Journal of the National Cancer Institute Advance Access originally published online on May 13, 2008
JNCI Journal of the National Cancer Institute 2008 100(10):698-711; doi:10.1093/jnci/djn134
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COMMENTARY |
Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma
Affiliations of authors: Mount Sinai Liver Cancer Program, Division of Liver Disease, Mount Sinai School of Medicine, New York, NY (JML, M. Schwartz); Barcelona Clínic Liver Cancer Group, Liver Unit, Hospital Clinic, CIBERehd, Institute for Biomedical Investigations August Pi Sunyer, Barcelona, Spain (JML, JB); Saint Louis University School of Medicine, St Louis, MO (AMDB); Office of Disease Prevention, National Institutes of Health, Bethesda, MD (BSK); Division of Radiology, Department of Oncology, University of Pisa, Italy (RL); Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA (AXZ); Department of Medicine, University of Toronto, Toronto, ON, Canada (M. Sherman); Department of Surgery and Bioengineering, University of Pittsburgh, Pittsburgh, PA (ML); Center of Digestive Diseases, Mayo Clinic, Rochester, MN (JT, GJG)
Correspondence to: Josep M. Llovet, MD, 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 (e-mail: jmllovet{at}clinic.ub.es).
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.
Manuscript received October 24, 2007; revised February 14, 2008; accepted March 4, 2008.
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