Fast track — ArticlesTwo different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial
Introduction
Malignant melanoma in patients with American Joint Committee on Cancer (AJCC) stage IIB–IIC disease (tumour thickness ≥4 mm without lymph-node metastases [T4N0M0]) or stage III disease (regional lymph-node metastases [TxN1–3M0]) has an adverse prognosis, with reported 5-year survival of 24–67%.1 Thus, efficient adjuvant therapies need to be developed to improve prognosis in these patients.
Up to now, interferon alfa-2b has been the most investigated drug for adjuvant therapy in high-risk patients with melanoma.2 In 1996, the Eastern Cooperative Oncology Group (ECOG) EST E1684 trial3 showed a significant improvement in both relapse-free survival (RFS) and overall survival in patients with high-risk melanoma with adjuvant treatment with high-dose interferon alfa-2b.3 However, this survival benefit was not reproduced in the confirmatory trial E1690. Although the E1690 trial showed an improved RFS, it did not show a benefit in overall survival with the high-dose interferon alfa-2b regimen.4
Because of the toxic effects of the high-dose interferon alfa-2b regimen, and the absence of an effect of adjuvant treatment with low-dose interferon,5 European investigators addressed the question of whether intermediate doses of interferon alfa-2b would be a less toxic alternative to high doses. Thus, both the European Organisation for Research and Treatment of Cancer (EORTC) and the Nordic Melanoma Collaborative Group undertook trials addressing this issue, and to explore whether an extension of therapy with interferon alfa-2b from 1 to 2 years would improve results. The EORTC 18952 trial explored intermediate-dose interferon alfa-2b with the same total dose delivered during either 1 or 2 years—ie, the dose during maintenance therapy was reduced by 50% in the 2-year treatment group. In the Nordic IFN trial, we chose a different design, giving the same dose of interferon alfa-2b (10 million units three times per week subcutaneously) during maintenance therapy for either 1 or 2 years. This design was preferred to facilitate interpretation of the results, since only one parameter, duration of treatment, differed between the two treatment groups. We report the long-term results of this trial of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma.
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Study design and patients
In this trial, 35 centres in the Nordic countries participated: two in Denmark, five in Finland, six in Norway, and 22 in Sweden. Patient inclusion criteria were: histologically verified resected cutaneous melanoma, AJCC stage IIB–IIC (T4N0M0), or stage III (TxN1–3M0); age 18 years or older; ECOG performance status 0–1; normal bone marrow function; and adequate liver chemistry and renal function. Excluded from the trial were patients with non-cutanous melanoma, those with melanoma with unknown
Results
Figure 1 shows the trial profile. Between Nov 11, 1996, and Sept 1, 2004, 855 patients were enrolled into the study. 284 were randomly assigned to group A (observation), 285 to group B (1-year treatment with interferon alfa-2b), and 286 to group C (2-year treatment with interferon alfa-2b). Patient characteristics were well balanced between the groups (table 1). The median follow-up time was 72·4 months (IQR 46·9–98·0). The median age of patients at randomisation was 52 years (range 18–77); 526
Discussion
In this large, randomised, phase 3 trial of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma, we recorded a significant improvement in RFS compared with untreated control patients in the 1-year treatment group. The overall survival analyses did not show a significant difference between patients given interferon alfa-2b and controls.
Our results are remarkably consistent with the previously reported pivotal trials comparing adjuvant interferon alfa-2b
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