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.
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 mug/kg per week for 8 weeks (induction) then 3 mug/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.


RESULTS
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.


CONCLUSIONS
Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival.
Eggermont
Alexander Mm
AM
Erasmus University Medical Center, Rotterdam, Netherlands. Electronic address: a.m.m.eggermont@erasmusmc.nl.
Suciu
Stefan
S
EORTC Headquarters, Brussels, Belgium.
Santinami
Mario
M
Istituto Nazionale dei Tumori, Milan, Italy.
Testori
Alessandro
A
Istituto Europeo di Oncologia, Milan, Italy.
Kruit
Wim Hj
WH
Erasmus University Medical Center, Rotterdam, Netherlands.
Marsden
Jeremy
J
University Hospital Birmingham, Birmingham, UK.
Punt
Cornelis Ja
CJ
University Medical Center St Radboud, Nijmegen, Netherlands.
Salès
François
F
Institut Jules Bordet, Brussels, Belgium.
Gore
Martin
M
Royal Marsden Hospital NHS, London, UK.
MacKie
Rona
R
University of Glasgow, Glasgow, UK.
Kusic
Zvonko
Z
University Hospital Sestre Milosrdnice, Zagreb, Croatia.
Dummer
Reinhard
R
University Clinic Zürich, Zürich, Switzerland.
Hauschild
Axel
A
University Hospital Kiel, Kiel, Germany.
Musat
Elena
E
EORTC Headquarters, Brussels, Belgium.
Spatz
Alain
A
Institut Gustave-Roussy, Villejuif, France.
Keilholz
Ulrich
U
Charité, Benjamin Franklin Campus, Berlin, Germany.
D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D008875:Middle Aged; D009362:Neoplasm Metastasis; D019370:Observation; D011092:Polyethylene Glycols; D016016:Proportional Hazards Models; D011994:Recombinant Proteins
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C417083:peginterferon alfa-2b