EXPERIMENTAL AND CLINICAL TRANSPLANTATION

More than 600 000 people die from hepatocellular carcinoma each year. Worldwide, research on the disease needs to be intensified in both the medical and pharmaceutical fields, with a focus on providing help to geographic areas where resources are limited. Treatment approaches depend on the stage of the disease at diagnosis and on access to complex treatment regimens. However, advanced disease is not curable, and treating these patients is expensive and only marginally effective for increasing quality-adjusted life-years. Although the Milan criteria are often used to determine which patients will benefit from liver transplantation, many centers have their own criteria for patient selection. According to criteria developed by Başkent University in Ankara, Turkey, patients with hepatocellular carcinoma and a cirrhotic liver but without extrahepatic disease should be candidates for liver transplant when possible, and living-donor liver transplant should be considered as an alternative rescue therapy for many of these patients. Tumor size and number should not be the sole criteria for excluding liver transplant. Although significant vascular invasion and extrahepatic dissemination definitely indicate major tumor dissemination, until sensitive tests for measuring circulating tumor cells are developed, we continue to recommend liver transplant regardless of tumor size and number. Various locoregional therapies for hepatocellular carcinoma are used before transplant to prevent tumor progression and to decrease the risk of recurrence after transplant. In turn, response to locoregional therapy to decrease tumor stage in hepatocellular carcinoma may be an indicator of tumor behavior and may determine a patient’s selection for liver transplant. The delivery of healthcare services for hepatocellular carcinoma could be improved by developing centers of excellence. Concentrating medical care in this way can lead to an increased level of expertise so that resections are performed by surgeons who understand liver disease and the limitations of these and other procedures.

Key words : Hepatocellular carcinoma, HCC surveillance, HCC prevention

Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths worldwide.¹ This cancer commonly arises against a background of chronic liver disease.² As a result, a patient with HCC requires multidisciplinary care. Treatment options vary widely based on tumor burden and metastases. The most widely used staging system is the Barcelona Clinic Liver Cancer (BCLC) staging system, which recommends treatments based on tumor size, underlying liver disease, and functional status of the patient.^3,4 Treatment options range from surgical resection or transplant to locoregional therapies (eg, radiofrequency ablation and transarterial chemoembolization) to systemic chemotherapies.⁵ Future standards of care will involve developing combination therapies that afford the best tumor response, further clarifying which patients are best suited for therapies, and developing new oral chemotherapeutic agents. Worldwide research on the disease needs to be intensified in both the medical and pharmaceutical fields, with a focus on providing help to geographic areas where resources are limited.

Epidemiologic burden of hepatocellular carcinoma
Hepatocellular carcinoma is a highly prevalent disease worldwide and the most common form of liver cancer.⁶ The impact of this disease is great, and more than 600 000 people die from HCC each year.¹ Its related mortality is affected by a person’s ethnicity and sex, and different mortality rates are apparent among different ethnicities and between male and female patients.^1,7 It is largely a problem among less developed regions, where 83% (50% in China alone) of the estimated 782 000 new cancer cases worldwide occurred in 2012. In the male population, the regions of highest incidence were Eastern and Southeast Asia. Intermediate rates were seen in Southern Europe and North America, and the lowest rates were in Northern Europe and South-Central Asia. In the female population, the rates were generally much lower, with the highest being in Eastern Asia and Western Africa and the lowest in Northern Europe.¹

Risk factors and prevention
In regions of the world where the incidence of HCC is particularly high, most cases occur in individuals with hepatitis B virus (HBV) and hepatitis C virus (HCV).^2,8,9 In developed countries, the rising incidence of HCC is related to high rates of alcohol consumption and obesity.^2,10 Failure to recognize groups at risk in the population or to expand social awareness about risk factors have been leading factors in the long delays in diagnosing HCC. It is well known that the more advanced stage the HCC, the fewer curative treatment options are available, the higher the costs of treatment, and the worse the survival outcomes. Therefore, preventive approaches should be emphasized, even in view of the high rates of treatment success with new-generation antiviral agents.¹¹

Primary prevention
Primary prevention is defined as preventing the causative agent from initiating the carcinogenic process.¹² It is theoretically an excellent method for cancer prevention. Primary prevention of hepatocarcinogenesis could be accomplished most effectively by universal immunization against the hepatotropic viruses.¹³ A vaccination against HBV is recommended for all newborns and individuals who are at increased risk of infection.¹⁴ Studies in Taiwan, where universal HBV vaccination was introduced in the early 1980s, have documented a significant decrease in the incidence of HCC, initially in children and now in adolescents. Development of a vaccine against HCV15 is more problematic because of the genetic heterogeneity of the virus.¹⁶ Additionally, appropriate interventions that may decrease the risk of HCV infection include health care providers encouraging safe injection practices for injection drug users and routine screening of hemodialysis patients and blood donors for the virus.¹⁷

