JCO-2012-Interferon - Pegilado en Melanomas PDF

Long-Term Results of the Randomized Phase III Trial
EORTC 18991 of Adjuvant Therapy With Pegylated

Interferon Alfa-2b Versus Observation in Resected
Stage III Melanoma
Alexander M.M. Eggermont, Stefan Suciu, Alessandro Testori, Mario Santinami, Wim H.J. Kruit,
Jeremy Marsden, Cornelis J.A. Punt, Franc ois Sale `s, Reinhard Dummer, Caroline Robert, Dirk Schadendorf,
Poulam M. Patel, Gaetan de Schaetzen, Alan Spatz, and Ulrich Keilholz
See accompanying editorial on page 3773
Author afliations appear at the end of
this article.
Submitted December 23, 2011;
accepted June 20, 2012; published
online ahead of print at www.jco.org on
September 24, 2012.
Supported by Schering-Plough
Research Institute and Fonds Cancer
(FOCA) in Belgium. Medical writing
assistance was supported by Merck.
PEG-IFN--2b was provided free of
charge by Schering-Plough, Kenilworth,
NJ.
Presented in part at the 47th Annual
Meeting of the American Society of
Clinical Oncology, Chicago, IL, June
3-7, 2011.
Authors disclosures of potential con-
icts of interest and author contribu-
tions are found at the end of this
article.
Clinical trial information: NCT00006249.
Corresponding author: Alexander M.M.
Eggermont, MD, PhD, Institute de
Cance rologie Gustave Roussy, 114 Rue
Edouard Vaillant, 94805 Villejuif, Paris-Sud,
France; e-mail: alexander.eggermont@igr.fr.
2012 by American Society of Clinical
Oncology
0732-183X/12/3031-3810/$20.00
DOI: 10.1200/JCO.2011.41.3799
A B S T R A C T
Purpose
Adjuvant pegylated interferon alfa-2b (PEG-IFN--2b) was approved for treatment of resected
stage III melanoma in 2011. Here, we present long-term follow-up results of this pivotal trial.
Patients and Methods
In all, 1,256 patients with resected stage III melanoma were randomly assigned to observation
(n 629) or PEG-IFN--2b (n 627) for an intended duration of 5 years. Stratication factors were
microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulcer-
ation and tumor thickness, sex, and center. Recurrence-free survival (RFS; primary end point),
distant metastasis-free survival (DMFS), and overall survival (OS) were analyzed for the intent-to-
treat population.
Results
At 7.6 years median follow-up, 384 recurrences or deaths had occurred with PEG-IFN--2b versus
406 in the observation group (hazard ratio [HR], 0.87; 95% CI, 0.76 to 1.00; P .055); 7-year RFS
rate was 39.1% versus 34.6%. There was no difference in OS (P .57). In stage III-N1 ulcerated
melanoma, RFS (HR, 0.72; 99% CI, 0.46 to 1.13; P .06), DMFS (HR, 0.65; 99% CI, 0.41 to 1.04;
P .02), and OS (HR, 0.59; 99% CI, 0.35 to 0.97; P .006) were prolonged with PEG-IFN--2b.
PEG-IFN--2b was discontinued for toxicity in 37% of patients.
Conclusion
Adjuvant PEG-IFN--2b for stage III melanoma had a positive impact on RFS, which was marginally
signicant and slightly diminished versus the benet seen at prior follow-up (median, 3.8 years).
No signicant increase in DMFS or OS was noted in the overall population. Patients with ulcerated
melanoma and lower disease burden had the greatest benet.
J Clin Oncol 30:3810-3818. 2012 by American Society of Clinical Oncology
INTRODUCTION
In 2011 the US Food and Drug Administration
approved pegylated interferon alfa-2b (PEG-IFN-
-2b; Sylatron, Merck, Whitehouse Station, NJ)
for the adjuvant treatment of patients with mela-
noma who have microscopic or gross nodal in-
volvement within 84 days of denitive surgical
resection, including complete lymphadenectomy,
based on the European Organisation for Research
and Treatment of Cancer (EORTC) 18991 [Inter-
feron Alfa Following Surgery in Treating Patients
With Stage III Melanoma] trial outcome data at a
medianfollow-upof 3.8years.
1
EORTC18991com-
pared adjuvant treatment with PEG-IFN--2b to
observationonly in1,256patients withstage III mel-
anoma. This trial was preceded by the EORTC
18952 [High-Dose or Low-Dose Interferon Alfa
Compared With No Further Therapy Following
Surgery in Treating Patients With Stage III Mela-
noma] trial comparingintermediatedoses of regular
IFN--2b with observation. It suggested better out-
come for the 25-month regimen compared with the
13-monthregimenor observation,
2
whichprovided
the rationale for investigating long-term therapy
with PEG-IFN--2b in EORTC18991.
Stage III disease is heterogeneous, and the
prognosis for patients with microscopic nodes only
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Copyright 2012 American Society of Clinical Oncology. All rights reserved.
(sentinel node [SN] positive patients) is much better than that of
patients with palpable lymph nodes.
3-5
In our trials, we accounted for
this important difference in prognosis by stratifying patients accord-
ing to method of diagnosis: SN staging (microscopic involvement
only: stage III-N1) or gross macroscopic relapse (stage III-N2). Pa-
tients were also stratied by the presence or absence of ulceration of
the primary tumor, another important prognostic factor.
3,4,6
We recently published a meta-analysis of the EORTC 18952
and EORTC 18991 trials at median follow-up of 4.9 and 3.8 years,
respectively, which demonstrated that lower tumor stage and ul-
ceration were predictive for IFN sensitivity and were strong prog-
nostic factors.
7
Results were highly consistent between these trials,
which are the only studies stratied for both stage and ulceration.
Ulceration of the primary tumor as a predictive factor also was
reported by the individual patient data meta-analysis of 13 adju-
vant IFN trials.
8
These reports are important in light of the modest
overall activity of adjuvant IFNtherapy seenin25 years of adjuvant
IFN trials. Meta-analyses demonstrate a consistent impact on
recurrence-free survival (RFS) but an inconsistent or marginal
effect on overall survival (OS; 2.8% to 5%).
8-10
We present here the mature results of EORTC18991, at a median
follow-up of 7.6 years. The goals of this analysis were to determine
whether theRFSbenet is maintainedat this timepoint andtoidentify
factors predictive of efcacy with adjuvant PEG-IFN--2b therapy.
PATIENTS AND METHODS
Patients
Eligible patients were age 18 to 70 years with histologically documented
stage III melanoma (TxN1-2M0) after complete regional lymphadenectomy.
1
Patients were required to have adequate hepatic, renal, and bone marrow
function. Patients with ocular or mucous membrane melanoma, evidence of
distant metastasis or in-transit metastasis, or prior systemic therapy for mela-
noma were ineligible. All patients provided written informed consent before
random assignment. Disease substage was dened as only microscopic, non-
palpable nodal involvement (patients identied by SN biopsy), or clinically
palpable nodal involvement. The protocol was approved by the EORTC pro-
