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Gemcitabine vs. 5-FU After Resection of Pancreatic Cancer

After resection of pancreatic cancer, median survival was longer with gemcitabine-based chemotherapy than with 5-FU–based chemotherapy. We still don’t know whether radiation therapy is needed.

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.

Comment: The RTOG trial results reinforce the superiority of gemcitabine over 5-FU in both advanced-disease and adjuvant-therapy settings. However, because European trials showed that adjuvant chemotherapy with either 5-FU or gemcitabine conferred survival benefits without radiation therapy (the magnitude approached that achieved in previous U.S. trials with combined postoperative chemoradiotherapy), the role of radiation therapy remains uncertain. The limited benefit of systemic therapy in pancreatic cancer might undercut any potential local disease control improvement imparted by radiation therapy. In an ongoing trial in Europe, investigators are addressing the role of radiotherapy by comparing gemcitabine alone versus gemcitabine plus radiation therapy after resection of pancreatic cancer.

— David H. Ilson, MD, PhD

Published in Journal Watch Oncology and Hematology March 4, 2008

Citation(s):

Regine WF et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: A randomized controlled trial. JAMA 2008 Mar 5; 299:1019.

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