July 11, 2008 — Pegylated interferon alfa-2b (Pegintron, Schering-Plough) offers an attractive alternative to high-dose interferon for many melanoma patients, according to an editorial published in the July 12 issue of the Lancet. It accompanies the publication of the results of a large phase 3 study showing that the product had a significant and sustained effect on recurrence-free survival.
Pegylated interferon alfa-2b is not indicated for melanoma; it is currently marketed for use in chronic hepatitis C, either alone or in combination with ribavirin. In pegylated interferon alfa-2b, interferon is attached to the inert polyethylene glycol molecule, which leads to slower elimination from the body. This means that it can be dosed once a week instead of 3 times a week, which is required for standard interferon.
The trial, known as EORTC 18991, was conducted under the auspices of the European Organization for Research and Treatment of Cancer, but Schering-Plough provided financial support and the product. Preliminary results were reported by lead investigator Alexander Eggermont, MD, PhD, from Erasmus University Medical Center, in Rotterdam, the Netherlands, at the American Society of Clinical Oncology 44th Annual Meeting in June.
"Advanced-stage melanoma remains difficult to treat," Dr. Eggermont said in a statement. "These results demonstrate the benefit of an increased relapse-free survival despite no difference in overall survival."
Largest Trial of Adjuvant Therapy to Date
The study involved 1256 patients with postsurgery stage 3 melanoma, and is said to be the largest trial to date of an adjuvant melanoma therapy. Half the patients were randomized to receive pegylated interferon, at a dose of 6 μg/kg body weight for 8 weeks (induction), which was then reduced to 3 μg/kg for an intended duration of 5 years (maintenance). The other half of the patients were followed with observation alone.
Dr. Eggermont and colleagues report that at a median follow-up of 3.8 years (range, 3.2–4.2 years), the median length of treatment was 1 year (range, 3.8–33.4 months). During that time, pegylated interferon reduced the risk for recurrence by 18%, the researchers report. There were 328 recurrences in the pegylated-interferon group and 368 recurrences in the observation group (hazard ratio [HR], 0.82; 95% confidence interval, 0.71–0.96, P = .01).
Response to therapy appeared to be most pronounced in a subgroup of patients with microscopic nodal disease (N1). In this subgroup, which accounted for 43% of the total trial population, there were 108 events in the pegylated-interferon group and 137 events in the observation group (HR, 0.71; P = .01 on multivariate analysis).
However, there was no significant difference in overall survival between the 2 groups, Dr. Eggermont and colleagues report. Distant metastasis-free survival was numerically better in the pegylated-interferon group than in the observation group, but this difference was not statistically significant.
Treatment with pegylated interferon was discontinued because of toxicity in 191 patients (31%). The most common grade 3 or 4 adverse effects were fatigue (97 patients; 16%), hepatotoxicity (66 patients; 11%), and depression (39 patients; 6%).
Follow-Up Too Short for Final Conclusions
The median follow-up of 3.8 years "is too short for final conclusions," comment the editorialists, Vernon Sondak, MD, from the H. Lee Moffitt Cancer Center and the University of South Florida College of Medicine, in Tampa, and Lawrence Flaherty, M, from the Karmanos Cancer Institute and Wayne State University School of Medicine, in Detroit, Michigan.
"The effect on recurrence-free survival could disappear after therapy ends, but further follow-up might show a significant survival advantage for the N1 population; that would represent the real advance we've been waiting for," they comment.
Recurrence-free survival, the end point used in this study, is appropriate in advanced melanoma, the editorialists comment, because many patients are willing to accept significant toxicity in exchange for a modest improvement in recurrence-free survival, even in the absence of an overall survival benefit. However, they question whether the toxicity of pegylated interferon, which is lower than that of the high-dose interferon currently used in the United States, will be sufficient to persuade skeptical clinicians who demand an overall survival benefit.
Approached for a comment, Jeffrey Weber, MD, from the H. Lee Moffitt Cancer Center, said: "In my view, this was a successful trial, with benefit for relapse-free survival. It should not to be discounted."
"This is apparently a better-tolerated product than standard high-dose interferon, and this trial has received a lot of attention in Europe," Dr. Weber told Medscape Oncology. "I am not sure if physicians will be able to use this product in the United States, but that wouldn't be unreasonable."
Dr. Weber and the editorialists stated, however, that pegylated interferon should be studied in combination with other products in further clinical trials.
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