The efficacy and safety of gemcitabine-based combination therapy vs. gemcitabine alone for the treatment of advanced pancreatic cancer: a systematic review and meta-analysis

Background: Gemcitabine (GEM) is used as a standard first-line drug to effectively alleviate symptoms and prolong survival time for advanced pancreatic cancer. Most randomized controlled trials (RCTs) show that GEM-based combination therapy is better than GEM alone, while some RCTs have the opposite conclusion. This study aimed to investigate whether GEM-based combination therapy would be superior to GEM alone by a systematic review and meta-analysis.Methods: According to the PICOS principles, RCTs (S) focused on comparing GEM-based combination therapy (I) vs. GEM alone (C) for advanced pancreatic cancer (P) were collected from eight electronic databases, outcome variables mainly include survival status and adverse events (AEs) (O). Review Manager 5.4 was used to evaluate the pooled effects of the results among selected articles. Pooled estimate of hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) were used as measures of effect sizes. Quality assessment for individual study was performed using the Cochrane tool for risk of bias.Results: A total of 17 studies including 5,197 patients were selected in this analysis. The pooled results revealed that GEM-based combination therapy significantly improved the overall survival (OS; HR =0.84; 95% CI: 0.79 to 0.90; P<0.001), progression-free survival (PFS; HR =0.78; 95% CI: 0.72 to 0.84; P<0.001), overall response rate (ORR; OR =1.92; 95% CI: 1.61 to 2.30; P<0.001), 1-year survival rate (OR =1.44; 95% CI: 1.02 to 2.03; P=0.04), respectively. Subgroup analysis showed that the efficacy of GEM plus capecitabine (CAP) and GEM plus S-1 was better than that of GEM alone, while GEM plus cisplatin (CIS) did not achieve an improved effect. GEM-based combination therapy can significantly increase the incidence of AEs, such as leukopenia (P<0.001), neutropenia (P<0.001), anemia (P<0.05), nausea (P<0.001), diarrhea (P<0.05), and stomatitis (P<0.001). No publication bias existed in our meta-analysis (P>0.10). Discussion: Our study supported that GEM-based combination therapy was more beneficial to improve patient's survival than GEM alone, while there was no additional benefits in GEM plus CIS. We also found that GEM-based combination therapy increased the incidence of AEs. Clinicians need to choose the appropriate combination therapy according to the specific situation.