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Clin Gastroenterol Hepatol. Author manuscript; available in PMC 2016 November 01. Published in final edited form as: Clin Gastroenterol Hepatol. 2015 November ; 13(12): 2140–2151. doi:10.1016/j.cgh.2015.08.014.

Hepatocellular Carcinoma from Epidemiology to Prevention: Translating Knowledge into Practice Amit G. Singal, MD MS and Division of Digestive and Liver Diseases University of Texas Southwestern Medical Center Dallas, TX 75390

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Hashem B El-Serag, MD, MPH Section of Gastroenterology and Hepatology and Center (iQUEST) Michael E DeBakey VA Medical Center and Baylor College of Medicine Houston, Texas

Abstract

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Hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer-related death worldwide and one of the leading causes of death in patients with cirrhosis.1]HCC incidence in the United States (US) has more than doubled over the past 2 decades and is anticipated to continue increasing over the next 20 y, due to the growing number of patients with advanced hepatitis C virus (HCV) and/or non-alcoholic steatohepatitis (NASH). At its current pace, HCC is projected to surpass breast and colorectal cancer to become the 3rd leading cause of cancer-related death in the US by 2030.2 Currently only 46% of HCC cases are diagnosed at an early stage and most do not receive curative therapy.2 Epidemiologic and clinical studies have identified many factors that affect risk for HCC and can be used to identify at-risk patients and implement prevention measures. Although several advances in HCC prevention, early detection, and diagnosis are efficacious and could reduce the incidence and mortality of HCC, widespread dissemination and successful implementation are essential for these strategies to be effective in clinical practice. Challenges include limited recognition of at-risk patients, availability of well-validated risk stratification measures, and surveillance in high-risk groups.

Efficacy vs Effectiveness

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Efficacy means the degree to which an intervention produces an expected result under carefully controlled conditions chosen to maximize the likelihood of observing an effect if it exists, whereas effectiveness means the extent to which an intervention is beneficial in usual practice settings, among broader populations.3 Whereas efficacy of an intervention is primarily determined by its biological effects, its effectiveness can be influenced by external patient, provider, system, and societal factors, including the availability and accessibility of the intervention by the health system, identification of patients who are appropriate for the intervention by providers, recommendation of the intervention by providers, acceptance of Corresponding Author: Hashem B. El-Serag ([email protected]). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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the intervention and adherence by patients, and high-quality test performance when delivered by health systems in usual practice. Given these external factors, efficacy studies can overestimate the intervention’s potential effect in clinical practice.

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Models of effectiveness can be operationalized to evaluate therapeutic (e.g., HCV treatment) or diagnostic (e.g., HCC surveillance) interventions in large populations. For example, HCV therapy is highly efficacious, producing rates of sustained viral responses greater than 90% in patients with genotype 1 infection (Table 1). However, its effectiveness in usual practice could be substantially lower (17%), given relatively small decrements in rates of access to care, accurate diagnostic tests for HCV, proper treatment recommendations by providers, and acceptance or adherence to treatment by patients. Even if a new anti-viral regimen with 100% efficacy was developed, its overall effectiveness would be only slightly higher (i.e., 24%) if all other parameters were unchanged.4 Similarly, ultrasound is efficacious in surveillance for HCC, detecting the cancer with 63% sensitivity. However its effectiveness in clinical practice is substantially lower due to under-recognition of patients with cirrhosis, low utilization among patients with known cirrhosis, and its operator-dependent nature. Effectiveness data more accurately reflect an intervention’s ability to decrease disease burden in clinical practice and therefore are equally, if not more, important than efficacy data.3 Therefore, it is imperative to evaluate and improve the effectiveness of HCC risk stratification, prevention, early detection, and diagnosis in usual practice settings.