tocol reviewcommittee and local institutional ethical committees.
Study Design
Patients were randomly assigned in a 1:1 ratio to PEG-IFN--2b
treatment for an intended duration of 5 years of observation. Randomiza-
tion was performed centrally at the EORTC data center by using minimi-
zation techniques.
11,12
Patients were stratied by disease substage (N1:
microscopic v N2: clinically palpable lymph nodes), number of involved
lymph nodes, Breslow thickness of the primary tumor, ulceration of the
primary tumor (present v absent v unknown), sex, and center. N1 patients
were almost exclusively SN-positive.
For the 8-week induction phase, 6 g/kg per week PEG-IFN--2b was
administered subcutaneously (SC), with 3 g/kg per week SCfor the mainte-
nance phase (intended treatment durationof up to 5 years if patient remained
at anEasternCooperative Oncology Groupperformance status [ECOGPS] of
0 to 1). Dose adjustments
1
were made to manage toxicity and maintain an
ECOGPS of 0 or 1 for each patient.
Efcacy and Toxicity Evaluation
The primary end point was RFS, dened as time from random assign-
ment to any local or regional recurrence, distant metastasis, or death for any
reason. Secondary end points included distant metastasis-free survival
(DMFS), denedas time fromrandomassignment toanydistant metastasis or
death for any reason, and OS, dened as time from random assignment to
death. (The primary end point in the original study design, DMFS, was
changed to RFS before any analysis of the trial was conducted on the basis of
regulatory feedback.) For all end points, patients who did not experience the
specied event were censored at date of last contact. Adverse events were
graded according to the National Cancer Institutes Common Toxicity Crite-
ria (NCI-CTC) version 2.0.
13
Additional details were published earlier.
1
Statistical Methods
Kaplan-Meier technique was used to estimate survival-type distribu-
tions, and SEs of the estimates were obtained via the Greenwood formula.
14
The Cox proportional hazards model was used for calculation of hazard ratio
(HR) to compare PEG-IFN--2b treatment versus observation. The assump-
tion of proportional hazards was checked according to Lin et al.
15
For sub-
group analyses, since the treatment comparison was assumed to be signicant
at 1%, the 99%CI of the HRwas calculated. Efcacy analyses were conducted
in the intent-to-treat (ITT) population; toxicity analyses included only those
patients who participated in the study and had documented adverse events.
The cutoff date was fall 2010, and the database (located at EORTCheadquar-
ters) was frozen in January 2011. SAS 9.2 software (SAS Institute, Cary, NC)
was used for statistical analyses.
RESULTS
BetweenOctober 2000 and August 2003, 1,256 patients from99 insti-
tutions in 17 countries, mainly in Europe were randomly assigned
(Appendix and Appendix Table A1, online only). There were 627
patients in the PEG-IFN--2b arm and 629 patients in the observa-
tion arm.
Patient Characteristics
Demographics and baseline characteristics have been described
in detail previously and were well balanced across treatment arms
(Appendix Table A2, online only).
1
Approximately 40% of patients
had microscopic nodal disease and 60%had clinically palpable nodal
disease. Current data fromthe American Joint Committee on Cancer
(AJCC) indicate that approximately 70% to 80% of stage III patients
are N1.
3
Treatment Feasibility and Inclusion in Analyses
According to CONSORT Statement
Of 1,256 patients, 23 (1.4%) were considered ineligible (nine in
PEG-IFN--2b and 14 in observation): six because of delays of more
than 70 days between surgery and randomassignment, six because of
incorrect staging, one because of additional malignancy, one with
unacceptable concomitant treatment, four with abnormal laboratory
values, and ve for other reasons.
Figure 1 shows the treatment allocation and follow-up details
by treatment arm. At 12 months after random assignment, 311
patients (50%) randomly assigned to treatment were receiving
PEG-IFN--2b, and 399 patients (63%) continued to be observed
without treatment in the observation arm. Finally, 97 patients
(15%) in the PEG-IFN--2b arm and 206 patients (33%) in the
observation arm completed 5 years of treatment.
Efcacy
After a median 7.6 years of follow-up, 790 recurrences or deaths
had occurred: 384 with PEG-IFN--2b and 406 with observation
(Table 1). Patients allocated to PEG-IFN--2b had a median RFS of
3.0 years versus 2.2 years for observation. This equates to a 13%
Long-Term Results of Adjuvant PEG-IFN--2b in Stage III Melanoma
www.jco.org 2012 by American Society of Clinical Oncology 3811
reduction in risk of recurrence or death with PEG-IFN--2b (HR,
0.87; 95% CI, 0.76 to 1.00) compared with observation (P .055).
There was a 4.5%(95%CI, 0.6%to 12.8%) absolute difference in the
estimated 7-year rate of RFS: 39.1%for PEG-IFN--2b versus 34.6%
for observation. The RFS benet seen at early analysis (median 3.8-
year follow-up) with an HR of 0.82, diminished to an HR of 0.87 at
maturity (Fig 2A).
Multivariate analysis indicated that treatment comparison, ad-
justed for all stratication factors used at random assignment, was of
borderline signicance (HR, 0.89; 95% CI, 0.77 to 1.02; P .10).
Assessed for eligibility
(N = 1,256)
Randomly assigned
(n = 1,256)
Allocated to 5-year PEG-IFN--2b (n = 627)
Started allocated intervention (n = 608)
Did not receive allocated intervention (n = 19)
) 9 = n ( l a s u f e R
Distant metastases (n = 5)
) 2 = n ( e l b i g i l e n I
) 0 = n ( p u - w o l l o f o t t s o L
) 3 = n ( r e h t O
Allocated to observation (n = 629)
Started allocated intervention (n = 613)
Did not receive allocated intervention (n = 16)
) 0 1 = n ( l a s u f e R
) 2 = n ( e l b i g i l e n I
) 3 = n ( r e h t O
) 0 = n ( y d u t s n o l l i t S
Discontinued intervention (n = 626)
) 7 5 = n ( * r e h t O
Death as result of other cause (n = 3)
) 8 2 2 = n ( y t i c i x o T
) 7 5 = n ( l a s u f e R
) 3 = n ( e l b i g i l e n I
5-year PEG-IFN--2b (n = 97)
) 5 2 = n ( p u - w o l l o f o t t s o L
) 0 = n ( y d u t s n o l l i t S
Discontinued intervention (n = 603)
) 5 6 = n ( * r e h t O
Death as result of other cause (n = 3)
) 0 = n ( y t i c i x o T
) 2 3 = n ( l a s u f e R
) 5 = n ( e l b i g i l e n I
5-year observation (n = 206)
Analyzed
(n = 627)
Analyzed
(n = 629)
) 0 = n ( d e d u l c x E
Did not meet inclusion criteria (n = 23)
Fig 1. CONSORT diagram. (*) Gener-
ally 50% because of locoregional re-
lapse. PEG-IFN--2b, pegylated interferon
alfa-2b.
Table 1. RFS, DMFS, and OS by Treatment Group in Intent-to-Treat Population
Variable
RFS DMFS OS
PEG-IFN-
-2b Obs HR 95% CI P
PEG-IFN-
-2b Obs HR 95% CI P
PEG-IFN-
-2b Obs HR 95% CI P
No. of events 384 406 370 375 332 336