Furthermore, many important lifestyle factors contribute to the burden of HCC, such as alcohol consumption, diabetes, obesity, and intake of toxin-contaminated food.¹⁸ People can be persuaded to acquire healthier eating habits using mass education and social media. Exposure to fungal toxin, aflatoxin, or toxic blue-green algae are common only in specific geographic locations and uncommon worldwide as causes of HCC.¹⁹ Their effects can be mitigated by altering agricultural practices and monitoring food contamination before it enters the commercial market, under the local scrutiny of governmental agencies.¹⁹

Secondary prevention
Secondary prevention of HCC is defined as interfering with the metabolism of the carcinogen or supporting and regulating the immune system response to it.¹² Along these lines, inhibiting the replication of HBV or completely eliminating HCV from the body could prevent hepatocarcinogenesis in patients with viral hepatitis.^9,20-22 Several clinical trials and observational studies have reported the beneficial effects of antiviral treatment for preventing HCC through persistent viral suppression.^21,22

Although current antivirals’ elimination effect on covalently closed circular DNA is imperfect, inhibiting viral replication and improving necroinflammatory activity using antivirals are expected to reduce substantially the risk of HCC in patients with chronic HBV infection.²³ Shim and colleagues have suggested that extending the antiviral indications for HBV is important for controlling the development of HCC as well.²⁴ Since interferon-based therapies have been replaced by newer, directly acting antiviral agents, the latter have completely changed the treatment landscape for HCV owing to their high efficacy and optimal safety profile.²⁵ However, their effects are not definitively beneficial in terms of HCC recurrence because they increase serum vascular endothelial growth factor, which may alter tumorigenesis.²⁶ It is important to note that despite the decrease in HCC risk in patients achieving a sustained virologic response, patients with advanced liver ﬁbrosis still remain at long-term risk for HCC.²⁷ This means that patients with HCV infection will require continuous monitoring, and future studies will need to validate any decrease in the incidence of HCC.

Tertiary prevention
Tertiary prevention of HCC is defined as preventing precancerous lesions from progressing to cancer.^2,12 Cirrhosis is a precancerous condition.²⁸ Thus, surveillance at regular intervals is recommended in all patients with cirrhosis to detect HCC at an early stage.²⁸

Screening and surveillance of hepatocellular carcinoma
The risk factors for HCC include liver cirrhosis, chronic HCV, chronic HBV, male sex, older age, alcohol consumption, smoking, obesity, and diabetes mellitus.²⁹ Of these risk factors, it is recommended that patients with chronic HCV, chronic HBV, or nonviral cirrhosis be screened at regular intervals for HCC.²⁸

Regular screening for HCC can lead to early detection and curative treatment and may improve prognosis.^30,31 To demonstrate the clinical utility of HCC surveillance, detection must be possible in the early stages using regular screening, and early detection must facilitate the implementation of highly curative therapies, thereby leading to improved prognosis.^30,31 One randomized controlled trial showed that surveillance of HBV carriers with semiannual alpha-fetoprotein (AFP) testing and ultrasonography reduced HCC-related mortality by 37%.³²

Evidence shows that the best surveillance tools, either accurate biomarkers or cost-effective advanced imaging tests with low or no risk of radiation, are necessary to improve the sensitivity of finding tumors at an early stage.^28,30 At present, ultrasonography and AFP testing play major roles and are widely used in HCC surveillance of high-risk patients.³¹ However, there is insufficient evidence to elucidate whether HCC prognosis improves with surveillance using only ultrasonography or ultrasonography combined with tumor marker testing. Additionally, the ability of ultrasonography to accurately visualize liver tumors in patients with cirrhosis may be impaired as a result of the patient’s obesity, blind spots such as the subphrenic space, the coarse echo pattern of liver parenchyma, nodules measuring < 2 cm, or operator inexperience.³³ Therefore, testing can be combined with computed tomography or magnetic resonance imaging, or other measures can be adopted to decrease the risk of missing a finding.³⁴ Serologic tumor biomarkers include AFP, des-gamma-carboxy prothrombin, the ratio of glycosylated AFP (L3 fraction) to total AFP, alpha-fucosidase, and glypican-3.^35,36

