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Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macrometastatic nodes: An open-label, randomised, phase 3 European Association for Dermato-Oncology (EADO) study

European Journal of Cancer, 1, 49, pages 166 - 174



Both low-dose interferon (IFN) alfa-2b and pegylated interferon (Peg-IFN) alfa-2b have been shown to be superior to observation in the adjuvant treatment of melanoma without macrometastatic nodes, but have never been directly compared. Peg-IFN facilitates prolongation of treatment, which could provide additional benefit. This multicentre, open-label, randomised, phase 3 trial compared standard low-dose interferon IFN and prolonged treatment with Peg-IFN.

Patients and methods

Patients with resected melanoma ⩾1.5 mm thick and without clinically detectable node metastases were randomised 1:1 to treatment with IFN 3 MU subcutaneously (SC) three times weekly for 18 months or Peg-IFN 100 μg SC once weekly for 36 months. Sentinel lymph node dissection (SLND) was optional. The primary endpoint was disease-free survival (DFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS) and adverse events (AEs) grade 3–4.


Of 898 patients enrolled, 896 (443 Peg-IFN, 453 IFN) were eligible for evaluation (median follow-up 4.7 years). SLND was performed in 68.2% of patients. There were no statistical differences between the two arms for the primary outcome of DFS (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.73–1.15) or the secondary outcomes of DMFS (HR 1.02, 95% CI 0.80–1.32) and OS (HR 1.09, 95% CI 0.82–1.45). Peg-IFN was associated with higher rates of grade 3–4 AEs (47.3% versus 25.2%; p < 0.0001) and discontinuations (54.3% versus 30.4%) compared with IFN.


This trial did not show superiority for adjuvant Peg-IFN over conventional low-dose IFN in melanoma patients without clinically detectable nodes. ClinicalTrials.gov identifier: NCT00221702 .

Keywords: Adjuvant drug therapy, Interferon alpha-2b, Melanoma, Peg-interferon alpha-2b, Randomised control trial.

1. Introduction

Clinical trials and meta-analyses have shown a consistent, significant improvement in relapse-free survival (RFS) with high- and low-dose interferon alfa (IFN) therapy versus observation as adjuvant treatment of melanoma.1, 2, 3, 4, 5, 6, 7, 8, and 9 A recent meta-analysis of 14 randomised clinical trials (n = 8122) of high- and low-dose IFN confirmed statistically significant improvements in RFS and overall survival (OS), with relative risk reductions of 28% and 11%, respectively, compared with observation. 9 In most European countries, a standard low-dose adjuvant IFN regimen of 3 MU three times weekly for 18 months is used for melanoma with tumour thickness ⩾1.5 mm and no clinically detectable node metastases, since this dose has shown disease-free survival (DFS) benefits versus observation.2, 3, and 10 High-dose IFN for 12 months is approved in the United States (US) and proposed in European countries for adjuvant therapy of resected melanoma at high risk of recurrence.

It has been hypothesised that prolonged treatment is critical for increasing the benefit of adjuvant IFN for resected melanoma, and this hypothesis has been tested in clinical trials.5 and 11 Pegylation prolongs the half-life of IFN without affecting its biological activity, allowing for more convenient once-weekly administration and potentially longer treatment. 12 In the european organisation for research and treatment of cancer (EORTC) 18991 study, pegylated IFN alfa-2b (Peg-IFN) was tested versus observation in patients with resected stage III melanoma at a dose of 6 μg/kg/week for 8 weeks followed by 3 μg/kg/week for up to 5 years. 13 The improved 4-year RFS with Peg-IFN (18% risk reduction versus observation), which was most pronounced in the microscopic nodal disease subgroup (27% risk reduction versus observation), demonstrated that adjuvant Peg-IFN has a beneficial effect in melanoma.

Peg-IFN and IFN have never been compared head to head in a melanoma clinical trial. In the present study, we compare the efficacy and safety of prolonged adjuvant low-dose Peg-IFN therapy (36 months) and standard European low-dose IFN therapy (18 months) in an intermediate-risk melanoma population (Breslow tumour thickness ⩾1.5 mm without clinically detectable nodes).