7-year rate
(SE), % 39.1 (2.0) 34.6 (1.9) 41.7 (2.0) 40.0 (2.0) 47.8 (2.0) 46.4 (2.0)
Median
years 3.0 2.2 3.9 3.2 6.2 5.6
0.87 0.76 to 1.00 .055 0.93 0.81 to 1.07 .33 0.96 0.82 to 1.11 .57
0.89 0.77 to 1.02 .10 0.95 0.83 to 1.10 .52 0.98 0.84 to 1.14 .77
.68 .53 .78
Abbreviations: DMFS, distant metastasis-free survival; HR, hazard ratio; Obs, observation; OS, overall survival; PEG-IFN-alfa-2b, pegylated interferon alfa-2b; RFS,
recurrence-free survival.
P value given by the Wald test (via a Cox model), unless otherwise noted.
Kaplan-Meier estimates along with standard error obtained via the Greenwood formula.
Univariate analysis.
Multivariate analysis (Cox model): treatment comparison adjusted for stage, number of lymph nodes involved, sex, ulceration, and Breslow thickness, as indicated
at randomization.
P value for treatment stage interaction (Cox model that included treatment, stage, and treatment stage).
Eggermont et al
3812 2012 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
Analysis stratied by stage and adjusted by all other factors approached
statistical signicance (HR, 0.88; 95%CI, 0.77 to1.02; P.08).
Results for DMFS in the whole population were consistent with
those for RFS, without reaching statistical signicance (Table 1; Fig
2B). The absolute difference in median DMFS was similar to that
observed for RFSabout 9 months (47 months for PEG-IFN--2b
and 38 months for observation). A total of 745 distant metastases or
deaths occurred: 370 with PEG-IFN--2b versus 375 with observa-
tion. The estimated 7-year DMFS rates were 41.7%and 40.0%for the
treatment and observation arms, respectively.
Overall survival was not signicantly different (P.57) between
the two treatment groups: the estimated 7-year OS rate was 47.8%for
PEG-IFN--2b and 46.4%for observation (Table 1; Fig 2C).
Subgroup Analysis
The benets of PEG-IFN--2b treatment were more pro-
nouncedinpatients withearlier-stageIII melanomathaninthosewith
later-stage disease (Table 2; Fig 3), with stage III-N2 patients having a
worse outcome thanstage III-N1patients, especially inthe rst 2years
after random assignment. In patients with microscopic nodal disease
(N1), an 18% reduction in the risk of recurrence or death (RFS HR,
0.82; 99% CI, 0.61 to 1.10; P .08) was observed in the PEG-IFN-
-2b armcompared with observation, with a median RFS of 6.4 years
versus 3.7 years; this equates to animprovement of 6.5%inthe 7-year
RFS rate with PEG-IFN--2b. Similarly, the risk of distant metastases
or death was reduced by 14%(DMFS HR, 0.86; 99%CI, 0.63 to 1.17;
P.22). The medianDMFS for the PEG-IFN--2barmwas 7.8 years
versus 6.1 years for observation, with a 5.3% improvement in the
7-year DMFS rate. The treatment difference in OS was not signicant
(P .26), with a median OS of 8.2 years for the observation armand
not yet reached for the PEG-IFN--2b arm. These results were con-
rmed by multivariate analyses. In contrast, in patients with palpable
nodal disease (N2), there was no evidence of a benet with PEG-IFN-
-2b for any end point (Table 2; Fig 4).
Similarly, patients withtumor involvement limitedtoone lymph
node achieved greater reductions in the risk of recurrence (including
death) withPEG-IFN--2btreatment (HR, 0.82; 99%CI, 0.62to1.08;
P.06; medianRFS, 7.1v4.3years), as well as reductions inthe riskof
distant metastases (including death) favoring PEG-IFN--2b treat-
ment (HR, 0.85; 99%CI, 0.64 to 1.13; P .14) and risk of death (HR,
0.85; 99%CI, 0.63 to 1.15) compared with patients having more than
one involved lymph node for whom such reductions were not seen.
Kaplan-Meier curves for patients withone involvedlymphnode showed
that the benet of PEG-IFN--2b treatment began quite early and was
maintained throughout the study period but decreased thereafter (data
not shown). The 7-year rate treatment benets for this patient subgroup
were 5.2%(RFS), 3.8%(DMFS), and4.1%(OS; Table 2).
In patients with the lowest tumor burden (microscopic nodal in-
volvement of only one node), treatment differences were not signicant
regardingRFS(HR, 0.80; 99%CI, 0.55to1.16; P.12), DMFS(HR, 0.83;
99%CI, 0.57to1.23; P.22), andOS(HR, 0.84; 99%CI, 0.55to1.29; P
.29). Moreover, these differences decreased over time: the estimated im-
provementsin4-yearrateswere12.0%, 11.8%, and6.9%, respectively, for
these three endpoints, anddifferences inthe 7-year rates were only 5.5%,
4.1%, and 2.9%, respectively (Table 3). In patients with microscopic
nodal involvement of more than one node, no improvement was
observed in the PEG-IFN--2b arm(Table 3).
0
P = .055
PEG-IFN--2b
Observation
k s i r t a . o N n O
PEG-IFN--2b 384 627 349 283 233 94 2
Observation 406 629 317 238 205 63 1
R
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(
%
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Time (years)
100
80
60
40
20
2 4 6 8 12 10
0
P = .33
PEG-IFN--2b
Observation
PEG-IFN--2b 370 627 385 300 251 98 2
Observation 375 629 361 274 238 74 1
