Hepatocellular Carcinoma: Targeted Therapy and Multidisciplinary P8

Chapter 4 Screening Program in High-Risk Populations Ryota Masuzaki and Masao Omata Keywords Screening · Surveillance · AFP · Ultrasonography Introduction Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide [1–5]. The majority of patients with HCC have a background of chronic liver dis-ease, especially chronic hepatitis due to hepatitis C virus (HCV) or hepatitis B virus (HBV) infection [6, 7]. Thus, at least some high-risk patients for HCC can be readily defined. Indeed, HCC surveillance is commonly performed as part of the standard clinical examination of patients with chronic viral hepatitis [8]. Ultrasonography and tumor marker tests, which play important roles in HCC surveillance in patients with chronic liver diseases, are widely used. However, insufficient evidence exists to suggest that surveillance by either of these meth-ods improves the prognosis of patients with HCC or increases the chances of local therapies such as resection and local ablation therapy or even that of radical treat-ments such as liver transplantation. Similarly, the utility of computed tomography (CT) or magnetic resonance imaging (MRI) in the surveillance of HCC remains unclear. The primary objective of screening and surveillance for HCC should be to reduce mortality as much as possible in patients who actually develop the cancer and in an acceptably cost-effective fashion. To attain this objective, two distinct issues deserve meticulous consideration: the target population and the mode of surveillance. M. Omata ( ) Department of Gastroenterology, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan K.M. McMasters, J.-N. Vauthey (eds.), Hepatocellular Carcinoma, 55 DOI 10.1007/978-1-60327-522-4_4, C Springer Science+Business Media, LLC 2011 56 R. Masuzaki and M. Omata Target Population HCC has been observed to show significant geographic regional clustering [9]. Moreover, HBV, HCV, and other environmental factors may play important roles in HCC development, with the relative importance of individual factors varying widely according to geographic area [7, 10–12]. In Japan, HCV infection is respon-sible for about 80% of HCC cases, whereas HBV infection is responsible for 10% and alcohol for about 5% [4, 13]. These values may differ substantially in other countries. For example, in China, HBV infection has a much higher prevalence and is therefore by far the predominant etiology behind HCC. In the United States, nonalcoholic steatohepatitis (NASH) is reportedly a major predisposing disease for HCC. Surveillance is not recommended for the general population, given the low inci-dence of HCC among individuals with no risk factors. Thus, the first step in HCC screening should be the identification of patients at risk of HCC development. Since chronic viral hepatitis due to either HBV or HCV may be asymptomatic, mass screening for hepatitis virus infection of either the HBV or HCV type is justi-fied if the prevalence of infection in the region is reasonably high. Indeed, mass screening of adults over 40 years of age for HBV and HCV infection has been per-formed in Japan since 2002, but the cost-effectiveness of this program has yet to be evaluated. Persistent infection with HBV is a major risk factor for HCC. HBV carriers have a 223-fold higher risk of developing the cancer than noncarriers [14]. Among HBV carriers, those who are HBe-antigen positive are at a higher risk of HCC than those who are negative for the antigen (relative risk, 6.3) [15, 16]. The results of a recent large-scale, long-term cohort study conducted in Taiwan showed that serum HBV DNA levels are the strongest risk factor for both the progression to cirrhosis and the development of HCC among HBV-positive patients, independent of serum HBe-antigen/antibody status or alanine aminotransferase (ALT) levels [17]. With the advent of reliable quantitative assays, the determination of HBV DNA levels may replace that of HBe-antigen/antibody status as a risk indicator of HCC. While the prevalence of chronic HBV infection is high in limited geographic areas, such as East and Southeast Asia and sub-Saharan Africa, the prevalence of chronic HCV infection has been increasing in many parts of the developed world, including Japan, southern Europe, and the United States. With chronic HCV infec-tion, the risk of HCC increases with progression to liver fibrosis [6, 18], and patients with chronic HCV infection who have cirrhosis stand a very high risk of develop-ing HCC [19]. In Japan, HCV infection spread throughout the country mainly in the 1950s and 1960s, and thus after the passing of a few decades required for pro-gression to cirrhosis, it is currently by far the most predominant cause of HCC. The peak of viral spread in the United States took place a couple of decades later; accordingly, the incidence of HCV-related HCC is now rapidly increasing [20, 21]. In addition to the degree of liver fibrosis, male gender, older age, and heavy alcohol 4 Screening of HCC 57 consumption are also known risk factors for HCV-related HCC. Human immunod-eficiency virus (HIV) coinfection is an important risk factor of rapid progression to liver fibrosis, which especially now in the United States constitutes a serious clinical problem. Cirrhosis due to etiologies other than chronic viral hepatitis also presents a risk for HCC development. Major etiologies include alcoholic liver disease and NASH [22–24], the relative importance of which may differ geographically. Hassan et al. reported that alcoholic liver disease accounted for 32% of all cases of HCC in an Austrian cohort [25]. In the United States, the approximate hospitalization rate for HCC related to alcoholic cirrhosis is 8–9/100,000/year compared to about 