Hepatocellular carcinoma (HCC) is responsible for more than 800,000 deaths globally. In the United States, HCC is the fastest growing cause of cancer deaths. Viral hepatitis is the leading cause of HCC, followed by alcoholic and nonalcoholic fatty liver disease. The contribution of nonalcoholic fatty liver disease to HCC incidence and mortality is expected to increase in future based on epidemiological and mathematical modeling studies. Routine HCC surveillance (or screening) is recommended in these high-risk groups, which can detect early-stage treatable cancers. Despite its important role in early HCC detection, adherence to surveillance remains low due to multiple provider- and patient-related issues. In order to increase the value of surveillance program to impact prognosis of future HCC cases, surveillance should be tailored according to the emerging risk factors to maximize its cost-effectiveness.

Introduction

Hepatocellular carcinoma (HCC) is responsible for 80–90% of primary liver cancer cases and is the third most common cause of cancer deaths worldwide [1, 2]. In the United States, HCC is the fastest growing cause of cancer deaths. While the overall cancer death rate has declined by 18% in the last two decades, HCC-related mortality has increased by 40% during the same period (Fig. 3.1 shows mortality in men, who are 4–8 times more likely than women to develop HCC) [3]. In addition, HCC incidence has increased threefold between 1975 and 2009, and the upward trend continues (Fig. 3.2) [4]. The rising burden of HCC was also highlighted by the 2015 Annual Report on the Status of Cancer [5]. Common risk factors for HCC include hepatitis C virus (HCV) infection, hepatitis B virus (HBV) infection, heavy alcohol use leading to alcoholic liver disease (ALD), and nonalcoholic steatohepatitis (NASH).

Fig. 3.1

Trend of cancer mortality change in men in the United States

Fig. 3.2

Trend of HCC incidence between 1975 and 2015

Survival after diagnosis of HCC is worse than that of almost every other major form of cancer, including the lung, esophagus, and stomach [5]. While patients with advanced HCC have a median survival of less than 1 year, patients with early HCC who receive potentially curative therapy such as liver transplantation or resection achieve 5-year survival rates near 70%. Early diagnosis, therefore, is critical to improved survival. However, unlike other major cancers such as breast, prostate, and colorectal cancers, surveillance for HCC has been underutilized in practice [6]. While ultrasound-based surveillance with or without α-fetoprotein (AFP) is recommended in high-risk individuals (e.g., cirrhosis), surveillance failures are common, and the majority of patients with HCC are diagnosed at an advanced stage [7]. Furthermore, fewer than 20% of patients with cirrhosis receive regular surveillance [8, 9]. Another key factor that distinguishes HCC from most other cancers is that it primarily occurs in the setting of end-stage liver failure, which severely limits treatment options such as curative resection as well as palliative locoregional therapy. Liver transplantation is a life-saving modality but is a highly restricted resource with long waiting lists.

HCC Incidence and Mortality Trends

According to the 2015 Global Burden of Disease Study [10], there were 854,000 incident cases of liver cancer and 810,000 deaths globally in 2015. According to the study, HBV is the most prevalent cause of HCC, accounting for 33% of all the HCC deaths globally. Alcohol is the second most common cause of HCC, accounting for 30% of all HCC deaths. HCV accounted for 21% of all HCC deaths and other causes including NASH accounted for the remaining 16%. These distributions of HCC-led death etiologies vary across different geographical regions (Table 3.1). The study also noted that the etiologies of HCC vary substantially across different countries and regions. The study also reported increasing trends in HCC incidence across all etiology groups from 1990 to 2015—HBV-related HCC incidence rates increased by 42%, HCV-related HCC incidence by 114%, ALD-related HCC incidence by 109%, and other causes by 56%. The increasing rates in HCC incidence occurred primarily due to population growth and aging of population.

Table 3.1

Contribution of hepatitis B, hepatitis C, alcohol, and other causes on absolute liver cancer deaths, both sexes, globally and by region, 2015

Asia presented very unique HCC etiologies among all the populations in the world, while a great majority of the HCC occurred in Asia.

The burden of HCC is in particular high in Asia. In 2018, around 47% of the 841,000 new hepatocellular carcinoma cases occurred in China alone [11]. The etiology of HCC in selected Asian countries is summarized in Table 3.2 [12]. Unlike other parts of the world, the leading cause of HCC in Asia has been HBV [13]. The only exception is Japan, where HCV is the leading cause for HCC. Since most Asian countries started implementing nationwide hepatitis B immunization programs in the last couple of decades, the seroprevalence of HBV among children and young adults has declined significantly in these countries [14–16]. It is expected that HBV-associated HCC incidence will decrease substantially in younger generations in these Asian countries. In addition, advanced HBV treatment methods have also significantly reduced the risk of HCC among HBV-infected people [17, 18]. However, other HCC-leading causes are on the rise, while HBV is on the decline. Specifically, the rapid socioeconomic development in many Asian countries has caused lifestyles and dietary patterns that lead to more cases of NASH-related HCC [19]. With the controlling of HBV in most Asian countries and HCV epidemics in Japan, NASH is gaining prominence and will likely become the new leading cause of HCC in the years to come.

