Design and endpoints of clinical trials in hepatocellular carcinoma.
The design of clinical trials in hepatocellular carcinoma (HCC) is complex because many patients have concurrent liver disease, which can confound the assessment of clinical benefit. There is an urgent need for high-quality trials in this disease. An expert panel was convened by the American Association for the Study of Liver Diseases to develop guidelines that provide a common framework for designing trials to facilitate comparability of results. According to these guidelines, randomized phase 2 trials with a time-to-event primary endpoint, such as time to progression, are pivotal in clinical research on HCC. Survival remains the main endpoint to measure effectiveness in phase 3 studies, whereas time to recurrence is proposed as an appropriate endpoint in the adjuvant setting. Because progression-free survival and disease-free survival are composite endpoints, they are more vulnerable than others in HCC clinical studies and may not be able to capture clinical benefits. Selection of the target population should be based on the Barcelona Clinic Liver Cancer staging system. New drugs should be tested in patients with well-preserved liver function (Child-Pugh A class). Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Further research is needed to incorporate biomarkers and molecular imaging into clinical research in HCC. These surrogate markers may help to enrich study populations and maximize the cost-benefit ratio of trial execution. Design and conduct of phase 3 trials should be coordinated by centers with appropriate expertise in HCC.
Llovet
Josep M
JM
HCC Translational Research Lab, Barcelona Clínic Liver Cancer Group, Liver Unit, Hospital Clinic, CIBERehd, Institute for Biomedical Investigations August Pi Sunyer, Villarroel 170, 08036 Barcelona, Catalonia, Spain. jmllovet@clinic.ub.es
Di Bisceglie
Adrian M
AM
Bruix
Jordi
J
Kramer
Barnett S
BS
Lencioni
Riccardo
R
Zhu
Andrew X
AX
Sherman
Morris
M
Schwartz
Myron
M
Lotze
Michael
M
Talwalkar
Jayant
J
Gores
Gregory J
GJ
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D016461:Chemoembolization, Therapeutic; D002986:Clinical Trials as Topic / Q000379:methods*; D017321:Clinical Trials, Phase I as Topic / Q000379:methods; D017322:Clinical Trials, Phase II as Topic / Q000379:methods; D017326:Clinical Trials, Phase III as Topic / Q000379:methods; D018450:Disease Progression; D018572:Disease-Free Survival; D023381:Endpoint Determination; D019317:Evidence-Based Medicine; D006801:Humans; D008111:Liver Function Tests; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D012107:Research Design; D016019:Survival Analysis; D016896:Treatment Outcome
D014408:Biomarkers, Tumor