Fighting the bushfire in HCC trials (2011)

Until recently, few options for systemic therapy have been available for hepatocellular carcinoma (HCC). However, significant benefits have now been demonstrated for the kinase inhibitor sorafenib [[1]Llovet J.M. Ricci S. Mazzaferro V. Hilgard P. Gane E. Blanc J.F. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (9750) Google Scholar] that have led to its approval for HCC therapy in the palliative setting. This has dramatically increased the previously timid interest of drug companies for HCC, and indeed there are now on their way more than 50 phase I–III clinical trials employing more or less targeted substances. This is certainly a positive development in the interest of HCC patients and clinical liver cancer research. Nevertheless, for the sake of the whole field, we have to point out aspects that may be decisive in whether this impact may be sustainable or just a bushfire ultimately leading to wasteland. According to current guidelines, HCC is the only relevant malignant tumor that does not require mandatory histological examination for the establishment of its specific diagnosis [[2]Bruix J. Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases Management of hepatocellular carcinoma.Hepatology. 2005; 42: 1208-1236Crossref PubMed Scopus (5208) Google Scholar]. Consequently, the spectrum of HCCs submitted to biopsy is shifting dramatically towards early, small lesions (<2 cm), that do not provide specific diagnostic imaging features. We do not want to address the resulting diagnostic problems that may come along with this; instead, it is necessary to elaborate on the consequences for study design and future strategies:•Since clinical diagnosis of HCC does not require mandatory tissue analysis, neither do clinical trials. Thus, clinical trials are set-up either without histology as inclusion criterion, or without upfront tissue availability or even retrospective tissue-based biomarker analysis. This may be driven by considerations regarding patient recruitment, or by the intention of some companies to avoid narrowing down the patient pool addressed by the drug. Even in the SHARP trial it is impossible to answer the questions whether certain molecularly defined tumor subgroups show a better or no response to sorafenib.•Companies’ interest in HCC is far from altruistic but is subjected to competitive considerations in comparison to other malignancies. In this context we should not forget that HCC has worse starting conditions compared to other tumors since study endpoint definitions and evaluations are more difficult due to confounding morbidity, such as cirrhosis. Accumulation of failed targeted approaches (non-superiority; failed market penetration) might rapidly cool down industries’ interest and divert it to other cancers. Is this scenario likely? We believe, yes. Evidence from the Phase III sunitinib trial that was recently halted because of unwanted effects and did not show overall significant benefit [[3]Pfizer press release 4/23/2010.Google Scholar] indicates that targeted approaches may fail in unspecified HCC collectives in terms of overall survival or time to progression (TTP). In the future the only possible way to save HCC trials from potentially undeserved failure is (retrospective) molecular analysis for defined patient subgroups that respond positively and patients that may have disadvantages by a specific therapy. This can only be achieved by having tumor tissue in hand not only for diagnosis but also for biomarker assessment. In the light of many ongoing trials and considerations about cost-benefit ratios it is unlikely that health agencies will wait long until they will tighten regulations for approval even when significant overall response is demonstrated. A likely scenario is mandatory subgroup analysis.•Is there any valid alternative to tumor tissue? We believe not! It is necessary to have blood/serum available, and serum marker assessment should always be attempted but the quest for predictive serum markers is a story of failures so far; not a single predictive serum tumor marker has been established to date, and many potential biomarkers may not show up in the serum at all; building biomarker analysis solely on serum is therefore building on sand.•Several types of cancer research fields that are far ahead of HCC give strong indications as to how future predictive testing in non-resectable malignant diseases will look. In mammary carcinoma, multiple systemic therapy options exist and upfront tissue-based molecular testing (e.g. ER, PR, Her2) is mandatory and guides therapeutic decision making [[4]Burstein H.J. Prestrud A.A. Seidenfeld J. Anderson H. Buchholz T.A. Davidson N.E. et al.American Society of Clinical Oncology American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer.J Clin Oncol. 2010; 28: 3784-3796Crossref PubMed Scopus (594) Google Scholar]. A similar scenario is about to develop in non-resectable non-small cell lung cancer (NSCLC). In the future, it may/will be tested upfront for e.g. EGFR-mutation, ELM4-ALK translocation, ERCC1 and TS expression. Multiple therapeutic options, testing logistics, and reimbursement strategies are dictating this path and novel adaptive trial strategies [[5]Barker A.D. Sigman C.C. Kelloff G.J. Hylton N.M. Berry D.A. Esserman L.J. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy.Clin Pharmacol Ther. 2009; 86: 97-100Crossref PubMed Scopus (577) Google Scholar] will further necessitate it. Interestingly, drug companies holding a non-restricted approval for targeted drugs in hand (e.g. in NSCLC) are intending to switch to approval with upfront molecular testing. Therefore, upfront tissue-based molecular testing prior to adjuvant or palliative systemic treatment is not a fiction but a fact in oncology, and if we are unable to provide this modality for HCC we will soon drop far behind in all trial priorities. Furthermore, clear cut indications now exist in tumors such as NSCLC and colon cancer that even conventional (chemo)therapeutic approaches should be subjected to molecular subgroup analyses in order to adjust treatment and potentially avoid exposure to toxic agents [[6]Olaussen K.A. Dunant A. Fouret P. Brambilla E. André F. Haddad V. et al.IALT Bio Investigators. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy.N Engl J Med. 2006; 355: 983-991Crossref PubMed Scopus (1590) Google Scholar]. Thus, we are convinced, there is no way around mandatory acquisition of HCC tissue in clinical trials (and consequently, in subsequent routine diagnostic setting). This shift in paradigm should happen soon; otherwise, the current positive trial constellation may turn out to be just a bushfire. Individualized HCC therapy will require defining the patient subgroups that benefit most or that should be protected from therapy failure and unwanted effects [[7]Boyault S. Rickman D.S. de Reyniès A. Balabaud C. Rebouissou S. Jeannot E. et al.Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets.Hepatology. 2007; 45: 42-52Crossref PubMed Scopus (920) Google Scholar]. Decision against mandatory biopsy of HCC was made in old times, when no differential systemic therapy was on the horizon and, clearly, it has to be revisited urgently in the light of upcoming diagnostic [8Katoh H. Ojima H. Kokubu A. Saito S. Kondo T. Kosuge T. et al.Genetically distinct and clinically relevant classification of hepatocellular carcinoma: putative therapeutic targets.Gastroenterology. 2007; 133: 1475-1486Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 9Hoshida Y. Villanueva A. Kobayashi M. Peix J. Chiang D.Y. Camargo A. et al.Gene expression in fixed tissues and outcome in hepatocellular carcinoma.N Engl J Med. 2008; 359: 1995-2004Crossref PubMed Scopus (1063) Google Scholar] and therapeutic options. In the end, it is also an ethical issue to set up clinical trials in a way that optimizes data interpretation for the sake of future patients. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.