Background: Gemcitabine (GEM) is the most widely utilized systemic agent in combination with radiation therapy (RT) for treating locally advanced pancreatic cancer (LAPC) in the concurrent setting. Despite recent interest in using two novel oral fluoropyrimidines (FUs), capecitabine and S-1, in this setting, there is a lack of randomized controlled trials (RCTs) to support this approach.
Methods: Trials published between 1994 and 2014 were identified by an electronic search of public databases (Medline, Embase, and the Cochrane Library). All prospective studies were independently identified by two authors for inclusion. Demographic data, treatment response, objective response rate (ORR), progression-free and overall survival (PFS and OS, respectively), and toxicities were extracted and analyzed using comprehensive meta-analysis software (version 2.0).
Results: Twenty-three cohorts with 843 patients were included: 497 patients were treated with GEM and 346 patients were treated with oral FU. Pooled OS was significantly higher at 1 and 2 years for S-1 plus RT than for GEM plus RT (relative risk [RR] 1.27; 95% confidence interval [CI], 1.00–1.65; P=0.03; and RR 1.75; 95% CI, 1.18–2.60, P=0.002, respectively), while 1-year PFS and ORR were not significantly different between S-1 and GEM-based chemoradiotherapy (P=0.37 and P=0.06, respectively). Additionally, comparable efficacy was found between capecitabine and GEM-based chemoradiotherapy in terms of OS, PFS, and ORR. As for grade 3 and 4 acute toxicity, oral FU plus RT significantly reduced the risk of developing hematologic toxicities, nausea, and vomiting when compared to GEM plus RT (P,0.001).
Conclusions: Oral FU plus RT may be a safe and feasible regimen for patients with LAPC, with similar efficacy and low rate of toxicities compared with GEM plus RT. Our findings support the need to compare S-1 with GEM in the concurrent setting in large prospective RCTs due to its potential survival benefits.
Keywords: pancreatic cancer, chemoradiotherapy, oral fluoropyrimidine, gemcitabine, meta-analysis
Pancreatic cancer (PC) is the 12th most commonly diagnosed malignancy, yet it is the eighth leading cause of cancer-related mortality worldwide, with an estimated 266,000 deaths in 2008.1 Of all treatment modalities available for PC, only resection offers an opportunity for a cure. However, only 10%–15% of patients have localized and resectable disease at diagnosis. Approximately 50% of PC patients present with distant metastatic disease, and 30% present with localized and unresectable disease. For these patients, both chemotherapy alone and chemoradiotherapy (CRT) are regarded as acceptable treatment options.2–4 However, randomized controlled trials that compared the two strategies have had conflicting results4,5 and therefore have not been able to define a preferred standard of care.
Currently, both fluoropyrimidines (FU) and gemcitabine (GEM) have been used concurrently with radiation therapy (RT) in patients with locally advanced pancreatic cancer (LAPC). FU drugs including 5-fluorouracil, capecitabine and S-1 have proven to be effective in LAPC treatment. In 1981, a modest prolongation of survival and a median survival of 10 months in LAPC patients treated with 5-fluorouracil-based CRT was reported by the Gastrointestinal Tumor Study Group (GITSG).6 Thus, 5-fluorouracil-based CRT is the most widely used treatment for LAPC.