A Model for Care

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The Quality in the Continuum of Cancer Care (QCCC) model provides a framework for evaluating the HCC prevention processes, including potential failures that create a gap between efficacy and effectiveness.5 It outlines several steps within the cancer prevention (e.g., screening) process, including identification of at-risk patients, primary prevention, early detection, diagnosis, treatment, and survivorship (Figure 1). The QCCC considers the complexity of the environment in which cancer prevention occurs, highlighting the influence of patient-, provider- and organizational-level factors. As for breast, cervical, and colorectal cancers6;7, the QCCC can help identify intervention targets and strategies to increase HCC prevention effectiveness in clinical practice.

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For example, HCC screening is a complex process in clinical practice.8 First, providers must be knowledgeable about HCC risk factors and the target patient population for whom prevention and/or surveillance is recommended.9 Second, providers must accurately identify patients with cirrhosis and refer eligible patients for primary prevention or HCC surveillance. Third, the healthcare system must have sufficient capacity to schedule and deliver surveillance tests; patients must comply with provider recommendations. Finally, providers must follow up on surveillance results and refer any patients with abnormal results for diagnostic evaluation and treatment. Each of these steps is prone to failure, and the screening process also depends on the availability of surveillance and diagnostic tests. The effectiveness of HCC screening can therefore be reduced by factors at the patient level (e.g., lack of medical insurance), provider level (e.g., poor knowledge of guidelines), and system level (e.g., insensitive surveillance tests or insufficient capacity).

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Identification of At-risk Patients, Based on Epidemiology Findings Accurate identification of patients who are high risk for HCC is the first step for delivery of prevention and early detection programs. This responsibility lies with clinic providers, who depend on a combination of clinical exam, laboratory, and radiology findings. Epidemiology studies have established several important risk factors for HCC that can help providers identify at-risk patients.

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Chronic hepatitis B virus (HBV) infection affects 350 million persons worldwide and is the most common risk factor for HCC worldwide. Cohort studies estimate HCC incidence rates among subjects with chronic HBV infection to be 0.02–0.2 per 100 person-years in inactive carriers, 0.3–0.6 per 100 person-years for those with chronic HBV infection without cirrhosis, and 2.2–3.7 per 100 person-years for those with compensated cirrhosis.10 Several demographic (male sex, older age, Asian or African ancestry, family history of HCC), viral (higher levels of HBV DNA and HB surface antigen; HB e antigen [HBeAg] positivity; HBV genotype; duration of infection; and co-infection with HCV, HIV, or HDV), and environmental (heavy intake of alcohol and possibly tobacco, exposure to aflatoxin) factors increase HCC risk among individuals with chronic HBV infection.10

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HCV infection is associated with a 15- to 20-fold increase in risk for HCC. Once HCVrelated cirrhosis is established, HCC develops at an annual rate of 1%–8% (average, 3.5%). Among HCV-infected individuals, risk factors for HCC include male sex, genotype 3 infection11, co-infection with HBV or HIV, diabetes, obesity, and high level of alcohol consumption.12 Hispanics with HCV are at a significantly higher risk, whereas African Americans are at a considerably lower risk, of developing cirrhosis and HCC than nonHispanic whites. HCV viremia of any level is a strong risk factor for HCC compared to no viremia. Although a few studies reported a correlation between HCV load and or HCC, most studies did not find such an association. Several components of the metabolic syndrome have been associated with increased risk of HCC.13 Meta-analyses of cross sectional, case control, and cohort studies report pooled odds ratios of approximately 2.5 for the association between type 2 diabetes and HCC, independent of viral hepatitis or alcohol use.14;15 Most studies reported a modest increase in the relative risk of HCC in obese persons. A systematic review of 10 cohort studies found a positive association between obesity (measured as body mass index) and risk of HCC in 7 studies (relative risks ranging from 1.4 to 4.1), no association in 2 studies, and an inverse association in 1 study.16

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The factors that affect risk of HCC among obese person are unclear and may include high waist to hip ratio17, altered levels of adipokines18, or development of NASH. There seems to be a synergistic interaction between obesity and hepatitis virus infection, with an increased risk of developing HCC at a young age in the absence of major HCC risk factors19. Epidemiologic studies support at least a modest association between non-alcoholic fatty liver disease (NAFLD) or NASH and HCC, but this association is mostly limited to those who develop cirrhosis. The few population-based cohort studies of patients with NAFLD have been limited by the low number of HCC cases and inability to identify high risk sub-