2. Methods

2.1. Study design

For this multicentre, open-label, randomised phase 3 study, patients were recruited at 70 centres in France, Germany and Austria. Patients were randomised 1:1 to open-label, low-dose treatment with Peg-IFN 100 μg once-weekly subcutaneously (SC) for 36 months or IFN 3 MU SC three times weekly for 18 months. The primary endpoint was DFS, defined as time from randomisation to any recurrence or death. Secondary endpoints were distant metastasis-free survival (DMFS), defined as time from randomisation to any distant metastasis or death; OS, defined as time from randomisation to death; first occurrence of adverse events (AEs) grade 3–4; and quality of life (QoL).

The protocol was approved by the ethics committee of Bordeaux for all French centres, by all ethics committees of participating centres in Germany and Austria, and by institutional review boards where present. The study was conducted in accordance with all applicable regulations and the ethical principles laid out in the Declaration of Helsinki. All patients provided written informed consent before randomisation.

2.2. Patients

Eligible patients were 18–75 years old, had histologically proven primary cutaneous melanoma with a Breslow tumour thickness of ⩾1.5 mm that had been completely resected with surgical margins of at least 1–2 cm, according to tumour thickness, and were free of clinically detectable/palpable regional node metastases and distant metastases (negative clinical examination and imaging studies).

Sentinel lymph node dissection (SLND) was optional as it was not a standard procedure in Europe when the study was initiated in 2003. However, the approach was consistent across centres. Patients who underwent sentinel lymph node biopsy (SLNB) or elective lymph node dissection (ELND) and had positive sentinel nodes could be included only if they had ‘microscopic’ disease. Study entry was required within 56 days after the last surgical procedure. Other inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hepatic, renal and bone marrow function within 14 days prior to treatment initiation. Key exclusion criteria included prior medical therapy for melanoma; severe cardiovascular disease; a history of depression requiring hospitalisation; thyroid dysfunction not responsive to therapy; uncontrolled diabetes mellitus; and diagnosis of malignancies within the past 5 years other than surgically cured non-melanoma skin cancer or cervical carcinoma in situ. Concomitant chemotherapy, immunotherapy and biologic or radiation therapy, colony-stimulating factors and chronic systemic corticosteroid therapy were prohibited.

2.3. Randomisation

Randomisation was carried out at the Central Data Centre in Bordeaux, France, based on computer-generated random numbers, stratified according to trial centre and SLNB/ELND status, with a block size of 6.

2.4. Dose reductions

Treatment was started within 7 days of randomisation and continued until disease progression, severe toxicity, patient request for discontinuation, or use of prohibited medications. Stepwise dose modifications if required were based on the severity of AEs and were maintained until recovery to grade 1 or better. Progressive reduction of Peg-IFN included an initial dose reduction to 50 μg, then to 35 μg, and finally treatment discontinuation. For IFN, a 50% dose reduction was the first step, followed by discontinuation.

2.5. Assessments

Clinical examinations were performed monthly for the first 3 months, then every 3 months up to 36 months, and every 6 months thereafter. Radiological imaging, including abdominal ultrasound and chest radiography and/or computerized tomography (CT) scans were carried out every 6 months. Regional and cutaneous metastases were confirmed by histopathology.

Safety assessments included physical examination, recording of AEs and blood tests performed at weeks 1, 4 and 8, then every 3 months until the end of follow-up under treatment (blood tests were not performed at week 1). The primary safety parameter was first occurrence of grade 3 or 4 clinical or laboratory AEs (Common Toxicity Criteria, version 2.0) during the treatment period or reported at the clinic visit immediately after treatment interruption. AEs were recorded according to World Health Organisation (WHO) recommendations for grading of acute and subacute toxicity. 14 Data monitoring was applied only for grade 3 or 4 AEs.

2.6. Power estimation and statistical analysis

The sample size of 890 subjects (445 per arm) was calculated to detect a 10% difference between treatment arms in the 5-year DFS rate, based on an expected 5-year DFS rate of 60% in the IFN arm, with a power of ⩾80%, a two-sided type I error of 5% and an expected discontinuation rate of ⩽10%. Interim and final analyses were planned to occur 3 and 5 years, respectively, after recruitment of the last patient. In August 2009, the scientific board concluded, based on 3-year interim results, that no major changes in results were to be expected with extended trial duration and mandated a final analysis for the cut-off date of 30th September 2009, allowing for a mean follow-up of 4 years.

