Articles for this review were found through searches of PubMed, Medline, and references from relevant articles by use of the search terms: “hepatocellular carcinoma”, “Asia”, “risk factors”, “screening”, “chronic hepatitis”, “liver transplantation”, “liver resection”, “Hepatitis B immunisation”, “transarterial chemoembolisation”, “radiofrequency ablation”, “percutaneous ethanol injection”, “TACE”, “selective internal radiotherapy”, and “novel targeted therapy”. Trials with the highest
ReviewManagement of hepatocellular carcinoma in Asia: consensus statement from the Asian Oncology Summit 2009
Introduction
Asian countries account for nearly 78% of the roughly 600 000 cases of hepatocellular carcinoma (HCC) reported globally each year.1 In Asia, risk factors for HCC include heavy exposure to aflatoxin,2 algal hepatotoxins in contaminated water,3 betel nut chewing,4 diabetes mellitus, and alcohol abuse leading to liver cirrhosis.5 The main aetiological factor is chronic hepatitis B virus (HBV) infection in northeast and southeast Asia, including China, Hong Kong, Indonesia, Korea, and Taiwan. The high prevalence of chronic HBV carriers in Asia constitutes the majority of the 360 million carriers worldwide. In Asia, there is wide variation in the prevalence of HBV infection; prevalence is 1–5% in Japan, Singapore, and Thailand, 6–10% in Indonesia and northern China, and higher than 10% in Taiwan, southern China, Korea, and the Philippines.6 Chronic hepatitis C virus (HCV) infection also has a substantial role in the development of HCC in Japan and Taiwan.7, 8 HCV infection is expected to increase as an aetiological factor associated with HCC in Asia. The synergistic interactions of interviral, viral, and environmental risk factors complicate matters.9, 10, 11 Knowledge of these predisposing factors enables planning of primary and secondary prevention measures. HBV immunisation of infants has increased to more than 60% worldwide, and such a programme has led to a decline in prevalence of chronic HBV infection among young people in participating Asian countries.12
Nonetheless, HCC mortality rates continue to increase in Asian countries where there is still a large population of HBV carriers. The situation in Taiwan, where the world's first HBV immunisation programme was initiated more than two decades ago, is representative of this phenomenon. A rise in mortality from HCC is attributable to an increased incidence of the disease since 1991 onwards, among people over the age of 50 years, who were born before 1944 and were not immunised against HBV.13 With the long natural history of chronic hepatitis leading to liver cirrhosis and development of HCC, the large pool of existing patients with chronic HBV infection in Asia, both the incidence and mortality rate of HCC are unlikely to decrease for another three to four decades. Therefore, HCC disease-control measures involving surgical, locoregional, and systemic strategies remain highly relevant in Asia.
Section snippets
Resource-stratified consensus framework
Most countries in Asia are in the low-income or middle-income category. Only Hong Kong, Japan, Macau, South Korea, Singapore, and Taiwan belong to the high-income category, as defined by the World Bank using 2007 data on gross national income per capita.14 Many of the current HCC control methods and interventions cannot be implemented in low-income and middle-income countries (LMCs). Evidence-based guidelines that outline optimum approaches to the management of HCC have been defined and
Vaccination
Mother-to-child transmission occurs in utero or, more often, through exposure to blood or blood-contaminated fluids at or around birth. Such perinatal transmission is thought to account for 35–50% of chronic HBV infection.18 Conventionally, the risk of perinatal transmission is associated with the hepatitis B e antigen (HBeAg) status of the mother. If a mother is positive for both hepatitis B surface antigen and e antigen, 70–90% of her children become chronically infected19, 20—because
Secondary prevention
A meta-analysis of three randomised controlled trials and 15 non-randomised controlled trials, and involving 4614 patients, compared interferon to no treatment in patients with HBV-related and HCV-related Child A liver cirrhosis. Overall incidence of HCC was significantly lower in the interferon versus the untreated groups.32 In subset analyses, the lower HCC risk was more pronounced in patients with HCV than in those with HBV, and also in sustained responders compared with non-responders to
HCC surveillance
Most studies of surveillance of HCC in chronic liver disease have been done in patients with chronic HBV infection (HBsAg positive) in endemic Asian countries. It is tenuous to extrapolate the results of these studies to individuals at risk of HCC from other causes, such as alcohol-related cirrhosis or HCV chronic infection. Cost-effectiveness of screening for HCC is directly related to the incidence of HCC in the population to be screened. Surveillance seems to be cost effective in patients
