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

Alexander MM Eggermont, Stefan Suciu, Mario Santinami, Alessandro Testori, Wim HJ Kruit, Jeremy Marsden, Cornelis JA Punt, François Salès, Martin Gore, Rona MacKie, Zvonko Kusic, Reinhard Dummer, Axel Hauschild, Elena Musat, Alain Spatz, Ulrich Keilholz

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)117-126
Number of pages10
JournalLancet
Volume372
Issue number9633
DOIs
Publication statusPublished - 2008

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Melanoma
Observation
Interferons
Recurrence
interferon alfa-2b
Survival
Therapeutics
Random Allocation
peginterferon alfa-2b
Fatigue
Maintenance
Depression
Safety
Research
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

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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. / Eggermont, Alexander MM; Suciu, Stefan; Santinami, Mario; Testori, Alessandro; Kruit, Wim HJ; Marsden, Jeremy; Punt, Cornelis JA; Salès, François; Gore, Martin; MacKie, Rona; Kusic, Zvonko; Dummer, Reinhard; Hauschild, Axel; Musat, Elena; Spatz, Alain; Keilholz, Ulrich.

In: Lancet, Vol. 372, No. 9633, 2008, p. 117-126.

Research output: Contribution to journalArticle

Eggermont, AMM, Suciu, S, Santinami, M, Testori, A, Kruit, WHJ, Marsden, J, Punt, CJA, Salès, F, Gore, M, MacKie, R, Kusic, Z, Dummer, R, Hauschild, A, Musat, E, Spatz, A & Keilholz, U 2008, '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', Lancet, vol. 372, no. 9633, pp. 117-126. https://doi.org/10.1016/S0140-6736(08)61033-8
Eggermont, Alexander MM ; Suciu, Stefan ; Santinami, Mario ; Testori, Alessandro ; Kruit, Wim HJ ; Marsden, Jeremy ; Punt, Cornelis JA ; Salès, François ; Gore, Martin ; MacKie, Rona ; Kusic, Zvonko ; Dummer, Reinhard ; Hauschild, Axel ; Musat, Elena ; Spatz, Alain ; Keilholz, Ulrich. / 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. In: Lancet. 2008 ; Vol. 372, No. 9633. pp. 117-126.
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abstract = "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.",
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T1 - Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma

T2 - final results of EORTC 18991, a randomised phase III trial

AU - Eggermont, Alexander MM

AU - Suciu, Stefan

AU - Santinami, Mario

AU - Testori, Alessandro

AU - Kruit, Wim HJ

AU - Marsden, Jeremy

AU - Punt, Cornelis JA

AU - Salès, François

AU - Gore, Martin

AU - MacKie, Rona

AU - Kusic, Zvonko

AU - Dummer, Reinhard

AU - Hauschild, Axel

AU - Musat, Elena

AU - Spatz, Alain

AU - Keilholz, Ulrich

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

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