Outcomes and Prognostic Factors of Patients with Unresectable or Metastatic Esophageal Squamous Cell Carcinoma Undergoing Immunotherapy- Versus Chemotherapy-Based Regimens: Systematic Review and Pooled Analyses.

Objective: Immunotherapy-based regimens (IMT) versus cytotoxic chemotherapy (CHT) improved overall survival (OS) of patients with unresectable or metastatic esophageal squamous cell carcinoma (mESCC), but the role of prognostic variables is unclear. The study aims to explore the interaction of prognostic factors with survival after IMT or CHT.

Methods: A systematic review was performed to select trials comparing IMT and CHT regimens in mESCC patients. A meta-analysis of upfront IMT + CHT vs. CHT trials evaluated the overall effect size and heterogeneity between studies. In view of the expected differences between chemotherapy and immunotherapy on the survival curve, to better explore the effect of any prognostic variables on OS, before and after progression, the treatment arms were evaluated as independent cohorts, and ten baseline variables were extracted and assessed by linear regression.

Results: Fourteen trials were identified. Seven studies compared upfront CHT + IMT vs. CHT documenting longer OS for CHT + IMT (HR 0.69, CI 0.65-0.72), without heterogeneity (Q = 1.43, p value = 0.968) or differences in the most represented subgroups. Twenty-nine study cohorts were selected from the 14 trials. Median OS and PPS, but not PFS, were significantly increased after IMT compared with CHT. The analysis of baseline variables after CHT documented a favorable prognostic effect for advanced age (β = 0.768, p value = 0.016), involvement of 0-1 metastasis sites (β = 0.943, p value = 0.005), and absence of previous radiation therapy (β =  - 0.939, p value = 0.006), while none of them influenced prognosis after IMT.

Conclusion: The introduction of upfront IMT prolonged mESCC patients OS, mostly improving the outcomes of young patients, with multiple metastasis sites and without previous radiotherapy.