Prospective Randomized Trial of Interferon Alfa-2b and
Interleukin-2 as Adjuvant Treatment for Resected
Intermediate- and High-Risk Primary Melanoma Without
Clinically Detectable Node Metastasis
By Axel Hauschild, Michael Weichenthal, Bernd-Ru ¨diger Balda, Ju ¨rgen C. Becker, Helmut H. Wolff, Wolfgang Tilgen,
Klaus-Werner Schulte, Johannes Ring, Dirk Schadendorf, Stephan Lischner, Gu ¨nter Burg, and Reinhard Dummer
shown to have limited effects in the adjuvant treatment of
patients with intermediate- and high-risk primary mela-
noma. We hypothesized that a combination regimen with
low-dose interleukin-2 (IL-2) may improve survival pros-
pects in these patients.
Patients and Methods:After wide excision of primary
melanoma without clinically detectable lymph node metas-
tasis (pT3 to 4, cN0, M0), 225 patients from 10 participating
centers were randomly assigned to receive either subcu-
taneous low-dose IFN?2b (3 million international units
[MU]/m2/d, days 1 to 7, week 1; three times weekly,
weeks 3 to 6, repeated all 6 weeks) plus IL-2 (9 MU/m2/d,
days 1 to 4, week 2 of each cycle) for 48 weeks, or
observation alone. The primary end point was prolonga-
tion of a relapse-free interval.
Results: Of the 225 enrolled patients, 223 were found
to be eligible. Median follow-up time was 79 months.
Low-dose interferon alfa (IFN?) has been
All evaluated prognostic factors were well balanced between
the two arms of the study. Relapses were noticed in 36 of 113
patients treated with IFN?2b plus IL-2 and in 34 of 110
patients with observation alone. Five-year disease-free sur-
vival of those who had routine surgery supplemented by
IFN?2b and IL-2 treatment was 70.1% (95% confidence inter-
val [CI], 61.3% to 78.9%), compared with 69.9% in those
receiving surgery and observation alone (95% CI, 60.7% to
79.1%) in the intention-to-treat analysis. Evaluation of the
overall survival did not show any difference between treated
and untreated melanoma patients (P ? .93).
Conclusion: Adjuvant treatment of intermediate- and
high-risk melanoma patients with low-dose IFN?2b and
IL-2 is safe and well tolerated by most patients, but it does
not improve disease-free or overall survival.
J Clin Oncol21:2883-2888.
Society of Clinical Oncology.
melanoma will die from metastasis. Since the various surgical
approaches to primary melanoma have not been found to clearly
improve the prognosis, effective systemic treatment modalities
are urgently needed.
Adjuvant chemotherapy with cytotoxic agents has not dem-
onstrated any improvement of survival prospects in randomized
trials.1Only treatment with interferon alfa (IFN?) has been
beneficial in terms of prolongation of disease-free survival
(DFS) in several prospective randomized studies.2-7In patients
with melanomas thicker than 1.5 mm, the application of low-
dose IFN?2a regimens demonstrated an improvement of DFS as
compared with untreated controls. However, an effect on overall
survival was lacking.5,6
Kirkwood et al3demonstrated for the first time in 1996 that
high-dose IFN?2b prolongs not only DFS, but also overall
survival in patients with melanomas thicker than 4.0 mm or
lymph node metastasis. In a subsequent trial of the Eastern
Cooperative Oncology Group (ECOG) comparing patients
treated with high-dose IFN?2b with untreated controls, the effect
of IFN?2b on the improvement of DFS was confirmed, but the
study failed to confirm the significant effect on overall survival.4
In a third trial, Kirkwood et al were able to demonstrate that in
lymph node–positive (77%) and lymph node–negative (23%) high-
risk melanoma patients, high-dose IFN?2b led to significant sur-
vival benefits in comparison with a ganglioside vaccination.2
ESPITE ADVANCES in prevention, early detection, and
treatment of melanoma, 20% to 25% of patients with
In contrast, Cascinelli et al8recently published a World Health
Organization (WHO) melanoma program study of patients with
clinically detectable lymph node metastasis. The study failed to
demonstrate any benefits of low-dose IFN?2a administered for a
period of 3 years.8
The aim of our study was to test whether the addition of
low-dose interleukin-2 (IL-2) to low-dose IFN?2b would im-
prove relapse-free survival. Secondary objectives of our study
were to assess overall survival and toxic adverse effects. In
addition, we carried out immunologic monitoring in a subgroup
of the study population.
