Comparing cytotoxic backbones for first-line trastuzumab-containing regimens in human epidermal growth factor receptor 2-positive advanced oesophagogastric cancer: A meta-analysis

According to the Trastuzumab for Gastric Cancer (ToGA) study, trastuzumab plus cisplatin and capecitabine/5-fluorouracil (5-FU) is standard first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive advanced oesophagogastric cancer. We examined the relative efficacy and safety of alternative trastuzumab-based cytotoxic backbone regimens compared to the standard ToGA regimen using meta-analysis. We searched Medline, EMBASE, CENTRAL and ASCO and ESMO up to March 2017 for studies investigating alternative first-line trastuzumab-based regimens for HER2-positive oesophagogastric cancer, defined as high protein expression IHC3+ or IHC2+ and gene amplification by in situ hybridisation. We compared primary outcome overall survival (OS) of alternative trastuzumab-based regimens to the ToGA regimen. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were calculated by extraction of the published Kaplan-Meier curves. Incidence counts and toxicity sample-sizes were extracted for adverse events and compared using single-arm proportion meta-analysis in R. Fifteen studies (N = 557 patients) were included. OS was significantly longer with regimen trastuzumab plus doublet oxaliplatin and capecitabine/5-FU (median OS = 20.7 months) versus ToGA (16.0 months, HR = 0.75, 95% CI = 0.59-0.99) and was less toxic. Trastuzumab plus doublet cisplatin and S-1 showed no OS difference versus ToGA, but showed a different toxicity profile, including less hand-foot syndrome. Trastuzumab plus cisplatin or capecitabine as singlet backbone showed significantly worse survival and more toxicity versus ToGA regimen. Trastuzumab with triplet cytotoxic backbones or with bevacizumab and doublet cytotoxic backbone showed no survival benefit and more toxicity. In conclusion, trastuzumab plus doublet cytotoxic backbone containing oxaliplatin is preferable over the ToGA regimen with cisplatin. S-1 can substitute capecitabine or 5-FU when specific toxicities are encountered.