PEG-IFN improved relapse-free survival in stage III melanoma

2011 ASCO Annual Meeting

CHICAGO — Long-term adjuvant pegylated interferon alpha-2b therapy significantly improved relapse-free survival in stage III melanoma patients, but not distant metastasis-free survival or OS, according to results shown in the largest adjuvant trial ever conducted in stage III melanoma.

The EORTC 18991 trial showed that sentinel-node positive and ulcerated melanoma were associated with the greatest benefit from pegylated interferon alpha-2b (PEG-IFN), according to Alexander Eggermont, MD, PhD, head of the department of surgical oncology at the Erasmus University Medical Center – Daniel den Hoed Cancer Center in Rotterdam, the Netherlands, who presented results from a median 7.6 years of follow-up at the 2011 ASCO Annual Meeting.

During the course of 5 years, 1,256 patients with stage III melanoma (characterized by TN1-2M0 without in-transit metastases) were randomly assigned either PEG-IFN (induction at one 6-mcg/kg injection per week for 8 weeks, followed by maintenance at 3 mcg/kg per week) or observation.

Assignment was stratified according to nodal involvement NI (microscopic) vs. N2 (palpable nodes), the number of nodes, Breslow’s thickness and ulceration. The primary endpoint was distant metastasis-free survival; relapse-free survival was the predetermined regulatory primary endpoint and OS was the secondary endpoint. Median follow-up was 7.6 years.

The median relapse-free survival in the observation arm was 2.2 years vs. 3 years in the PEG-IFN arm (HR=0.87; 95% CI, 0.76-1.00), for a 13% relative risk reduction. The median distant metastasis-free survival was 3.2 years for the observation group and 3.9 years in the treatment group (HR=0.93; 95% CI, 0.81-1.07). The median OS was 5.6 years in the observed arm vs. 6.2 years in the PEG-IFN group (HR=0.96; 95% CI, 0.82-1.11).

According to Eggermont, grade 3 adverse events included fatigue and liver toxicity (14%) and depression (6%), which did not worsen as treatment progressed.

Eggermont said efficacy hinged on tumor type. “Basically, at 7.6 years, the effect that is mediated is restricted to the sentinel-node patient population, so stage and interferon interact significantly if you stratify for this at randomization and you define it as sentinel-node positive disease vs. palpable nodal disease,” he said, adding that treatment of palpable disease failed all endpoints.

“For the non-ulcerated patient population, there is no effect of adjuvant interferon therapy. In the ulcerated population, there is a borderline significant effect. For relapse-free survival and distant metastasis-free survival, ulcerated primary sentinel-node positive patients have a highly significant benefit from interferon therapy. Overall survival for patients who have an ulcerated primary and sentinel-node positive status have a 41% risk reduction. When you look at the median overall survival, the difference goes from 3.7 years to longer than 9 years. This is the targeted patient population that basically carries the whole effect.” – by Whitney McKnight and Carey Cowles

For more information:

• Eggermont A. #8506B. Presented at: 2011 ASCO Annual Meeting; June 3-7; Chicago.

Disclosure: Dr. Eggermont has served in several roles for Schering-Plough, including consultant, researcher and expert; and has received honoraria from Schering-Plough.

The data we heard poses the question: Do these data change our current practice? Pegylated interferon approval in March 2011 for stage III melanoma, both microscopic and macroscopic, raises some skepticism because of the short follow-up of 3.8 years and the fact that pegylated interferon was approved for all stage III patients. And we have heard during this session that the principal investigator supports its use only in microscopic disease. It has a sustained benefit on relapse-free survival, which has raised skepticism about the efficacy of extended pegylated interferon. As it has been shown that sentinel lymph nodes ulcerated primaries have benefit on all endpoints, the prospective validation will give us the answer.

A meta-analysis by Mocellin in the Journal of the National Cancer Institute in 2010, which included over 8,000 patients, did not show any optimal interferon dose or treatment duration or subset of patients more responsive to treatment. I think we have been going in circles for several decades. We need to be able to identify patients that are most likely to benefit from therapy.

- Helen Gogas, MD
Assistant professor of medical oncology, Athens University Medical School , Greece
Director of the Oncology Outpatient Clinic of the 1st Department of Internal Medicine,
Laiko University Hospital of Athens, Greece

Disclosure: Dr. Gogas has served in a consultant or advisory role for and received honoraria from Schering-Plough.

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