Current and future trials in hepatocellular cancer


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Tim Meyer

Royal Free Hospital, London, UK

Abstract

Current and future trials in hepatocellular cancer

The BCLC staging system has provided a useful algorithm for the allocation of evidence based therapy for hepatocellular cancer (HCC). Accordingly early disease is managed with curative intent by the application of surgical or ablative therapy while for intermediate disease, the standard of care is transarterial chemoembolisation. For advanced disease the multi-targeted kinase inhibitor sorafenib is the current standard of care based on the results of two recently reported placebo controlled randomised trials. The identification of a proven effective systemic therapy opens up the possibility of improving outcomes in early stage disease, and adjuvant trials of sorafenib following surgical resection and radiofrequency ablation or in combination with TACE are planned to start in the near future. Systemic chemotherapy has been widely used in the past but evidence that is prolongs survival compared to best supportive care is lacking. However there is intriguing evidence from a randomised phase II trial showing a doubling of survival using the combination of doxorubicin and sorafenib compared with doxorubicin alone. This exceeds the 45% improvement that is obtained by sorafenib alone compared to placebo and raises the possibility of a synergistic interaction that will now be tested in a randomised phase II/III comparing doxorubicin and sorafenib with sorafenib alone.

While sorafenib is clearly an advance in the treatment of HCC, the absolute benefit is rather modest and there is a need to build on this success. The real challenge ahead lies in selecting the best of a wide range of potentially active systemic agents to take forward into phase three trials. Candidates include other inhibitors of angiogenesis and drugs that block the EGFR, Wnt, mTOR and IGFR signal pathways which are known to be active in HCC. However traditional signals of efficacy such as response have proven to be a poor predictor of survival benefit as demonstrated by the objective response to sorafenib which is less than 3%. It has therefore been proposed that randomised phase II trials, with a time to progression endpoint, might provide a more reliable indicator of activity and justify the expense of moving to phase III. Advances in the molecular classification of HCC and the validation of predictive biomarkers may also help to refine future trials.

Declaration of competing interest: Tim Meyer is a member of the Bayer Advisory Board.