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A Randomized Controlled Trial

William F. Regine, MD; Kathryn A. Winter, MS; Ross A. Abrams, MD; Howard Safran, MD; John P. Hoffman, MD; Andre Konski, MD; Al B. Benson, MD; John S. Macdonald, MD; Mahesh R. Kudrimoti, MD; Mitchel L. Fromm, MD; Michael G. Haddock, MD; Paul Schaefer, MD; Christopher G. Willett, MD; Tyvin A. Rich, MD

JAMA. 2008;299(9):1019-1026.

Context  Among patients with locally advanced metastatic pancreatic adenocarcinoma, gemcitabine has been shown to improve outcomes compared with fluorouracil.

Objective  To determine if the addition of gemcitabine to adjuvant fluorouracil chemoradiation (chemotherapy plus radiation) improves survival for patients with resected pancreatic adenocarcinoma.

Design, Setting, and Participants  Randomized controlled phase 3 trial of patients with complete gross total resection of pancreatic adenocarcinoma and no prior radiation or chemotherapy enrolled between July 1998 and July 2002 with follow-up through August 18, 2006, at 164 US and Canadian institutions.

Intervention  Chemotherapy with either fluorouracil (continuous infusion of 250 mg/m² per day; n = 230) or gemcitabine (30-minute infusion of 1000 mg/m² once per week; n = 221) for 3 weeks prior to chemoradiation therapy and for 12 weeks after chemoradiation therapy. Chemoradiation with a continuous infusion of fluorouracil (250 mg/m² per day) was the same for all patients (50.4 Gy).

Main Outcome Measures  Survival for all patients and survival for patients with pancreatic head tumors were the primary end points. Secondary end points included toxicity.

Results  A total of 451 patients were randomized, eligible, and analyzable. Patients with pancreatic head tumors (n = 388) had a median survival of 20.5 months and a 3-year survival of 31% in the gemcitabine group vs a median survival of 16.9 months and a 3-year survival of 22% in the fluorouracil group (hazard ratio, 0.82 [95% confidence interval, 0.65-1.03]; P = .09). The treatment effect was strengthened on multivariate analysis (hazard ratio, 0.80 [95% confidence interval, 0.63-1.00]; P = .05). Grade 4 hematologic toxicity was 1% in the fluorouracil group and 14% in the gemcitabine group (P < .001) without a difference in febrile neutropenia or infection. There were no differences in the ability to complete chemotherapy or radiation therapy (>85%).

Conclusions  The addition of gemcitabine to adjuvant fluorouracil-based chemoradiation was associated with a survival benefit for patients with resected pancreatic cancer, although this improvement was not statistically significant.

Trial Registration  clinicaltrials.gov Identifier: NCT00003216

Author Affiliations: Department of Radiation Oncology, University of Maryland Medical Center, Baltimore (Dr Regine); Radiation Therapy Oncology Group, Philadelphia, Pennsylvania (Ms Winter); Rush University Medical Center, Chicago, Illinois (Dr Abrams); Division of Hematology-Oncology, Brown University, Providence, Rhode Island (Dr Safran); Fox Chase Cancer Center, Philadelphia, Pennsylvania (Drs Hoffman and Konski); Division of Hematology-Oncology, Northwestern University, Chicago, Illinois (Dr Benson); St Vincent's Cancer Care Center, New York, New York (Dr Macdonald); Department of Radiation Medicine, University of Kentucky, Lexington (Dr Kudrimoti); Akron General Medical Center, Akron, Ohio (Dr Fromm); Mayo Clinic, Rochester, Minnesota (Dr Haddock); Natalie Warren Cancer Center, Tulsa, Oklahoma (Dr Schaefer); Department of Radiation Oncology, Duke University, Durham, North Carolina (Dr Willett); and Department of Radiation Oncology, University of Virginia, Charlottesville (Dr Rich).

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