Expanding the Treatment Options for Hepatocellular Carcinoma

Abstract

HEPATOCELLULAR CARCINOMA (HCC) REPRESENTS a challenging malignancy of worldwide importance: it is the sixth most common cancer and the third most common cause of cancer-related death globally. The incidence rates for HCC in the United States and Western Europe have been increasing. Despite many efforts in prevention and screening for HCC, only 20% to 30% of patients present with early stage disease amenable to curative treatments, including surgical resection and liver transplantation. Although many interventional-based treatment options are available for unresectable HCC, the benefits and limitations of these individual treatment approaches remain controversial. In this issue of JAMA, Cheng and colleagues report their results using combined transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) in a randomized phase 3 trial involving patients with HCC. This important study provides the rationale, safety profiles, and evidence of improved disease control and survival benefits that lend support for the use of a novel treatment option for HCC. Radiofrequency ablation is typically performed percutaneously by advancing a specially designed electrode into the tumor and applying radiofrequency energy to generate a zone of thermal destruction that encompasses the tumor and a 1-cm margin of surrounding liver. Extensive worldwide experience has supported the use of RFA as an excellent treatment option for small HCC ( 3 cm), with 3-year disease control rates up to 80% to 90% in most series. For patients with intermediate-stage disease with multinodular lesions or tumors greater than 4 cm in diameter, TACE has been the default treatment option with some studies supporting it. TACE takes advantage of the dual blood supply of the normal liver by which the liver is perfused by both the portal vein and the hepatic artery. On the other hand, HCC derives its blood supply almost entirely from the hepatic artery. Duringtheprocedure,anangiographiccatheter isadvanced into branches of the hepatic artery supplying the tumor and chemotherapeutic agents (eg, doxorubicin, cisplatin) typically mixed with an oily contrast agent (eg, lipiodol or ethiodol) are injected, followedbyanoccludingagent suchaspolyvinyl alcohol beads. These beads are carried by the circulation into the terminalhepatic arterioles,where they lodgeand occlude the vessels, resulting in ischemic tumor necrosis. The experience with TACE has been mixed, leaving many unanswered questions and controversies. While several studies have failed to show a survival benefit, 2 studies have demonstrated improved overall survival compared with best supportive care alone in highly selected patient populations. In a randomized controlled trial, Llovet and colleagues demonstrated that patients ( 80% with underlying hepatitis C–related cirrhosis) who received doxorubicin-based TACE had improved overall survival compared with those who received best supportive care (P=.009). Survival probabilities at 1 and 2 years, respectively, were 82% and 63% for chemoembolization and 63% and 27% for control. In another single-center study conducted in Hong Kong where themajorityofpatientshadunderlyinghepatitisB infection, Lo and colleagues showed that patients with unresectable HCC who received cisplatin-based TACE had improved survival (1 year, 57%; 2 years, 31%; 3 years, 26%) compared with those who received only symptomatic control (1 year, 32%; 2 years, 11%; 3 years, 3%; P=.002). Despite these 2 positive studies, it is clear that this approach is applicable only in highly selected patients. To maintain the benefits of sustained response, patients often need repeated procedures. Both RFA and TACE have limitations and drawbacks when used alone. As tumor size increases, the effectiveness of RFA is generally reduced. This is likely due to the incomplete ab-