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