7/100,000/year for hepatitis C [26]. NASH is a chronic liver disease that is gaining increasing importance due to its high prevalence worldwide and its potential pro-gression to cirrhosis, HCC, and liver failure. Although NASH has been described in cohorts of patients with HCC [27, 28], the incidence of HCC with respect to cirrho-sis due to NASH is not well known. In certain areas of the world, aflatoxin also may play a role in HCC development. In brief, evaluation of the degree of liver fibrosis is of paramount importance in assessing the risk of HCC development in patients with chronic liver diseases of any etiology. Histological evaluation of liver biopsy samples has been consid-ered the gold standard for the assessment of liver fibrosis, but the invasiveness accompanying liver biopsy poses considerable limits to its clinical feasibility. In clinical practice, repeated assessment of liver fibrosis often will be required because a once non-cirrhotic liver may become cirrhotic over time, sometimes rather rapidly. Consequently, the noninvasive evaluation of liver fibrosis is currently one of the main interests of hepatology. Results obtained from the recently developed technique of transient elastography correlate well with liver fibrosis stage, as determined histologically [29–31]. The cutoff value for the diagnosis of histological cirrhosis is 12.5–14.9 kPa [29, 31]. Higher values of liver stiffness may need proper attention as they indicate decom-pensation and HCC development. The fibrotest is based on the age and gender of the patient combined with measurements of five biochemical markers (total bilirubin, haptoglobin, gamma glutamyl transpeptidase, alpha-2 macroglobulin, and apolipoprotein A1) [32]. An index of 0–0.10 has a 100% negative predictive value, while an index of 0.60–1.00 has a greater than 90% positive predictive value for a Metavir score of F2 to F4. The APRI is the aspartate aminotransferase (AST) level/upper limit of normal divided by the platelet count (109/L) multiplied by 100 [33]. For a hypothetical patient with AST 90 IU/L (upper limit of normal, 45) and platelet count 100 (×109/L), the APRI score is 2.0, which means that the positive predictive value for significant fibrosis is 0.88. Nonetheless, the applicability of any of these methods for surveillance remains to be determined in prospective studies. Patients who are considered to be at a non-negligible risk of developing HCC should participate in a surveillance program, as discussed below. Possible excep-tions may be patients with severe liver dysfunction who could not receive any treatment even if diagnosed with HCC or those with other life-threatening diseases. 58 R. Masuzaki and M. Omata Surveillance Methodology Traditionally, two methodologies have been employed in HCC surveillance for high-riskpatients:tumormarkerdetermination,specificallyserumalpha-fetoprotein (AFP) concentration, and diagnostic imaging via liver ultrasonography. The util-ity of a surveillance program should be evaluated based on its beneficial effects in terms of outcome of patients diagnosed with HCC relative to the cost. However, few prospective randomized trials have compared the outcome of patients with HCC enrolled or not in a surveillance program. Consequently, evidence regarding the benefits of surveillance on decreasing overall or disease-specific mortality has come mostly from retrospective or case–control studies. Alpha-Fetoprotein (AFP) The glycoprotein AFP has a molecular weight of 72 kDa. Its main physiologic func-tion appears to be the regulation of fatty acids in both fetal and proliferating adult liver cells [34]. Since 1968, AFP has been used as a serum marker in the detection of human HCC [35], with a sensitivity of 39–65%, a specificity of 76–94%, and a posi-tive predictive value of 9–50% (Table 4.1) [36–41]. Studies assessing the usefulness of AFP in HCC screening have varied widely in their design and in the characteris-tics of the targeted patients in terms of, for example, disease etiology and severity of background liver diseases. Moreover, the reported specificity and sensitivity values inevitably vary depending on the cutoff level chosen for the diagnosis of HCC. An intrinsic disadvantage of AFP as a tumor marker is the fact that serum AFP levels can increase in patients who have active hepatitis, but not HCC; this is partly due to the accelerated cellular proliferation during liver regeneration. An AFP con-centration of 20 ng/mL is often adopted as the upper limit of normal because this level is rarely exceeded in healthy people. However, slightly higher concen-trations are hardly diagnostic of HCC among patients with chronic hepatitis, and the adoption of a cutoff value that is too low would result in an inappropriately low specificity. AFP levels above 400 ng/mL can be considered almost definitively diagnostic of HCC but sensitivity is inevitably lower at this higher cutoff value. Moreover, an additional disadvantage exists in using AFP for HCC surveillance. Small HCC tumors, the detection of which is the primary objective of surveillance, are less likely to be AFP producing, but even if the marker is expressed by these tumors, the levels may not be high enough to result in a diagnosis of HCC. For this and other reasons, AFP determination has been frequently dismissed as a screening test for HCC, except when ultrasonography is either not available or of such poor quality that lesions smaller than 2 cm in diameter cannot be detected. Moreover, as shown in HCC screening of Alaskan carriers of hepatitis B, AFP test-ing allowed the detection of tumors at an earlier, treatable stage [42], but although screened patients survived longer than their historic controls, the difference could 4 Screening of HCC 59 ... - tailieumienphi.vn