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FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer N Engl J Med 2011;364:1817-25. R3 Ye-Ri So / Prof. Seok-Ho Dong BACKGROUND Pancreatic adenocarcinoma: - 4TH leading cause of death from cancer in the US in 2010 - grim prognosis: 5yr survival rate is 6% in Europe and the US Gemcitabine: reference regimen for advanced pancreatic cancer as compared with fluorouracil (5.6 vs. 4.4 months, P = 0.002) The combination of gemcitabine with a variety of cytotoxic and targeted agents: generally shown no significant survival advantage as compared with gemcitabine alone. Some studies have suggested a significant benefit associated with gemcitabine based cytotoxic combinations in patients with good performance status. 2 Irinotecan: against advanced pancreatic cancer. synergistic activity when administered before Fluorouracil and Leucovorin. Oxaliplatin: against pancreatic cancer only when combined with Fluorouracil. Oxaliplatin and Irinotecan: synergistic activity Phase 1 trial: regimen combining “fluorouracil, leucovorin, irinotecan, and oxaliplatin” showed responses in advanced pancreatic cancer. Phase 2 study: FOLFIRINOX regimen (fluorouracil, leucovorin, irinotecan, and oxaliplatin) involving 46 patients with good performance status → associated with encouraging efficacy and grade 3 or 4 neutropenia in half the patients. Phase 2-3 trial: FOLFIRINOX compared with single agent gemcitabine as first-line treatment in patients with metastatic pancreatic cancer. 3 METHODS Patients Inclusion criteria age of 18 yrs or older age of 76 yrs or older histologically and cytologically confirmed, measurable metastatic pancreatic adenocarcinoma endocrine or acinar pancreatic carcinoma previous radiotherapy for measurable lesions cerebral metastases history of another major cancer active infection chronic diarrhea clinically significant history of cardiac disease pregnancy or breast-feeding had not previously been treated with chemotherapy ECOG performance status score of 0 or 1 adequate bone marrow - granulocyte count, ≥1500 - platelet count, ≥100,000 adequate liver function - bilirubin ≤1.5 times the upper limit 4 Exclusion criteria adequate renal function Study Design and Oversight multicenter, randomized, phase 2–3 trial Patients were randomly assigned to receive FOLFIRINOX or gemcitabine Randomization was performed centrally in a 1:1 ratio with stratification according to center, performance status (0 vs. 1), and primary tumor localization (the head vs. the body or tail of the pancreas). Treatment Gemcitabine: at a dose of 1000 mg/m² of BSA, 30-minute iv infusion weekly for 7 weeks, followed by a 1-week rest, then weekly for 3 weeks in subsequent 4-week courses. FOLFIRINOX: oxaliplatin at a dose of 85 mg/m², 2 hr iv infusion, immediately followed by leucovorin at a dose of 400 mg/m², 2 hr iv infusion, after 30 minutes, irinotecan at a dose of 180 mg/m², 90 min iv immediately followed by fluorouracil at a dose of 400/m², iv bolus, followed by a continuous iv infusion of 2400 mg/m² over 46 hr period every 2 weeks. 5 Assessments At the start of every cycle, the patient’s status was assessed according to his or her medical history, complete physical examination by a physician, ECOG performance status, and complete blood counts and blood chemical tests. 6 RESULTS 7 Characteristics of the Patients P = 0.05 8 Response to Therapy 9 Survival 10 11 Adverse Events > > > < 12 CONCLUSIONS As compared with Gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. 13