Chemotherapy for advanced gastric cancer

Abstract

BACKGROUND: Gastric cancer is the fifth most common cancer worldwide. In "Western" countries, most people are either diagnosed at an advanced stage, or develop a relapse after surgery with curative intent. In people with advanced disease, significant benefits from targeted therapies are currently limited to HER-2 positive disease treated with trastuzumab, in combination with chemotherapy, in first-line. In second-line, ramucirumab, alone or in combination with paclitaxel, demonstrated significant survival benefits. Thus, systemic chemotherapy remains the mainstay of treatment for advanced gastric cancer. Uncertainty remains regarding the choice of the regimen. OBJECTIVES: To assess the efficacy of chemotherapy versus best supportive care (BSC), combination versus single-agent chemotherapy and different chemotherapy combinations in advanced gastric cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE and Embase up to June 2016, reference lists of studies, and contacted pharmaceutical companies and experts to identify randomised controlled trials (RCTs). SELECTION CRITERIA: We considered only RCTs on systemic, intravenous or oral chemotherapy versus BSC, combination versus single-agent chemotherapy and different chemotherapy regimens in advanced gastric cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently identified studies and extracted data. A third investigator was consulted in case of disagreements. We contacted study authors to obtain missing information. MAIN RESULTS: We included 64 RCTs, of which 60 RCTs (11,698 participants) provided data for the meta-analysis of overall survival. We found chemotherapy extends overall survival (OS) by approximately 6.7 months more than BSC (hazard ratio (HR) 0.3, 95% confidence intervals (CI) 0.24 to 0.55, 184 participants, three studies, moderate-quality evidence). Combination chemotherapy extends OS slightly (by an additional month) versus single-agent chemotherapy (HR 0.84, 95% CI 0.79 to 0.89, 4447 participants, 23 studies, moderate-quality evidence), which is partly counterbalanced by increased toxicity. The benefit of epirubicin in three-drug combinations, in which cisplatin is replaced by oxaliplatin and 5-FU is replaced by capecitabine is unknown.Irinotecan extends OS slightly (by an additional 1.6 months) versus non-irinotecan-containing regimens (HR 0.87, 95% CI 0.80 to 0.95, 2135 participants, 10 studies, high-quality evidence).Docetaxel extends OS slightly (just over one month) compared to non-docetaxel-containing regimens (HR 0.86, 95% CI 0.78 to 0.95, 2001 participants, eight studies, high-quality evidence). However, due to subgroup analyses, we are uncertain whether docetaxel-containing combinations (docetaxel added to a single-agent or two-drug combination) extends OS due to moderate-quality evidence (HR 0.80, 95% CI 0.71 to 0.91, 1466 participants, four studies, moderate-quality evidence). When another chemotherapy was replaced by docetaxel, there is probably little or no difference in OS (HR 1.05; 0.87 to 1.27, 479 participants, three studies, moderate-quality evidence). We found there is probably little or no difference in OS when comparing capecitabine versus 5-FU-containing regimens (HR 0.94, 95% CI 0.79 to 1.11, 732 participants, five studies, moderate-quality evidence) .Oxaliplatin may extend (by less than one month) OS versus cisplatin-containing regimens (HR 0.81, 95% CI 0.67 to 0.98, 1105 participants, five studies, low-quality evidence). We are uncertain whether taxane-platinum combinations with (versus without) fluoropyrimidines extend OS due to very low-quality evidence (HR 0.86, 95% CI 0.71 to 1.06, 482 participants, three studies, very low-quality evidence). S-1 regimens improve OS slightly (by less than an additional month) versus 5-FU-containing regimens (HR 0.91, 95% CI 0.83 to 1.00, 1793 participants, four studies, high-quality evidence), however since S-1 is used in different doses and schedules between Asian and non-Asian population, the applicability of this finding to individual populations is uncertain. AUTHORS' CONCLUSIONS: Chemotherapy improves survival (by an additional 6.7 months) in comparison to BSC, and combination chemotherapy improves survival (by an additional month) compared to single-agent 5-FU. Testing all patients for HER-2 status may help to identify patients with HER-2-positive tumours, for whom, in the absence of contraindications, trastuzumab in combination with capecitabine or 5-FU in combination with cisplatin has been shown to be beneficial. For HER-2 negative people, all different two-and three-drug combinations including irinotecan, docetaxel, oxaliplatin or oral 5-FU prodrugs are valid treatment options for advanced gastric cancer, and consideration of the side effects of each regimen is essential in the treatment decision. Irinotecan-containing combinations and docetaxel-containing combinations (in which docetaxel was added to a single-agent or