Landmark survival analysis and impact of anatomic site of origin in prospective clinical trials of biliary tract cancer

Background: Inclusion of all patients with advanced biliary tract cancer (aBTC), irrespective of anatomic location, in prospective trials, is debated. Survival rates from landmark analysis offer more relevant information once patients have survived for some time. Aim: assess survival impact of BTC anatomic site origin and landmark survival (LS). Patients and Methods: Patients enrolled into prospective first-line aBTC clinical trials were included. OS was analysed using Cox-proportional-hazard-regression; LS and 95% confidence intervals (CIs) were calculated. Results: Overall: 1333 patients included (Jan 97-Dec 15); median age 63-years (range 23-85); 46%-male; 84%-ECOG-PS0/1; 25%-locally-advanced (LA), 72%-metastatic, 3%-not reported (NR); gallbladder-(GBC): 385 (29%), cholangiocarcinoma not-specified-(CCA-NS): 363 (27%), extrahepatic-(EHC): 247 (19%), intrahepatic-(IHC): 209 (16%), ampulla: 53 (4%), 76 (6%) NR. Treatment was mono-chemotherapy: 310-(23%), cisplatin/gemcitabine: 482-(36%), other combination: 520-(39%), NR: 21-(2%). Median OS: 10.2-months (95%-CI 9.6-10.9). All sites (treatment-adjusted) had decreased risk of death vs GBC: EHC-(P<.001), IHC-(P<.002), CCA-NS-(P<.003), ampulla-(P=.003). This reduced risk vs GBC was maintained in those receiving cisplatin/gemcitabine in EHC-(P<.001) and IHC-(P<.001), but not in CCA-NS-(P=.82) or ampulla-(P=.96). Probabilities of surviving an additional year given survival to 1, 2, 3, and 4 years post-trial registration were 37%, 45%, 61%, and 63% respectively. For patients who survived 1 year; those receiving combination therapy vs mono (P=.008) (acknowledging potential selection bias), and those with IHC and CCA-NS vs GBC had better LS (both P<.05). Metastatic stage vs LA was associated with shorter LS (P=.002). ECOG-PS and gender had no evidence of effect on LS (P>.05, P=.08 respectively). Conclusions: Patients with GBC have worse OS compared to other anatomic BTC sites; should be considered as a stratification factor in clinical trials. LS rates allow adjusted prognosis prediction for aBTC survivors.