Diagnosis of HCC
A systematic review estimated the sensitivity of ultrasound as 60% (95% CI 44–76%) and specificity as 97% (95–98%), sensitivity as 68% (55–80%) and specificity as 93% (89–96%) for dynamic CT, and sensitivity as 81% (70–91%) and specificity as 85% (77–93%) for dynamic MRI, compared with pathological examination of an explanted or resected liver as the reference standard.38 Ultrasound can miss smaller lesions in a cirrhotic liver and is usually a screening tool. MRI can be more useful than CT in
Staging
Extrahepatic metastases are rarely present if the primary tumour is stage T1 or T2, according to the American Joint Committee on Cancer (AJCC), where tumours are less than 5 cm in diameter, do not involve a major branch of the portal or hepatic vein, and do not invade adjacent organs or perforate visceral peritoneum. In a large series, extrahepatic metastases were present in 86% of cases with T3 and T4 primary tumours.41 55% of extrahepatic metastases where in the lungs, 41% in the regional
Resection
In Asia, where HCC has a high incidence, only 10–15% of newly diagnosed patients have resectable disease. This percentage is doubled in low-incidence regions in North America and Europe. The reason for this disparity remains unclear, but differences in tumour biology, impairment of hepatic reserve due to HBV and HCV infection, and different health-care standards have been cited. The size of the tumour does not matter if it is solitary and devoid of vascular invasion.48 Although tumour rupture,
Neoadjuvant and adjuvant therapy
For tumours that are surgically resected, there is currently no proven survival benefit conferred by use of neoadjuvant or adjuvant therapy. Several types of neoadjuvant therapy—including TACE, systemic chemoimmunotherapy, hepatic-artery infusion of radiolabelled lipiodol, and regional irradiation with or without chemotherapy or TACE—can decrease the size of previously unresectable tumors and even lead to pathological complete response,61, 62 but these outcomes have not resulted in a survival
Radiofrequency ablation
Radiofrequency ablation (RFA) has replaced percutaneous ethanol injection (PEI) in most institutions in Asia. Prospective randomised studies comparing both modalities show an advantage for RFA compared with PEI in terms of local recurrence risk, progression-free and overall survival. In the largest study, done in Japan, 232 patients with tumours 3 cm or larger (most patients were Child-Pugh class A with HCV) were given either PEI or RFA. Fewer treatment sessions were required for RFA than for
Systemic therapy for metastatic HCC
The multicentre European SHARP trial randomly assigned 602 patients with inoperable HCC and Child-Pugh A cirrhosis to receive sorafenib (400 mg twice daily) or placebo. Overall survival was significantly longer in the sorafenib group (10·7 vs 7·9 months), but objective response rates were low, with seven partial responses (2%).76 Liver-function decompensation was more common in patients with Child-Pugh B cirrhosis in the phase 2 trial, so use of sorafenib in this group is not prudent until more
Conclusion
The management of HCC in Asia is challenging. Improving the access to, and quality of, health-care resources aimed at primary prevention of HCC is the most cost-effective strategy to reduce the burden of disease in LMCs. We hope this resource-stratified framework, used in conjunction with the best available evidence, will facilitate the improvement of health-care services in Asia to better manage HCC.
Search strategy and selection criteria
References (77)
- et al.
Elevated aflatoxin and increased risk of hepatocellular carcinoma
Hepatology
(1996) - et al.
Interactions between alcohol and hepatitis viruses in the liver
Clin Lab Med
(1996) - et al.
Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus
Hepatology
(2002) - et al.
Global control of hepatitis B virus infection
Lancet Infect Dis
(2002) - et al.
Impact of hepatitis B immunisation as part of the EPI
Vaccine
(2000) - et al.
Inteferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach
J Hepatol
(2001) - et al.
Screening for hepato-cellular carcinoma in patients with hepatitis C cirrhosis: a cost-utility analysis
Am J Gastroenterol
(2003) - et al.
Outcomes of liver transplantation in 490 patients with hepatocellular carcinoma: validation of a uniform staging after surgical treatment
J Am Coll Surg
(2007) - et al.
Prognostic accuracy of 12 liver staging systems in patients with unresectable hepatocellular carcinoma treated with transarterial chemoembolization
J Vasc Interv Radiol
(2006) - et al.
Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival
Hepatology
(2001)