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

Background & Aims: Whether all patients with advanced biliary tract cancer (aBTC) should be included in prospective trials, irrespective of the anatomic site of origin, is debated. Herein, we aimed to assess the survival impact of anatomic site of origin in prospective clinical trials of aBTC using landmark survival analysis.
Methods: Patients enrolled into prospective first-line aBTC clinical trials (Jan 97-Dec 15) were included. Overall survival (OS) was analysed using Cox proportional hazard regression; landmark survival (LS) and 95% CIs were calculated.
Results: Overall, 1,333 patients were included: median age 63 years (range 23-85); 46% male; 84% ECOG-PS0/1; 25% with locally advanced disease, 72% with metastatic, 3% not reported (NR). Patients were treated with mono-chemotherapy (23%), cisplatin/gemcitabine (36%), other combinations (39%), or NR (2%). Median OS was 10.2 months (95% CI 9.6-10.9). All sites (treatment-adjusted) had decreased risk of death vs. gallbladder cancer (GBC) (p <0.001). This reduced risk vs. GBC was maintained in those receiving cisplatin/gemcitabine for extrahepatic cholangiocarcinoma (p<0.001) and intrahepatic cholangiocarcinoma (IHC, p<0.001), but not in cholangiocarcinoma-not specified (CCA-NS, p = 0.82) or ampullary carcinoma (p = 0.96). One-year OS rates amongst patients who survived beyond 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 = 0.008) (acknowledging potential selection bias) and those with IHC and CCA-NS vs. GBC had better LS (both p <0.05). Metastatic disease was associated with shorter LS than locally advanced disease (p = 0.002). ECOG-PS and gender were not associated with LS (p >0.05, p = 0.08 respectively).
Conclusions: GBC is associated with worse OS than other BTC sites and should be considered as a stratification factor in clinical trials. LS rates enable adjusted prognostication for aBTC survivors.
Lay Summary: Patients with gallbladder cancer have worse overall survival compared to those with biliary tract cancers of different primary origin. Thus, gallbladder cancer should be considered as a stratification factor in future clinical trials. Landmark survival rates enable adjusted prognosis prediction for patients with advanced biliary tract cancer who survive for some time.
Competing Interests: Conflict of interest MMN has received honoraria from Ipsen, NuCana and Mylan, research funding from Ipsen, NuCana and Servier (previously SHIRE) and travel assistance from Ipsen, Bayer and Novartis. AL has no conflicts of interest to declare. HW has received honoraria from Lilly, Merck, Roche, and Celgene, speaker fees from Merck and Celgene, research funding from Sirtex and Pfizer, and travel assistance from Merck, Sirtex, Lilly, and Celgene. DM has honoraria and non-financial support from Amgen, Bayer, Ipsen, Merck Serono, Merck Sharp and Dohme, Roche, Sanofi, Servier; honoraria from Incyte, Shire, HalioDx and Agios. DG receives indirect research funding from Amgen, Celgene, and Pfizer and has stock ownership in Sirtex. JS has received consultancy fees from Merck and Amgen. TO receives honoraria from Chugai Pharmaceutical Co., Ltd, Pfizer Japan, Inc., Novartis Pharma K.K., Taiho Pharmaceutical Co., Ltd, Merck Serono Co., Ltd, Eli Lilly Japan K.K., Dainippon Sumitomo Pharma Co., Ltd, Eisai Co., Ltd, Bayer, Ltd, FUJI FILM Co., Ltd, and Yakult Honsha Co., Ltd. He also has a consulting or advisory role with Eli Lilly Japan K.K., Yakult Honsha Co., Ltd, Amgen, Dainippon Sumitomo Pharma Co., Ltd, Taiho Pharmaceutical Co., Ltd, OncoTherapy Science, Inc., Nobelpharma Co., Ltd, Ono Pharmaceutical Co., Ltd, Nippon Boehringer Ingelheim Co., Ltd, Nano Carrier Co., Ltd, Chugai Pharmaceutical Co., Ltd, Novartis Pharma K.K., and Zeria Pharmaceutical Co., Ltd. He receives indirect research funding from Chugai Pharmaceutical Co., Ltd, Eli Lilly Japan K.K., Eisai Co., Ltd, Novartis Pharma K.K., Shizuoka Industry, Takeda Bio Development Center Ltd, Yakult Honsha Co., Ltd, OncoTherapy Science, Inc., Otsuka Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, Sceti Medical Labo K.K., Nippon Boehringer IngelheimCo., Ltd, Kowa Company, Ltd,KyowaHakko Kirin Co., Ltd, Merck Serono Co., Ltd, Ono Pharmaceutical Co., Ltd, Bayer, Ltd, Pfizer Japan, Inc., AstraZeneca K.K., and Dainippon Sumitomo Pharma Co., Ltd. JK receives research funding from Astra Zeneca. DW has received educational grant support from Roche, and honoraria from Bristol-Myers Squibb, Servier Suisse, Merck Sharp & Dohme, Bayer, EMD Serono, Lilly, Sanofi, Celgene, Astra Zeneca, AbbVie, Sanofi-Aventis Deutchland, SHIRE and Pfizer outside this submitted work. TA has served in a consulting/advisory role and or received honoraria from, Amgen, Bristol-Myers Squibb, Chugai, Clovis, Halliodx, MSD Oncology, Pierre Fabre, Roche/Ventana, Sanofi, Servier and has received travel, accommodation, and expenses from Roche/Ventana, MSD Oncology, and Bristol-Myers Squibb. DC receives indirect research funding from AstraZeneca, Amgen, Celgene, Merck, Serono, Sanofi, Merrimack, and Medimmune, Bayer, 4SC, Clovis, Eli Lilly and Janssen. MM receives research funding from Bayer and Lilly. LJ has received travel and accommodation funding from Amgen, Roche, and Sanofi. DK has not declared any conflicts of interest. TBS research funding (to institution): Boston Biomedical, Bayer, Amgen, Merck, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Array Biopharma, Genentech, Abgenomics, Incyte, BMS. Consulting (to institution): Ipsen, Array Biopharma, Bayer, Genentech, Incyte and Merck. IDMC/DSMB (to self): Astra Zeneca, Exelixis, Lilly, PanCan and 1Globe. Scientific Advisory Board: Imugene, Immuneering and Sun Biopharmahas. JB has received honoraria from Merck Serono, Roche, Sanofi, and Bayer. JWV received honoraria in advisory capacity from Astra Zeneca, Agios, Taiho, Merck, Celgene, QED, PCI Biotech, Incyte, Pieris Pharmaceuticals, Genoscience Pharma, Mundipharma EDO and research funding from Lilly. Please refer to the accompanying ICMJE disclosure forms for further details.
(Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)