Adjuvant mFOLFIRINOX associated with a significantly longer overall and progression free survival in patients with resected pancreatic ductal adenocarcinoma
In a randomized phase III trial, patients with surgically removed pancreatic cancer who received adjuvant mFOLFIRINOX lived a median of 20 months longer and were cancer-free 9 months longer than those who received standard of care gemcitabine. The superiority of mFOLFIRINOX over gemcitabine was seen in all investigated subgroups, but did come at the cost of increased toxicity. As such, the investigators concluded that mFOLFIRINOX should now be considered a new standard of care after pancreatic cancer resection in patients with a good performance status.
After pancreatic cancer surgery, adjuvant chemotherapy with gemcitabine can substantially prolong survival compared to surgery alone. Gemcitabine has been the standard adjuvant therapy for the past 10 years, but with this treatment almost 75% of patients will still relapse within 2 years illustrating the need for more effective therapies. FOLFIRINOX is more effective than gemcitabine as first-line treatment for metastatic pancreatic cancer patients with a good performance status. A modification of this regimen (mFOLFIRINOX), without a bolus of intravenous fluorouracil is associated with less hematologic toxicity and less diarrhoea, without compromising efficacy. In the study at hand, (PRODIGE 24/CCTG PA.6), this mFOLFIRINOX regimen was compared to gemcitabine as adjuvant therapy in patients with a resected pancreatic ductal adenocarcinoma.
In total, 493 patients with histologically proven pancreatic ductal adenocarcinomas were randomised to mFOLFIRINOX or gemcitabine after a R0 or R1 resection. In order to be eligible for the study, patients had to have a WHO performance status of 0 or 1, have an adequate hematologic and renal function, and were not allowed to have cardiac ischemia. Gemcitabine was given in 28-day cycles on days 1, 8 and 15 for a total of 6 cycles. The mFOLFIRINOX schedule consisted of intravenous oxaliplatin (85 mg/m²), leucovorin (400 mg/m²) and irinotecan (150 mg/m²) on day 1, followed by a continuous infusion of 5-FU (2.4 g/m² over 46 hours every 14 days) for 12 cycles. The primary endpoint of the trial was disease-free survival (DFS), with overall survival (OS), metastasis-free survival (MFS), and toxicity as key secondary objectives.
At a median follow-up of 33.6 months, the median DFS was 21.6 months with mFOLFIRINOX as compared to 12.8 months with gemcitabine (HR[95%CI]: 0.58[0.46-0.73]; p<0.0001). At 3 years, 39.7% of the mFOLFIRINOX treated patients was still disease free as compared to 21.4% with gemcitabine. This benefit was seen in all investigated subgroups. Looking at the OS data it became clear that mFOLFIRINOX treated patients had a median OS that was almost 20 months longer than what was seen in the gemcitabine arm (median OS 54.4 vs. 35 months; HR[95%CI]: 0.64[0.48-0.86]; p=0.003). The OS rate in the mFOLFIRINOX treated cohort was 63.4%, which was 15% higher than the 48.6% seen with gemcitabine. Similarly, the 3-year cancer specific survival was also 15% higher in the mFOLFIRINOX arm (66.2% vs. 51.2%). Finally, mFOLFIRINOX also markedly extended the time until metastases (median MFS 30.4 vs. 17.7 months; HR[95%CI]: 0.59[0.46-0.76]; p< 0.01).
Overall, more patients experienced severe side effects (mainly hematologic) in the mFOLFIRINOX group than in the gemcitabine group (grade 3/4 adverse events: 76% vs. 53%), but the side effects were generally manageable. The most frequent grade 3/4 adverse events seen with mFOLFIRINOX were diarrhoea (18.6% vs. 3.7%; p< 0.001), fatigue (11% vs. 4.6%; p= 0.014), sensory peripheral neuropathy (9.3% vs. 0%; p< 0.001) and vomiting (5.0% vs. 1.2%; p= 0.039). Grade 3/4 thrombocytopenia was more frequently seen with gemcitabine (4.5% vs. 1.3% with mFOLFIRINOX; p= 0.03). Other common side effects of gemcitabine were headache, fever, flu-like symptoms, swelling, and low white blood cell counts. There was no difference in the risk of febrile neutropenia between the two groups. Regrettably one toxic death occurred in the gemcitabine arm.
Conroy T, et al. 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. Presented at ASCO 2018; Abstract LBA4001.