Table 3.2

Etiology distribution of HCC in selective Asian countries

In the United States, the HCC incidence has increased sharply in the past a couple of decades. A population-based descriptive study showed that the age-adjusted incidence rates of HCC increased by 52% from year 2000 to 2012 [20]. The rising HCC incidence is primarily related to an aging population with chronic HCV infection [21], but this is expected to change in the near future because of the availability of highly effective HCV treatments [22, 23]. NASH-related HCC incidence, on the other hand, is rising because of obesity and nonalcoholic fatty liver disease (NAFLD) [24, 25]. The incidence of HBV-led HCC is likely to remain steady [26]. The mortality rates due to HCC have also increased over the past a couple of decades. As shown by an observational study [27], from year 1999 to 2006, the annual HCC-related deaths double to 11,073, particularly highlighting alcohol as the reason for HCC-related deaths among young people between ages 25 and 34.

Future trends in HCC-related incidence and mortality and underlying etiology can be projected using decision-analytic modeling. A modeling study projected current and future impact of HCV disease burden in 16 countries [28]. It projected a 245% increase in HCC incidence rates from 2013 to 2030 in these countries. Similarly, the number of liver-related death is projected to increase up to 230% in all countries except for Sweden. Table 3.3 summarizes the model projected HCC and LRD trend in these 16 countries. However, with aggressive HCV screening along with unrestricted access to new antivirals, HCC incidence can be reduced substantially.

Table 3.3

Model-projected HCC incidence and associated deaths in 16 countries from 2013 to 2030 [28]

In the United States, HCV disease burden and related HCC burden in the era of Direct-acting antivirals (DAAs) have been projected using decision-analytic modeling. For instance, Hepatitis C Disease Burden Simulation (HEP-SIM) has projected the changing HCV prevalence and associated disease burden in the United States from 2001 to 2050 [22, 23]. The HEP-SIM model closely replicated the HCV prevalence as estimated by the National Health and Nutrition Examination Survey (NHANES). The model predicted that the number of viremic patients will decrease over time—from 2.5 million people in 2010 to below 1.0 million by 2020 (Fig. 3.3). At the same time, the number of individuals living with a sustained virologic response (SVR), a surrogate for HCV cure, is expected to increase from 0.8 million to 1.6 million by 2020. This study showed that despite the expected decrease of HCV-associated outcomes with implementation of the DAA therapy, HCC incidence would continue to increase until 2020. However, the cumulative incidences of HCC and LRD from 2015 to 2050 would be reduced substantially. It was estimated that the cumulative incidence of HCC when treated with DAAs, pre-DAA therapies, and no treatment from 2015 to 2050 were 157,000, 305,000, and 415,000 respectively, while the corresponding liver-related deaths were 320,000, 587,000, and 776,000, respectively. Moreover, the study showed that increasing the annual treatment rate to 280,000 from 2015 onward would prevent 5400 cases of HCC and 9700 deaths.

Fig. 3.3

Predicted trend of HCV-related patients. SVR, sustained virologic response

Another modeling study projected trends in NASH and related disease burden from 2015 to 2030 [29]. The study estimated that the number of NASH cases would increase by 63% from year 2015 to year 2030. The prevalence of NASH-associated HCC would increase by 146% from 10,100 to 24,900 from 2015 to 2030. The incidence rate of NASH-HCC is also expected to increase by 137% from 5200 in 2015 to 12,200 in 2030. With potential availability of NASH treatments in the near future, NASH-associated HCC could be lower than what has been projected by the above studies.

While ALD accounts for 30% of all the HCC cases worldwide [10], the future burden of ALD-associated HCC has not been well studied [10, 30]. The Global Burden of Disease Study estimated the proportion of ALD-HCC among all-cause HCC cases across different geological regions as shown in Table 3.1. HCC patients with ALD are more prone to adverse disease prognosis and less frequent access to curative therapies [9, 31–36]. The Global Burden of Disease Study concluded that the contribution of alcoholic is expected to increase further due to improved preventive and treatment measures of nonalcoholic HCC etiologies, such as HBV vaccination, HCV treatment with DAA therapies, and potential stabilization of obesity in the United States, Europe, and China [12, 30, 37].

Knowledge Gaps in HCC Surveillance

Though HCC surveillance can detect early-stage treatable cancers, its use remains controversial and highly variable in practice [7]. Many professional societies recommend regular HCC surveillance in high-risk patients (e.g., having cirrhosis) using liver ultrasound and/or AFP measurements to increase the likelihood of detecting early-stage treatable cancer [38–40]. However, the US Preventive Services Task Force (USPSTF) does not endorse routine HCC surveillance.

