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Hepatocellular carcinoma (HCC) is a major worldwide public health problem, representing the fifth most common malignancy in the world. In the developing world, HCC has long been considered a priority oncological problem and in certain parts of the world is the most common solid organ tumor, with approximately 500,000 cases diagnosed annually. There is wide geographic variability with regard to incidence rates, which reflects the different patterns of exposure to underlying risk factors for the development of the disease. Approximately 80% of cases worldwide arise in the developing world where the major etiological factor is exposure to hepatitis B virus (HBV) or C virus (HCV). The highest risk areas include Eastern and Southeastern Asia, and middle, eastern, and parts of western Africa. In high-risk areas, the age-specific incidence rates begin to increase after 20 years of age, reflecting the importance of vertical transmission of HBV or acquisition of HBV in early childhood, but the risk stabilizes at age 50 and older. In low-risk areas the incidence rate steadily increases with age, reflecting the later acquisition of viral infection or the impact of other factors such as alcohol-related cirrhosis. North America, although still categorized as a low-incidence region, has had a dramatic increase in the incidence of HCC primarily due to an increasing incidence of HCV infection. Recent studies have noted a marked increase in the age-adjusted rates for HCC associated with HCV.

An estimated 60% to 80% of HCC patients have developed the disease due to cirrhosis from associated liver parenchymal disease, which is most often due to chronic viral hepatitis from either hepatitis B or hepatitis C, but may also be due to alcohol-related cirrhosis. The risk for development of HCC in the setting of hepatitis B-related cirrhosis is approximately 0.5% per year, whereas development of HCC in the setting of hepatitis C may occur in up to 5% of cirrhotic patients per year. The pattern of exposure to risk factors is age and region dependent. Because of the risk of vertical transmission, HCC occurring in developing countries is generally related to hepatitis B infection in a younger population. Nonalcoholic fatty liver disease (NAFLD) has emerged in recent times as an important cause of liver disease, including HCC. This condition is associated with obesity, insulin resistance, and hyperlipidemia and commonly manifests with an asymptomatic elevation of liver enzymes. Other causes of HCC include hereditary hemachromatosis, Wilson's disease, and exposure to chemicals such as arsenic.

The management of this disease is made more difficult because the tumor arises in the setting of underlying liver disease. It has been estimated that the risk of dying solely due to hepatic failure may be as high as 20%, even in those with small (<3 cm) HCC. The severity of the liver dysfunction also greatly limits treatment options. The prognosis therefore depends not only on an anatomic assessment of the tumor as reflected by the TNM system, but also on the extent of underlying liver damage. Scoring systems that evaluate only tumor characteristics (eg, TNM) or only liver function (eg, Child-Pugh) do not accurately reflect the prognosis. Several scoring systems have attempted to incorporate non-tumor-related factors to better define the prognosis. The Barcelona Clinic Liver Cancer (BCLC) staging classification divides cases into 4 categories of differing severity. The Cancer of the Liver Italian Program (CLIP) evaluates the Child-Pugh stage, tumor morphology (number of nodules and volume), alfa-fetoprotein (AFP) level, and presence of portal vein thrombosis. This scoring system has been externally validated by several studies and has been recommended by the American Hepato-Pancreatic-Biliary Association/American Joint Commission on Cancer Consensus Conference on Staging of Hepatocellular Carcinoma. Due to differing prognosis of HCC related to ethnic diversity and viral etiology (either HBV- or HCV-related), it is unlikely that any single scoring system will suffice for all populations.

The primary curative treatment for patients with HCC is surgical, either in the form of partial hepatectomy or total hepatectomy with liver transplantation. Resectability for any hepatic tumor, including HCC, is dependent on the patient's ability to withstand a major surgical intervention, absence of extrahepatic disease, and anatomic resectability. The results of surgical resection are influenced greatly by the preoperative liver functional status. Cirrhosis adversely influences surgical outcome in many ways, and often is the only determinant that results in an unresectable status. Many complex methods of evaluating liver function have been tested to assist in patient selection. Assessment by Childs-Pugh classification is one of the most widely used in Western series, although indocyanine green (ICG) retention rate is used commonly in Asia. Few surgeons are willing to perform hepatic resection for patients with Childs-Pugh C liver status, and the operative mortality rate may be as high as 30% for patients with Childs-Pugh B cirrhosis. These patients are clearly better served with transplantation if they meet accepted criteria. Therefore, most surgeons will only consider resection for patients with Childs A, or, in some cases, Childs B, liver function. In patients undergoing resection for HCC, the overall 5-year survival rate is 30%.

Total hepatectomy and liver transplantation is an attractive option for patients with cirrhosis and cancer, since it can treat both the underlying liver disease and the tumor. Generally well-accepted indications for liver transplant (Milan Criteria) are dependent on tumor size—a single HCC smaller than 5 cm in size, or fewer than 3 tumors, all less than 3 cm. Using these criteria, the 5-year survival is approximately 70%, with a 15% chance for recurrence. When comparing the results of transplantation to those of resection, one must remember the inherent selection bias in patients treated with transplantation: these patients with early stage HCC have an inherent better prognosis than those with more advanced tumors that do not meet the Milan criteria. In addition, only patients who have not progressed while waiting for an organ are transplanted, which is indicative of better tumor biology. This is demonstrated by the fact that recent studies that have evaluated the outcome of patients undergoing liver resection with tumors that fit the Milan criteria have overall 5-year survival rate of 70%, similar to the outcome after liver transplantation. As expected, the risk of intrahepatic recurrence in patients undergoing resection was higher than after liver transplantation. To address this problem, some surgeons have utilized a strategy of salvage transplantation for those patients that recur after hepatectomy, thereby improving organ allocation only to those that have the greatest need.

Treatment of patients with surgically unresectable disease is primarily guided by the extent of disease and whether it is confined to the liver or is extrahepatic. A greater investigational energy has been focused on HCC recently, and better systemic therapies are emerging for those patients with widespread liver disease or extrahepatic disease. Because of the low response rates to systemic chemotherapy, there has been an increasing focus on molecularly targeted agents, including sorafenib. This drug is a multikinase inhibitor that has been found to enhance overall survival and time to progression compared with placebo in a randomized trial for patients with metastatic HCC. This approach clearly holds promise for future trials evaluating systemic therapy options for HCC.