From the Department of Dermatology, University of Kiel, Kiel; St. Georg
Hospital, Hamburg; Klinikum Augsburg, Augsburg; University of Wu ¨rzburg,
Wu ¨rzburg; University of Lu ¨beck, Lu ¨beck; University of Heidelberg and
University of Homburg/Saar, Heidelberg/Homburg; University of Du ¨ssel-
dorf, Du ¨sseldorf; Technical University of Mu ¨nchen, Mu ¨nchen; Rudolf-
Virchow Hospital, Berlin; Skin Cancer Unit, DKFZ Heidelberg; and
University Hospital of Mannheim, Germany; and University of Zu ¨rich,
Submitted July 18, 2002; accepted May 5, 2003.
Supported by grants from Essex Pharma GmbH (Munich, Germany) and
Chiron Therapeutics (Ratingen, Germany).
Address reprint requests to Axel Hauschild, MD, University of Kiel,
Department of Dermatology, Schittenhelmstrasse 7, 24105 Kiel, Germany;
© 2003 by American Society of Clinical Oncology.
Journal of Clinical Oncology, Vol 21, No 15 (August 1), 2003: pp 2883-2888
IL-2 has been shown to be effective at higher doses in
advanced metastatic melanoma cases.9-11Also, combination
regimens of IFN? and different doses of subcutaneous or
intravenous IL-2 have been used in metastatic melanoma and
metastatic renal cell carcinoma cases, with varying effects.12-17
To the best of our knowledge, this is the first controlled clinical
trial on IL-2, in an adjuvant setting, for primary melanoma.
PATIENTS AND METHODS
This prospective randomized trial was conducted in 10 different depart-
ments of dermatology at university centers and community hospitals in
Germany and Switzerland. All centers were experienced in the care of
patients with melanoma.
Between October 1990 and April 1995, 225 patients were randomly
assigned to receive either the study medication or close observation alone.
The institutional review boards of the participating centers approved the
protocol, and the study patients provided informed consent. Randomization
was centrally done using computer-generated random numbers, and stratified
To be eligible, patients had to meet the following criteria: age between 18
and 70 years; histologically proven melanoma with pT3 to 4, Clark level IV
or V, and/or tumor thickness greater than 1.5 mm according to the 1987
International Union Against Cancer (UICC) classification18; absence of
clinically detectable regional node metastasis (neither elective lymphadenec-
tomy nor sentinel node biopsy was performed); absence of visceral metas-
tasis verified by at least a chest radiograph and abdominal ultrasound (scans
of the thorax and abdomen, magnetic resonance imaging of the brain, and
bone scintigraphy were considered optional); no history of other cancer
(except basal cell carcinoma or carcinoma-in-situ of the cervix); complete
surgical excision of the melanoma primary tumor, with safety margins of at
least 3 cm; no clinically apparent thyroid dysfunctions; and WBC count
greater than 4 ? 109/L, platelet count greater than 100 ? 109/L, and
hemoglobin levels greater than 11 g/dL.
Other routine laboratory parameters (ie, creatinine, bilirubine, and liver
enzymes) had to be less than 1.5 times that of the upper normal value.
Pregnant and lactating women were excluded from the study. In women of
childbearing age, effective contraception was required. Treatment had to be
initiated within 4 weeks of final removal of the primary melanoma.
A central histology review was not performed; however, all participating
centers were uniformly well trained in dermatohistopathology and thus
self-reviewed all external diagnoses, including measurement of tumor
thickness, at their institutions.
Patients randomly assigned to the treatment arm received the schedule
displayed in Figure 1. One treatment cycle, lasting for 6 weeks, consisted of
IFN?2b (Intron A; Essex Pharma, Munich, Germany) at a dose of 3 million
international units (MU)/m2/d subcutaneously, on days 1 to 7 in the first
week, followed by subcutaneously administered IL-2 (Proleukin; Chiron
Therapeutics, Ratingen, Germany) in doses of 9 MU/m2/d on days 1 through
4 in the second week. During weeks 3 to 6, IFN?2b at a dose of 3 MU/m2/d
was given three times per week. Altogether, eight treatment cycles, account-
ing for a 48-week schedule without resting periods, were administered.
Patients were trained to self-administer the drugs subcutaneously at their
homes. In most cases, the initiation of treatment was performed concurrently
with the postsurgical follow-up at the hospitals of the participating centers.
