Faculty Opinions recommendation of Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma.

Purpose Adjuvant pegylated interferon alfa-2b (PEG-IFN-α-2b) was approved for treatment of resected stage III melanoma in 2011. Here, we present long-term follow-up results of this pivotal trial. Patients and Methods In all, 1,256 patients with resected stage III melanoma were randomly assigned to observation (n = 629) or PEG-IFN-α-2b (n = 627) for an intended duration of 5 years. Stratification factors were microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumor thickness, sex, and center. Recurrence-free survival (RFS; primary end point), distant metastasis-free survival (DMFS), and overall survival (OS) were analyzed for the intent-to-treat population. Results At 7.6 years median follow-up, 384 recurrences or deaths had occurred with PEG-IFN-α-2b versus 406 in the observation group (hazard ratio [HR], 0.87; 95% CI, 0.76 to 1.00; P = .055); 7-year RFS rate was 39.1% versus 34.6%. There was no difference in OS (P = .57). In stage III-N1 ulcerated melanoma, RFS (HR, 0.72; 99% CI, 0.46 to 1.13; P = .06), DMFS (HR, 0.65; 99% CI, 0.41 to 1.04; P = .02), and OS (HR, 0.59; 99% CI, 0.35 to 0.97; P = .006) were prolonged with PEG-IFN-α-2b. PEG-IFN-α-2b was discontinued for toxicity in 37% of patients. Conclusion Adjuvant PEG-IFN-α-2b for stage III melanoma had a positive impact on RFS, which was marginally significant and slightly diminished versus the benefit seen at prior follow-up (median, 3.8 years). No significant increase in DMFS or OS was noted in the overall population. Patients with ulcerated melanoma and lower disease burden had the greatest benefit.

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Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macro-metastatic nodes: EADO trial.

Journal of Clinical Oncology ◽

10.1200/jco.2010.28.18_suppl.lba8506 ◽

2010 ◽

Vol 28 (18_suppl) ◽

pp. LBA8506-LBA8506 ◽

Cited By ~ 5

Author(s):

J. J. Grob ◽

T. Jouary ◽

B. Dreno ◽

R. Gutzmer ◽

A. Hauschild ◽

...

Keyword(s):

Adjuvant Therapy ◽

Low Dose ◽

Pegylated Interferon ◽

Interferon Alfa ◽

Phase Iii ◽

Type I ◽

Duration Of Treatment ◽

Free Survival ◽

Pegylated Interferon Alfa ◽

Grade 3

LBA8506 Background: Adjuvant therapy with low-dose adjuvant interferon alfa-2b (IFN) as well as with pegylated interferon alfa-2b (PEG-IFN) were both shown to be superior to observation in melanoma (M) patients (pts) without macro-metastatic nodes. However, the two strategies have never been assessed head to head. Weekly injection of PEG-IFN facilitates a longer duration of treatment which may be critical for benefit. We thus compared adjuvant therapy of flat low-dose PEG-IFN (36 months) versus low-dose IFN (18 months) in intermediate-risk M pts without macro-metastatic nodes. Methods: In this multicenter, open-label, prospective randomized phase III trial, pts with resected M ≥ 1.5 mm in thickness and without clinically detectable nodes were randomized either to IFN (3 MU subcutaneously [sc] 3 times a week for 18 months) or to PEG-IFN (100 mcg sc once weekly for 36 months). Sentinel node procedure (SNP) was not a standard in 2003 and thus was optional. Approach was consistent by center. Randomization was stratified for centers and SNP procedure. Primary endpoint was relapse-free survival (RFS), and secondary were distant metastasis-free survival (DMFS), overall survival (OS), and grade 3-4 severe adverse events (SAE). Sample size (890 pts) was calculated to detect a 10% difference (power >80%, type I error of 5%, 2-sided) for RFS. Analysis describes 5-year probability of survival. Comparisons were done by intent-to-treat using Cox proportional models. Results: Of 898 pts enrolled, 896 (443 PEG vs 453 IFN) were eligible for evaluation after a median follow-up of 4.7 years. SLNB was performed in 68.2% of pts. Neither RFS (PEG-IFN 66.2% vs IFN 64.8%, p=0.43; HR, 0.91; 95% CI, 0.73 to 1.15) nor DMFS (71.3% vs 72.6%, p=0.86; HR, 1.02; 95% CI, 0.80 to 1.32) or OS (77.0% vs 78.4%, p=0.55; HR, 1.09; 95% CI, 0.82 to 1.45) showed statistical difference. There was an excess of SAE grade 3-4 in PEG-IFN arm (44.6% vs 26.6% in the first 18 months) which impacted on median duration of treatment (17.8 months in IFN arm; 19.2 in PEG-IFN arm, with only 28% completing 36 months treatment). Conclusions: Flat low-dose PEG-IFN did not show superiority over conventional low dose IFN. Attempts to increase benefit by prolonging treatment with PEG-IFN over 3 years were hampered by a high rate of treatment discontinuation possibly linked to SAEs with PEG-IFN. [Table: see text]

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