Pattern of tumor progression in liver cancer: The missing partner in trial design

T he success of sorafenib has prompted a major research activity in the systemic treatment of hepatocellular carcinoma (HCC). This includes phase II and III trials, which aim to improve the benefits of sorafenib, and real-life studies to better understand the mechanisms of action and the factors associated to better or worse survival of treated patients. To date, all phase III trials in first line versus sorafenib or in combination with other agents, and trials in second line versus placebo have failed despite promising results in earlier phases of development. These negative results are deceiving, but should trigger critical thinking about the strength of the data used to gauge antitumoral activity and the safety of new drugs. At the same time, there is a need to revisit the key aspects of trial design, such as survival assumptions and stratification parameters, to ensure a balance between arms. It is critical to improve our knowledge of the natural history of patients under sorafenib treatment and the predictors of survival once it is interrupted owing to intolerance or disease progression. Understanding these aspects should provide explanations regarding trial failures, but, most important, it should lead to modification of the current methods used to evaluate new drugs or novel combinations. What are the possible explanations for the trial failures? The first ones that come to mind are that the agents were not active, not safe, or both. Sunitinib, linifanib, and brivanib had some activity according to objective response rate, disease control rate, or time to progression, but failed to improve survival, as compared to sorafenib or even placebo, as was the case in secondline studies. The potential antitumoral activity could have been counterbalanced by toxicity, but the relevant finding is that signals of activity have not translated into improved survival. Hence, criteria to detect a positive signal in phase I/II studies should be refined and move beyond the mere assessment of tumor burden measured by imaging. Cutoffs used to register response were developed because of the capacity of physicians to detect a change in tumor size by palpation, but the values defined for diameter, area, or volume have never been demonstrated to be a surrogate for a better or worse survival. Assessment of necrosis has been validated for locoregional treatments, but such usefulness for systemic therapy still awaits proper prospective validation. Time to progression may be a better parameter in the absence of a significant rate of objective responses. Sorafenib delayed tumor progression, and this was associated with improved survival. However, progression registration requires some refinement for HCC in order to make clinical sense. More important, it has to be understood that progression pattern may determine a different impact on prognosis. Hence, is there proof that an increase in the size of target lesions implies a poor prognosis? Or is there proof that development of new tumor sites has the same negative impact on survival irrespective of location? Or should progression be considered a predictor of poor short-term outcome only if associated with development/increase of cancer-related symptoms? We raised these questions when we designed a prospective study in HCC patients treated with sorafenib. We envisioned that progression pattern could be one of the main drivers of postprogression survival. This neglected concept was not so novel given that it is well known that progression pattern after resection, transplant, ablation, or chemoembolization determines outcome. The data confirmed our hypothesis: growth of existing sites or appearance of new intrahepatic nodules had no significant impact on survival, whereas the development of Abbreviations: BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; PS, performance status. Received April 2, 2015; accepted May 3, 2015. J.B. is supported by a grant of the Instituto de Salud Carlos III (PI14/ 00962). Address reprint requests to: Jordi Bruix, M.D., BCLC Group, Liver Unit, Hospital Cl ınic, C/Villarroel 170, 08036 Barcelona, Spain. E-mail: jbruix@ clinic.ub. es; fax: 13493 2275792. Copyright VC 2015 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.27881 Potential conflict of interest: Dr. Bruix consults for, advises for, and received grants from Bayer. He consults for and advises for Biocompatibles and Novartis. He consults for and received grants from Daiichi and Arqule. He consults for Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Kowa, Lilly, and Roche. Dr. Reig advises Bayer.