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(
%
)
Time (years)
100
80
60
40
20
2 4 6 8 12 10
0
P = .57
PEG-IFN--2b
Observation
PEG-IFN--2b 332 627 457 345 290 110 2
Observation 336 629 453 331 274 83 2
O
v
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a
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u
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(
%
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Time (years)
100
80
60
40
20
2 4 6 8 12 10
A
B
C
Fig 2. Survival comparison for overall population. (A) Relapse-free survival (O,
observed number of relapses [local, regional or distant metastasis] or deaths), (B)
distant metastasis-free survival (O, observed number of distant metastasis or
deaths), and (C) duration of survival (O, observed number of deaths irrespective
of cause), all according to randomly assigned treatment arm. All P values
calculated by log-rank test. n, number of patients in each arm; PEG-IFN--2b,
pegylated interferon alfa-2b.
An unplanned analysis was conducted in the subgroup of 186
patients withmicroscopic nodal involvement of any number of nodes
who had an ulceration in the primary tumor. For this subgroup only,
the impact of PEG-IFN--2b was important and was sustained over
time for RFS (median 2.7 v 1.7 years; HR, 0.72; 99% CI, 0.46 to 1.13;
P .06), DMFS (median 4.0 v 2.3 years; HR, 0.65; 99% CI, 0.41 to
1.04; P.02), andOS (not reachedv median3.6 years; HR, 0.59; 99%
CI, 0.35 to 0.97; P .006; Table 3). This was not the case for the 322
patients with microscopic nodal involvement who had a nonulcer-
ated primary tumor, in whom no clear positive impact was ob-
served on RFS (HR, 0.90), DMFS (HR, 1.05), or OS (HR, 1.12;
Table 3). The same was true in the remaining 230 patients with
microscopic involvement and unknown ulceration status. In pa-
tients with macroscopic involvement, no signicant treatment ef-
fect was seen for any end point.
Toxicity and Cause of Death: Treatment Comparison
Adverse events of any severity recorded in more than 4% of
patients in the PEG-IFN--2b and observation arms are listed in
Appendix Table A3 (online only). NCI-CTC grade 3 events oc-
curred in 348 patients (57%) in the PEG-IFN--2b arm and 77
patients (14%) in the observation arm. Grade 4 events occurred in
49 patients (9%) inthe PEG-IFN--2b armand23 patients (4%) in
the observation arm. In the PEG-IFN--2b group, the most com-
mon grade 3 or 4 adverse events were fatigue (98 patients; 16%),
hepatotoxicity (668 patients; 11%), and depression (40 patients;
7%). A total of 227 patients (37%) who started PEG-IFN--2b
discontinued treatment because of toxicity. Of note is that grade 3
and 4 toxicities were also observed in the observation patients
(14% and 4%, respectively).
Atotal of 668 deaths were reported, 332 in the PEG-IFN--2b
arm and 336 in the observation arm. The crude incidence of the
most frequent cause of death, malignant disease, was similar in the
two arms: 318 (51%) of 627 in the PEG-IFN--2b arm and 316
(50%) of 629 in the observation arm. Other causes of death were
rare and equally distributed between the two treatment arms
(seven v six).
Table 2. RFS, DMFS, and OS by Treatment Group in Patient Subgroups
Variable
RFS DMFS OS
PEG-IFN-
-2b Obs HR 99% CI P
PEG-IFN-
-2b Obs HR 99% CI P
PEG-IFN-
-2b Obs HR 99% CI P
Microscopic nodal
involvement
No. of events 143 161 134 146 111 125
7-year rate (SE), % 47.0 (3.1) 40.5 (3.0) 51.4 (3.1) 46.1 (3.1) 65.6 (3.0) 62.4 (3.1)
Median years 6.4 3.7 7.8 6.1 N/R 8.2
0.82 0.61 to 1.10 .08 0.86 0.63 to 1.17 .22 0.86 0.62 to 1.21 .26
0.81 0.60 to 1.09 .07 0.85 0.62 to 1.16 .17 0.85 0.61 to 1.19 .22
Clinically palpable
nodes
No. of events 241 245 236 229 221 211
7-year rate (SE), % 32.8 (2.5) 30.2 (2.5) 33.1 (2.5) 34.9 (2.6) 38.7 (2.6) 40.0 (2.7)
Median years 1.5 1.1 1.8 1.8 3.0 3.4
0.89 0.71 to 1.13 .21 0.96 0.76 to 1.22 .66 1.00 0.78 to 1.29 .97
0.91 0.72 to 1.15 .29 0.98 0.77 to 1.25 .86 1.03 0.81 to 1.33 .73
One positive lymph
node
No. of events/No. of
patients 168/339 183/337 160/339 170/337 138/339 151/337
7-year rate (SE), % 50.4 (2.7) 45.2 (2.8) 53.1 (2.8) 49.3 (2.8) 59.9 (2.7) 55.8 (2.8)
Median years 7.1 4.3 N/R 7.0 N/R N/R
0.82 0.62 to 1.08 .06 0.85 0.64 to 1.13 .14 0.85 0.63 to 1.15 .17
0.81 0.62 to 1.07 .05 0.83 0.63 to 1.11 .10 0.85 0.62 to 1.15 .15
One positive lymph
node
patients 216/288 223/292 122/288 116/292 194/288 185/292
7-year rate (SE), % 25.9 (2.6) 22.2 (2.5) 28.3 (2.7) 28.5 (2.7) 33.6 (2.8) 35.3 (2.9)
Median years 1.3 1.1 1.8 1.7 2.8 3.3
0.93 0.73 to 1.19 .47 1.03 0.80 to 1.33 .76 1.07 0.82 to 1.40 .49
0.94 0.73 to 1.21 .53 1.04 0.80 to 1.34 .72 1.07 0.82 to 1.40 .50
Abbreviations: DMFS, distant metastasis-free survival; HR, hazard ratio; N/R, not reached; Obs, observation; OS, overall survival; PEG-IFN-alfa-2b, pegylated
interferon alfa-2b; RFS, recurrence-free survival.
P value given by the Wald test (via a Cox model).