Comparative analyses were based on the intent-to-treat population. Categorical variables were compared using chi-square or Fisher’s tests. Time-to-event data with 95% confidence intervals (CI) were estimated using the non-parametric Kaplan–Meier method. Treatment arms were compared using a non-parametric log-rank test. Cox multivariate regression analysis included factors that were significantly associated with DFS in a univariate analysis. Additional sensitivity analyses were performed with censoring at treatment discontinuation (‘on treatment’ analysis).

3. Results

3.1. Patients

Enrolment started in June 2003 and patient accrual was completed in November 2005. Overall, 55 of 443 patients (12.4%) in the Peg-IFN arm and 55 of 453 (12.1%) in the IFN arm discontinued study participation ( Fig. 1 ). In addition, 10 and 5 patients in the Peg-IFN and IFN arms, respectively, never received study treatment. In general, patients’ baseline characteristics were balanced between the two randomisation groups ( Table 1 ). However, among patients who underwent SLND, the rate of positive biopsies was slightly higher in the IFN arm than in the Peg-IFN arm. Median time between surgery and randomisation was 32 and 34 days, respectively, with 6.1% and 6.2% of patients randomised more than 56 days after surgery. Median time between randomisation and treatment start was 3 and 2 days, respectively, with 13.5% and 11.5% starting treatment more than 7 days after randomisation. The median (range) duration of treatment was 19.2 (0.1–41.2) months in the Peg-IFN arm and 17.8 (0.1–21.5) months in the IFN arm. Table 2 shows the proportions of patients who received dose reductions or interruptions and reasons for discontinuation.


Fig. 1 CONSORT flow diagram. IFN = interferon alfa-2b. Peg-IFN = pegylated interferon alfa-2b.

Table 1 Patient demographics, prognostic factors and clinical stage.

n = 443 n = 453
Age in years, median/mean (range) 53/51.2 (18–75) 55/53.2 (20–76)
 18 to <50, n (%) 183 (41.3) 165 (36.4)
 50 to <65, n (%) 178 (40.2) 185 (40.8)
 ⩾65, n (%) 82 (18.5) 103 (22.7)
Sex, n (%)
 Male 266 (60.0) 236 (52.1)
 Female 177 (40.0) 217 (47.9)
Breslow tumour thickness, n (%)
 <2 mm a 139 (31.4) 156 (34.4)
 ⩾2 to <4 mm 205 (46.3) 189 (41.8)
 ⩾4 mm 99 (22.3) 108 (23.8)
Ulceration, n (%)
 Yes 129 (29.1) 151 (33.3)
 No 314 (70.9) 302 (66.7)
Clark level, n (%)
 Missing 12 (2.7) 8 (1.8)
 I/II/III 113 (25.5) 128 (28.3)
 IV 278 (62.8) 277 (61.1)
 V 40 (9.0) 40 (8.8)
SLND, n (%)
 Not performed 147 (33.2) 143 (31.6)
 Performed 296 (66.8) 310 (68.4)
  Negative 230 (77.7) 214 (69.0)
  Positive 66 (22.3) 95 (30.6)
  Failure 1 (0.3)
AJCC stage b , n (%)
 Patients staged with SLND 296 309
  IB 88 (29.7) 82 (26.5)
  IIA 85 (28.7) 70 (22.7)
  IIB 42 (14.2) 44 (14.2)
  IIC 15 (5.1) 18 (5.8)
  IIIA 41 (13.9) 61 (19.7)
  IIIB 25 (8.4) 34 (11.0)
 Patients staged without SLND 147 144
  IB 35 (23.8) 36 (25.0)
  IIA 50 (34.0) 65 (38.2)
  IIB 42 (28.6) 36 (25.0)
  IIC 20 (13.6) 17 (11.8)

a Tumour thickness was <1.5 mm for 2 patients in the Peg-IFN arm (1.40 and 1.42 mm) and for 2 patients in the IFN arm (1.25 and 1.30 mm).

b AJCC 6th edition, 2001.

Peg-IFN = pegylated interferon alfa-2b. IFN = interferon alfa-2b. SLND = sentinel lymph node dissection. AJCC = American Joint Committee on Cancer.

Table 2 Dose modifications and definitive treatment discontinuation (excluding recurrences or death).

