Abstract
BackgroundSingle-agent gemcitabine (GEM) is a standard treatment for advanced and metastatic pancreatic cancer. This study examines the question whether GEM-based combination chemotherapy can further improve treatment efficacy.MethodsA meta-analysis was performed to evaluate randomized trials comparing GEM versus GEM+X (X = cytotoxic agent). Fifteen trials including 4465 patients were eligible for an analysis of overall survival, the primary end-point of this investigation.ResultsThe meta-analysis revealed a significant survival benefit for GEM+X with a pooled hazard ratio (HR) of 0.91 (95% CI: 0.85 – 0.97, p = 0.004). The overall test for heterogeneity resulted in p = 0.82 (I2 = 0%). The analysis of platinum-based combinations indicated a HR of 0.85 (95% CI: 0.76 – 0.96, p = 0.010), while for fluoropyrimidine-based combinations the HR was 0.90 (95% CI: 0.81 – 0.99, p = 0.030). No risk reduction was observed in the group of trials combining GEM with irinotecan, exatecan or pemetrexed (HR = 0.99). A meta-analysis of the trials with adequate information on baseline performance status (PS) was performed in five trials with 1682 patients. This analysis indicated that patients with a good PS had a marked survival benefit when receiving combination chemotherapy (HR = 0.76; 95% CI: 0.67 – 0.87; p < 0.0001). By contrast, application of combination chemotherapy to patients with an initially poor PS appeared to be ineffective (HR = 1.08; 95% CI: 0.90 – 1.29, p = 0.40).ConclusionThe meta-analysis of randomized trials indicated a significant survival benefit when GEM was either combined with platinum analogs or fluoropyrimidines. Based on a preliminary subgroup analysis (representing 38% of all patients included in this meta-analysis), pancreatic cancer patients with a good PS appear to benefit from GEM-based cytotoxic combinations, whereas patients with a poor PS seem to have no survival benefit from combination chemotherapy.
Highlights
Single-agent gemcitabine (GEM) is a standard treatment for advanced and metastatic pancreatic cancer
Characteristics of the 15 randomized trials of the metaanalysis This meta-analysis evaluated 4465 patients in 15 randomized trials, of whom 2243 patients were included into the control arm and 2222 patients into the combination arm
Single-agent gemcitabine was generally applied in the control arms: ten trials [3,4,6,7,9,10,12,13,15,17] used the gemcitabine regimen introduced by Burris et al where gemcitabine was given at a dose of 1000 mg/m2 (either as 30-minute infusion or as fixed-dose rate (FDR) infusion with 10 mg/m2/ min) for seven out of eight weeks, followed by a weekly drug application for three out of four weeks [22]
Summary
Single-agent gemcitabine (GEM) is a standard treatment for advanced and metastatic pancreatic cancer. This study examines the question whether GEM-based combination chemotherapy can further improve treatment efficacy. Due to its predominantly late diagnosis, most patients are diagnosed with advanced or metastatic disease at first presentation [1,2]. A median survival of only 3 to 4 months is expected in metastatic disease. Gemcitabine-based two-drug combination chemotherapy in the experimental arm. The availability of adequate survival data was an inclusion criterion for the selected randomized phase II and phase III studies. Single-agent gemcitabine has evolved as a standard of care for treatment of locally advanced and metastatic pancreatic cancer. Treatment effects remain moderate with median overall survival (OS) times in the range of 5 to 8 months and 1-year survival rates in the range of 17–25%
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