Abstract: We identified 41 RCTs with 11,853 participants for inclusion in the review as well as 49 ongoing studies. For the main comparison of adding a cytostatic and/or targeted agent to a control arm, we included 11 studies with 1347 participants. This analysis demonstrated an increase in overall survival in favor of the arm with an additional cytostatic or targeted therapeutic agent with a hazard ratio (HR) of 0.75 (95% confidence interval (CI) 0.68 to 0.84, high-quality evidence). The median increased survival time was one month. Five studies in 750 participants contributed data to the comparison of palliative therapy versus best supportive care. We found a benefit in overall survival in favor of the group receiving palliative chemotherapy and/or targeted therapy compared to best supportive care (HR 0.81, 95% CI 0.71 to 0.92, high-quality evidence). Subcomparisons including only people receiving second-line therapies, chemotherapies, targeted therapies, adenocarcinomas, and squamous cell carcinomas all showed a similar benefit. The only individual agent that more than one study found to improve both overall survival and progression-free survival was ramucirumab. Palliative chemotherapy and/or targeted therapy increased the frequency of grade 3 or higher treatment-related toxicity. However, treatment-related deaths did not occur more frequently. Quality of life often improved in the arm with an additional agent. People who receive more chemotherapeutic or targeted therapeutic agents have an increased overall survival compared to people who receive less. These agents, administered as both first-line or second-line treatments, also led to better overall survival than best supportive care. With the exception of ramucirumab, it remains unclear which other individual agents cause the survival benefit. Although treatment-associated toxicities of grade 3 or more occurred more frequently in arms with an additional chemotherapy or targeted therapy agent, there is no evidence that palliative chemotherapy and/or targeted therapy decrease quality of life. Based on this meta-analysis, palliative chemotherapy and/or targeted therapy can be considered standard care for esophageal and gastroesophageal junction carcinoma.

Plain-language summary: We searched reference lists, biomedical databases (Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Web of Science, PubMed Publsiher, and Google Scholar), and trial registries up to 13 May 2015. Additional searches were run in September 2017 prior to publication, and they are listed in the 'Studies awaiting assessment' section. We identified 41 randomized controlled trials (RCTs) that met our inclusion criteria for inclusion in the review, as well as 49 ongoing studies. This review and meta-analysis shows that people who receive more chemotherapeutic or targeted therapeutic agents live longer and with less disease progression than people who receive best supportive care or less therapy. The only individual agent that more than one study found to improve survival was ramucirumab. We found severe treatment-associated toxicities (grade 3 or above) more frequently in the arms with an additional chemotherapy or targeted therapy agent. However, there is no evidence that palliative chemotherapy and/or targeted therapy decreases quality of life. Our meta-analysis indicates that chemotherapy and targeted therapy are effective palliative treatments for people with esophageal and gastroesophageal junction cancer. The evidence that more chemotherapeutic or targeted therapeutic agents increase survival is of high quality, as is the evidence for improved survival compared to best supportive care. The evidence for the increased occurrence of severe treatment-related toxicities is of very low quality, while the evidence showing no decrease in quality of life is also low quality.