  Peg-IFN IFN  
n = 443 n = 453
Withdrawal from the trial, n (%) 14 (3.2) 6 (1.3)  
Treatment deviation, n (%)      
 Never started 10 (2.3) 5 (1.1)  
 Started with lower dose 3 (0.7) 4 (0.9)  
Discontinuation or dose reductions a , n (%) 319 (74.2) 199 (44.8)  
Definitive discontinuation only b , n (%) 235 (54.3) 136 (30.4)  
  Months 0–18 Months 18–36 Months 0–18
Definitive discontinuation, n (%) 156 (36.0) 79 (35.3) 136 (30.4)
 Adverse event 86 (55.1) 36 (45.6) 58 (42.6)
 Not treatment-related 0 (0.0) 1 (1.3) 1 (0.7)
 Patient decision 25 (16.0) 6 (7.6) 20 (14.7)
 Lost to follow-up 2 (1.3) 1 (1.3) 2 (1.5)
 Other condition 2 (1.3) 0 (0) 2 (1.5)
 Missing 41 (26.3) 35 (44.3) 53 (39.0)

a Among patients who started with the full dose.

b Among patients who started the treatment.

Peg-IFN = pegylated interferon alfa-2b. IFN = interferon alfa-2b.

3.2. Clinical efficacy

The median (range) follow-up time was 56.9 (0–77.9) months for Peg-IFN and 55.0 (0–78.0) months for IFN. The estimated 5-year DFS, DMFS and OS are shown in Fig. 2 A–C. Table 3 shows the patterns of recurrence by SLND status. A significant difference in recurrence pattern was observed only among the 125 patients who did not undergo SLND, with a higher recurrence rate of local satellite/in-transit metastases among IFN-treated than Peg-IFN-treated patients. However, the total numbers of patients with satellite/in-transit metastases in the Peg-IFN (21) and IFN arms (22) were very similar ( Table 3 ).


Fig. 2 (A) Estimated 5-year DFS, (B) estimated 5-year DMFS and (C) estimated 5-year OS. DFS = disease-free survival. Peg-IFN = pegylated interferon alfa-2b. IFN = interferon alfa-2b. DMFS = distant metastasis-free survival. OS = overall survival. Bars indicate 95% confidence intervals (CI).

Table 3 Patterns of first recurrence by sentinel node status.

  Peg-IFN IFN p value c
n = 443 n = 453
Total recurrences or death a 144 157  
Sentinel node status unknown (SLND not performed) b , n (%) 62 63 0.03
 Local metastases 1 (1.6) 5 (7.9)  
 Satellite/in-transit metastases 1 (1.6) 8 (12.7)  
 Lymph node metastases 20 (32.3) 17 (27.0)  
 Distant metastases 36 (58.1) 32 (50.8)  
 Death 4 (6.5) 1 (1.6)  
Sentinel node positive, n (%) 34 36 0.54
 Local metastases 1 (2.9) 4 (11.1)  
 Satellite/in-transit metastases 10 (29.4) 7 (19.4)  
 Lymph node metastases 2 (5.9) 4 (11.1)  
 Distant metastases 17 (50.0) 18 (50.0)  
 Death 4 (11.8) 3 (8.3)  
Sentinel node negative, n (%) 48 58 0.32
 Local metastases 1 (2.1) 4 (6.9)  
 Satellite/in-transit metastases 10 (20.8) 7 (12.1)  
 Lymph node metastases 5 (10.4) 12 (20.7)  
 Distant metastases 22 (45.8) 26 (44.8)  
 Death 10 (20.8) 9 (15.5)  

a When different types of recurrence were observed at the same date, only the most pejorative was considered.

b 1 patient with SLND failure was classified as SLND not performed.

c p-values correspond to comparisons of recurrence pattern distribution between the two treatment arms according to sentinel node status.

Peg-IFN = pegylated interferon alfa-2b. IFN = interferon alfa-2b. SLND = sentinel lymph node dissection.

