Thalidomide Doubles Disease-Free Liver Cancer Survival Rate

Daniel M. Keller, PhD

April 06, 2011

April 6, 2011 (Berlin, Germany) — In a small, double-blind, randomized, placebo-controlled pilot study, thalidomide was associated with a doubling of the disease-free survival rate of patients who had undergone curative liver resection for hepatocellular carcinoma. Currently, there is no standard adjuvant therapy in this setting, and recurrence after curative resection is common. However, 2-year overall survival rate was not improved.

Dr. Ho

Results showed that 65% (95% confidence interval [CI], 40.3 to 81.5) of patients in the thalidomide group were disease-free at 2 years, compared with 33% (95% CI, 14.9 to 53.1) in the placebo group (= .06), Ming-Chih Ho, MD, PhD, assistant professor, Department of Surgery, National Taiwan University Hospital in Taipei, reported here at the European Association for the Study of the Liver 46th Annual Meeting.

This phase 2 study involved 42 patients with American Joint Committee on Cancer stage II or IIIa hepatocellular carcinoma. Twenty-one patients received oral thalidomide 200 mg a day and 21 received oral placebo. Treatment was initiated within 6 weeks of surgery and continued for 12 months or until disease recurrence, intolerable toxicity, or withdrawal of patient consent.

Overall, thalidomide was well tolerated, but 13 patients did require dose reductions because of adverse effects and 1 patient in the thalidomide group discontinued treatment because of persistently elevated liver enzyme values.

The 2-year overall survival rate was 84.2% (95% CI, 58.7 to 94.6) in the thalidomide group and 85.7% (95% CI, 62.0 to 95.2) in the placebo group. Dr. Ho explained that patients with recurrent disease might be eligible for salvage treatments, such as surgery, transarterial chemoembolization, or radiofrequency ablation of tumors.

"The patient still survives, even if he has recurrent disease," Dr. Ho said. "I think it's because these patients can receive other treatments. We would like to see long-term survival [data], maybe after 5 years. Then we can see if the recurrence has some effect on the long-term survival."

More patients in the placebo group had elevated levels of alpha-fetoprotein, a risk factor for recurrence. More patients in the thalidomide group had microvessel invasion by tumor, also a risk factor for recurrence, Dr. Ho noted.

Adverse events, mostly grade 1 or 2, were more common in the thalidomide group than in the placebo group. There was more constipation (57.1% vs 9.5%), increases in alanine transaminase (47.6% vs 19.0%), increases in aspartate transaminase (33.3% vs 19%), limb edema (47.6% vs 4.8%), abdominal distension (33.3% vs 0%), pruritis (28.6% vs 9.5%), and skin rash (28.6% vs 14.3%) in the thalidomide group than in the placebo group. Hyperbilirubinemia and leukocytosis occurred more frequently in the placebo group. Three patients in the thalidomide group experienced serious adverse events, but none was judged to be drug-related.

At this point, Dr. Ho said he can conclude that "this medication is safe and tolerable. [As for] the efficacy, we need more study to verify." Patients have now been followed for a median of 35.9 months, and Dr. Ho is planning a multicenter study of more than 300 patients.

Although sorafenib has proven to be effective in liver cancers, Dr. Ho is testing thalidomide because "it is an old drug and relatively cheap," he said. "We are trying to do work that may benefit more people without [great] cost."

Evidence from his institution suggests that thalidomide is active against some advanced liver cancers. "We have stable disease, about 30% to 35%, and some patients will have partial response with thalidomide for advanced cancers. We think it may antagonize some process of cancer recurrence if we use it after resection," he noted.

For any adjuvant treatment, a question is always how long to administer it, taking into consideration benefits, adverse effects, and cost. Dr. Ho said data from his hospital have indicated that rates of recurrence of hepatocellular carcinoma decreased in the second year after surgical resection, "so we don't know whether, if we prolong the medication, we will improve the survival. This study cannot answer this question."

Dr. Bernardi

Mauro Bernardi, MD, professor of internal medicine, University of Bologna, Italy, who was not involved in the Taiwanese study, pointed out that thalidomide has been used as an investigational drug to treat hepatocellular carcinoma "based on the fact that thalidomide is an antiangiogenic drug." But, he said, "as far as I know, the data [overall] are not so encouraging in terms of efficacy, and thalidomide also has some important neurological side effects. . . . Up to now, I don't think thalidomide has shown [that it is] preferred to the current dominant approach with sorafenib."

The study was funded by TTY Biopharm Corporation of Taipei, Taiwan. Dr. Ho and Dr. Bernardi have disclosed no relevant financial relationships.

European Association for the Study of the Liver (EASL) 46th Annual Meeting. Presented April 2, 2011.

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