Originally published as JCO Early Release 10.1200/JCO.2008.19.1973 on January 12 2009

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Testing Molecular Therapies in Hepatocellular Carcinoma: The Need for Randomized Phase II Trials

Mount Sinai Liver Cancer Program, Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY; Barcelona Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clinic; and Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain

Jordi Bruix

Barcelona Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clinic, Barcelona, Catalonia, Spain

Hepatocellular carcinoma (HCC) is the third largest cause of cancer-related death behind only lung and colon cancers.¹ Overall, one third of cirrhotic patients will develop HCC during their lifetime, and this neoplasm is currently their principal cause of death.² The incidence is increasing in the United States and Europe.³ Thus, HCC is becoming a major health problem, particularly because the majority of patients are still diagnosed at advanced stages or will experience progression after locoregional therapies.

Clinical trial research in HCC is exploding. The advent of sorafenib as an effective molecular targeted therapy has recently changed the scope of clinical investigations in this neoplasm.⁴ There is a blossoming of early- and late-stage clinical trials in all scenarios, including trials of first- and second-line treatments in patients with advanced disease and also of adjuvant therapies after surgery or local ablation and in combination with chemoembolization. The uniqueness of HCC as a neoplasm mostly results from the fact that clinicians deal with two diseases, cancer and cirrhosis, which occur in 80% of patients. The complexity of trial design was recently addressed by a consensus panel of experts including hepatologists, oncologists, surgeons, radiologists, trialists, and regulatory experts convened by the American Association for the Study of Liver Disease (AASLD) and published in Journal of the National Cancer Institute (AASLD-JNCI).⁵ The document frames the design and end points of clinical trials in HCC and will be instrumental as a common ground for information exchange among specialists. We use these guidelines for the commentary on the phase II study combining bevacizumab and erlotinib in HCC published in this issue of Journal of Clinical Oncology.⁶

There is scientific rationale for combining bevacizumab and erlotinib in HCC.⁷ Overexpression of proangiogenic factors, such as vascular endothelial growth factor (VEGF), platelet-derived growth factor, and angiopoietin-2, has been demonstrated in HCC.^7,8 Numerous preclinical and clinical investigations support the role of VEGF activation in the development of this cancer, and in some instances, VEGF levels have been associated with poor prognosis. Recently, focal high-level amplifications of VEGF-A have been reported in 5% to 8% of patients, pointing to the fact that this gene can drive tumor progression in a selected group of patients.⁹ Early phase II studies assessing bevacizumab as a single agent in HCC suggest potential clinical activity, which needs to be further explored.¹⁰ Similarly, there is rationale to abrogate epidermal growth factor receptor signaling in HCC, where gain of function seems mediated through increase in ligand-receptor interaction, rather than by point mutations or amplifications.^7,8 Pathway activation can be successfully inhibited by small molecules against the catalytic domain of epidermal growth factor receptor, such as erlotinib, which has shown activity in preclinical studies. Two small early clinical trials^11,12 reported divergent results, with median survival times of 13 and 6.2 months, respectively, suggesting likely heterogeneous selection criteria.

Thomas et al⁶ report a single-arm phase II study with 40 HCC patients treated with the combination of bevacizumab (10 mg/kg every 14 days) and erlotinib (150 mg daily). Regarding efficacy, objective response rate was 25%, and the median progression-free survival and overall survival times were 9 and 15.6 months, respectively. To interpret the results posed in the study, we need to understand the target population included and compare the outcomes obtained with the outcomes expected from the natural course of the disease or if patients would have received the standard of care, sorafenib. The AASLD-JNCI guidelines recommend a common staging system to select trial populations and, for stratification purposes, the Barcelona classification (Barcelona Clinic Liver Cancer [BCLC] staging system).¹³ According to this classification, patients with early-stage disease (class A) are suitable for locoregional therapies (resection or local ablation) and have median survival times greater than 40 months. Patients with intermediate-stage disease (class B) have multinodular asymptomatic tumors without vascular invasion or extrahepatic spread. The median survival time of these patients, if untreated, is 16 to 17 months, and this natural history can be effectively increased to 20 to 22 months after chemoembolization. Patients with advanced-stage disease (class C) present with either symptomatic tumors (Eastern Cooperative Oncology Group performance status of 1 or 2) or evidence of macroscopic vascular invasion or extrahepatic spread. The natural history of these patients results in a survival time of 6 months (range, 4 to 8 months), which can be increased to approximately 11 months with sorafenib.⁴ Patients with end-stage disease (class D) present with a median survival time of less than 3 months. Of note, the term unresectable HCC is considered inappropriate to stage HCC patients because it can refer to patients with heterogeneous outcomes, with a median survival time range of 3 to 22 months.

