First-Line Chemotherapy Regimens for Unresectable Locally Advanced or Metastatic Biliary Tract Cancer: A Systematic...

Biliary tract cancers (BTCs) are aggressive malignant neoplasms with a dismal prognosis. Recent advancements, including immunotherapy and targeted therapies, have expanded therapeutic options, yet head-to-head comparisons between regimens remain limited.

To conduct a comprehensive network meta-analyses (NMA) to include latest advances in BTC therapy to guide clinical practice.

PubMed, Embase, and Cochrane Central were searched for randomized clinical trials (RCT) from 2000 to 2024, with manual updates through August 2025 and conference abstracts and ClinicalTrials.gov screened.

Phase 2 to 3 RCTs of unresectable, locally advanced, or metastatic BTC reporting progression-free survival (PFS) or overall survival (OS) were eligible.

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline was followed. Two reviewers independently extracted data, resolving discrepancies with a third. Data were pooled with a fixed-effect model.

Primary outcomes were PFS and OS; secondary outcomes included objective response rate (ORR) and grade 3 to 4 adverse events.

This systematic review and bayesian NMA synthesized data from 33 RCTs involving 7303 patients (median [IQR] age, 64 [63-65] years; 3704 [51.5%] male). Compared with gemcitabine plus cisplatin (GC), GC plus sintilimab plus anlotinib (hazard ratio [HR], 0.47; 95% CI, 0.28-0.80), GC plus S-1 (HR, 0.75; 95% CI, 0.59-0.97), and GC plus durvalumab (HR, 0.80; 95% CI, 0.66-0.97) were associated with highest PFS benefits. Capecitabine plus oxaliplatin (HR, 0.64; 95% CI, 0.44-0.92), GC plus durvalumab (HR, 0.71; 95% CI, 0.61-0.84), and gemcitabine plus oxaliplatin (GO) (HR, 0.78; 95% CI, 0.63-0.96) were associated with improved OS. ORR was highest with GC plus S-1 (odds ratio [OR], 4.13; 95% CI, 2.20-7.70), GC plus cediranib (OR, 3.20; 95% CI, 1.40-7.20), and GC plus durvalumab (OR, 1.60; 95% CI, 1.10-2.28) compared with GC. Toxicity profiles showed no significant hematological differences between regimens, but nonhematological risks varied. Overall, GC plus durvalumab, GC plus S-1, GO plus panitumumab, and GO plus cetuximab showed the greatest consistency in the surface under the cumulative ranking curve value for PFS, OS, ORR, and safety.

This NMA establishes GC plus durvalumab and GC plus S-1 as potential leading first-line options for advanced BTC due to a consistent clear benefit in PFS, OS, ORR, and safety. This study also establishes that GC remains among the top regimens, as most other therapy lacked a clear superior benefit or were associated with worse PFS or OS compared with GC.