Progress has been made in several aspects of HCC management, including improved treatment of HCV,51–53
decreased incidence of HBV infection as a result of widespread successful vaccination efforts,54–56
enhanced screening and early HCC detection in high-risk patients in some countries,13
and the approval in 2007 of the oral anticancer agent sorafenib for treatment of advanced HCC.57,58
A variety of treatment options are available for HCC patients; however, at present, the only curative option is liver transplantation, which benefits a small minority of HCC patients. Given the projected increase in incidence of HCC due to HCV and obesity-related cirrhosis,59–61
there is a looming need for accelerated clinical and translational research in this disease.
The standard surgical management for early-stage HCC consists of resection or liver transplantation. However, only 10% to 30% of patients initially presenting with HCC will be eligible for surgery.62
In general, the treatment of HCC is dependent not only on the extent of tumor but also on the level of underlying hepatic dysfunction. Patients with cirrhosis may be candidates for limited surgical resection, liver transplantation, or locoregional ablative treatment, depending on the severity of the cirrhosis. In patients with no evidence of cirrhosis, hepatic resection has been the mainstay of surgical treatment. In patients with moderate to severe cirrhosis (Child-Pugh class B or C), transplantation is potentially optimal therapy for small-size, otherwise resectable HCC, because it eliminates the underlying cirrhosis that puts the liver at risk for subsequent new primary tumors.63–65
The ideal treatment strategy, but also more controversial for small HCC in patients with mild cirrhosis may include resection or transplantation.66,67
However, because of limited donor organ availability and also for cultural and economic reasons, surgical resection is the mainstay of therapy worldwide for patients with liver-confined HCC.
The selection of patients for surgical resection is based on several criteria, including the absence of extrahepatic disease, the degree of hepatic dysfunction, and technical considerations such as the adequacy of the future liver remnant and tumor involvement of major vascular structures such as the portal vein or vena cava. Patients with normal liver parenchyma are usually eligible for extensive resection, whereas patients with compensated cirrhosis may be candidates for minor or major partial hepatectomy only in selected cases. Surgery in patients with underlying cirrhosis can be associated with substantial morbidity and mortality.68,69
Although perioperative mortality can be as high as 30% to 50% in patients who are Child-Pugh class B or C, patients who are Child-Pugh class A have a surgical mortality of only 5% to 10%.70,71
The model for end-stage liver disease (MELD) includes serum bilirubin, creatinine, and international normalized ratio and has been shown to be a simple yet accurate method for predicting postoperative liver failure and mortality. Patients with MELD score < 9 had a mortality rate of zero in two recent large institutional series of patients undergoing resection of HCC.69,72
In most series, surgical resection of early HCC reported 5-year survival rates of 45% to 50% compared with 65% to 70% for transplantation.64
However, direct comparison of resection to transplantation survival data is difficult outside of a study designed to do that. The favorable results with transplantation likely reflect more stringent selection of patients.73,74
Initial results for orthotopic liver transplantation (OLT) for all-stage HCCs were associated with high early recurrence (18%) and lower 5-year survival rates (40%) compared with other indications for OLT.75
As a result of these discouraging experiences, in the early 1990s, HCC was considered a contraindication to OLT in many transplantation centers. Subsequently, it was observed on examination of liver explants that incidental small HCC not detected by preoperative imaging had no adverse impact on the post-transplantation outcome. Patients with HCC meeting these criteria (a single tumor < 5 cm in diameter, or 2-3 tumors each < 3 cm) had similar post-transplantation survival compared with patients without HCC, with 4-year actuarial and recurrence-free survival rates of 75% and 83%, respectively.76,77
These results have been confirmed by multiple centers and have led to the acceptance of liver transplantation for HCC in cirrhotic patients who meet these criteria. HCC patients who undergo OLT within United Network for Organ Sharing (UNOS) criteria have median 5-year survivals of 65% to 80%. While there is interest in expanding the criteria for liver transplantation for patients with HCC to include patients with larger and more numerous tumors (the University of California at San Francisco [UCSF] criteria),78–81
these criteria have not been universally accepted or adopted.
