A European Clinical Trials Study Group, the EORTC, reported on the effects of long-term (5 years) pegylated interferon-alpha2b (a long-acting form of interferon, PEG-IFN) administration as adjuvant therapy for patients with stage III melanoma. These are patients who have had metastasis of melanoma to the lymph nodes, which were surgically excised. Thus the patients were clinically disease-free, but at high risk for recurrence due to microscopic deposits of melanoma cells that might remain after the surgery.

This was the largest adjuvant trial ever conducted in patients with stage III melanoma; 1,256 patients participated in the study. Patients were randomized to receive PEG-IFN or observation (control subjects). The results showed that the administration of PEG-IFN had no effect on overall survival in the treated patients but did cause a delay in the time to recurrence, termed relapse-free survival. These results are similar to those reported in the US and elsewhere for non-pegylated interferon-alpha.

EORTC 18991: Long-term adjuvant pegylated interferon-alpha2b (PEG-IFN) compared to observation in resected stage III melanoma, final results of a randomized phase III trial.
Sub-category: Melanoma
Category: Melanoma
Meeting: 2007 ASCO Annual Meeting
Abstract No: 8504
Citation: Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 8504
Author(s): A. M. Eggermont, S. Suciu, M. Santinami, W. Kruit, A. Testori, J. Marsden, C. Punt, A. Hauschild, M. Gore, U. Keilholz, EORTC Melanoma Group

Abstract: Background: EORTC 18991 is the largest adjuvant trial ever conducted in stage III melanoma. It assessed the efficacy and toxicity of long term PEG-IFN vs Observation (Obs.). Methods: PEG-IFN (Induction at 6µg/Kg/wk, sc, 8 weeks; followed by Maintenance at 3µg/Kg/wk, sc) for a total treatment duration of 5 years was compared to Obs. in 1256 patients (pts) with stage III melanoma (anyTN1-2M0 without in-transit metastases).

Randomization was stratified for nodal involvement N1 (microscopic) vs N2 (palpable nodes), # of nodes, Breslow and ulceration of primary, sex and center. Distant Metastasis-Free Survival (DMFS) was the primary endpoint. Relapse-Free Survival (RFS) was the pre-specified regulatory primary endpoint. Overall survival (OS) was the secondary endpoint. Intent-to-treat analysis was performed.

Results: Median follow-up was 3.8 yrs: HR = Hazard Ratio; NR = Not Reached In N1-pts (n=543) the benefit of PEG-IFN seemed more pronounced than in N2-pts (n=713): RFS (HR 0.73 p=0.02 and HR 0.86 p=0.12 for N1 and N2, respectively), DMFS (HR 0.75 p=0.03 and HR 0.94 p=0.53) and OS (HR 0.88 p=0.43 and HR 1.01 p=0.91). PEG-IFN therapy relative dose intensity (actual/planned dose while treated) reached median 88% (induction) and 83% (maintenance). 251 pts (40 %) stopped PEG-IFN because of toxicity. Grade 3-4 - mostly grade 3 - toxicities were reported in 45% (PEG-IFN), vs 12% (Obs.), including most frequently fatigue (15%), hepatotoxicity (10%) and depression (6%) with ECOG 0-1 Performance Status maintained in 83% of pts during maintenance.

Conclusions: Long term PEG-IFN therapy in stage III melanoma had a significant and sustained impact on RFS, but not on DMFS and OS. Pts with only microscopic nodal involvement (Sentinel Node positive) seemed to have greater benefit in terms of both RFS and DMFS. Similar better effects of adjuvant IFN therapy in pts with lower disease burden are observed in 2 consecutive EORTC trials (18952 and 18991) involving 2644 pts.