Novel Strategy for the Management of Liver Cancer
In the quest towards molecular targeted strategies and personalized medicine for the management of liver cancer, ongoing research will benefit from a multidisciplinary debate among the interrelated specialties involved, such as hepatology, radiology, oncology, surgery, epidemiology, vaccine/prevention intervention, pathology, biochemistry, molecular biology and genetics. This objective led to the formation of the International Liver Cancer Association (ILCA) which aims to be a forum for active multidisciplinary debate in the discipline of hepatic oncology.
At the recent 2010 conference of the Asia Pacific Association for the Study of the Liver (APASL) held in Beijing, ILCA and APASL had a joint session on 28 March to discuss novel strategies for the management of liver cancer. The session was co-moderated by Dr Donald Poon from the National Cancer Centre of Singapore and Professor Kwang-Hyub Han from the Yonsei University College of Medicine in Seoul, Korea.
Lectures:
Treatment Algorithm for Hepatocellular Carcinoma
On the Frontier of Molecular Targeted Therapy for HCC
Molecular Targeted Therapy of HCC in China
Prevention of HCC in Chronic Viral Hepatitis
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Treatment Algorithm for Hepatocellular Carcinoma
Associate Professor Jordi Bruix, Director of the Barcelona Clinic Liver Cancer Group in Spain, begun the session by reiterating that the end-point of treatment for hepatocellular carcinoma (HCC) is to improve survival for patients. In the race to develop more effective therapy options, it is essential that clinicians address their capacity to determine a standard of care, as well as to identify optimal candidates and absolute contraindications in aiming for optimal results and risk assessment.
A/Prof Bruix underscored the importance of guidelines being evidenced-based in order to correctly inform practice. He cited pivotal examples such as the AASLD Practice Guideline on the management of HCC (next review to be updated in 2010), Llovet et al’s seminal paper on design and endpoints in clinical trials of HCC, and the Spanish consensus on diagnosis and treatment of HCC which was adopted by the National Health System of Spain.
The staging and treatment algorithm from the Barcelona Clinic Liver Cancer Group has been acknowledged as the best tool for management of HCC. The approach focuses on improving survival with early detection and selection of therapies based on patient and disease stage. At the early stages of disease, conventional curative therapies such as resection, liver transplantation, percutaneous ethanol injection and radiofrequency ablation, offers patients a survival of 50–75% at 5 years. Patients with intermediate stage HCC may benefit from non-curative treatments (3-year survival of 10–40%) such as chemoembolization and sorafenib, a multikinase inhibitor.
“Until the advent of sorafenib, there was no effective systemic treatment available for patients with advanced HCC,” said A/Prof Bruix. Sorafenib is currently the reference standard for patients in HCC therapy with proven efficacy for lower progression rate and increased survival. “Second-line agents should be tested within research trials planned upon progression or intolerance post-sorafenib and combination proposals should have sorafenib as the backbone of therapy,” opined A/Prof Bruix.
On the Frontier of Molecular Targeted Therapy for HCC
Professor Ann-Lii Cheng from the National Taiwan University Hospital in Taipei highlighted the efficacy of sorafenib for both Western and Asia Pacific populations. He noted that the Phase III SHARP trial equivalent in Asia Pacific of sorafenib treatment in advanced HCC versus placebo has a hazard ratio (HR) for overall survival of 0.68 (P = 0.014), representing a 32% relative reduction in risk of death. This is notably comparable to the HR of 0.69 (P = 0.00058) in the SHARP trial.
Tyrosine kinase inhibitors such as sorafenib, sunitinib and brivanib represent the first generation of multi-target anti-angiogenic agents (MTAs). “The success of sorafenib has resulted in trials combining sorafenib with those targeting other pathways,” said Professor Cheng. Combining sorafenib with second-generation novel MTAs such as EGFRi, mTORi, Akti and proteasome inhibitors also gives rise to the development of various sorafenib combinations (vertical and parallel blockades). Future investigations will also explore the combination of novel MTAs.
The development of novel MTAs is driven by the targeted angiogenic pathways for HCC and mechanisms of resistance to anti-angiogenic therapy. “Successful drugs need a specific driver mutation in order for targeted therapy to work”, explained Professor Cheng. As such, there is a wealth of ongoing and planned trials exploring treatment options using a single novel MTA, sorafenib-based MTA combinations, MTA combined with local therapy such as transcatheter arterial chemoembolization (TACE) and MTA as adjuvant after curative therapy (e.g. surgery, radiofrequency ablation).
Professor Cheng concluded that the development of molecular targeted therapy in HCC will be in the direction of novel anti-angiogenic agents, particularly those which can cope with known mechanisms of drug resistance; sorafenib combinations which enhance the activity of this class of agents; and the identification of biomarkers and driver mutations for HCC. However, judicious pursuit of these molecular strategies is cautioned as too much intense blockade may result in liver toxicity, especially among Asian populations.
Molecular Targeted Therapy of HCC in China
HCC is the most common malignancy globally and at least 300,000 of the 600,000 deaths worldwide occur in China alone. “The challenges in treating HCC in China include severe cirrhosis, intrahepatic spread and distant metastasis, high post-operative recurrence and low resectability,” remarked Professor Ye from the Liver Cancer Institute of Zhongshan Hospital Fudan University in Shanghai, China.
Against this dire backdrop, molecular targeted therapy presents a significant magnitude of promise for patients with HCC, particularly the Chinese population. Potential targets in the molecular pathogenesis of HCC include monoclonal antibodies, cell cycle modulators and inhibitors of growth factors, receptors, angiogenesis and signal transduction pathways. Professor Ye elaborated on several examples of ongoing molecular approaches investigating potential targets of organ-specific metastasis, viral gene therapy targeting AFP-expression and antisense gene therapy.
Prevention of HCC in Chronic Viral Hepatitis
Hepatitis B virus (HBV) infection has been identified as the main etiologic agent of HCC. Professor Richard Man-Fung Yuen from the University of Hong Kong, Queen Mary Hospital spoke about the prevention of HCC by HBV vaccination and chronic hepatitis B (CHB) treatment. Following the World Health Organization’s (WHO) call in 1992 to introduce HBV vaccine into national routine infant immunization programs, more than 162 countries have made this a reality by 2006. In a Taiwanese example of these successful implementations, the average incidence of HCC and brain tumour in children aged 6–14 years declined from 0.7 per 100,000 in the 1980s to 0.36 in the early 1990s.
In patients with CHB, interferons (IFNs) and nucleo(s)tide analogues (NAs) are the main therapy options. Although there are indications that IFN treatment may decrease the risk of HCC in selected group of patients such as IFN responders and those with cirrhosis, the effect of IFNs in decreasing the risk of HCC still remain controversial. In comparison, long-term treatment with lamivudine has been associated with a reduced chance of developing cirrhosis and HCC in patients without advanced disease. However, the use of long-term NA treatment as prevention for HCC is hampered by the selection of antiviral-resistant mutations, a main concern particularly with long-term lamivudine therapy.