Multivariate analysis (Cox model): treatment comparison adjusted for stage (for analyses according to ulceration status), number of positive lymph nodes (all
subgroups but one positive lymph node), sex, and Breslow thickness, as indicated at randomization, and ulceration status, as indicated on the case report forms.
Eggermont et al
0
PEG-IFN--2b (N1) 143 271 189 156 124 45 1
Observation (N1) 161 272 166 130 111 33 0
PEG-IFN--2b (N2) 241 356 160 127 109 49 1
Observation (N2) 245 357 151 108 94 30 1
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Time (years)
100
80
60
40
20
2 4 6 8 10
0
PEG-IFN--2b (N1) 134 271 209 166 134 49 1
Observation (N1) 146 272 190 149 128 36 0
PEG-IFN--2b (N2) 236 356 176 134 117 49 1
Observation (N2) 229 357 171 125 110 38 1
D
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(
%
)
Time (years)
100
80
60
40
20
2 4 6 8 10
0
PEG-IFN--2b
Observation
PEG-IFN--2b
Observation
PEG-IFN--2b (N1) 111 271 230 186 157 54 1
Observation (N1) 125 272 232 180 150 41 0
PEG-IFN--2b (N2) 221 356 227 159 133 56 1
Observation (N2) 211 357 221 151 124 42 2
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(
%
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Time (years)
100
80
60
40
20
2 4 6 8 10
PEG-IFN--2b
Observation
PEG-IFN--2b
Observation
PEG-IFN--2b
Observation
PEG-IFN--2b
Observation
A
B
C
Stage III N1
Stage III N2
Stage III N1
Stage III N2
Stage III N1
Stage III N2
Fig 3. Outcome according to stage III (microscopic v macroscopic nodal
involvement) and randomly assigned treatment arm. (A) Relapse-free survival (O,
observed number of relapses [local, regional, or distant metastasis] or deaths),
(B) distant metastasis-free survival (O, observed number of distant metastasis or
deaths), and (C) duration of survival (O, observed number of deaths irrespective
of cause), all according to randomly assigned treatment arm. For all treatment
comparisons in each stage subgroup, P values were calculated by using the
log-rank test. n, number of patients in each stage subgroup and treatment arm;
PEG-IFN--2b, pegylated interferon alfa-2b.
0 2 4 6 8 10
0 2 4 6 8 10
0
P = .06
PEG-IFN--2b
Observation
R
e
l
a
p
s
e
-
F
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e