How can we interpret the median survival time of 15.6 months described in the current study?⁶ According to the stage described by the authors, 65% of patients presented with BCLC C stage, and 35% had BCLC A or B stage. This population is slightly less advanced than the target population of the Sorafenib HCC Assessment Randomized Protocol trial, which had a median survival time of 10.7 months in the active arm and in which 82% of patients presented with stage C BCLC.⁴ Interestingly, subgroup analysis of the Sorafenib HCC Assessment Randomized Protocol trial showed that patients with stage B BCLC had a median survival time of close to 15 months in the sorafenib arm. Therefore, the issue of patient selection emerges as a relevant point. However, the small sample size and short follow-up time might also have induced an overestimation of the outcome data. In fact, the median survival time of the present cohort changed from 19 months to 15.6 months from the original abstract to the current article,^6,14 exposing the need to be cautious with such preliminary data. Other informative end points, such as time to progression, were not described in this phase II study but are recommended to be captured by the AASLD-JNCI Panel⁵ because they are less vulnerable than progression-free survival in HCC research. Thus, the question of whether the survival difference can only be explained by the selection criteria applied or whether it is a true result of the efficacy of this combination cannot be resolved by the current data. The 25% objective response rate favors the latter interpretation, but the small sample size precludes discarding a random effect. To our knowledge, only one other single-arm trial testing the combination is currently underway under the National Cancer Institute umbrella.¹⁵ To overcome all of these major concerns affecting the evaluation of novel treatment regimens, the AASLD-JNCI guidelines recommend randomized phase II studies.⁵ This strategy will prevent overinterpretation of results obtained in small single-arm trials, as might be the case in the study presented in this issue.⁶

The safety data also deserve a thorough analysis. The authors state that GI bleeding was observed in five patients (12.5%), with two patients having severe GI bleeding and one patient experiencing death. In addition, minor bleeding was described in 29 patients (72%). The authors amended the protocol to prevent primary GI bleeding with banding of esophageal varices identified by endoscopy prior to the initiation of the treatment drugs. These data are informative. Of note, two of 33 HCC patients treated by bevacizumab in a previous trial developed major GI bleeding,¹⁰ with one of them experiencing death, whereas this complication occurred in three of 30 patients in a similar French study.¹⁶ These data indicate caution concerning the use of bevacizumab, which, although leading to some antitumor efficacy, might cause collateral severe bleeding complications that are life threatening in cirrhotic patients. Preventing primary bleeding in patients with otherwise well-preserved liver function seems a reasonable strategy.

Finally, we want to point out that sorafenib has become the standard of care as a result of robust data obtained in the setting of phase III investigations both in the West and Asia. The level of evidence obtained is the highest according to the National Cancer Institute classification (class 1iA),¹⁵ and the magnitude of the difference is comparable with other accepted drugs, with a hazard ratio of 0.69. Data obtained in exploratory phase II studies, even in the context of randomized strategies, should not overshadow the perspective of treatment strategy for HCC patients until unquestionable data are available. Accordingly, although the results of this phase II study are encouraging, modification of current recommendations will have to wait until properly designed phase III investigations are conducted.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Josep M. Llovet, Bayer (C), Bristol-Myers Squibb Co (C), Novartis (C), Biocompatibles (C); Jordi Bruix, Bayer (C), Novartis (C), Biocompatibles (C) Stock Ownership: None Honoraria: Josep M. Llovet, Bayer Research Funding: Josep M. Llovet, Bayer, Exelixis Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Josep M. Llovet

Financial support: Josep M. Llovet

Administrative support: Josep M. Llovet

Provision of study materials or patients: Josep M. Llovet

Collection and assembly of data: Josep M. Llovet

Data analysis and interpretation: Josep M. Llovet

Manuscript writing: Josep M. Llovet, Jordi Bruix

Final approval of manuscript: Josep M. Llovet, Jordi Bruix

Acknowledgment

Supported by Grant No. 1R01DK076986-01 from the National Institutes of Health–National Institute of Diabetes and Digestive Kidney Diseases (J.M.L.), Grant No. SAF-2007-61898 from the National Institute of Health (Spain) Grant I + D Program (J.M.L.), the Samuel Waxman Cancer Research Foundation (J.M.L.), and Grant No. PI 05/150 from the National Institute of Health (Spain) Fondo de Investigaciones Sanitarias Program (J.B.).

REFERENCES

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