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.

Locoregional Ablation Therapies

When a patient’s disease burden or comorbidities are significant enough to make the prospect of surgical intervention inappropriate, nonsurgical invasive therapies play an important role in managing HCC. Either as a primary mode of therapy or adjuvant to transplantation, locoregional treatments include a spectrum of therapeutic tools that include both localized ablative techniques and chemoembolization. Percutaneous ablation therapies involve localized destruction of tumor cells through direct exposure to toxic substances (eg, ethanol) or modifying the temperature (eg, radiofrequency, microwave). The most common ablation modalities include percutaneous ethanol injection (PEI) and RFA. Among patients with tumors less than 2 cm in size, PEI and RFA have similar efficacies, achieving tumor necrosis in 90% to 100%. The performance of PEI among larger tumors is less consistent, and generally requires a greater number of treatment sessions compared with RFA. Given the fewer number of treatment sessions needed, greater tolerability, and better survival outcomes in recent studies, RFA is often preferred over PEI even in patients with smaller tumors. Regardless of modality, the overall efficacy of any ablation technique declines with increasing tumor size, and tumors larger than 3 cm generally do not have consistently successful outcomes.

Although RFA remains the most utilized locoregional ablative therapy, newer techniques that incorporate novel ideas and alternative methods of tumor destruction continue to be developed. MWA is an emerging form of thermal ablation for the treatment of HCC that utilizes electromagnetic waves with frequencies greater than 900 kHz to irradiate and ablate tumor foci. Unlike RFA, which relies primarily on passive heating, MWA utilizes active heating, which by virtue of its form of heat distribution, enables continuous and uniform ablation. This method is able to generate higher temperatures and larger zones of ablation, leading to higher rates of tumor necrosis compared with more conventional ablative techniques. MWA therapy also overcomes the “heat sink” effect, a common limitation of RFA that involves the cooling of blood flow in the immediate proximity of tumors, which can lead to incomplete ablation and necrosis. This ability to overcome the “heat sink” is related to the ability of MWA to heat the tumor faster and hotter, but may also result in increased risk of damage to nearby structures, including blood vessels. The clinical advantages of MWA over RFA, and its potential to demonstrate a greater rate of tumor necrosis with fewer treatment sessions owing to more rapid and thorough tumor heating, needs to be investigated further in large clinical trials.

Locoregional Ablation Therapies

When a patient’s disease burden or comorbidities are significant enough to make the prospect of surgical intervention inappropriate, nonsurgical invasive therapies play an important role in managing HCC. Either as a primary mode of therapy or adjuvant to transplantation, locoregional treatments include a spectrum of therapeutic tools that include both localized ablative techniques and chemoembolization. Percutaneous ablation therapies involve localized destruction of tumor cells through direct exposure to toxic substances (eg, ethanol) or modifying the temperature (eg, radiofrequency, microwave). The most common ablation modalities include percutaneous ethanol injection (PEI) and RFA. Among patients with tumors less than 2 cm in size, PEI and RFA have similar efficacies, achieving tumor necrosis in 90% to 100%. The performance of PEI among larger tumors is less consistent, and generally requires a greater number of treatment sessions compared with RFA. Given the fewer number of treatment sessions needed, greater tolerability, and better survival outcomes in recent studies, RFA is often preferred over PEI even in patients with smaller tumors. Regardless of modality, the overall efficacy of any ablation technique declines with increasing tumor size, and tumors larger than 3 cm generally do not have consistently successful outcomes.

Although RFA remains the most utilized locoregional ablative therapy, newer techniques that incorporate novel ideas and alternative methods of tumor destruction continue to be developed. MWA is an emerging form of thermal ablation for the treatment of HCC that utilizes electromagnetic waves with frequencies greater than 900 kHz to irradiate and ablate tumor foci. Unlike RFA, which relies primarily on passive heating, MWA utilizes active heating, which by virtue of its form of heat distribution, enables continuous and uniform ablation. This method is able to generate higher temperatures and larger zones of ablation, leading to higher rates of tumor necrosis compared with more conventional ablative techniques. MWA therapy also overcomes the “heat sink” effect, a common limitation of RFA that involves the cooling of blood flow in the immediate proximity of tumors, which can lead to incomplete ablation and necrosis. This ability to overcome the “heat sink” is related to the ability of MWA to heat the tumor faster and hotter, but may also result in increased risk of damage to nearby structures, including blood vessels. The clinical advantages of MWA over RFA, and its potential to demonstrate a greater rate of tumor necrosis with fewer treatment sessions owing to more rapid and thorough tumor heating, needs to be investigated further in large clinical trials.