Alpha-fetoprotein is still the most widely tested biomarker for HCC despite its suboptimal performance for surveillance.³⁴ Serum levels of AFP can fluctuate along with exacerbation of underlying liver disease and can present in the normal range when HCC is at an early stage.³⁴ Thus, AFP should be used as a complement of imaging tests in HCC surveillance.³⁵ Combination of biomarkers can offer substantial advantages with respect to AFP alone.³⁶ In a nested case-control study, des-gamma-carboxy prothrombin and AFP had sensitivities of 74% and 61% for HCC at any stage, but these increased to 91% by using the 2 markers in combination.³⁷ The removal of AFP from the American Association for the Study of Liver Diseases guidelines has been still questioned.³⁸ The sensitivity of using ultrasonography and AFP in combination was found to be significantly higher than that of ultrasonography alone, with minimal loss in specificity.³⁹

Surveillance interval depends on several factors: mean HCC volume doubling time, tumor incidence in the target population, and cost of surveillance modalities.³⁴ A 6-month interval represents a reasonable choice based on the features of an imaging test, size of the liver nodule, and whether the patient is at higher risk.⁴⁰

Regular surveillance every 3 to 6 months, primarily using ultrasonographic examination and AFP testing combined with dynamic computed tomography or dynamic magnetic resonance imaging, increases HCC detection at the solitary and small nodular stage. Unfortunately, poor patient compliance, inadequate adherence to surveillance programs, and resultant late presentation with metastatic tumors have complicated the treatment process.³⁴ Moreover, HCC surveillance is currently recommended for all patients with cirrhosis, regardless of other risk factors even though the risk of developing HCC is not uniform.⁴⁰ Thus, further refinement of predictive risk models in larger data sets is still necessary in clinical practice.⁴⁰

Considering the fact that HCC surveillance has been widely adopted but that randomized controlled trials are difficult to implement, there is no choice but to recommend that the status quo be confirmed to a certain extent. Going forward, we are faced with the urgent task of identifying markers associated with hepatocarcinogenesis and designing countermeasures to prevent the development of HCC.

Staging
Treatment approaches depend on both the stage of the disease at diagnosis and access to complex treatment regimens.⁴¹ Many groups have developed staging systems to evaluate patients with HCC, including the Chinese University Prognostic Index (CUPI) and the Japanese Integrated Staging System (JISS) score, which are widely used in Asia, and the American Joint Committee on Cancer (AJCC), the tumor-node-metastasis (TNM) staging system, the BCLC staging system, and the Cancer of the Liver Italian Program (CLIP) staging system used in the West. All systems include an assessment of tumor stage, and most also include liver function.

The BCLC staging system has been applied most often and adopted for the management of HCC. It determines cancer stage and patient prognosis based on tumor burden, severity of liver disease, and the patient’s performance status.^3,42 Very early and early-stage HCC (BCLC 0 or BCLC A) includes patients with a solitary lesion or up to 3 nodules ≤ 3 cm (without macrovascular invasion or extrahepatic spread) with preserved liver function. These patients can benefit from potentially curative treatments such as resection, transplant, or radiofrequency ablation. Patients with intermediate-stage HCC (BCLC B) do not have symptoms, but they have large multifocal tumors without vascular invasion or spread beyond the liver. If their liver function is preserved, they may be candidates for transarterial chemoembolization. Various locoregional therapies for HCC are used to prevent tumor progression before transplant and to decrease the risk of recurrence after transplant. Response to locoregional therapy during treatment to decrease tumor staging in HCC may be an indicator of tumor behavior and determine the patient’s selection for liver transplant. The current definition of intermediate-stage HCC encompasses a wide range of patients who can be stratified. Patients with advanced-stage HCC (BCLC C) have tumors that have spread beyond the liver, and/or vascular invasion, and/or mild cancer-related symptoms. In these patients, the tyrosine kinase inhibitor sorafenib is the only treatment found to prolong survival. Patients with end-stage disease (BCLC D) have poor liver function and are not candidates for transplant and/or have marked cancer-related symptoms (performance status > 2). They have a poor prognosis and require supportive care.

Although the Milan criteria are often used to determine which patients will benefit from a liver transplant, many centers have their own criteria for patient selection. According to criteria developed by Başkent University, every patient with HCC and a cirrhotic liver but without extrahepatic disease is considered to be a candidate for liver transplant when possible, and living-donor liver transplant is considered an alternative rescue therapy for many of these patients. Tumor size and number cannot be the sole criteria for excluding patients from liver transplant. Although major vascular invasion and extrahepatic dissemination definitely indicate tumor dissemination, until sensitive tests for measuring circulating tumor cells are developed, our institution continues to recommend liver transplant for these patients regardless of tumor size and number.

Volume: 15 Issue: 2 March 2017 - Supplement - 2

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