For selected patients with HCC confined to the liver whose disease is not amenable to resection or transplantation, locoregional therapies can be considered. These include percutaneous ethanol injection, cryotherapy, radiofrequency or microwave ablation (RFA), stereotactic radiation therapy, radioactive microspheres, transarterial (bland) embolization (TAE), and transarterial chemoembolization (TACE). While nonresectional locoregional therapies are not curative, these approaches do produce tumor destruction while preserving nontumorous liver parenchyma and may serve as a bridge to more definitive therapy, such as liver transplantation or as salvage treatment for postresection recurrence.82–86
RFA uses radiowaves delivered via an electrode directly inserted into a tumor to create a zone of thermal necrosis to destroy the tumor. RFA can be performed percutaneously, laparoscopically, or through an open incision and is most effective in tumors < 3 cm in diameter. Larger tumors generally require multiple overlapping ablations or the use of multiple-array probes. Traditionally, RFA (and any ablative technique) has been limited by the inability to accurately evaluate treatment margins in all three dimensions. In a nonrandomized, comparative study of 148 patients with solitary, small (< 4 cm) HCC, the rate of local (near the margin of ablation) recurrence was found to be as high as 7.3% after RFA compared with 0% after surgery.87
However, in a recent prospective randomized trial of 180 patients with a solitary HCC tumor < 5 cm, percutaneous RFA and surgical resection were associated with similar overall survival (OS; 68% v
64%) and disease-free survival (46% v
52%) rates at 4 years.88
It has been suggested that RFA may be more effective in patients with cirrhosis because the fibrotic liver can act as insulation and confine the heat to the tumor, creating the so-called “oven effect.”89
Nevertheless, there is no consensus regarding the efficacy of RFA as first-line treatment for HCC; currently, this technique is generally accepted as the best treatment for small HCC in a patient whose tumor cannot be resected safely as a means of preventing tumor progression before liver transplantation, or as salvage treatment for patients who have tumor recurrence after surgical treatment.
TACE is a locoregional therapy option that delivers chemotherapy and embolic materials via hepatic arterial infusion. It is based on the fact that HCC tumors > 2 cm preferentially receive their blood supply from the hepatic arterial circulation. Chemotherapy agents may be either infused into the liver before embolization or impregnated in the gelatin sponges used for the embolization.90,91
Lipiodol has also been used in conjunction with TACE because this agent will remain selectively in the tumors for an extended period, allowing the delivery of locally concentrated therapy. The objective of TACE is to bring arterial flow to stasis to effect ischemia as well as direct cytotoxic tumor damage.92–94
TAE can also be performed omitting the chemotherapeutic agent.
The advantage of TACE compared with the best supportive care has been suggested in two small randomized controlled trials. The first study from the University of Hong Kong randomly assigned 80 patients with advanced HCC to TACE with an emulsion of cisplatin in lipiodol and gelatin-sponge particles versus conservative management. Two-year survival rates were significantly higher for the TACE arm compared with the control group (31% v
In the second TACE trial performed in Western Europe, patients were randomly assigned to receive bland TAE, or supportive care doxorubicin combined with lipiodol and absorbable gelatin (Gelfoam; Pfizer, Hayward, CA). The 2-year survival rates were significantly better for the TACE group than for the symptomatic control group (63% v
However, subsequent controlled trials have not demonstrated a survival benefit of TACE.97,98
Morbidity rates have been reported to be as high as 23% after TACE, especially among patients with HCC tumors > 10 cm in diameter.99,100
Postembolization syndrome, including fever, nausea, and pain, is common. Other complications, such as fatal hepatic necrosis and liver failure are rare. TACE is generally contraindicated in patients with decompensated liver failure.
HCC tumors are clinically chemotherapy-resistant tumors, an observation supported by low response rates across a wide variety of cytotoxic chemotherapy agents101
and, until recently, a lack of level 1 evidence that systemic therapy improves median OS in HCC patients. In a pivotal, international, placebo-controlled clinical trial (Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol [SHARP]), sorafenib significantly improved OS (10.7 v
7.9 months; P
< .001), in patients with advanced HCC and Child-Pugh class A cirrhosis.102
Sorafenib is a multikinase inhibitor with activity against Raf kinase and several other cellular receptors, including vascular endothelial growth factor 2 (VEGF2), platelet-derived growth factor, FLT3, and c-Kit. In HCC cell lines, sorafenib inhibits proliferation and induces apoptosis.57,103,104
The approval of sorafenib in 2007 for the treatment of HCC patients in both the United States and the European Union represents a true paradigm shift in the treatment of advanced HCC and is a clinically meaningful therapeutic advancement in this challenging malignancy. Interestingly, a subsequent prospective controlled trial of sorafenib in Asian patients with the same design and eligibility criteria as the SHARP trial showed an improvement in OS with a hazard ratio similar to that of the SHARP trial. However, the Asian study showed significantly lower absolute benefit (6.2 months median survival in the study arm v
10.7 months in SHARP) and possibly overall lower tolerance of sorafenib.105
Understanding the reasons for such differential effects is essential to inform the design of future trials in HCC and underscores the importance of identifying stratification factors in future clinical trials, such as hepatic function, ethnicity, disease etiology, and tumor molecular profile.
There remains a great need for safe and effective systemic therapies for HCC patients who progressed on or do not tolerate sorafenib and for patients with more advanced hepatic dysfunction. Sorafenib provides a platform on which to build future clinical trials in both the adjuvant and advanced disease settings.