Unicancer GI PRODIGE 24/CCTG PA.6 trial: A multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas.

Abstract

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.

Borderline resectable pancreatic cancer—At the crossroads of precision medicine

“…However, other guidelines recommend an initial surgical approach, to be followed by chemotherapy . Seemingly supportive of this latter strategy, data from the recently presented Gastrointestinal PRODIGE 24/Canadian Cancer Trials Group PA.6 study revealed that the survival of patients who received adjuvant folinic acid (leucovorin), 5‐fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) after pancreatectomy was 54.4 months, which was longer than that reported in any previously published therapeutic trial for any stage of pancreatic cancer . However, we cannot overemphasize the degree to which the patients enrolled in that trial were super‐selected: all were required to have a postoperative carbohydrate antigen19‐9 level less than 180 U/dL, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no major comorbidity; and all needed to be physiologically suitable to receive FOLFIRINOX within 12 weeks of pancreatectomy.…”

Adjuvant chemotherapy and outcomes in patients with nodal and resection margin‐negative pancreatic ductal adenocarcinoma: A systematic review and meta‐analysis

“…A recent study reported at ASCO this year, which was not included in this meta‐analysis as was not within timeframe studied, describing the results of a phase III randomized clinical trial investigating adjuvant modified 5‐fluorouracil/irinotecan/oxaliplatin (FOLFIRINOX) versus gemcitabine in 493 patients with resected PDAC, reported an improvement in median DFS for the modified FOLFIRINOX arm (21.6 vs 12.8 months respectively). Node positive disease (HR, 1.67; 95% CI, 1.25‐2.22; P < 0.001) and R1 resection status (HR, 1.45; 95% CI, 1.16‐1.81; P = 0.001), were identified as poor prognostic markers for DFS …”

Pancreatic cancer: An update on diagnosis and management

“…FOLFIRINOX (fluorouracil, folinic acid, irinotecan and oxaliplatin) improves disease-free survival when compared with gemcitabine alone (21.6 months versus 12.8 months) but is associated with increased toxicity. 26,27 Gemcitabine plus oral capecitabine is superior to gemcitabine alone (overall survival of 28.0 months versus 25.5 months). 28 The use of neoadjuvant chemotherapy for resectable disease is of uncertain benefit, although there is a trend towards increased use.…”