Treatment had to be discontinued if severe or life-threatening adverse
effects (WHO scales III or IV) occurred, in case of progression of melanoma
to metastatic disease, or on the patients’ own decisions. As a policy of the
study, at least 90% of the scheduled total doses were to be administered to
the patients. Therefore, dose reductions to 50% of the scheduled dose for an
extended period led to treatment discontinuation.
Follow-up examinations took place every 3 months for the first 3 years,
every 6 months for the subsequent 2 years, and yearly thereafter. If
symptoms arose, patients were instructed to come earlier for examinations.
At follow-up, patients had complete clinical examinations, abdominal
ultrasound 3 times monthly in the first 2 years (yearly thereafter), as well as
yearly chest radiographs. If necessary, additional scans were performed. We
performed routine blood evaluations weekly during the first month and once
per month thereafter. Blood assessment included RBC and WBC counts, and
evaluation of liver enzymes, glucose levels, thyroid hormones (TSH, T3, T4),
creatinine levels, and creatinkinase concentrations.
We documented the dates and sites of recurrences, and the dates and
causes of deaths. The WHO toxicity scale was used to report adverse events.
Written information instructed patients to use acetaminophen or metamizole
to treat flu-like symptoms. A patient’s diary was given to the patients to
document adverse or toxic effects of the medication. Physicians at the
participating centers who were responsible for the patients received training
courses on the management of adverse reactions to IFN?2b or IL-2, once or
twice per year from 1991 to 1995.
To assess immunomonitoring in a subgroup of treated patients, the
following parameters were evaluated by blood collection and processing:
soluble IL-2 receptors, ?2-microglobulin and neopterin serum concentra-
tions, development of autoantibodies to cardiolipin and thyroglobulin, and
detection of antibodies to IFN?2b and IL-2 (solid enzyme immunoassay).
The results have been published elsewhere.19The influence of a combination
of IFN?2b and IL-2 on the lysis of melanoma cells was evaluated in vitro.20
The primary objective of the study was the prolongation of DFS.
Secondary end points included overall survival and tolerability of the
treatment. The trial was designed to detect a treatment effect of 15%
improvement in 5-year DFS (observation alone, 60% v IFN?2b ? IL-2
therapy, 75%), with 80% power and a (one-sided) type I error of 5%. For
survival analyses of the eligible patients, the Kaplan-Meier estimates were
used and compared by the log-rank test. The principal analysis was carried
out on an intent-to-treat basis.
The distribution of continuous variables was compared between the
treatment arms using Student?s t test, and categorical factors were tested by
(IFN?2b) subcutaneously at 3 million inter-
national units (MU)/m2/d on days 1 to 7;
interleukin-2 (IL-2) subcutaneously at 9 MU/
m2/d on days 8 to 11; followed by IFN?2b
at 3 MU three times weekly for four weeks.
These cycles were performed eight times for
a total of 48 weeks.
Scheme of treatment. Treatment
HAUSCHILD ET AL
?2test or Fisher’s exact test, as appropriate. In addition, a Cox regression
analysis was applied to adjust for the effect of individual centers and known
prognostic factors. Calculations were performed using SPSS version 9.0
software (SPSS Inc, Chicago, IL).
Figure 2 summarizes the profile of the study. Two of 225
patients originally randomly assigned to the study and who were
assigned to the observation arm were not found to be eligible as
a result of missing basic and follow-up data. Thus, 223 patients
were eligible and assessable for the study and for long-term
follow-up (median, 79.4 months). Major prognostic factors for
primary melanoma (sex, site of melanoma, tumor thickness,
Clark level, and histologic subtype) showed a similar distribution
between treated and untreated study patients (Table 1). Slight
differences regarding primary site, subtype, and Clark level in
favor of the observation group were not statistically significant.
Disease-Free Survival (DFS)
In the treated population, 36 of 113 patients (31.9%; 95%
confidence interval [CI], 23.3% to 40.5%) relapsed during
follow-up. In the observation group, a similar proportion of 34 of
110 patients (30.9%; 95% CI, 22.3% to 39.5%) developed
metastasis (Fig 3A, Table 2). The Kaplan-Meier analysis indi-
cated that there was no significant difference in the DFS
distribution (log-rank: P ? .93).
A further statistical analysis of DFS excluded patients with
treatment discontinuation (n ? 9), but the results were unaf-
fected (data not shown).
A similar analysis was performed comparing the time to
distant metastasis in treated patients with that of untreated
controls. There was no significant difference between the groups
Fig 2.Study profile.
