Advanced extrahepatic cholangiocarcinoma and gallbladder cancer: Post-hoc analysis of the ABC-01, -02 and -03 clinical trials

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BACKGROUND & AIMS: Previous data suggest that patients with intrahepatic cholangiocarcinoma (iCCA) have a better prognosis compared with those with other biliary tract cancers (BTC). However, granularity on outcomes for advanced extrahepatic cholangiocarcinoma (eCCA) (including distal- [dCCA] and perihilar cholangiocarcinoma [pCCA]) and gallbladder cancer (GBC) is lacking. With targeted therapies being developed for these subgroups, benchmark data are of value to understand the natural history and inform future trial design. METHODS: The aim of this post hoc analysis was to provide reference survival data for patients with advanced eCCA treated with first-line cisplatin-gemcitabine (CisGem) chemotherapy within the prospective, randomised Advanced Biliary tract Cancer (ABC)-01, -02, and -03 studies. Individual-level data from patients with eCCA and GBC recruited to these studies were retrieved. Survival analysis was performed using Kaplan-Meier and univariate and multivariable Cox regression. Logistic regression was utilised whenever required. RESULTS: Of 534 patients recruited into the ABC-01, -02, and -03 studies, eligible patients for this analysis included a total of 117 eCCA treated with CisGem (including 68 with pCCA and 49 with dCCA) and 112 with GBC. Patients with pCCA had less previous surgery (4.08%) and the highest rate of biliary stenting (26.53%). Patients with dCCA were predominantly metastatic at study entry (77.94%), while those with pCCA had a rate of 40.82% and 59.18% for locally advanced and metastatic disease at study entry, respectively. Most patients in the GBC cohort were women (62.50%) and predominantly metastatic (81.25%). Estimated median overall survival (OS) for dCCA was 14.25 months (95% CI: 8.80-17.44) and 12.18 months (95% CI: 8.31-16.12) for pCCA. Estimated median progression-free survival (PFS) was 8.28 months (95% CI: 6.31-9.39) for dCCA and 8.37 months (95% CI: 6.53-10.61) for pCCA. PFS and OS for GBC were 6.86 months (95% CI: 5.75-8.51) and 10.84 months (95% CI: 8.97-12.41), respectively. Objective radiological response was 23.93% for eCCA: (dCCA [27.94%] and pCCA [18.37%]) and 26.79% for the GBC cohort. Prognostic factors of interest for OS included performance status (PS) and CA125 for eCCA, and grade of differentiation for GBC. For OS in iCCA, dCCA, pCCA, and GBC, multivariable analysis confirmed that patients with GBC had the shortest OS (hazard ratio 2.01 [95% CI: 1.18-3.43]; p value 0.011 [vs. iCCA]) when adjusted for other prognostic factors (PS, stage, and tumour markers). CONCLUSIONS: Within the BTC subgroups, GBC had the worse survival. PS and baseline tumour markers (CA125 and CEA) were strongly associated with worse survival. These subgroup data provide a reference for future studies incorporating immunotherapy and other new treatment strategies for BTCs. IMPACT AND IMPLICATIONS: The data presented here provide benchmark outcome data for subgroups of patients with eCCA and GBC treated with CisGem for future clinical trial design. Despite the absence of immunotherapy, the lack of alternative comprehensive series highlights the value of the current series. The data presented here could be utilised for interpretation of current studies and design of future trials, by providing outcome data for main BTC subgroups of interest. CLINICAL TRIAL REGISTRATION NUMBERS: ABC-01/ABC-02 (NCT00262769), ABC-03 (NCT00939848).

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