Key research issues in the management of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an extremely diverse and heterogeneous disease and improving patient outcome is a difficult undertaking. While many therapeutic options exist, few have been subjected to rigorous study, so patient benefit is uncertain. Comparative trials need to be performed to determine the value of these and, of course, newer treatments. However, there are numerous challenges to the design and conduct of such studies. While stratification parameters are important in most clinical trials, they are particularly critical when studying HCC. The cancer staging of HCC must reflect prognosis and, therefore, must include parameters of liver disease. This is because the underlying hepatic dysfunction may often determine how long patients survive and confuse the interpretation of anti-HCC treatment trials. Two new staging paradigms--Cancer of the Liver Italian Program (CLIP) and Chinese University Prognostic Index (CUPI)--have been developed, and these need to be validated. The role of the many different treatment options must be determined. However, the diverse nature of presentation of HCC and the proliferation of many routine procedures--such as chemoembolization or radiofrequency ablation--make controlled trials nearly impossible. Even drug development is a special circumstance, because HCC patients with underlying liver disease may need different dosing regimens and schedules compared to other cancer patients. This makes clinical trial design more cumbersome and the risks of participating in clinical trials for HCC greater. The immense unique challenges of this disease make it imperative for investigators to identify the most promising agents for HCC. At the same time, all patients with HCC should, if possible, be treated on well-designed clinical trials.