PD-1 Systematic review and meta-analysis of the efficacy of chemotherapeutic regimens in advanced gallbladder cancer: Assessing current practice and treatment benefit

Abstract

Biliary tract cancers (BTC) are a heterogeneous group of malignancies, including gallbladder cancer (GBC). Treatment for GBC is based on studies recruiting patients with all BTC primary sites rather than GBC alone. GBC represents a different molecular entity to other BTCs, which may impact the response to treatment. The benefit of chemotherapeutic regimens specifically for the treatment of patients with GBC, including the current standard first- and second-line regimens for BTC, is poorly understood. This study explored the benefit derived from palliative cytotoxic chemotherapeutic regimens in GBC. A systematic review and meta-analysis were designed and registered with the PROSPERO database prior to commencement (CRD42019155745). A systematic search was conducted on MEDLINE; key bibliographies were reviewed and selected annual conferences were used to identify articles. Eligible studies reported data on patients with advanced GBC treated with systemic chemotherapeutic regimens. Phase II and III trials, case series, and cohort studies were eligible; phase I studies and small cohorts (< 10 in the first line, < 5 in second/third line) were excluded. Data were pooled using random effects models. 3,035 studies were identified; 58 studies with 66 study arms (n= 1,986 patients with GBC) were eligible for meta-analysis. In patients with GBC, estimated pooled radiological overall response rates (ORR), mean progression-free survival (PFS) and overall survival (OS) were 23.2% [95% confidence interval (CI), 20.0-26.5], 4.8 months (95% CI, 4.3-5.2) and 8.3 months (95% CI, 7.6-8.9), respectively. In patients with GBC, the use of ≥3 chemotherapy agents in combination was associated with increased ORR [35.8% (95% CI, 25.4-46.8)], mean PFS [5.9 months (95% CI 5.2-6.7)] and OS [9.9 months (95% CI, 8.5-11.3). There was a significant improvement in ORR, disease-free survival (DFS), mean PFS and OS with increasing numbers of chemotherapeutic agents (all spearman rho coefficients=1; P< 0.001). Patients with GBC had a lower ORR than non-GBC BTC [odds ratio (OR) 0.65 (95% CI, 0.50-0.84)]; specifically, patients with GBC have lower ORR when compared with the individual subgroups of BTC: cholangiocarcinoma (not otherwise specified) [OR 0.63 (95% CI, 0.48-0.83)], intrahepatic cholangiocarcinoma [OR 0.51 (95% CI 0.32-0.83)] and extrahepatic cholangiocarcinoma [OR 0.64 (95% CI, 0.40-1.00)]. Patients with GBC respond differently to systemic therapy compared with other BTC primary sites; they achieve lower ORR. In GBC, increasing numbers of chemotherapy agents are associated with better outcomes. Although differences may be due to selection bias, intensification of chemotherapy in fitter patients may be investigated either in a GBC-specific trial or (with a planned statistical and reporting approach) within a large randomised BTC trial.