Table 4 shows the results of univariate and multivariate regression analyses of DFS. Adjusted analyses revealed no significant differences between the two treatment arms in DFS, DMFS, or OS; adjusted hazard ratios (HRs) were 0.90 (95% CI, 0.72–1.14), 1.07 (95% CI, 0.83–1.38) and 1.13 (95% CI, 0.85–1.50), respectively. On-treatment analyses showed no differences in outcomes between treatments after censoring at premature definitive treatment discontinuation; HRs were 0.96 (95% CI, 0.73–1.26) for DFS, 1.10 (95% CI, 0.80–1.50) for DMFS and 1.29 (95% CI 0.90–1.84) for OS. Additional sensitivity analyses (data not shown), including undertreatment analyses or systematic imputation of recurrence to patients lost to follow-up in the PEG-IFN or IFN arm, did not suggest that early treatment interruption or loss to follow-up altered the results. Furthermore, Cox multivariate regression analysis of DFS stratified by ulceration status showed no impact of ulceration on the results (data not shown).

Table 4 Cox regression analysis of disease-free survival.

  Univariate Multivariate
HR 95% CI p value HR 95% CI p value
Age (for additional 10 years) 1.18 (1.07–1.28) 0.0004 1.09 (0.99–1.19) 0.06
Tumour thickness     <0.0001     <0.0001
⩾2 mm to <4 mm versus <2 mm 1.64 (1.20–2.22)   1.44 (1.05–1.96)  
⩾4 mm versus <2 mm 3.68 (2.70–5.02)   2.61 (1.88–3.64)  
Sex (male versus female) 1.64 (1.29–2.08) <0.0001 1.42 (1.11–1.82) 0.005
Treatment arm (Peg-IFN versus IFN) 0.92 (0.73–1.15) 0.47 0.91 (0.72–1.14) 0.42
Sentinel node (SLND versus no SLND) 0.62 (0.49–0.78) <0.0001 0.70 (0.56–0.89) 0.003
Ulceration (yes versus no)     <0.0001     <0.0001
HR for ulceration was time-dependent            
 Time <24 months 3.15 (2.36–4.21)   2.34 (1.74–3.17)  
 Time ⩾24 months 1.37 (0.59–3.15)   1.09 (0.73–1.62)  

HR = hazard ratio; CI = confidence interval; Peg-IFN = pegylated interferon alfa-2b; IFN = interferon alfa-2b; SLND = sentinel lymph node dissection.

3.3. Toxicity

Grade 3–4 AEs occurring for the first time in at least 1% of patients in either arm are shown in Table 5 . Overall, the rate of these events was higher with Peg-IFN than IFN (47.3% versus 25.2%; p < 0.0001). In the Peg-IFN arm most of these events occurred within the first 18 months of treatment, with a higher rate for Peg-IFN versus IFN (43.9% versus 25.2%; p < 0.0001). First occurrence of grade 3–4 AEs after month 18 was observed in only 6.6% of patients still receiving Peg-IFN.

Table 5 Grade 3–4 AEs occurring in at least 1% of patients in either treatment arm, n (%).

  Peg-IFN IFN p value
n = 433 a n = 448 a
Fatigue 73 (16.9) 39 (8.7) 0.0003
Depressive symptoms 29 (6.7) 21 (4.7) 0.20
Fever 5 (1.2) 2 (0.4) 0.28
Weight loss 22 (5.1) 11 (2.5) 0.04
Myalgia/arthralgia 14 (3.2) 13 (2.9) 0.78
Nausea/vomiting 8 (1.8) 0 (0) 0.003
Diarrhoea 6 (1.4) 2 (0.4) 0.17
Pain 12 (2.8) 9 (2.0) 0.46
Leukocytopenia 23 (5.3) 4 (0.9) 0.0001
Granulocytopenia 66 (15.2) 20 (4.5) <0.0001
Elevated SGOT 11 (2.5) 5 (1.1) 0.11
Elevated SGPT 22 (5.1) 8 (1.8) 0.007

a Patients who did not start treatment were not included in the calculation.

AE = adverse event. Peg-IFN = pegylated interferon alfa-2b. IFN = interferon alfa-2b. SGOT = serum glutamic oxaloacetic transaminase. SGPT = serum glutamic pyruvic transaminase.

4. Discussion

In this study, adjuvant therapy with a flat, low dose of Peg-IFN (100 μg/week) for an intended duration of 36 months was not superior to IFN 3 MU three times weekly for 18 months in terms of DFS, DMFS, or OS in patients with intermediate-risk melanoma. Our results do not support the hypothesis that low doses of Peg-IFN facilitate prolonged therapy and thereby increase the benefit over standard European low-dose IFN in patients with stage IB–IIIB melanoma who have not yet developed macrometastases.

