Design and Endpoints of Clinical Trials in Hepatocellular Carcinoma

Abstract

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.

Lipiodol transarterial chemoembolization for hepatocellular carcinoma: A systematic review of efficacy and safety data

“…On the other hand, TACE and sorafenib are recommended for patients at different stages of the disease, and thus a direct comparison was not foreseen. (42,43) With this in mind, and recognizing the importance of a comprehensive understanding of updated efficacy and safety data of lipiodol TACE, we performed a systematic review of available clinical studies selected according to predefined inclusion/exclusion criteria and assessed according to a standardized methodology. Separate analyses were performed for efficacy and safety data.…”

What is the best staging system for hepatocellular carcinoma in the setting of liver transplantation?

“…These stages defined the BCLC staging system in the initial proposal, 6 which was prospectively validated by a number of later studies. [22][23][24][25] In addition to these prospective validations, several studies have demonstrated the ability of the model. 26,27 It has been recently endorsed by numerous groups 1,21,28 and is included in the guidelines for the management of HCC from the American Association for the Study of Liver Diseases.…”

Drug Therapy: Sorafenib

“…1). 7 Potentially curative treatments for HCC require surgical expertise; however, both hepatic resection and orthotopic liver transplantation require careful patient selection. Both modalities are limited in their practical implementation by the fact that most patients present with an advanced tumor burden.…”

“…29 More recently, changes in enhancement have been incorporated into assessing response to molecular therapeutics in the management of HCC. 7 If sorafenib does not cause tumor shrinkage, outside of unmanageable toxicity, the question of when to stop the drug becomes important. Typically the appearance of a new lesion would suggest clear progression.…”