Hepatocellular Carcinoma: Locoregional and Targeted Therapies

Hepatocellular carcinoma (HCC) is the sixth most common cancer and is the third leading cause of cancer-related deaths worldwide. The continued rise in HCC incidence and mortality emphasizes the need for novel therapeutic approaches. The ability to significantly impact disease epidemiology hinges on 2 important factors: cancer screening and surveillance programs and the existence of effective therapeutic tools. The success of any cancer screening program relies on principles of early detection of cancer among at-risk populations affording greater therapeutic options and more effective treatment potential. Many factors can influence HCC risk, chief among them HCC etiology, and recent updates by the American Association for the Study of Liver Diseases attempt to better define at risk groups for which routine HCC screening is recommended, including those with cirrhosis from any cause, and certain populations of patients with hepatitis B without cirrhosis.

The clinical evaluation and management of HCC encompasses a multidisciplinary assessment combining comprehensive therapeutic approaches along with cancer surveillance implementation. Therapeutic options available to patients with HCC span a spectrum that includes less invasive locoregional therapies that utilize localized thermal ablation or intra-arterial infusion and embolization therapies, potentially curative operative resection or transplantation, and more novel molecular-based targeted therapies and external beam radiotherapy. The challenging aspect of HCC management revolves around optimizing available therapy for each individual patient, an often difficult task that involves selecting appropriate candidates for appropriate therapies in an effort to maximize benefits and minimize harms in an era of limited resources.

Updates in the management of HCC continue to push the limits of conventional therapies, attempting to expand qualifying criteria for potentially curative surgical resection and liver transplantation. The role of locoregional approaches such as radiofrequency ablation (RFA)/microwave ablation (MWA) and transarterial chemoembolization (TACE), bead embolization, and radioembolization continue to play important roles either as primary treatment modalities for patients not appropriate for surgery or as neoadjuvant therapy in potential transplant candidates. The advent of molecular targeted therapies, namely inhibitors of angiogenesis and other molecular pathways in HCC [eg, sorafenib (Nexavar)], may provide patients and practitioners with another viable option in their treatment armamentarium. Although currently approved for primary treatment among advanced HCC, the greatest potential benefits of these molecular agents lie in their possible roles as adjuvant or neoadjuvant therapy in conjunction with other locoregional therapies or surgical modalities. In this article, we review recent updates in HCC treatment with a focus on well-established locoregional and molecular targeted therapies.

Surgical Approaches

Early detection of HCC with cancer screening and surveillance programs allows implementation of the most appropriately aggressive therapy. The surgical approach, whether via potentially curative resection or transplantation, offers the greatest benefit among patients with small, localized tumors. Postresection 5-year survival rates for solitary tumors in noncirrhotic patients exceed 70% in some studies. Although the presence of cirrhosis or multiple foci of tumor is not an absolute contraindication for operative resection, postresection outcomes are less ideal owing to higher rates of hepatic decompensation and/or tumor recurrence. Selection of the most appropriate candidates for resection involves an accurate assessment of multiple factors including tumor characteristics, comorbidities, liver functional status, presence of portal hypertension, and evidence of decompensated disease. The most ideal candidates for surgical resection are patients with small, solitary tumors with good liver functional status. Among patients with advanced disease or significant cirrhosis and impaired liver functional status, the role of surgical resection is less beneficial and may in fact contribute to the development of liver failure. Although large tumor size is not an absolute contraindication to resection, larger tumors harbor greater risks of underlying vascular invasion and dissemination, resulting in higher rates of postresection recurrence. When it does occur, the approach to postresection tumor recurrence is not well-studied, and repeat resection is complex; patients often demonstrate multifocal presentations reflective of disseminated disease. These patients may be more suitable to undergo salvage liver transplantation, or other locoregional therapies with or without oral multikinase inhibitors.

Liver transplantation remains a viable option for patients with disease or tumor characteristics that are not appropriate for primary surgical resection. Often in conjunction with less invasive neoadjuvant locoregional therapies, outcomes among appropriate candidates are promising, with posttransplant 5-year survival rates exceeding 70%. However, liver transplantation is not appropriate for all individuals and a comprehensive evaluation and selection process are necessary to best allocate the scarce resources available.

The Milan criteria, defined by the presence of a solitary tumor less than 5 cm or up to 3 tumors, each no more than 3 cm, has emerged as the international standard by which potential transplant candidates are evaluated. When these guidelines are utilized, the posttransplant 5-year survival rates reach 70% to 80% and tumor recurrence rates are approximately 10%. Whereas several studies have investigated the potential expansion of these criteria, those proposed by the University of California, San Francisco (UCSF) group have demonstrated the most promising results. Using the UCSF criteria (solitary lesion ≤6.5 cm, ≤3 lesions, each ≤4.5 cm with the total combined tumor diameter not exceeding 8 cm) the initial report by Yao and colleagues demonstrated acceptable survival rates (90% 1-year survival and 75% 5-year survival), similar to those achieved with the Milan criteria. Further challenging the limits of current transplantation criteria, recent studies have focused on preoperative “downstaging” approaches whereby patients with HCC beyond transplant criteria are treated with locoregional therapies to decrease tumor burden and downgrade lesions to fall within transplantation guidelines. One recent prospective intention-to-treat analysis by Yao and colleagues implemented a downstaging protocol using TACE and/or RFA in HCC patients exceeding the UCSF criteria. Early results from this 61-patient cohort are promising, with 96.2% 1-year and 92.1% 4-year posttransplant survival rates. The success of these recent studies continue to raise debate about the need for reevaluation of transplantation criteria and the potential expansion of selection guidelines for patients who currently are not eligible based on Milan criteria. Whereas advances in both surgical and adjuvant medical therapy lead to more significant improvements in posttransplant outcomes, the complexity of the selection process for liver transplantation will continue to evolve along with the novel ideas that bring forth such challenges.

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