Table 1.Patient Characteristics According to Treatment Group
IFN?2b ? IL-2Observation Only
No. of patients, total
Primary tumor site
Tumour invasion depth
Breslow thickness, mm
Abbreviations: IFN?2b, interferon alfa-2b; IL-2, interleukin-2; SSM,
superficial spreading melanoma; NM, nodular melanoma; ALM, acral
lentiginous melanoma; LM; lentigo maligna melanoma; SD, standard
Table 2. Disease Recurrence
IFN?2b ? IL-2 (n ? 113) Observation Only (n ? 110)
No. of Patients% No. of Patients%
Site of first recurrence
Abbreviations: IFN?2b, interferon alfa-2b; IL-2, interleukin-2.
ADJUVANT IFN?2b/IL-2 IN MELANOMA
based on either the intention-to-treat population (Fig 3B) or after
excluding the patients (n ? 9) who had early treatment with-
drawal (data not shown).
Twenty-six patients (23%) in the group treated with IFN?2b
plus IL-2 died during the observation period. In the control
group, 28 deaths (25.5%) were recorded. In the study group, one
patient died as a result of pulmonary embolism; in the observa-
tion group, two patients died as a result of myocardial infarction;
and one patient each died as a result of metastatic bladder
carcinoma and immunocytoma, respectively. Thus, tumor-re-
lated death occurred in 25 treated patients (22.1%) and in 24
patients under close observation alone (21.8%; Table 2). No
treatment-related deaths occurred. Figure 3C illustrates the survival
plots with respect to all patients included in the study (intention-to-
treat analysis). No difference in overall survival was detectable
between the two arms of the study (log-rank: P ? .93).
The results were unaffected by an analysis excluding patients
with treatment discontinuation (n ? 9). No statistically signifi-
cant differences were obtained for patients treated according to
schedule as compared with control patients (data not shown).
Analysis of Prognostic Covariates
To further explain the influence of potential cofactors, a Cox
regression analysis was performed, including sex, age, melanoma
subtype, site of primary tumor, Clark level of invasion, tumor
thickness, study center, and study arm. The only significant variable
in this multivariate model was the invasion depth of the primary
tumor (P ? .001). None of the other factors, including adjuvant
treatment with IFN?2b plus IL-2, had significant influence on DFS,
the time to distant metastasis, or overall survival.
Low-dose IFN?2b and IL-2 treatment was given to 113
patients. At the follow-up visits, all patients were monitored for
adverse events during treatment. Furthermore, we received data
from the patient’s diary. Frequent low-grade (WHO grade 1 and
2) adverse effects included flue-like symptoms, weight loss, hair
loss, cutaneous erythema, leukopenia, and lymphopenia. In 9 out
of 113 patients (8%) treatment discontinuation was documented.
Therapy had to be stopped because of adverse events according
to the protocol in one patient with WHO grade-3 liver toxicity,
and in another patient with severe depression. Reasons for
withdrawal from the study on the patient’s request (WHO grade
1 and 2) included persistent fever (n ? 1), chronic fatigue (n ? 2),
weight loss (n ? 2), and hair loss (n ? 1). All patients with
within 6 weeks. We did not notice long-term adverse effects.
Of the 113 treated patients, 104 received more than 90% of the
scheduled dose of IFN?2b and IL-2. Prolonged dose reductions
were not necessary in these patients, though all patients reported
mild to moderate flu-like symptoms at the initiation of IFN?2b
treatment and during the weeks of IL-2 application. Regarding
IL-2, tachyphylaxia was not reported by the majority of our
with IFN?2b plus IL-2, as compared with untreated control patients, in terms of (A)
disease-free survival, (B) time to distant metastasis, and (C) overall survival.
Kaplan-Meier estimates of the event-free proportion of patients treated
HAUSCHILD ET AL
patients. Life-threatening adverse events or treatment-related
deaths did not occur.
Although previous trials with adjuvant low-dose IFN? alone
have shown an impact on DFS in patients with malignant
melanoma, they have not achieved satisfactory results in terms of
overall survival benefit.5,6Since IFN? and IL-2 have been
reported to exhibit synergistic immunologic effects,21we com-
bined IFN? and IL-2 in an adjuvant setting to treat patients with
primary malignant melanoma.
