Hepatocellular Carcinoma (HCC) What’s On The Horizon?

Epidemiology. Recent data from the U.S. Cancer Statistics registry show that hepatocellular carcinoma (HCC) continues to rise albeit at a slower rate recently (4.5 percent increase annually from 2000 to 2009, and 0.7 percent from 2010 to 2012). Men between 55 and 64 years of age, Hispanics and, at state-level, Texans, are the most commonly affected groups. Hepatitis C infection (HCV) is still the most common underlying etiological risk factor of HCC including those wait-listed for liver transplant. New and highly potent direct-antiviral agents (DAAs) are expected to decrease the risk of HCV-related HCC depending on the extent to which these medications are used in the population. Sustained virological response (SVR) considerably reduces HCC and complications of portal hypertension, but does not eliminate the risk or need for surveillance in the presence of advanced fibrosis or cirrhosis. Metabolic syndrome with or without non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of HCC, even in the absence of cirrhosis. NAFLD/non-alcoholic steatohepatitis (NASH) related HCC seems to account for close to 10 percent of HCC in the United States; however, given the high prevalence of metabolic syndrome in the general population, there is a considerable potential for anther epidemic of HCC.

HCC surveillance. American and European guidelines recommend ultrasound with or without alpha-fetoprotein (AFP) as surveillance tools for HCC; however, contrast-enhanced ultrasound and magnetic resonance imaging (MRI) are being tested. In many transplant facilities across the United States, MRI is the preferred surveillance imaging technique as it has shown higher sensitivity and specificity to detect biopsy and explant-proven HCC compared to ultrasound or CT. Recently, Kim et al. in South Korea performed a prospective cohort study of 407 cirrhotic patients with 1,100 HCC surveillance episodes with paired ultrasonography and MRI, and found that the HCC detection rate of MRI was 86 percent, significantly higher than the 27.9 percent of ultrasound. Ultrasonography also had higher false-positive rate findings than MRI (5.6 percent vs. 3 percent, P = .004). Is MRI ready for HCC population-based surveillance? Probably not, as it takes longer and costs more than conventional abdominal ultrasound; however, recent data suggests that an abbreviated screening MRI protocol — utilizing only dynamic contrast-enhanced images compared to a conventional liver MRI — can be accurate for the characterization of observations in atrisk patients. Excellent agreement was found between the abbreviated T1-only MRI protocol and a full liver MRI, with only 5 percent of cases changing radiological categorization with only seven to 10 minutes duration. While an area of active research, there have been no new biomarkers. Three biomarkers — AFP, AFP-3 and des-gamma-carboxy prothrombin (DCP) — either alone or in combination with age and alanine aminotransferase (ALT), increase the sensitivity of detecting HCC during surveillance but are also associated with an increase in the false positive tests. Similarly, calculators combining AFP with demographic risk (age) and clinical (ALT and platelets levels) are being developed to improve AFP performance.

In many transplant facilities across the United States, MRI is the preferred surveillance imaging technique as it has shown higher sensitivity and specificity to detect biopsy and explant-proven HCC compared to ultrasound or CT.

Treatment. Several staging systems can be applied including the Barcelona Clinic Liver Cancer staging or the Hong Kong Liver Cancer staging system, and whereas none are perfect, they guide clinicians to treat each stage. Early stage small HCC can be managed with percutaneous ablation, resection or transplant with similar long-term outcomes. In those with more advanced stages, best survival and recurrence-free survival are obtained with transplantation following strict selection protocols (e.g. Milan criteria). Novel techniques in ablation, such as laser and cryoablation, have shown promising results, associated with less local side effects than microwave or radiofrequency ablation. Palliative therapies, such as arterially directed therapies, continue to be used either as end-therapy or, sometimes, as a bridge to transplantation. Radioembolization with Yttrium-90 microspheres is becoming more widely available with good results in otherwise untreatable tumors (e.g. vascular invasion), and with the advantage of being performed in an outpatient setting.

The treatment of advanced HCC has seen some advancements. Regorafenib is a new oral multi-kinase inhibitor that has shown some benefit in those patients who progress while on sorafenib, adding approximately two months median survival time. Combining sorafenib with other therapies including resection, ablation or transarterial chemoembolization (TACE) is not useful. In 2017, FDA approved a supplemental new drug application for lenvatinib, an oral multitargeted receptor tyrosine, as a frontline systemic treatment for patients with advanced HCC. A median survival of 13.2 months was shown in a Phase III randomized non-inferiority trial of lenvatinib vs. sorafenib. Further results from immune checkpoint inhibitors such as nivolumab, tremelimumab and ipilimumab, are expected in the near future.

In summary, HCC continues to be an important public health problem — likely as a result of baby-boomer HCV-related cirrhosis — and while we expect some plateau or decease of the HCV-related HCC, attaining DAA related SVR reduces but does not eliminate HCC in patients with cirrhosis. Future directions will likely show improvement on surveillance techniques (abbreviated MRI) and treatment options of incurable HCC with new oral agents.

Dr. Hernaez has no conflicts to disclose. Dr. Hernaez serves on the Practice Guidelines Steering Committee of the American Association for the Study of Liver Diseases.

Dr. El-Serag is a member of the EAB Committee for Lilly, and has received research grants from Gilead, Merck and Wako. Dr. El-Serag is vice president-elect at AGA and serves on the AGA Institute Leadership and Publications Committee. He is a past Clinical Gastroenterology and Hepatology editor.

1. Hernaez, R., El-Serag, H.B. HCC: An Update. Am J Gastroenterology. 2017 (accepted).
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3. White, D.L., Richardson, P., Tayoub, N., Davila, J.A., Kanwal, F., El-Serag, H.B. The Updated Model: An Adjusted Serum Alpha-Fetoprotein-Based Algorithm for Hepatocellular Carcinoma Detection With Hepatitis C Virus-Related Cirrhosis. Gastroenterology. 2015;149(7):1986-7.
4. Singal, A.G., El-Serag, H.B. Hepatocellular Carcinoma From Epidemiology to Prevention: Translating Knowledge into Practice. Clin Gastroenterol Hepatol. 2015;13(12):2140-51.

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