Although patients enrolled in this study represented a wide range of 7th American Joint Committee on Cancer (AJCC) stages (IB–IIIB), their prognosis was compatible with the definition of ‘intermediate risk’, with an estimated 5-year DFS of 65.3% and estimated 5-year OS of 77.6%. Treatment groups were well balanced for the main prognostic factors except that the proportion of patients with positive sentinel nodes among those who underwent SLND was slightly higher in the IFN arm. However, sensitivity analyses (data not shown) suggested that this imbalance did not affect outcomes.

The main reason for the lack of difference in outcome between treatment arms in this study is likely due to an absence of intrinsic superiority of Peg-IFN 100 μg/week over the standard low-dose IFN in intermediate-risk melanoma. Other contributing factors may include our difficulty in prolonging treatment with Peg-IFN beyond 18 months, and the administered dose of Peg-IFN. The EORTC 18991 trial has shown a benefit of Peg-IFN adjuvant therapy over observation, 13 but showing a benefit over low doses of IFN is a greater challenge. Indeed, several trials consistently showed that low-dose IFN improved DFS in a melanoma subpopulation similar to that in our trial.3, 4, and 6 Furthermore, a meta-analysis has recently shown that IFN, independent of dose, reduces the relative risk of disease recurrence by nearly 18% and of melanoma-related death by more than 10% compared with observation. 9

The intended prolonged treatment with Peg-IFN (36 months versus 18 months with IFN) was not achieved because of a high discontinuation rate in this arm, resulting in similar median treatment durations in both arms (19.2 versus 17.8 months). Only 36.9% of patients in the Peg-IFN arm who remained disease-free completed the study. It is noteworthy that in EORTC 18991, the median duration of Peg-IFN therapy was only 12 months, in contrast to the intended treatment duration of 5 years, with only 23% of patients remaining on treatment at 3.8 years follow-up. 13 Although Peg-IFN doses were higher in EORTC 18991 than in the present study, the results of both studies suggest that it may be difficult to maintain prolonged adjuvant Peg-IFN treatment in patients with melanoma, regardless of dose. However, this may not be crucial since results of recent meta-analyses and a trial of adjuvant IFN do not support our initial hypothesis that treatment benefits of IFN are dependent on treatment duration.8, 9, and 11

The Peg-IFN dose was chosen based on tolerability data in hepatitis C. A flat dose was chosen since the comparator IFN regimen was also a flat dose. The chosen dose of 100 μg/week was lower than the weight-based dose used in EORTC 18991, 13 but probably corresponded to a higher dose of IFN than the conventional low-dose IFN regimen of 3 MU three times weekly. This, combined with differences in pharmacokinetics, may explain the higher rates of grade 3–4 toxicities with Peg-IFN versus IFN.

Treatment discontinuations (excluding those attributable to recurrence or death) occurred in 54% of patients in the Peg-IFN arm and 30% in the IFN arm, despite the high degree of experience of all participating centres with IFN side effects management and supportive care. Moreover, only 50.6% of Peg-IFN interruptions could be directly attributed to AEs. For a large proportion of discontinuations the reasons remained unclear, which suggests that discontinuation was not related to a specific event, but the result of general difficulty to cope with the treatment. It was probably attributable to a general loss of motivation to continue with a treatment that compromises QoL.15 and 16 In this regard, patients with intermediate-risk disease are probably less concerned about prognosis and treatment compared with patients with high-risk melanoma who already experienced regional relapse. Quality-of-life data from this study are currently being analysed and will be published elsewhere. High discontinuation rates have also been observed in previous trials with long duration of IFN 11 or Peg-IFN treatment. 13

In conclusion, in patients with intermediate-risk melanoma without clinically detectable nodal metastases, the use of adjuvant low-dose Peg-IFN intended for 36 months was not superior to standard 18-month low-dose IFN. The high rates of toxicities and discontinuations in the Peg-IFN arm, which may be due to the possibly higher dose in this arm compared with standard low-dose IFN, illustrate the difficulty in maintaining adjuvant therapy with Peg-IFN for several years despite its convenient administration schedule.

Author contributions

All authors contributed to the writing of the manuscript and provided final approval of the manuscript for submission.

Jean Jacques Grob: Study conception and design, data collection, data analysis and interpretation.

Thomas Jouary: Data collection.

Brigitte Dréno: Conception and design.

