1.98; 95 %CI 1.39-2.80), being an inpatient (OR 2.45; 95 %CI 1.76-3.41) and rebleeding (OR 2.6; 95 %CI 1.85-3.64). Anticoagulant therapy was not associated with dreaded outcomes. Conclusions The 6-week mortality rate remained high after UGIB, especially for inpatients. Predictors of mortality underlined the weight of comorbidities on outcomes.

Rationale and Design of the IROCAS Study: Multicenter, International, Randomized Phase 3 Trial Comparing Adjuvant Modified (m) FOLFIRINOX to mFOLFOX6 in Patients With High-Risk Stage III (pT4 and/or N2) Colon Cancer-A UNICANCER GI-PRODIGE Trial.

BACKGROUND: According to the IDEA trial, 6-month adjuvant chemotherapy should remain the treatment standard in stage III T4 or N2 colon cancer. The relatively poor survival in this high-risk subgroup-a 3-year disease-free survival (DFS) rate of 65%-and the potential synergistic efficacy of 5-fluorouracil (5-FU), oxaliplatin, and irinotecan suggest that FOLFIRINOX may be a regimen of particular interest in this setting. PATIENTS AND METHODS: This multicenter international phase 3 trial (ClinicalTrials.gov NCT02967289) being conducted in 49 centers in France and Canada plans to randomize (1:1; minimization method) 640 patients aged 18 to 70 years with Eastern Cooperative Oncology Group performance status ≤ 1. Randomization occurs within 42 days (with treatment initiated within 56 days) after curative-intent R0 surgical resection of a pT4N1 or pT1-4N2 colon adenocarcinoma. Patients will be randomized to receive adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2, and 5-FU 2.4 g/m2 over 46 hours) or modified FOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-FU bolus 400 mg/m2, then 2.4 g/m2 over 46 hours) every 2 weeks for 24 weeks (12 cycles). Patients will be followed for 5 years after the end of adjuvant chemotherapy. A gain of 9% in 3-year DFS (primary end point) is expected (74% in the experimental arm vs. 65% in the control arm; α, 5% [2-sided log-rank test]; 1-ß, 80%). Secondary end points of this study include 2-year DFS, overall survival, and toxicity.

A multicenter phase II study of personalized FOLFIRI-cetuximab for safe dose intensification.

We conducted a multicenter proof of concept phase II trial in patients with advanced colorectal cancer receiving FOLFIRI-cetuximab regimens to explore individual drug tailoring using pharmacogenetics and pharmacokinetics (PK) monitoring. Patients were stratified by their pharmacogenetic/phenotypic status: the irinotecan dose was adjusted according to the number of TA tandem repeats in the UGT1A1 promoter, while the 5-fluorouracil (5-FU) dose was initially adjusted according to dihydropyrimidine dehydrogenase (DPD) activity at initial screening (5-FUODPM Tox) followed by PK-guided dose optimization (5-FUODPM Protocol). An advanced cetuximab PK/pharmacodynamics (PD) study was performed but dosage remained unchanged. Eighty-five patients receiving second-line chemotherapy were enrolled. Mean irinotecan doses at 3 months were 247 ± 50, 210 ± 53 and 140 ± 21 mg/m2 for those with 6/6 (33), 6/7 (26), and 7/7 (7) TATA repeats in the UGT1A1 promoter region, respectively. The 5-FU dose was initially reduced in four patients with DPD deficiency, but mean 5-FU dose at 3 months was 2,412 ± 364 mg/m2 (1,615-3,170 mg/m2). Grade 4 toxicities were not encountered and grade 4 neutropenia occurred in 6.8%, 5.9%, and 0% of patients with 6/6, 6/7, and 7/7 UGT1A1 genotypes. The objective response rate was 25.8% among the 85 patients, 57.3% in patients with tumors wild type (WT) for KRAS, and 25% in those whose tumor harbored a mutant-KRAS. Secondary resection of hepatic metastases was performed in 31.7% of patients. Median progression-free survival (PFS) for all 85 patients was 181 days and 200, 132, and 121 days for patients with 6/6, 6/7, and 7/7 UGT1A1 genotypes, respectively; these differences were not statistically different. In parallel, a strong relationship was shown between cetuximab AUC and regimen efficacy. We conclude that personalized drug tailoring when administering in FOLFIRI + cetuximab allows for safe and efficient individual dose intensification.