Expanding the Treatment Options for Hepatocellular Carcinoma: Title and subTitle BreakCombining Transarterial Chemoembolization With Radiofrequency Ablation

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.¹ The incidence rates for HCC in the United States and Western Europe have been increasing.^{2 - 3} 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.^{4 - 5} 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 colleagues⁶ 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.^{7 - 9} 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.^{10 - 11} 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.

During the procedure, an angiographic catheter is advanced 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, followed by an occluding agent such as polyvinyl alcohol beads. These beads are carried by the circulation into the terminal hepatic arterioles, where they lodge and 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,^{12 - 15} 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 colleagues¹⁰ 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 the majority of patients had underlying hepatitis B infection, Lo and colleagues¹¹ 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 ablation and increased blood flow in larger lesions leading to heat loss. It has been hypothesized that by giving TACE prior to RFA administration (TACE-RFA), it would be possible to reduce or eliminate the heat loss that is mediated by tissue perfusion.^{16 - 19} As a result, the ablation volume of coagulation necrosis could be increased, enabling more effective treatment of larger HCCs than with RFA alone. This combination approach has been attempted in single centers with encouraging preliminary results for larger lesions.^{17 - 19}

As reported in their article in this issue of JAMA, Cheng and colleagues⁶ took this approach in a carefully designed randomized phase 3 study to compare the efficacy and safety of combined TACE-RFA vs TACE or RFA alone. The investigators randomly assigned 291 patients with HCC larger than 3 cm to treatment with combined TACE-RFA (n = 96), TACE (n = 95), or RFA (n = 100). During a median follow-up of 28.5 months, median survival for patients treated with TACE-RFA was 37 months compared with 24 months for those who received TACE alone (P < .001) and 22 months for those who had RFA alone (P < .001). The predefined treatment courses were performed in each group. The safety profiles for patients receiving TACE-RFA were comparable to those receiving TACE alone. The strength of the study was the prospective, randomized design with long-term survival data. In a preplanned subgroup analysis, the observed survival benefits were similar when comparing TACE-RFA with RFA alone for patients with uninodular HCC, or with TACE alone for patients with multinodular HCC. In addition, the benefits were still present in the TACE-RFA group for lesions ranging in size between 5 and 7.5 cm.

This study also has several limitations. First, because the study was conducted in a single center in China and all treatments were administered by only 5 investigators, the results from this study need to be confirmed in other centers globally, especially because patient demographics and risk factors for HCC development are different than in other countries. Second, the selection of patients participating in this study was very stringent and the findings may be applicable only to a relatively small percentage of the patient population. Third, it is unclear if the predefined 3 treatments need to be delivered routinely in clinical practice. If the initial procedure(s) was successful, there may not be an immediate need to repeat the procedure routinely.

Despite aggressive local treatments including RFA, TACE, or TACE-RFA, recurrence and distant metastases continue to have a significant effect on the overall survival of patients with HCC. The chemotherapeutic agents routinely used in TACE are suboptimal for systemic disease control. Therefore, combining effective systemic therapy with local treatments holds the promise of further improving the treatment outcomes. Recently, results of a phase 3 randomized placebo-controlled trial demonstrated that sorafenib improved survival in patients with advanced HCC.²⁰ Sorafenib is an oral multikinase inhibitor that blocks tumor cell proliferation by targeting the Raf/MEK/ERK (Raf/mitogen-activated protein kinase/extracellular signal-related kinase) signaling pathway and exerts an antiangiogenic effect by targeting the tyrosine kinases VEGFR-2 (vascular endothelial growth factor receptor 2), VEGFR-3, and PDGF (platelet-derived growth factor) receptor β.^{21 - 22} The results from this study provide the first evidence of improved overall survival benefit in advanced disease. Other molecularly targeted agents are under active development.

Combining an antiangiogenic agent with TACE or giving it after TACE may inhibit the increase in plasma VEGF levels seen after the procedure and block neovascularization and tumor regrowth. In the case of RFA, a key component of the size limitation is the heat-sink effect of tumor blood flow. TACE can improve RFA efficacy by decreasing tumor blood flow.^{17 - 19} Using an antiangiogenic agent may provide a potential pharmacologic alternative strategy to decrease tumor blood flow. In support of this hypothesis, sorafenib was shown to increase the RFA-induced coagulation zone, decrease microvascular density, and decrease tumor blood flow on arterial spin labeling magnetic resonance imaging in a mouse xenograft renal cell carcinoma model.²³

The study by Cheng et al⁶ provides initial evidence to support the use of TACE-RFA as a new treatment option in highly selected patients with unresectable HCC. This study points toward an important mechanistic possibility—namely that altering the tumor microenvironment and supporting vasculature may help improve the efficacy of localized therapy in this disease. However, despite the positive findings in this study, the exact role for TACE-RFA in the treatment of patients with unresectable HCC remains a controversial and unresolved issue, similar to the situation for many of the interventional-based therapies. For patients with early stage disease either surgery or RFA will remain the initial treatment choice and the recent approval of sorafenib has provided a new treatment option for advanced HCC. A logical extension will be studies to evaluate the potential additive benefit offered by complementary treatment modalities, such as targeted agents in combination with either TACE or RFA. However, adding to the complexity of evaluating these approaches will be the potential continued approval of new systemic therapies for treating “unresectable” HCC.