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groups.20 Several case–control studies have evaluated this association indirectly and reported the prevalence of diabetes and obesity to be greater among NAFLD-related cases of HCC than controls (patients with other chronic liver diseases).20 A polymorphism in the patatin-like phospholipase domain-containing 3 gene (PNPLA3) has been associated with an increased risk of cirrhosis and possibly HCC.21 Studies have shown low risk of HCC among patients with primary sclerosing cholangitis22 or most liver disorders without cirrhosis.

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Most risk factors for HCC in the US and Europe are associated with cirrhosis; patients with cirrhosis can therefore be identified and targeted for cancer prevention and surveillance. The risk of HCC among patients with cirrhosis is highest in those with HCV infection (5 y incidence, 17% in the West and 30% in Japan) or hemochromatosis (5 y incidence, 21%), followed by HBV (5 y incidence, 10% in the West and 15% in Asia)23 and alcoholic cirrhosis (5 y incidence, 8%– 12%24). Among patients with NASH-related cirrhosis, the incidence of HCC ranges from 2.4% within 7 y to 12.8% within 3 y. HCC rarely develops in patients with HCV infection without cirrhosis, and when it does it affects patients with bridging hepatic fibrosis. Although HBV infection can lead to HCC in patients without advanced fibrosis or cirrhosis, more than 85% of cases of HBV-related HCC in Western countries occurred in patients with cirrhosis.25 There have also been reports of NASH-related HCC in patients with mild or no hepatic fibrosis26;27, but it is not clear what factors might contribute to development of HCC in patients with NASH without cirrhosis.

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Although cirrhosis is easy to identify in patients with jaundice or ascites, it can be more difficult to detect in patients with well-compensated cirrhosis. Patients can have compensated cirrhosis for several years and have a high risk for developing HCC. Underrecognition of cirrhosis is one of the main reasons for the underuse of HCC surveillance in the United States (US); more than 20% of patients who present with HCC have unrecognized cirrhosis.28 Patients with NASH have the highest risk for unrecognized liver disease. In a study of 251 patients with NAFLD, 54 (21.5%) had NAFLD mentioned as a possible diagnosis, 37 (14.7%) were counseled regarding diet and exercise, and 26 (10.4%) were referred to a specialist.29 With the prevalence of NAFLD increasing in the US and worldwide, unrecognized cirrhosis is likely to become a larger problem.30 Men have a 2-fold to 4-fold greater risk for HCC than women, across almost all liver disease etiologies. Sex-based differences in behavior and environmental exposures such as alcohol use might account for some of this difference. However, male and female sex hormones may also have roles in HCC risk.

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Translating Epidemiology into Risk Stratification in Clinical Practice Scoring systems to estimate risk for HCC, based on risk factors such as cirrhosis, can be used to help identify high-risk patients most likely to benefit from prevention and early detection programs.31 They might also be used to identify low-risk patients (how have an annual incidence of HCC below 1.5%) for whom HCC surveillance is not cost-effective. However, these types of algorithms must be sufficiently accurate, validated in diverse patient populations, and based on available data to be widely useful. Clin Gastroenterol Hepatol. Author manuscript; available in PMC 2016 November 01.