S
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v
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v
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(
%
)
Time (years)
100
80
60
40
20
2 4 6 8 10
P = .02
PEG-IFN--2b
Observation
D
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a
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a
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u
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(
%
)
Time (years)
100
80
60
40
20
P = .006
PEG-IFN--2b
Observation
O
v
e
r
a
l
l

S
u
r
v
i
v
a
l

(
%
)
Time (years)
100
80
60
40
20
O n No. at risk
PEG-IFN--2b 64 96 54 43 35 11
Observation 70 90 41 27 22 6
O n No. at risk
PEG-IFN--2b 58 96 66 47 41 13
Observation 67 90 48 30 25 6
O n No. at risk
PEG-IFN--2b 46 96 78 57 51 16
Observation 61 90 68 41 32 6
A
B
C
Fig 4. Stage III-N1 (microscopic nodal involvement only) patients with ulcerated
melanoma. (A) Relapse-free survival (O, observed number of relapses [local,
regional, or distant metastasis] or deaths), (B) distant metastasis-free survival (O,
observed number of distant metastasis or deaths), and (C) duration of survival (O,
observed number of deaths irrespective of cause), all according to randomly
assigned treatment arm. All P values were calculated by using the log-rank test.
n, number of patients in each arm; PEG-IFN--2b, pegylated interferon alfa-2b.
DISCUSSION
The EORTC 18991 long-term results presented here indicate that
at a median follow-up of 7.6 years, adjuvant PEG-IFN--2b for
stage III melanoma had a modest but sustained impact on RFS in
the ITT population across all strata, which approached but did not
reach statistical signicance (P .055). There was no survival
benet, however. The RFS benet seen in the ITT population was
driven by N1 patients (median increase of 2.7 years), patients with
one involved lymph node (2.8 years), and those with an ulcerated
primary (1.0 years).
This study was designed to administer adjuvant PEG-IFN--2b
for an extended treatment period based on earlier results, suggesting
that prolonged therapy could delay relapse.
2
To continue therapy, it
was necessary toreduce dosing tomaintainpatients at anECOGPS of
0 to 1 as much as possible. Discontinuation because of toxicity oc-
curredmainlyduringyear 1. Thereafter, only12%of patients dropped
out because of toxicity. Dosing to tolerance may be an important
reason to keep patients on prolonged treatment. The median total
duration of treatment was 25 months in the SN-positive patients
compared with 16.3 months for the ITTpopulationand 9 months for
the N2 group (patients who have a high relapse rate in year 1).
Our study suggests that patients with lower disease burden (ie,
SN-positive patients [stage III-N1]) benetedmore fromtherapywith
PEG-IFN--2b than those with greater disease burden, and patients
with ulcerated melanoma had the greatest benet. Moreover, both
lower tumor stage and ulceration were predictive factors for response
toPEG-IFN--2b. This is consistent withour previous EORTC18952
trial of IFN--2b and was conrmed by the meta-analysis of EORTC
trials 18991 and 18952.
7
It is noteworthy that in this patient popula-
tion (ie, SN-positive patients with an ulcerated primary tumor), there
is a signicant impact on RFS, DMFS, and OS, indicating true IFN
sensitivity and IFN benet. Although this subgroup analysis was not
preplanned, the mature data fromthis long-termanalysis clearlydem-
onstrate the sustained effects of PEG-IFN--2b in patients with an
ulcerated primary tumor and stage III-N1. There is a big impact on
Table 3. RFS, DMFS, and OS by Treatment Group
Variable
RFS DMFS OS
PEG-IFN-
-2b Obs HR 99% CI P
PEG-IFN-
-2b Obs HR 99% CI P
PEG-IFN-
-2b Obs HR 99% CI P
One positive lymph