Locoregional Chemoembolization

In addition to ablation-based therapies, the treatment approach to the nonsurgical management of HCC includes utilizing methods of chemoembolization. The underlying mechanism by which chemoembolization achieves its therapeutic potential hinges on principles of cytotoxicity and induced ischemia. The concept of TACE involves localized intra-arterial injection of chemotherapy agents followed by angiographically induced ischemia via selective embolization of the tumor’s vascular supply. The success of conventional TACE, which utilizes a lipiodol-suspended emulsion of chemotherapy for drug delivery was demonstrated by one of the early systematic reviews by Llovet and Bruix, reporting improved 2-year survival among advanced HCC treated with chemoembolization when compared with more conservative therapies. As is the case with surgical approaches, the success of TACE depends on appropriate patient selection. Subsequent subset analyses demonstrated that, although TACE was generally associated with improved outcomes when compared with conservative symptom-directed therapy among nonsurgical candidates, the improved survival was most significant among patients without evidence of decompensated cirrhosis, vascular invasion, or extrahepatic spread of tumor.

Although there has been greater experience with conventional forms of lipiodol-based TACE, the recent advent of embolic, drug-eluting microspheres offers a promising alternative. The success of drug-eluting spheres has resulted in replacement of conventional TACE at many institutions with this new therapy. The major advantages of embolic microspheres loaded with doxorubicin include the ability to deliver therapy in a controlled, sustained fashion to tumor foci. This method not only improves drug delivery, but also helps to minimize the effects of systemic chemotherapy exposure. Several recent studies have compared the performance of doxorubicin (Adriamycin)-eluting beads (DEB) with conventional methods of TACE. The PRECISION V study—a multicenter, phase II, randomized, controlled trial—demonstrated a trend toward greater treatment response rate and tumor necrosis among patients treated with DEB when compared with conventional TACE. A subset analysis of patients with more advanced tumor stages demonstrated significantly greater treatment responses. However, patients randomized to the conventional TACE group achieved higher than expected treatment response rates (44% compared with an expected 35%), resulting in criticisms that this trial was underpowered to detect a significant difference between the DEB and conventional TACE groups. Furthermore, the lack of evaluating differences in progression-free and overall survival raises questions about the impact of greater treatment responses on actual patient outcomes.

One of the major theoretical advantages of a targeted drug delivery system is the ability to minimize toxicities that arise from undesired systemic distribution of the drug. Although some of the early studies comparing DEB and conventional TACE have raised questions about the clinical significance of study outcomes on patient survival, DEB–TACE therapies have demonstrated better tolerability and safety. DEB–TACE is associated with significantly lower rates of serious liver toxicity and lower rates of chemotherapy related side effects, the major limitations of conventional TACE. A recent study by Malagari and colleagues further investigated the safety profiles of DEB–TACE therapies, focusing primarily on complications associated with microsphere bead diameters, the extent of embolization, and quantity of loaded beads, reflecting amount of doxorubicin delivered. This large, descriptional study reported no increased risk of complications associated with smaller bead diameters, and emphasized the safety profiles of DEB therapies, even among patients treated with higher doses of doxorubicin. The advent of chemotherapy-eluting microspheres has created a new treatment regimen for patients with intermediate and advanced stages of HCC. The improved safety and tolerability profile offers an advantage to conventional therapies, and the greater treatment response rates indicate promise for this form of therapy. The potential impact of DEB–TACE alone on patient survival outcomes is unclear, but large, randomized, controlled trials combining DEB–TACE with sorafenib that are currently enrolling patients may revitalize interest in DEB–TACE as an adjuvant form of therapy.