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Studies performed in Asia have derived and validated HCC risk scores for HBV-infected patients based on age, sex, level of alanine aminotransferase, viral load, HBeAg status, and the presence of cirrhosis. Generally, these scores have high negative predictive values (above 95%) for development of HCC over a 3–10 y period. For example, the REACH-B score identified patients who developed HCC with area under the receiver operating characteristic curve values greater than 0.80, but this system can only be applied to patients without cirrhosis. Other risk scoring systems, such as the GAG-HCC and CU-HCC, consider factors such as presence of cirrhosis and core promoter mutations and may be more accurate, particularly for non-Asian cohorts.32 HCC risk scoring systems for patients receiving antiviral therapy with adequate viral suppression, and/or in other racial/ethnic groups, including patients from the US and Europe, require further evaluation.33

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A multivariate analysis model was developed, using data from the using HALT-C trial, to determine the risk of HCC in patients with HCV infection based on older age, black race, lower platelet count, higher level of alkaline phosphatase, esophageal varices, and smoking.34 The model allowed for risk stratification of patients, with 5 y HCC incidence rates of 0.4%, 4.2%, and 17.8% in the low-risk, intermediate-risk, and high-risk groups, respectively. However, this model had an area under the curve value of only 0.60 (95% confidence interval [CI], 0.50–0.70) when externally validated.35

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Genetic factors, such as the single nucleotide polymorphism 61*G (rs4444903) in the epidermal growth factor gene (EGF), may help identify which patients with HCV infection are at highest risk for HCC.36 Longitudinal clinical, laboratory, and histologic data can also be used to predict clinical outcomes of patients, including development of HCC.37 However, these models must be validated, particularly in patients with sustained responses to directacting antiviral (DAA) agents. Irrespective of etiology of chronic liver disease, the degree of hepatic fibrosis seems to be associated with HCC risk. The degree of liver stiffness measured using elastography is associated with HCC risk.38

Prevention Preventing HCC is an important aspect in the care of any patient with chronic liver disease. Primary prevention focuses on preventing the occurrence of HCC risk factors, or treating them at an early stage. The best targets for prevention programs are usually identified using the population-attributable fraction (PAF)—the proportional reduction in disease that would occur if exposure to a risk factor were eliminated.

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Worldwide, HBV infection contributes the largest PAF for HCC. However, in the US and several regions in Europe, obesity, diabetes, and NAFLD appear to contribute the largest PAF.39 For example, the European Prospective Investigation into Cancer and Nutrition found obesity to account for approximately 16% of cases of HCC in Europe.40 Similarly, based on data from a Surveillance, Epidemiology, and End Results (SEER) analysis of the Medicare population, diabetes and or obesity to contribute to 36.6% of cases of HCC.41 However, calculation of the PAF assumes that all cases of HCC that develop in patients with metabolic syndrome are etiologically related to this condition, which is unlikely to be true. Clin Gastroenterol Hepatol. Author manuscript; available in PMC 2016 November 01.

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In cross-sectional studies of HCC, viral hepatitis accounted for most cases; there have been no convincing studies of temporal trends of increasing NASH- or obesity-related HCC. Among 1500 patients at Veterans Administration hospitals who developed HCC from 2005 through 2010, the annual proportion of NASH-related HCC remained relatively stable (7.5%–12.0%). In contrast, the proportion of HCC cases associated with HCV increased from 61.0% in 2005 to 74.9% in 2010. The proportion of HCC cases associated with alcohol abuse alone decreased from 21.9% in 2005 to 15.7% in 2010, and the annual proportion of HCC cases associated with hepatitis B remained relatively stable (1.4%–3.5%).42 Given that HBV and HCV appear to make the greatest contribution to HCC burden, the highest quality data for primary prevention support HBV vaccination and/or anti-viral treatment programs. However, some data support evaluation of chemoprevention agents for patients with nonviral liver disease.

