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LBA4001 Background: FOLFIRINOX is more effective than gem as first-line treatment in metastatic pancreatic cancer for patients (pts) with good performance status. This trial assessed the benefit of mFOLFIRINOX in the adjuvant setting. Methods: PRODIGE 24/CCTG PA.6 is a phase III multicenter, randomized clinical trial. Pts aged 18-79 years with histologically proven pancreatic ductal adenocarcinomas, 21-84 days after R0 or R1 resection, WHO PS ≤1, adequate hematologic and renal function, and no cardiac ischemia, were eligible. Randomization was stratified by center, pN, R margin status, and post-operative CA 19-9 level (≤ 90 U/mL vs 91-180). Arm A pts received 28-day cycles of gem on days 1, 8, and 15 for 6 cycles. Arm B pts received mFOLFIRINOX (oxaliplatin 85 mg/m², leucovorin 400 mg/m², irinotecan 150 mg/m² D1, and 5-FU 2.4 g/m² over 46 h) every 14 days for 12 cycles. Primary endpoint was disease-free survival (DFS). Secondary endpoints were overall survival (OS), metastasis-free survival (MFS), and adverse events (AE). 490 pts were required to observe 342 events to show a gain in 3-year DFS from 17% to 27% (HR = 0.74) with a two-sided α = 0.05 and 80% power. Hazard ratios (HR) and 95% CI were estimated by a stratified Cox proportional hazard model. We observed 91.5% of the events required. The IDMC approved early ITT analysis before March 15, 2018. Surgical procedures, pathology and postoperative CT scans reports were centrally reviewed. Results: From Apr 2012 to Oct 2016, 493 pts were enrolled in 77 centers: Arm A/B: 246/247. With a median follow up of 30.5 months [m] (95% CI, 29.5-33.7), median DFS was 12.8 (95% CI, 11.7-15.2) in Arm A vs 21.6 m (95% CI, 17.5-26.7) in Arm B, HR = 0.59 (95% CI, 0.47-0.74). The median OS (Arm A/B) was 34.8 (95% CI, 28.6-43.8) vs 54.4 m (95% CI, 41.5- --), HR = 0.66 (95% CI, 0.49-0.89). The median MFS (Arm A/B) was 17.7 (95% CI, 14.2-21.7) vs 30.4 m (95% CI, 21.6- --), HR = 0.59 (95% CI, 0.46-0.76). Grade 3-4 AE (Arm A/B) were reported in 51.1% vs 75.5%, including 12% grade 4 in each arm, with a toxic death in Arm A. Conclusion: Adjuvant mFOLFIRINOX is safe and significantly improves DFS, MFS and OS compared to gem. Clinical trial information: NCT01526135.

ImportanceEarly 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.ObjectiveTo report 5-year outcomes and explore prognostic factors for overall survival.Design, Setting, and ParticipantsThis 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.InterventionsA 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.Main Outcomes and MeasuresPrimary 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.ResultsOf 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.Conclusions and RelevanceThe 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.Trial RegistrationEudraCT: 2011-002026-52; ClinicalTrials.gov Identifier: NCT01526135

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BackgroundImatinib is a long-term, oral, targeted therapy for high-risk resected and advanced gastrointestinal stromal tumours (GIST). It is known that sarcopenia affects prognosis and treatment tolerance in patients with various solid cancers. We analysed lumbar skeletal muscle index changes in imatinib-treated GIST patients. Imatinib tolerance was also assessed to evaluate the influence of pre-treatment sarcopenia.MethodsThirty-one patients with advanced (n = 16) or high-risk resected (n = 15) GIST treated with imatinib (400 mg/day) were analysed retrospectively. Lumbar skeletal muscle indexes were evaluated on computed tomography images obtained before starting imatinib for all patients and at 6 months for those initially sarcopenic. Sarcopenia was defined using consensual cutoffs. Imatinib-induced toxicities were assessed after 3 months of administration.ResultsTwelve (38.7%) of the 31 patients were sarcopenic, including one unassessable at 6 months. Seven (63.6%) of the 11 assessable sarcopenic patients became non-sarcopenic after 6 months of imatinib. Pre-treatment sarcopenia was not associated with grades 3–4 toxicities, but the mean number of all-grade toxicities per sarcopenic patient was significantly higher for those non-sarcopenic (4.1 vs. 1.7, respectively, p < 0.01) after 3 months of treatment. Grades 1–2 anaemia and grades 1–2 fatigue were more frequent for sarcopenic than non-sarcopenic patients (83% vs. 26%, P < 0.01 and 42% vs. 5%, P = 0.02, respectively).ConclusionsSarcopenia is reversible in some GIST patients treated with imatinib. Pre-imatinib sarcopenia is predictive of non-severe toxicities, particularly anaemia and fatigue.