Locoregional Radioembolization

The role of radiation therapy in the treatment of HCC has traditionally been avoided secondary to the exacerbation of liver disease by the radiation treatment itself. Radiation-induced liver disease, which had previously been noted as radiation-induced hepatitis, results from accumulated parenchymal damage, especially in cirrhotic livers that have low tolerances to radiation-induced injuries. The advent of microsphere-based technology for chemoembolization therapies raised the clinical idea of potentially utilizing this method for delivery of radiation treatments. The underlying treatment regimen relies on similar concepts that form the basis for TACE. Utilizing the hypervascularity of tumors, microspheres can be preferentially delivered to tumor foci, allowing targeted treatment and limiting systemic toxicities. The development of yttrium-90 (Y90)-coated microspheres hinges on these concepts in an attempt to offer novel treatment alternatives to patients with intermediate and advanced HCC. In addition, the safety profile of Y90-based treatments, especially its minimally embolic effects, allows it to be utilized in patients with portal vein thrombosis. However, Y90 is absolutely contraindicated in patients with significant hepatopulmonary shunting, which could result in very high levels of pulmonary radiation exposure.

Several recent studies have demonstrated efficacy for Y90 therapies. In 1 study by Riaz and colleagues, an analysis of patients who underwent Y90 radioembolization before transplantation demonstrated complete pathologic necrosis in 61% of the cohort. Although no randomized, controlled trials have compared Y90 head to head with other locoregional therapies, several nonrandomized trials report promising results that demonstrate a trend toward improved outcomes among those treated with Y90. One recent large study by Salem and colleagues evaluated 245 patients with unresectable HCC that had received locoregional therapies (122 received chemoembolization and 123 received radioembolization). Over 80% of patients were Barcelona Clinic Liver Cancer stage A or B, and the majority of patients had hepatitis C. Overall, patients treated with radioembolization demonstrated a trend toward higher treatment response rates (49% vs 36%; P = .104), significantly longer time to progression (13.3 vs 8.4 months; P = .046), but no difference in median survival times (20.5 vs 17.4 months; P = .232) when compared with those treated with chemoembolization. Although no randomized, controlled trials have been published demonstrating clinical benefit of Y90 compared with more established treatment modalities, many studies have reported on the efficacy of Y90-based therapies and the potential trend toward improved outcomes for patients with intermediate and advanced HCC. Future studies evaluating Y90 treatment in randomized, controlled trials are needed and further investigation of Y90 in combination with other locoregional or systemic therapies in treating intermediate and advanced staged HCC may hold promise for novel approaches to the management of HCC.

Molecular Targeted Therapies

The field of systemic therapies for the treatment of HCC has been limited. Traditional cytotoxic chemotherapy regimens have failed to demonstrate significant improvements in HCC survival, and their extensive toxicity profile further contributed to their lack of efficacy. However, research in the area of angiogenesis inhibition in the management of cancer has contributed to a novel approach for the treatment of HCC. The rationale for targeting angiogenesis as a treatment approach is supported by its integral role in tumor growth and progression. Angiogenesis promotes development of vascular networks, and thereby enables tumor growth via enhanced delivery of nutrients and oxygen to tumor foci. Furthermore, tumor invasion and metastasis are enabled as the vascular supply links tumor foci with more distant sites. HCC is a hypervascularized malignancy, whose growth and progression relies heavily on angiogenesis; thus, the use of anti-angiogenic agents is a reasonable approach to systemic treatment of HCC.

One of the earlier models of success in targeting angiogenesis as a treatment approach for HCC, sorafenib, a multitargeted tyrosine kinase inhibitor, was the first molecular targeted therapy to be approved by the US Food and Drug Administration for the treatment of unresectable HCC. The SHARP trial demonstrated a 2.8-month survival advantage among patients with advanced HCC treated with sorafenib compared with best supportive care (10.7 vs 7.9 months; hazard ratio, 0.69; P < .001). Furthermore, the time to radiologic progression of tumor was also significantly extended among the sorafenib group (5.5 vs 2.8 months; P <.001). Although subsequent studies continued to demonstrate significantly improved survival among patients treated with sorafenib, the early trials had limited data for Asian subpopulations, a cohort that often harbored concomitant hepatitis B infection and impaired liver functional status. A subsequent randomized, phase III trial that evaluated sorafenib among Asians with advanced HCC demonstrated results similar to the SHARP trial, with significant improvements in both survival and time to progression. Mounting evidence clearly supports the efficacy of sorafenib in treatment of advanced HCC among a more diverse patient cohort and current guidelines by the American Association for the Study of Liver Diseases recommend sorafenib as first-line therapy among patients with unresectable HCC who are not appropriate candidates for percutaneous ablation or TACE, but maintain preserved liver function.