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HBV Vaccination

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HBV vaccination programs are a prime example of primary prevention strategies for HCC, and have been the most successful in reducing its incidence, in specific areas. A large randomized controlled trial (RCT) in China demonstrated the efficacy of HBV vaccination in reducing liver-related mortality (hazard ratio, 0.30; 95% CI, 0.11–0.85) and primary liver cancer (hazard ratio, 0.16; 95% CI, 0.03–0.77) over a 25 y period.18 In practice, these programs greatly reduced the prevalence of HBV infection (from 16% to 1.4% in China, from 9.8% to 1.3% in Taiwan, and from 9.3% to 0.9% in Spain) along with the incidence of HCC. Since the implementation of universal HBV vaccination program for newborns in Taiwan in 1986, the average annual incidence of HCC in children from 6 to 14 y old has decreased 65%–75%43 . The effectiveness of HBV vaccination programs are primarily limited by lack of diffusion into some rural parts of East Asia and Africa; continued effort is needed to increase implementation of HBV vaccination programs. Treatment of HBV Infection There are approximately 400 million persons with chronic HBV infection worldwide, with about 800,000 living in the US. These people cannot benefit from immunization and remain at increased risk for HCC. However, there is evidence from RCTs that antiviral agents strongly and durably reduce levels of HBV DNA levels and improve liver function and histology. However, there is limited robust evidence on patients’ long-term clinical outcomes, and whether these agents prevent HCC.

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In a study performed in Taiwan, patients with chronic HBV infection and cirrhosis or advanced fibrosis were randomly assigned to groups given 100 mg lamivudine/day or placebo for up to 5 y. This trial was terminated early because of a significant difference between treatment groups in the number of end points reached; the incidence of HCC was significantly reduced in the lamivudine group compared with the placebo group (3.9% vs 7.4%; hazard ratio, 0.49; P=.047).44 Papatheodoridis et al systematically reviewed data on HCC incidence from 21 studies, including 2881 patients with HBV who were treated with medium-term nucleos(t)ide analogues (19 studies of lamivudine, 1 of emtricitabine, and 1 of adefovir).45 A total of 168

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patients (4.3%) receiving nucleos(t)ide analogue therapy were diagnosed with HCC during a mean or median follow-up period of 40 months. In the 3 studies including untreated patients with HBV infection followed for at least 24 months, the rate of HCC was significantly lower among treated (22/779, 2.8%) than untreated patients (34/534, 6.4%; P=.003).

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Although fewer data are available on the effects of anti-viral agents such as entecavir and tenofovir, a multi-national European cohort study reported clinical outcomes in patients treated with entecavir for a median of 20 months.46 Patients with a virologic response (serum level of HBV DNA below 80 IU/ml) had a significantly lower probability of developing hepatic decompensation or HCC or death (hazard ratio, 0.29; 95% CI, 0.08–1.00; P=.05). In a subgroup analysis, this effect was statistically significant only among patients with cirrhosis (hazard ratio, 0.22; 95% CI, 0.05–0.99; P=.04). These encouraging findings were limited by a relatively small number of clinical events, but only 3 of 372 patients developed HCC. There have been reports of HBV treatment-related reductions in HCC risk in non-Asian US populations.47 The effect of interferon on HCC incidence in patients with chronic HBV has also been evaluated in several studies and meta-analyses; most data indicate that interferon treatment decreases overall HCC incidence in sustained responders.48;49 Patients receiving antiviral treatment, especially those in virologic remission, seem to develop HCC less frequently than untreated persons. However, the risk for development of HCC cannot be eliminated. Therefore, surveillance for the development of HCC in patients with chronic HBV infection must be life-long, or continue until treatments are available to completely eradicate HBV from the liver. Treatment of HCV Infection

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Successful HCV treatment has been reported to slow liver disease progression and reduce the risk of cirrhosis and HCC.50 A systematic review of observational studies associated a 51 sustained virologic response (SVR) with reduced risk for HCC in patients with all stages of liver disease (hazard ratio, 0.24, 95% CI, 0.18–0.31). Approximately 1.5% of patients with SVRs developed HCC, compared with 6.2% of those who did not respond. A SVR was associated with a similar reduction in the risk for HCC in patients with cirrhosis (hazard ratio, 0.23; 95% CI, 0.16–0.35; P

Hepatocellular Carcinoma From Epidemiology to Prevention: Translating Knowledge into Practice.

The epidemiology of hepatocellular carcinoma (HCC) is characterized by dynamic temporal trends, several major established (i.e., HCV, HBV, alcohol) an...
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