node
patients 93/194 100/188 87/194 91/188 70/194 76/188
7-Year rate (SE), % 52.3 (3.6) 46.8 (3.7) 55.7 (3.6) 51.6 (3.7) 64.3 (3.5) 61.4 (3.6)
Median years N/R 5.9 N/R 7.9 N/R N/R
0.80 0.55 to 1.16 .12 0.83 0.57 to 1.23 .22 0.84 0.55 to 1.29 .29
0.78 0.54 to 1.14 .09 0.81 0.55 to 1.19 .16 0.85 0.55 to 1.30 .32
One positive lymph
node
patients 50/77 61/84 47/77 55/84 41/77 49/84
7-Year rate (SE), % 35.5 (5.6) 26.9 (4.9) 41.0 (5.7) 34.0 (5.2) 48.5 (5.8) 40.5 (5.5)
Median years 2.2 2.3 3.7 4.1 6.2 5.8
0.92 0.56 to 1.50 .66 0.99 0.59 to 1.66 .97 0.97 0.56 to 1.68 .89
0.89 0.53 to 1.49 .56 0.95 0.55 to 1.62 .79 0.94 0.53 to 1.69 .80
Ulceration present
patients 64/96 70/90 58/96 67/90 46/96 61/90
7-Year rate (SE), % 34.4 (4.9) 22.9 (4.5) 41.4 (5.0) 27.4 (4.8) 52.6 (5.1) 34.5 (5.1)
Median years 2.7 1.7 4.0 2.3 N/R 3.6
0.72 0.46 to 1.13 .06 0.65 0.41 to 1.04 .02 0.59 0.35 to 0.97 .006
0.74 0.47 to 1.16 .08 0.65 0.40 to 1.03 .02 0.56 0.33 to 0.95 .005
Ulceration absent
patients 72/156 81/165 69/156 70/165 59/156 58/165
7-Year rate (SE), % 61.7 (4.1) 56.5 (4.0) 64.4 (4.1) 63.6 (4.0) 69.4 (4.0) 72.9 (3.8)
Median years N/R 9.0 N/R N/R N/R N/R
0.90 0.59 to 1.37 .52 1.05 0.68 to 1.63 .77 1.12 0.70 to 1.80 .54
NOTE. Subgroup analysis in stage III-N1 (microscopic) patients according to the number of positive lymph nodes or to ulceration status of primary melanoma (as
indicated on case report forms).
Abbreviations: DMFS, distant metastasis-free survival; HR, hazard ratio; N/R, not reached; Obs, observation; OS, overall survival; PEG-IFN-alfa-2b, pegylated
interferon alfa-2b; RFS, recurrence-free survival.
P value given by the Wald test (via a Cox model).