Julien Asselineau: Data analysis, and data collection and interpretation.

Ralf Gutzmer: Data collection.

Axel Hauschild: Data collection, data analysis and interpretation.

Marie Thérèse Leccia: Data collection.

Michael Landthaler: Data collection.

Claus Garbe: Study conception and design, data collection, data analysis and interpretation.

Bruno Sassolas: Data collection.

Rudolf A Herbst: Data collection.

Bernard Guillot: Study conception and design, data collection.

Genevieve Chene: Study conception and design, data analysis and interpretation.

Hubert Pehamberger: Study conception and design, data collection, data analysis and interpretation.

Conflict of interest statement

Jean Jacques Grob: Consultancy, honoraria, research funding, and travel grants from Merck & Co. Inc. (formerly Schering-Plough Corp.).

Brigitte Dréno: Consultancy, honoraria and research funding from Merck & Co. Inc. (formerly Schering-Plough Corp.).

Ralf Gutzmer: Consultancy, honoraria, research funding, and travel grants from Roche and Merck & Co. Inc. (formerly Schering-Plough Corp./Essex Pharma).

Axel Hauschild: Consultancy, honoraria, and research funding from Roche and Merck & Co. Inc. (formerly Schering-Plough Corp.).

Claus Garbe: Consultancy for Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), Roche, GlaxoSmithKline, Genta, Inc., Swedish Orphan Biovitrum (SOBI); honoraria from MSD, BMS, Roche, SOBI; research funding from MSD, BMS, Roche, Genta, and SOBI.

Genevieve Chene: Honoraria from Roche; accommodation/meeting expenses from Lundbeck and Lilly; grants to institution from Gilead, Tibotec, Roche, MSD, Janssen, Boehringer Ingelheim, BMS, GlaxoSmithKline, ViiV Healthcare.

Hubert Pehamberger: Consultancy and honoraria from Merck & Co. Inc. (formerly Schering-Plough Corp.).

Thomas Jouary, Julien Asselineau, Marie Thérèse Leccia, Michael Landthaler, Bernard Guillot, Rudolf A Herbst and Bruno Sassolas have no relevant conflict of interest.


The study was sponsored by the University Hospital Bordeaux, France. Partial financial support was provided by Merck & Co. Inc. (formerly Schering-Plough Corp.). The University Hospital Bordeaux delegated the study design, data management and data analysis and interpretation to their academic clinical epidemiology unit. The authors had full access to all study data and had final responsibility for the decision to submit for publication. Merck & Co. Inc. had no role in the study design, data collection, data analysis, data interpretation, or writing of the report, but reviewed the manuscript before submission.

The authors acknowledge Dr. M. Delaunay for her contribution in initiating the trial. They would also like to acknowledge the individuals at the following study centres:

National data centre, Marseille, France: J.F. Aubin, P. Souteyrand, D. Lambert, P. Celerier, M. Beylot-Barry, S. Boulinguez, P. Joly, P. Saiag, V. Descamps, P. Bernard, C. Bedane, D. Cupissol, J.L. Schmutz, G. Safa, C. Lok, Dr. Schubert, C. Lebbe, P. Plantin, J.J. Bonerandi, I. Gorin, P. Modiano, F. Cambazard, H. Naman, J. Chevrant-Breton, L. Machet.

National data centre, Tuebingen, Germany: R. Linse, B. Hermes, U. Trefzer, H. Gollnick, R. Kaufmann, J. Becker, P. Mohr, J. Hassel, P. Kohl, R. Stadler, M. Kaatz, R. Hein, A. Stein, D. Frosch, F. Abuzahra, G. Gross, C. Zouboulis, E. Dippel, E. Hölzle, C. Bayerl, M. Hertl, T. Vogt, M. Weise, F.W. Kleinsorge, D. Mechtel, J. Welzel.

National data centre, Vienna, Austria: T. Berger, W. Pachinger, G. Klein, K. Rappersberger, R. Strohal, B. Volc-Platzer, F. Trautinger, G. Weinlich.

Editorial support was provided by Helen Varley, Ph.D., of Evidence Scientific Solutions, Horsham, United Kingdom (UK) and was supported by Merck & Co. Inc.