Several gaps remain in the comparative effectiveness data that inform surveillance policies [41]. First, conclusive evidence from randomized controlled trials (RCTs) showing that HCC surveillance reduces mortality is lacking. To date, only two clinical trials have evaluated the effectiveness of HCC screening—one found that surveillance was effective in reducing all-cause mortality, but the second did not find any benefits [42, 43]. Notably, these studies included only HBV patients from China; no trial has evaluated screening in patients with other etiologies of HCC, which cause 85–90% of all HCC cases in the United States. Any future trial evaluating a no-screening scenario may be deemed unethical because clinical practice guidelines are already in place [44]. Furthermore, the vast majority of patients are not willing to participate in trials that have a no-screening arm [45]. Many observational studies have shown that HCC surveillance increases survival [46]; however, these studies are prone to lead- and length-time bias [47, 48], as has been observed in other cancer screening programs [49–51].

Second, the current screening guidelines fail to capture many at-risk individual [52]. Though current guidelines primarily recommend surveillance in cirrhotic patients, 20–50% of patients presenting with HCC have previously undiagnosed cirrhosis [53]. Furthermore, nearly 50% of all cases of HCC originate in noncirrhotic livers, and HCV patients without cirrhosis are also at risk of developing HCC [54–57]. Many of these patients would not enter into a surveillance program if the presence of cirrhosis alone were used to define a target population. Therefore, data on the risk and benefit of regular surveillance in this cohort are needed.

Third, existing guidelines do not tailor surveillance according to an individual’s risk and instead follow a “one-size-fits-all” paradigm, making them inefficient or ineffective for many individuals [58]. For a successful effectiveness program, it is important to distinguish patients in whom aggressive surveillance in needed from those who require less frequent surveillance, if at all. Despite the heterogeneous nature of HCC, published studies have not evaluated individualized surveillance based on patients’ risk factors including age, liver disease, comorbidity, and access to liver transplant. For example, current guidelines do not specify when to start or stop surveillance in most patients, which makes it difficult to define the populations for which surveillance could be cost-effective. Furthermore, recent exciting advances in molecular biomarkers that can aid in early HCC detection have not been incorporated in surveillance guidelines [59].

Fourth, current surveillance practices are based on the cost-effectiveness studies that have not considered recent changes in liver transplant practice and advances in the treatment of HCC [38, 60–63] and therefore could have underestimated the value of surveillance.

Finally, there is a need to balance the benefits of regular surveillance with harms. Potential harms of HCC screening include serious complications from liver biopsy, which occur in about 1% of patients [64], and, rarely, death from liver biopsy (0.009–0.12% patients) [65]. Other harms include complications from liver resection and from other tests and treatments offered because of findings from ultrasonography [66]. Surveillance could also result in the overdiagnosis of HCC in patients with comorbidities, especially in older age, who are not eligible for curative treatments such as liver transplantation.

Significance of Mathematical Modeling for Surveillance of HCC

RCTs on HCC surveillance would likely be prohibitively expensive, time-consuming, and considered unethical by many. To sufficiently address the evidence gaps, a large RCT will need to incorporate and compare a prohibitively large number of arms [67], which is not realistically achievable. Under such situation, mathematical modeling can capture many of the complex intricacies to healthcare delivery in the real world, incorporate risks and benefits, and predict the long-term outcomes of different strategies that can guide decision-makers in establishing evidence-based guidelines [67, 68]. Results of such analyses have been used by the USPSTF and the Centers for Medicare and Medicaid Services (CMS) for determining screening recommendations for breast [69], colorectal [70, 71], cervical [72], and lung cancers [73].

To develop an effective and cost-effective surveillance for HCC, the first step is to determine which patients will (or will not) benefit from routine surveillance. Populations at risk of developing HCC are highly heterogeneous because of multiple possible etiologies, liver disease stage, comorbidities, and access to treatment. Mathematical modeling can consider such complex dynamics and provide insights to determine the frequency of surveillance personalized to individual’s risk factors based on clinical and/or molecular indices [74].

Cost-Effectiveness of HCC Surveillance by Etiology

The risk of developing HCC varies with the underlying etiology—5-year cumulative risk is 17% in patients with HCV cirrhosis, 10% with HBV cirrhosis, and 2–8% with alcoholic cirrhosis [26, 75]. Therefore, a surveillance policy tailored to the underlying etiology could be more effective and cost-effective than a single policy across all etiologies. Another gap in the current surveillance recommendations is that they exclude noncirrhotic patients (except for HBV). However, up to 54% of all cases of HCC originate in noncirrhotic livers according to various etiologies [56, 57]. Finally, many HCV patients have multiple comorbidities; therefore, a surveillance program needs to weigh the harms and benefits in this population.

Conclusions

HCC is responsible for 80–90% of primary liver cancer cases and is the third most common cause of cancer deaths worldwide. In the United States, HCC is the fastest growing cause of cancer deaths. HCC incidence has increased threefold between 1975 and 2009. HCC etiology has changed in the last decade and is further projected to change. HCV-associated HCC is projected to decrease substantially because of the availability of new antivirals for HCV; however, NAFLD- and ALD-associated HCC is likely to increase in the near future.

Routine surveillance plays an important role in early detection of HCC, but the adherence to surveillance remains low. In order to increase the value of surveillance programs, surveillance should be tailored to underlying etiology and other risk factors. Current screening guidelines are based on cost-effectiveness data that are old, and there is a need to evaluate the new threshold to HCC incidence above which routine HCC surveillance can be deemed cost-effective.

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