Multivariate analysis (Cox model): treatment comparison adjusted for number of positive lymph nodes (all subgroups but one positive lymph node), sex, and
Breslow thickness, as indicated at randomization, and ulceration status (for analyses according to number of positive lymph nodes), as indicated on the case report
forms.
Eggermont et al
mediansurvival (8years inthe PEG-IFN--2barmv3.7years inthe
observation arm; Fig 4). However, neither DMFS nor OS benet was
observedwiththis treatment regimeninN2 patients withbulky nodal
disease (comparable to AJCCstage IIIB).
Adjuvant treatment with PEG-IFN--2b is more convenient
than treatment with regular IFN because it requires only one weekly
self-administered SCinjection. The most frequently observed adverse
effects were fatigue, liver enzyme disturbances, and depression that
did not worsen over time compared with standard IFN.
1,2
This is
illustratedbyadiscontinuationrateof 25%intherst year followedby
lowsubsequent discontinuationrates due totoxicity of 5.5%, 2%, 1%,
and 3.5%in years 2, 3, 4, and 5, respectively.
Palpable nodal disease may be more aggressive fromthe onset
or may become more aggressive through acquisition of mutations.
For the same Breslowthickness, an ulcerated primary melanoma is
associated with signicantly worse survival compared with a non-
ulcerated melanoma, suggesting differences in the underlying bi-
ology.
3
This hypothesis is strengthened by several observations: (1)
ulcerated primaries have a unique genetic prole,
16
(2) SNs asso-
ciated with ulcerated primaries are severely immunosuppressed,
17
and(3) ulceratedandnonulceratedprimaries have distinct stromal
responses.
18
Concordant with our ndings is the recently pub-
lished analysis of the Sunbelt adjuvant IFN trial
19
in patients with
SN-positive stage III disease, in which only patients with an ulcer-
ated primary tumor beneted from adjuvant IFN therapy. In con-
trast, this was not the case in the Nordic adjuvant IFN trial,
20
in
which almost all patients had palpable nodal disease. These results
are consistent with our ndings of a much reduced effect of PEG-
IFN in stage III-N2 melanoma.
The hypothesis that lower stage andulcerationare crucial predictive
factors for IFN sensitivity will be prospectively evaluated in the EORTC
18081trial comparingPEG-IFNandobservationin1,200stageII patients
with primary ulcerated melanoma. If the efcacy of PEG-IFN in this
populationconrmsthedataobservedinSN-positivepatientswithulcer-
ated melanoma in the EORTC 18991 trial, it could lead to a more
selective use of IFN in patients with low tumor burden and ulcerated
tumors. Cytokine proles have been reported as potential predictive
factors for adjuvant IFN treatment,
21
but conrmation is pend-
ing.
22
The presence of autoimmune antibodies seemed promising
in this regard,
23
but when evaluated within the context of the
EORTC 18952, Nordic adjuvant, and EORTC 18991 trials, it is
clear that autoimmune antibodies are not predictive for outcome
with these IFN regimens.
24,25
In conclusion, the results of this median 7.6-year follow-up of
EORTC 18991, the largest adjuvant melanoma trial to date, demon-
strate a sustained improvement in RFS in patients treated with pegy-
lated IFN, with greatest benet in patients with lower tumor burden
and ulcerated primaries.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) and/or an authors immediate family member(s) indicated a
nancial or other interest that is relevant to the subject matter under
consideration in this article. Certain relationships marked with a U are
those for which no compensation was received; those relationships marked
with a C were compensated. For a detailed description of the disclosure
categories, or for more information about ASCOs conict of interest policy,
please refer to the Author Disclosure Declaration and the Disclosures of
Potential Conicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory
Role: Alexander M.M. Eggermont, MSD (C), Roche (C), Bristol-Myers
Squibb (C), GlaxoSmithKline (C); Alessandro Testori, Bristol-Myers
Squibb (C), GlaxoSmithKline (C), Amgen (C); Reinhard Dummer, MSD
(C); Caroline Robert, Roche (C), Bristol-Myers Squibb (C),
GlaxoSmithKline (C); Dirk Schadendorf, Merck (C); Poulam M. Patel,
Bristol-Myers Squibb (C), Roche (C), GlaxoSmithKline (C); Alan Spatz,
Merck (C) Stock Ownership: None Honoraria: Alexander M.M.
Eggermont, MSD; Alessandro Testori, Bristol-Myers Squibb,
GlaxoSmithKline, Amgen; Reinhard Dummer, MSD; Poulam M. Patel,
Schering-Plough Research Institute, Bristol-Myers Squibb, Roche,
GlaxoSmithKline; Ulrich Keilholz, Essex Pharma Research Funding:
Reinhard Dummer, MSD; Dirk Schadendorf, Merck Expert Testimony:
None Other Remuneration: Alessandro Testori, travel expenses from
ONCOVISION, IGEA
AUTHOR CONTRIBUTIONS
Conception and design: Alexander M.M. Eggermont, Stefan Suciu,
Alessandro Testori, Francois Sale`s, Alan Spatz, Ulrich Keilholz
Administrative support: Gaetan de Schaetzen, Ulrich Keilholz
Provision of study materials or patients: Alexander M.M. Eggermont,
Alessandro Testori, Mario Santinami, Wim H.J. Kruit, Jeremy Marsden,
Cornelis J.A. Punt, Francois Sale`s, Reinhard Dummer, Caroline Robert,
Dirk Schadendorf, Poulam M. Patel, Alan Spatz, Ulrich Keilholz
Collection and assembly of data: Stefan Suciu, Mario Santinami, Wim
H.J. Kruit, Jeremy Marsden, Cornelis J.A. Punt, Francois Sale`s, Reinhard
Dummer, Caroline Robert, Dirk Schadendorf, Poulam M. Patel, Gaetan
de Schaetzen, Alan Spatz, Ulrich Keilholz
Data analysis and interpretation: Alexander M.M. Eggermont, Stefan
Suciu, Cornelis J.A. Punt, Poulam M. Patel, Gaetan de Schaetzen,
Ulrich Keilholz
Manuscript writing: All authors
Final approval of manuscript: All authors
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Afliations
Alexander M.M. Eggermont and Caroline Robert, Institut de Cancerologie Gustave Roussy, Villejuif, France; Stefan Suciu and Gaetan de
Schaetzen, EuropeanOrganisationfor Researchand Treatment of Cancer Headquarters; Francois Sale`s, Institut Jules Bordet, Brussels, Belgium;
Alessandro Testori, Istituto Europeo di Oncologia; Mario Santinami, Istituto Nazionale dei Tumori, Milan, Italy; Wim H.J. Kruit, Erasmus
University Medical Center, Rotterdam; Cornelis J.A. Punt, Academic Medical Center, Amsterdam, the Netherlands; Jeremy Marsden, University
Hospital Birmingham, Birmingham; PoulamM. Patel, NottinghamUniversity, Nottingham, United Kingdom; Reinhard Dummer, University
Clinic Zurich, Zurich, Switzerland; Dirk Schadendorf, University Hospital Essen, Essen; Ulrich Keilholz, Charite, Campus Benjamin Franklin,
Berlin, Germany; and Alan Spatz, Segal Cancer Centre and McGill University, Montreal, Quebec, Canada.

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Long-Term Results of the Randomized Phase III Trial

EORTC 18991 of Adjuvant Therapy With Pegylated

No. of events 384 406 370 375 332 336

P value given by the Wald test (via a Cox model).

One positive lymph

P value given by the Wald test (via a Cox model).

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