Pattern of tumor progression in liver cancer: The missing partner in trial design
Authors: Maria Reig, Jordi Bruix
Journal: Hepatology (2015)

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. J.B. is supported by a grant of the Instituto de Salud Carlos III (PI14/00962). See Article on Page 784 The 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.1 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 second‐line 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,2 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.3 However, progression registration requires some refinement for HCC in order to make clinical sense.1 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.4 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 new extrahepatic foci or vascular invasion were independent predictors of impaired survival.4 Symptomatic progression and liver function impairment were also predictors of poor outcome, but patients with such clinical features do not enter into second‐line trials.1 This is the explanation for the apparently surprising absence of major differences between the survival of the patients in first‐ and second‐line trials. Obviously, second‐line trials select patients with a less‐aggressive tumor progression, which is not associated with severe cancer symptoms or impaired liver function. If this was not predicted in the survival assumptions at trial design, the negative results of the studies could also be owing, in part, to a suboptimal sample‐size calculation. Hence, for second‐line trials, we proposed to stratify patients according to their progression pattern (Fig. 1). As any new proposal in clinical research, validation was eagerly awaited. In the current issue of Hepatology, Iavarone et al.5 support our findings. In the Italian system, sorafenib is interrupted at the time of tumor progression at radiology, irrespective of its pattern. This has allowed them to assess the survival of HCC patients after interrupting therapy (time of potential entry into second‐line trials). The clinical profile of the patients is the usual in this setting: 60‐70 years median age, most suffering hepatitis C, and half still Child‐Pugh A. The majority presented impaired performance status (PS), 41% showed macroscopic vascular invasion, and 38% extrahepatic spread. Predictors of postsorafenib survival were impaired PS, prothrombin time, extrahepatic spread, macrovascular invasion, and reasons for discontinuation (decompensation worse than progression and progression worse than adverse events). Interestingly, progression pattern, as defined in our study, determined a significantly different patient survival. Thus, the researchers provide the first external validation of our findings. In addition, they also report the association between discontinuation owing to adverse events and better survival, thus supporting previous studies describing such associations.6Figure 1: BCLC model for stratification upon tumor progression at radiology. Pattern of progression determines a division of BCLC patients into separate categories, and this is key for trial design and analysis.According to all the available data, it seems sound to refine trial designs by incorporating these parameters. If not used for patient stratification, they should at least be part of the preplanned assessment. Otherwise, an imbalance between arms could lead to a flawed result in any direction. In this sense, we should ask ourselves whether the active arm in some of the negative trials may have had an enrichment of the more deleterious progressions and thus explain why, despite significant signals of activity, there was no change in survival. The need to consider pattern of progression in trial design could also affect first‐line trials. The sorafenib‐placebo trials were designed with a stratification according to the Barcelona Clinic Liver Cancer (BCLC) parameters to distinguish between stage B and C. However, the patient landscape has changed in the last years owing to the increased use of sorafenib in BCLC‐B patients as a result of treatment‐stage migration. BCLC‐B patients may have first received chemoembolization and then have been shifted to systemic therapy (sorafenib in conventional practice or first‐line trial in research settings) upon detecting failure or progression not amenable to new treatment sessions. In such a scenario, BCLC B patients still within stage B offer no controversy for stratification, but their higher prevalence in trials would induce an improved survival, as compared to earlier investigations. However, if BCLC C patients have been chemoembolized (in some centers, this is common practice despite guideline recommendations) and present progression, should they be stratified by progression pattern? There are no robust data for such cases, but it seems sound to say that trial analysis should, at the very least, incorporate this concept. These considerations are not the only ones to explain trial failures. There are high expectations for trial enrichment based on molecular profiling so that the molecular targets are present in the patients to be treated with the investigational drug. Though this is also sound, it faces a major challenge: Tumors are heterogeneous and biopsy may not capture the profile.7 Nevertheless, even if enrichment may not be robust, the recommendation is to collect tumor tissue before trial entry so that, irrespective of the trial outcome, exploration of tissue biomarkers may help identify the population that can benefit the most, and even rescue negative trials for a subset of patients identified by such profiling. In summary, clinical research and trial design are not dogma. Continuous evolution and critical thinking should be seen as the source of "technology" innovation. This does not affect machinery or laboratory processes, but, in its absence, advancements will not take place. Author names in bold designate shared co‐first authorship.