Elsevier

The Lancet

Volume 372, Issue 9633, 12–18 July 2008, Pages 117-126
The Lancet

Articles
Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial

https://doi.org/10.1016/S0140-6736(08)61033-8Get rights and content

Summary

Background

Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability.

Methods

1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 μg/kg per week for 8 weeks (induction) then 3 μg/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249.

Findings

All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3·8–33·4) months. At 3·8 (3·2–4·2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0·82, 95% CI 0·71–0·96; p=0·01); the 4-year rate of recurrence-free survival was 45·6% (SE 2·2) in the interferon group and 38·9% (2·2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 (31%) patients.

Interpretation

Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival.

Funding

Schering Plough Research International.

Introduction

Interferon alfa-2b is the best studied agent for adjuvant treatment of patients with stage IIb (primary tumour thickness ≥4 mm, node-negative) and stage III (any primary tumour, node-positive) melanoma, both groups at high risk of recurrence after definitive surgery.1 However, the role of an induction period, the optimum dose, and duration for adjuvant interferon alfa in high-risk melanoma remain to be defined.2, 3 Trials of both high and intermediate doses of interferon alfa-2b for patients at high risk of recurrence after resection have shown improvements in recurrence-free survival, but without showing consistent effects on overall survival compared with observation alone.4, 5, 6, 7 Increased length of interferon alfa administration, in the range 12–25 months, has been shown to produce transient improvements in recurrence-free survival or distant metastasis-free survival, again without a significant effect on overall survival.7, 8, 9, 10, 11 A meta-analysis of 13 randomised trials estimated that interferon alfa reduced the risk of recurrence or death by 13% (hazard ratio 0·87, 95% CI 0·81–0·93 for recurrence-free survival; p<0·0001) and the risk of death by 10% (0·90, 0·84–0·97 for overall survival; p=0·008) compared with observation or vaccination, without defining the optimum dose or duration of interferon therapy.12 Trials have also shown that the effect of interferon on recurrence-free survival is rapidly lost after stopping treatment.7, 8

Pegylation of interferon alfa-2b has been shown to maintain maximum exposure to interferon alfa with less frequent subcutaneous injections than with unpegylated interferon,13 and has been assessed for safety in a number of types of cancer.14, 15, 16, 17 By enabling prolonged, weekly self-administered adjuvant therapy, pegylated interferon has the potential to improve the benefit–toxicity balance for patients with resected stage III melanoma. The European Organisation for Research and Treatment of Cancer (EORTC) trial 18991 was designed to investigate the effect of long-term administration of pegylated interferon alfa-2b in patients with stage III melanoma, for a maximum of 5 years.

Section snippets

Patients

In this phase III randomised controlled trial, done in 99 centres in 17 countries (mainly in Europe), patients aged 18–70 years with histologically documented stage III melanoma (TxN1–2M0) were eligible for enrolment.1 The primary cutaneous melanoma must have been completely excised with adequate surgical margins and complete regional lymphadenectomy must have occurred 70 days or less before randomisation. Patients were required to have adequate hepatic, renal, and bone marrow function before

Results

The trial profile is shown in figure 1. The median age of the study population was 50 (IQR 18–70) years, with 144 (11%) patients aged over 65 years (table 1). Demographics and baseline characteristics were well balanced across both groups. 543 (43%) of patients had microscopic nodal disease and 713 (57%) had clinically palpable nodal disease. At baseline, 1061 (84%) patients had an ECOG performance status of 0, and 195 (16%) a performance status of 1.

23 (1·8%) randomised patients were deemed to

Discussion

The results of this large phase III study of adjuvant therapy in patients with stage III melanoma suggest that prolonged treatment with pegylated interferon alfa-2b significantly improves recurrence-free survival compared with observation alone. Although distant metastasis-free survival was numerically better in patients treated with pegylated interferon than in those who received observation alone, this difference was not statistically significant. No effect on overall survival was seen.

The

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