Experts Debate Interferon’s Role in High-Risk Melanoma

ATHENS—High-dose interferon-alfa-2b (Intron A, IFN) is the only regimen shown to improve relapse-free survival in high-risk melanoma and should be considered a reference standard for adjuvant therapy in this disease, John Kirkwood, MD, of the University of Pittsburgh, said in a debate at this year’s European Society for Medical Oncology (ESMO) Congress.

This view was challenged by his debate opponent Alexander Eggermont, MD, of the Daniel den Hoed Cancer Center, Rotterdam, who argued that toxicity, cost, and the failure to prove a consistent overall survival benefit rule out IFN as a standard therapy.

In a survey of early randomized, controlled trials, Dr. Kirkwood reminded the audience of the results of ECOG trial 1684. In this study of 286 patients with T4, node-positive melanoma, 1 year of treatment with high-dose IFN boosted overall survival from 2.8 years to 3.8 years (P = .027) and relapse-free survival from 0.93 years to 1.72 years (P = .0023).

“Cox model analysis showed that IFN was second only to stage of disease in predicting, to a highly significant confidence, both relapse-free survival and overall survival,” Dr. Kirkwood said. “We also showed an improved quality of life and a cost efficacy comparable to that of adjuvant therapy for breast and colorectal cancer.”

In contrast, Dr. Kirkwood acknowledged, the NCCTG 83-7052 trial yielded disappointing results, revealing no significant impact of 3 months of high-dose IFN in either forestalling relapse or prolonging survival. Although there was a trend toward benefit in patients with stage III melanoma, the group was too small to allow any conclusions to be drawn regarding IFN efficacy.

Likewise, the World Health Organization (WHO) trial of low-dose IFN in stage III melanoma fell short of demonstrating an effect on relapse rate or survival at 3 years. “Low doses do not have a role in high-risk patients,” said Dr. Kirkwood, pointing to an imploding, or disappearing, benefit in the relapse-free survival curves.

Dr. Kirkwood unveiled newly available preliminary data from the Intergroup ECOG 1690/SWOG 9111/CALGB 9190 trial. This study compared the effects of the ECOG 1684 high-dose IFN regimen (20 mU/m²/day IV, 5 to 7 days a week for 4 weeks, followed by 10 mU/m²/day SC, three times a week for 48 weeks) versus the WHO low-dose IFN regimen (3 mU/m²/day SC, three times a week for 104 weeks) vs observation.

The study population included 162 patients with stage T4cN0 melanoma, 68 patients with T1-4cN1cN0 disease, 83 with T1-4cN1 disease, and 326 with recurrent N+ disease.

“There is consistency between the results of ECOG 1684 and ECOG 1690,” Dr. Kirkwood said. He noted that high-dose IFN significantly prolonged relapse-free survival by 42% in study 1684 and by 28% in study 1690. These benefits were achieved across-the-board in node-positive as well as node-negative patients.

Dr. Kirkwood conceded that no overall survival advantage has yet become apparent in ECOG 1690, despite the absence of any toxic deaths with the high-dose regimen. Instead, he said, the lack of an improvement in overall survival might be attributable to the fact that the outcome for the observation group was markedly better in ECOG 1690 than in ECOG 1684.

“Any potential survival benefit of IFN in high doses will require much longer or much larger trials to detect,” he said.

Ongoing North American trials of high-dose IFN are attempting to build on these results, he said. ECOG 1694 is comparing high-dose IFN with a new vaccine, GM2, and a recently completed Intergroup study has tested the combination of IFN and GM2 against the vaccine alone.

The hypothesis that peak dose exposure might account for the benefit of IFN is being explored in an ECOG/National Cancer Institute of Canada trial, which will evaluate the efficacy of 4 weeks of high-dose IFN treatment in patients with stage II melanoma.

Dr. Eggermont, in his presentation, said that it comes as no surprise that contemporary trials of adjuvant therapy in melanoma are failing to replicate the findings of trials conducted in the 1980s, since better staging procedures have led to stage migration. Indeed, he said, promising early results with therapies other than IFN—including BCG with or without DTIC, levamisole, adjuvant chemotherapy with bone marrow transplant, and vaccination—have similarly not been borne out in phase III or confirmatory trials.

Dr. Eggermont stressed that in ECOG 1684, the only trial to date that has shown a survival advantage for IFN, 78% of patients developed grade 3-4 toxicity and two-thirds required a dose reduction or interruption of therapy. As a result, he pointed out, although a total dose of 3,500 mU had been planned, the actual dose achieved was only 2,100 mU.

With treatment costs approaching $50,000 to $60,000 per patient, Dr. Eggermont argued, high-dose IFN could only be recommended if the survival benefit reported in ECOG 1684 were to be confirmed in ECOG 1690. This prerequisite has not been fulfilled, he said.

Intermediate-dose IFN may prove to be a less toxic and less expensive strategy, and may allow prolonged maintenance treatment, possibly the key to efficacy, he said. The ongoing EORTC-MCG 18952 trial is comparing IFN, 10 mU/day SC for 4 weeks, followed by 10 mU for 1 year or 5 mU for 2 years, vs observation in high-risk melanoma; thus far, 950 patients are enrolled. “With these regimens, we see only 15% grade 3-4 toxicity, which means we need much smaller dose reductions,” he said (see Table). “We end up with a total dose of 1,550 mU, which comes close to the ECOG 1684 dose range.”

At present, he said, unfortunately, there is no standard adjuvant therapy for any stage of malignant melanoma. “This is regrettable, but convincing data to state differently do not exist.”