  • 1 J.M. Kirkwood, M.H. Strawderman, M.S. Ernstoff, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14(1):7-17
  • 2 J.J. Grob, B. Dreno, P. de la Salmoniere, et al. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Lancet. 1998;351(9120):1905-1910 Crossref
  • 3 H. Pehamberger, H.P. Soyer, A. Steiner, et al. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group. J Clin Oncol. 1998;16(4):1425-1429
  • 4 J.M. Kirkwood, J.G. Ibrahim, V.K. Sondak, et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000;18(12):2444-2458
  • 5 A.M. Eggermont, S. Suciu, R. MacKie, et al. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005;366(9492):1189-1196 Crossref
  • 6 C. Garbe, P. Radny, R. Linse, et al. Adjuvant low-dose interferon {alpha}2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis. Ann Oncol. 2008;19(6):1195-1201 Crossref
  • 7 K. Wheatley, N. Ives, B. Hancock, et al. Does adjuvant interferon-α for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials. Cancer Treat Rev. 2003;29(4):241-252 Crossref
  • 8 K. Wheatley, N. Ives, A. Eggermont, et al. Interferon-α as adjuvant therapy for melanoma: an individual patient data meta-analysis of randomised trials. J Clin Oncol (Meeting Abstracts). 2007;25(18 suppl):8526
  • 9 S. Mocellin, S. Pasquali, C.R. Rossi, D. Nitti. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010;102(7):493-501 Crossref
  • 10 C. Garbe, K. Peris, A. Hauschild, et al. Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline. Eur J Cancer. 2010;46(2):270-283 Crossref
  • 11 A. Hauschild, M. Weichenthal, K. Rass, et al. Efficacy of low-dose interferon {alpha}2a 18 versus 60 months of treatment in patients with primary melanoma of ⩾1.5 mm tumor thickness: results of a randomized phase III DeCOG trial. J Clin Oncol. 2010;28(5):841-846 Crossref
  • 12 R. Bukowski, M.S. Ernstoff, M.E. Gore, et al. Pegylated interferon alfa-2b treatment for patients with solid tumors: a phase I/II study. J Clin Oncol. 2002;20(18):3841-3849
  • 13 A.M. Eggermont, S. Suciu, M. Santinami, et al. 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. 2008;372(9633):117-126 Crossref
  • 14 A.B. Miller, B. Hoogstraten, M. Staquet, A. Winkler. Reporting results of cancer treatment. Cancer. 1981;47(1):207-214 Crossref
  • 15 Y. Brandberg, S. Aamdal, L. Bastholt, et al. Health-related quality of life in patients with high-risk melanoma randomised in the Nordic phase 3 trial with adjuvant intermediate-dose interferon alfa-2b. Eur J Cancer. 2011 Dec 22;
  • 16 C. Loquai, I. Schmidtmann, M. Beutel, et al. Quality of life in melanoma patients during adjuvant treatment with pegylated interferon-2b: patients’ and doctors’ views. Eur J Dermatol. 2011;21(6):976-984


a Aix-Marseille University, CRO2, Service de Dermatologie, Hopital de la Timone, 264 Rue St Pierre, 13885 Marseille CEDEX 05, Marseille, France

b Skin Cancer Unit, St André’s Hospital, Bordeaux, France

c Skin Cancer Unit, Nantes University Hospital, Nantes, France

d CHU Bordeaux, Clinical Epidemiology Unit, Bordeaux, France

e Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany

f Department of Dermatology, Venereology and Allergology, University Hospital Schleswig-Holstein, Kiel, Germany

g Department of Dermatology and Venereology, University Hospital Albert Michallon, Grenoble, France

h Department of Dermatology, University Hospital Regensburg, Regensburg, Germany

i Department of Dermatology, University Hospital Tübingen, Tübingen, Germany

j Department of Internal Medicine and Pneumology, CHRU Cavale Blanche, Brest, France

k Department of Dermatology and Allergology, HELIOS Skin Cancer Center, Erfurt, Germany

l Department of Dermatology, Hospital Saint Eloi, CHU de Montpellier, Montpellier I University, France

m CHU de Bordeaux, CIC-EC7, Université Bordeaux Segalen, Bordeaux, France

n Department of Dermatology, Medical University of Vienna, Vienna, Austria

lowast Corresponding author: Tel.: +33 0 4913 88591/7991); fax: +33 0 4913 87989.

o From the European Association for Dermato-Oncology (EADO).