Given the success of sorafenib, several additional anti-angiogenic agents currently under investigation demonstrate great promise. Brivanib is an anti-angiogenesis agent that inhibits both fibroblast growth factor and vascular endothelial growth factor pathways. The major theoretical advantage of this dual inhibitory mechanism of action is its potential to overcome development of compensatory signaling and subsequent loss of drug efficacy. Early phase II trials with brivanib in patients with advanced HCC demonstrated significantly improved survival outcomes, with a mean overall survival of 10 months. In addition, this early phase II evaluation reported low incidences of adverse events, and current phase III trials are underway to further elucidate the efficacy of this emerging therapeutic agent. Other agents such as sunitinib (Sutent) and bevacizumab (Avastin) have been less successful in the management of HCC owing to treatment-related toxicities and lack of survival efficacy.

Erlotinib (Tarceva) is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has played a major role in the treatment of patients with advanced non-small cell lung cancer. Recent studies have investigated the role of EGFR in the tumorigenesis of HCC. Prior studies have indicated that EGFR is expressed frequently in HCC cells and have postulated that an EGFR-mediated mechanism may be involved in promoting tumor growth and metastasis. Early studies on human HCC cells demonstrated the efficacy of erlotinib to induce growth inhibition, apoptosis, and cell-cycle arrest. A recent phase II study of erlotinib in patients with advanced unresectable HCC yielded promising results with improved progression-free survival and overall survival among treated patients. Whereas the majority of prior research evaluated the efficacy of erlotinib as monotherapy, the inhibition of EGFR-mediated pathways has been postulated to enhance the therapeutic potential of other therapies. The combination of erlotinib and sorafenib in the treatment of advanced colorectal and non–small-cell lung cancers have shown promising results in early reports. Further studies evaluating the role of erlotinib in the treatment of HCC are needed. Although early reports demonstrate great promise for erlotinib as monotherapy in HCC patients, the potential for treatment synergy in combination with other targeted therapies will likely yield the greatest potential.

Another emerging class of molecular targeted therapies are the mammalian targets of rapamycin (mTOR) inhibitors. The antineoplastic potential of mTOR inhibitors hinges on its multilevel modulation of tumor proliferation and metabolism. Although not traditionally considered an angiogenesis inhibitor, mTOR also modulates angiogenesis through indirect regulation of vascular endothelial growth factor expression. One of the early mTOR inhibitors demonstrating promise as an antineoplastic therapy is everolimus (Zortress; Afinitor). Early studies demonstrated efficacy in treatment of patients with advanced renal cell cancer, and recently the US Food and Drug Administration approved everolimus for treatment of renal cell cancer in patients who have disease progression on sunitinib (Sutent), sorafenib, or both, Given the similar tumorigenic pathways involved in HCC and the previously reported efficacy of anti-angiogenic therapies on advanced HCC, recent studies have investigated the antineoplastic potential of everolimus among HCC patients. In a phase I/II study evaluating 28 patients with advanced HCC, everolimus demonstrated promising results, producing a mean progression-free survival of 3.9 months and a disease control rate of 44%. Currently, a large, multicenter, phase III, randomized, double-blind, placebo-controlled trial (EVOLVE-1) is underway to compare everolimus with best supportive care in patients with advanced HCC who failed sorafenib therapy. As with the spectrum of targeted therapies currently available and under investigation, the role of everolimus as monotherapy and/or combination therapy continue to offer patients and practitioners greater tools to treat and manage HCC.

Many additional targeted therapies are currently under investigation. The success of sorafenib in particular has set a precedent for the emergence of molecular targeted therapies for the management of HCC. As newer agents continue to push the limits of improving morbidity and mortality among patients with HCC, the role of these novel agents in conjunction with operative resection, liver transplantation, ablation therapies, and/or concurrent oral systemic therapies that target different components of malignancy progression in an adjuvant or neoadjuvant fashion will likely offer the most potential and is under active investigation. The application of advancing locoregional approaches to the management of HCC in earlier staged disease may offer not only benefits in prolonged survival, but perhaps a potential cure.