Combination Therapy Improves Survival in Patients With Large Hepatocellular Carcinoma Tumors

Roxanne Nelson

April 09, 2008

April 9, 2008 — Transcatheter arterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) is an effective and safe treatment for patients with large hepatocellular carcinoma tumors, and might improve long-term survival. The combination of TACE-RFA was found to be superior to either TACE or RFA alone in improving survival in patients with hepatocellular carcinoma tumors larger than 3 cm, according to the results of a study published in the April 9 issue of the Journal of the American Medical Association.

"From our randomized controlled study results, I think that TACE-RFA treatment is a new treatment option for unresectable hepatocellular carcinomas larger than 3 cm," lead author Bao-Quan Cheng, MD, PhD, from the department of gastroenterology at Shandong University, in Jinan, China, told Medscape Oncology. "It can prolong the survival of these patients, compared with TACE or RFA alone."

The incidence rates of hepatocellular cancer have been rising in the United States and Western Europe; globally, it remains the sixth most common cancer and the third most common cause of cancer-related mortality. Most cases are not diagnosed until they reach intermediate or advanced stages, and only 20% to 30% of patients present with early-stage disease that is amenable to curative treatments such as surgical resection or transplantation.

A standard treatment for hepatocellular carcinoma has not yet been established, and although a number of interventional-based options are available for patients with unresectable disease, the benefits and limitations of these approaches remain controversial. Extensive worldwide experience has supported the use of RFA as an excellent treatment option for small tumors (less than 3 cm), with rates of 3-year disease control of up to 80% to 90%, write Andrew X. Zhu, MD, PhD, of the Massachusetts General Hospital Cancer Center, in Boston, and Ghassan K. Abou-Alfa, MD, from Memorial Sloan-Kettering Cancer Center, in New York, New York, in an accompanying editorial.

TACE has been the default treatment option for patients with intermediate-stage disease with multinodular lesions or tumors larger than 4 cm in diameter. And although some studies support its use, they note, the "experience with TACE has been mixed, leaving many unanswered questions and controversies."

Both procedures have limitations and drawbacks when used alone, but this study provides initial evidence to support the use of combination TACE-RFA as a new treatment option in a select patient population, they note.

"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," write the authors, although despite the positive findings in this study, the exact role of TACE-RFA in this patient population remains controversial.

In the current study, Dr. Cheng and colleagues hypothesized that if TACE were performed before RFA treatment, the ablation volume of coagulation necroses could be increased, thus enhancing treatment efficacy in patients with larger hepatocellular carcinoma. Although there have been no randomized controlled trials comparing TACE-RFA with TACE alone and RFA alone in patients with larger hepatocellular tumors, the efficacy of this combination has been confirmed by other researchers.

In this single-center, prospective, randomized controlled trial, 291 consecutive patients with hepatocellular carcinoma larger than 3 cm were assigned to combined TACE-RFA (n = 96), TACE alone (n = 95), or RFA alone (n = 100). The primary end point was survival and the secondary end point was objective response rate.

The researchers noted a lower mortality rate in the TACE-RFA group than in the other 2 groups. Overall, 80 patients in the TACE group (84%), 84 in the RFA group (84%), and 66 in the TACE-RFA group (69%) died by the end of the follow-up period. The lower mortality rate among patients in the TACE-RFA group was due to the lower number of deaths related to tumor progression than in the other 2 groups.

The median follow-up was 28.5 months, and median survival was 24 months in the TACE group, 22 months in the RFA group, and 37 months in the TACE-RFA group. Overall survival was significantly better in the TACE-RFA group than in to the other 2 groups (hazard ratio, 1.87).

A subgroup analysis of patients by lesion size showed increased survival among patients who received combination therapy, and survival was also superior in patients with lesions larger than 5 cm.

The researchers explained that because RFA appears to be the appropriate treatment for patients with uninodular hepatocellular carcinoma and TACE the preferred therapy for multinodular hepatocellular carcinoma, they preplanned an analysis according to nodularity group.

Among patients with uninodular disease, the overall survival was statistically significantly better in the TACE-RFA group than in the RFA group; survival rates at 1, 3, and 5 years were 87%, 50%, and 15%, respectively, in the RFA group, and 93%, 79%, and 53%, respectively, in the TACE-RFA group. The analysis of multinodular hepatocellular carcinomas showed that the overall survival rate was also statistically significantly higher in the TACE-RFA group than in the TACE group; survival rates at 1, 3, and 5 years were 75%, 36%, and 13%, respectively, in the TACE-RFA group, and 56%, 13%, and 0%, respectively, in the TACE group.

For their secondary end point, the researchers also observed that the rate of objective response sustained for at least 6 months was higher among patients in the TACE-RFA group (54%) than among those in the TACE group (35%) or the RFA group (36%).

"Clinicians should choose this combined treatment to improve survival if the patients meet the eligibility criteria stated in our paper," said Dr. Cheng.

JAMA. 2008;299:1669-1677, 1716-1717.


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