High-dose interleukin-2 has demonstrated significant effects
in terms of remission rates (16%) and long-term survival in
advanced metastatic melanoma patients.22However, high-dose
bolus IL-2 seems far too toxic to be transferred into an adjuvant
setting with long-term treatment in potentially cured patients.23
Low-dose interleukin-2 administered subcutaneously has been
used in combination regimens for metastatic melanoma and renal
cell carcinoma with a favorable safety profile and thus appears to
IFN?2b.10,13,15Since it is completely unclear whether low-dose
IL-2 is effective as a monotherapy for patients with melanoma ,
we chose a combination regimen, which could be performed by
the patient at home without impairing his or her social functions
or working capabilities.
Our results show that IFN?2b plus IL-2 treatment in the given
setting does not affect DFS or overall survival. Whereas an
interim report on our study published in 1998 demonstrated a
trend for extended survival in patients treated with IFN?2b plus
IL-2, as compared with untreated controls,24the final statistical
evaluation showed virtually identical survival curves. Since the
relapse rates in our study population were apparently lower than
originally expected, one can argue that the study is underpow-
ered in terms of the sample size. However, even for a larger
sample size, it would seem unlikely to expect a clinically
meaningful effect from low-dose IFN?2b and IL-2 treatment on
the basis of our results.
A lack of synergistic effects from combined IFN?2b plus IL-2
treatment is further evidenced by three recent studies that failed to
detect favorable effects of combining IL-2 with IFN?2a alone,16
IFN?2a with cisplatin,17or IFN? with dacarbazine (DTIC)15in the
treatment of advanced metastatic melanoma.
Today, there are three prospective-randomized studies with a
patient population and eligibility criteria comparable to those of
our study. Grob et al5published results pertaining to an 18-
month treatment regimen with low-dose IFN?2a alone, which
revealed a prolongation of DFS. Pehamberger et al6showed that
12.75 months of low-dose IFN?2a (induction phase: 3 MU/m2/d;
3 times weekly thereafter) improved DFS as compared with
observation alone. In a third trial on low-dose interferon, the
Scottish Melanoma Group observed an apparent improvement in
DFS and overall survival in patients receiving 6 months of
low-dose IFN?2b (3 MU/m2/d, 3 times weekly), though the
study sample size was small.7Taken together, low-dose IFN?
has shown an impact on DFS in all three studies. It does not seem
likely that the duration of treatment is an important issue, because
patients in these three studies were treated for rather different time
within this range, but nevertheless, it is clear we failed to confirm
the effect of low-dose IFN? on DFS. However, one should be
cautious in drawing conclusions from our study data about the
inefficacy of low-dose IFN?2b in the adjuvant treatment of mela-
noma, since it is clear that the actual type II error is larger than
It remains to be discussed whether the addition of low-dose
IL-2 to the IFN?2b treatment might have diminished the
potential positive effects of the IFN?2b in our study, but so far,
there is no evidence to support such a hypothesis.
Encouraging results from high-dose IFN?2b were obtained in
melanoma patients with tumor thickness greater than 4.0 mm, or
with lymph-node metastasis only.2-4Remarkably, the results
from an early report on the first positive study, EST 1684,3could
not fully be confirmed by the long-term results, and the issue of
adjuvant interferon treatment in malignant melanoma is still
controversial.25Regarding intermediate-risk melanoma (tumor
thickness, 1.5 to 4.0 mm) studies are still underway to elaborate
on the effects of high-dose IFN?2b. In this group of patients, the
risk of recurrence is moderate, and the possible benefits have to
be carefully outweighed against the substantial toxicity and risks
of high-dose interferon therapy.
In this prospective multicenter study, we failed to demonstrate
any effect of low-dose IFN?2b and IL-2 administered for 48
weeks. In the meantime, we conducted two further prospective
randomized studies in patients with intermediate- and high-risk
primary melanoma with tumor thickness greater than 1.5 mm.
The first study will elaborate upon the usefulness of a high-dose
IFN?2b induction phase before a low-dose regimen; a subse-
quent trial compares an 18 months to 60 months low-dose
IFN?2a treatment in a multi-institutional setting.
Unless better data on the optimal dosage and duration of IFN?
treatment are available, it is preferable that patients with inter-
mediate- and high-risk melanoma be treated within controlled
We thank Tilo Henseler, MD, PhD, Department of Dermatology, Univer-
sity of Kiel, Kiel, Germany, for his help with the statistical evaluations from
1994 to 1998.
The appendix is included in the full text version of this article only, available on-line at www.jco.org.
It is not included in the PDF version.
ADJUVANT IFN?2b/IL-2 IN MELANOMA
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