SUMMARY: The American Cancer Society estimates that in 2018, about 55,440 people will be diagnosed with pancreatic cancer and about 44,330 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Curative surgical resection has been shown to significantly improve Overall Survival (OS) when compared to Chemoradiation, for resectable Pancreatic Cancer. The standard surgical procedure for tumors of the Pancreatic head is the Pancreaticoduodenectomy (Whipple procedure), whereas distal Pancreatectomy is performed for tumors of the body or tail of the Pancreas. Previously published studies concluded that 6 months of Gemcitabine based adjuvant therapy improves Overall Survival for patients with resectable Pancreatic Cancer. FOLFIRINOX chemotherapy regimen however, is more effective than Gemcitabine as first-line treatment, in metastatic pancreatic cancer, for patients with good Performance Status. The following study was conducted to assess the benefit of mFOLFIRINOX regimen in the adjuvant setting.
PRODIGE 24/CCTG PA.6 is a phase III multicenter, randomized clinical trial in which 493 patients were enrolled. Eligible patients had histologically proven, nonmetastatic, pancreatic ductal adenocarcinomas, and had undergone R0 (curative resection) or R1(microscopic residual tumor/positive margins) resection, with no residual tumor on a postoperative CT scan. Patients had a WHO Performance Status of 1 or less and were randomized in a 1:1 ratio, 3-12 weeks after surgery, to receive Gemcitabine on days 1, 8, and 15 every 28 days for 6 cycles (Group A, N=246)) or mFOLFIRINOX regimen, which consisted of Oxaliplatin 85 mg/m², Leucovorin 400 mg/m², Irinotecan 150 mg/m² D1, and 5-FU 2400mg/m² over 46 hours, all drugs given IV, every 14 days for 12 cycles (Group B, N=247). The Primary endpoint was Disease Free Survival (DFS) and Secondary endpoints included Overall Survival (OS), Metastasis Free Survival (MFS), and Adverse Events (AE).
After a median follow up of 33.6 months, patients who received mFOLFIRINOX had a median DFS of 21.6 months compared with 12.8 months with Gemcitabine (HR=0.59; P<0.001) and the 3-year DFS was 39.7% with mFOLFIRINOX and 21.4% with Gemcitabine. The median OS was nearly 20 months longer with a mFOLFIRINOX regimen than with Gemcitabine (54.4 months versus 35 months). This represented a 34% reduction in the risk of death with mFOLFIRINOX (HR=0.66; P=0.003). The median MFS with mFOLFIRINOX regimen was 30.4 months versus 17.7 months with Gemcitabine (HR =0.59). Patients receiving mFOLFIRINOX experienced higher rates of grade 3 or 4 Adverse Events than with Gemcitabine for vomiting, diarrhea, fatigue, mucositis and sensory peripheral neuropathy. In the Gemcitabine group, the rate of grade 3/4 Adverse Events was higher for thrombocytopenia and febrile neutropenia.
It was concluded that adjuvant mFOLFIRINOX significantly improves Disease Free Survival, Metastasis Free Survival and Overall Survival, compared to Gemcitabine, after pancreatic cancer resection, in good Performance Status patients and should therefore be considered the new standard of care. It should be noted that patients with pancreatic cancer who undergo surgical resection, are fit enough to undergo this procedure and these patients would be the most likely candidates for mFOLFIRINOX. For those patients whose Performance Status is poor 12 weeks after surgery, and in those with clear contraindications to mFOLFIRINOX regimen, single agent Gemcitabine is an alternative treatment option. 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. Conroy T, Hammel P, Hebbar M, et al. J Clin Oncol 36, 2018 (suppl; abstr LBA4001)