SummaryBackgroundThe treatment of esophageal cancer has entered a new phase with the development of immunotherapy. The current investigation purpose is to investigate and contrast the efficacy and safety of immunotherapy, immunochemotherapy, chemotherapy, and targeted therapy as first-line treatment for individuals suffering from advanced and metastatic esophageal cancer.MethodsWithin the framework of this systematic review and network meta-analysis, clinical trials published or reported in English up until 01 May, 2022, were retrieved from Embase, PubMed, Cochrane Central Register of Controlled Trials, theClinicalTrials.govdatabases, ESMO, and ASCO. The analysis incorporated randomized controlled trials (RCTs) from phase 2 to 3 that evaluated a minimum of two first-line therapeutic regimens for metastatic esophageal cancer were included in the analysis. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary clinical outcomes included the incidence of objective response rate (ORR), and adverse events (AEs) of any grade and ≥3 grade. Relative summary data were extracted from included studies by GZ, HS, WS, and TD. For clear statistical analysis, chemotherapy was divided into two categories of fluorouracil-based chemotherapy (FbCT) and fluorouracil-free chemotherapy (FfCT). Bayesian frequentist approach was employed to conduct the network meta-analysis. The indirect intercomparison between regimens was presented with league tables (HRs and 95% CI for OS and PFS, ORs and 95% CI for ORR and AEs). A greater surface value under the cumulative ranking (SUCRA) indicates a higher potential ranking for the corresponding treatment. A further calculation of relative results about esophageal squamous cell cancer was performed in the subgroup analysis. The current protocol for the systematic review has been properly registered on PROSPERO (registration number: CRD42021241145).FindingsThe final analysis comprised 17 trials that involved 9128 patients and 19 distinct treatment regimens. Within the scope of investigated immunotherapy (IO) combinations, toripalimab + FfCT (tori + FfCT) demonstrated the best OS advantages (tori + FfCT vs. FbCT, HR 0.57, 95% CI 0.38–0.85; tori + FfCT vs. FfCT, HR 0.58, 95% CI 0.43–0.78). In terms of PFS, camrelizumab + FfCT (cam + FfCT) demonstrated the best PFS advantages (FbCT vs. cam + FfCT, HR 1.79, 95% CI 1.22–2.63; FfCT vs. cam + FfCT, HR 1.79, 95% CI 1.47–2.17). Nivolumab + FbCT (nivo + FbCT vs. FfCT, OR 3.29, 95% CI 1.43–7.56) showed the best objective responses. Compared to the conventional chemotherapy regimen, the toxicity was observed to be the slightest for the tori + FfCT (FbCT vs. tori + FfCT, OR 3.07, 95% CI 1.22–7.7) and sintilimab + FfCT (FbCT vs. sin + FfCT, OR 2.93, 95% CI 1.16–7.37). The results in this study were evaluated as having a low heterogeneity since the I2value was ≤25% in all analyses.InterpretationCompared to foreign IO combinations, sin + FfCT, tori + FfCT, cam + FfCT, and tisle + FbCT are superior first-line treatment options for patients with advanced and metastatic esophageal cancer. Although foreign IO combinations, such as pembro + FbCT and nivo + FbCT obtained better objective response rates than other IO combinations, the addition of chemotherapy to IO worsens the safety profiles. Our findings could provide complementary evidence for current guideline recommendations.FundingThis work was supported by a grant from theScience and Technology Program of Guangzhou, China(202206010103); and10.13039/501100003453Natural Science Foundation of Guangdong Province(2022A1515012469).