Gemcitabine vs. 5-FU After Resection of Pancreatic Cancer

Pancreatic cancer is the fourth most common cause of cancer-related deaths in the U.S., and nearly all patients who develop pancreatic cancer die from the disease. Only 20% of patients present with localized disease that is amenable to curative resection, and most of these patients develop recurrent disease within 2 years after surgery. Adjuvant 5-fluorouracil (5-FU) combined with radiotherapy is the standard of care in the U.S., although the benefit of radiotherapy has been brought into question by results from recent European trials, which showed a survival benefit for adjuvant chemotherapy without radiation. The European trials involved resection of pancreatic cancer followed by treatment with 5-FU or, more recently, gemcitabine (Gemzar; JAMA 2007; 297:267). In the advanced-disease setting, gemcitabine resulted in better antitumor response and survival rates than did 5-FU. U.S. investigators now report a comparison of gemcitabine versus 5-FU in patients who underwent resection and postoperative chemoradiotherapy for pancreatic cancer.

In a Radiation Therapy Oncology Group randomized trial, 451 patients who underwent resection of pancreatic adenocarcinoma (86% pancreatic-head lesions) were assigned to treatment with four cycles of gemcitabine (1000 mg/m² weekly for 3 weeks followed by 1 week off therapy) or four cycles of continuous-infusion 5-FU (250 mg/m² daily for one 3-week cycle and then three 4-week cycles with 2-week breaks in between). All patients received radiation therapy (5040 cGy) after the first cycle of chemotherapy. The primary endpoint was overall survival in the subset of patients with pancreatic-head cancers. A substantial number of patients had T3 or T4 disease (70% in the 5-FU group and 81% in the gemcitabine group), node-positive disease (66% overall), and either positive (34%) or unknown (24%) surgical margins.

Among patients with pancreatic-head tumors, the gemcitabine group had superior median and 3-year overall survival (20.5 months; 31%) compared with the 5-FU group (16.9 months; 22%; hazard ratio, 0.82; P=0.09). After adjustment for pretreatment stratification variables (including nodal status, tumor diameter, and margin status), gemcitabine’s positive effect on 3-year survival was significant (P=0.05). Inclusion of the patients with pancreatic-body and -tail lesions in the survival analysis resulted in median and overall survival rates that did not differ between treatment groups. Although gemcitabine was associated with a higher rate of grades 3 and 4 toxicity (58% vs. 9% for 5-FU; P<0.001), the differences were mainly hematologic and did not result in higher rates of infection or neutropenic fever.