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Long-Term Results of the Randomized Phase III TrialEORTC 18991 of Adjuvant Therapy With PegylatedInterferon Alfa-2b Versus Observation in ResectedStage III Melanoma
Alexander M.M. Eggermont, Stefan Suciu, Alessandro Testori, Mario Santinami, Wim H.J. Kruit,Jeremy Marsden, Cornelis J.A. Punt, Francois Sales, Reinhard Dummer, Caroline Robert, Dirk Schadendorf,Poulam M. Patel, Gaetan de Schaetzen, Alan Spatz, and Ulrich Keilholz
See accompanying editorial on page 3773
Author affiliations 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-
flicts 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
Cancerologie Gustave Roussy, 114 Rue
Edouard Vaillant, 94805 Villejuif, Paris-Sud,
France; e-mail: [email protected].
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
PurposeAdjuvant pegylated interferon alfa-2b (PEG-IFN--2b) was approved for treatment of resectedstage III melanoma in 2011. Here, we present long-term follow-up results of this pivotal trial.
Patients and MethodsIn 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. Stratification factors weremicroscopic (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.
ResultsAt 7.6 years median follow-up, 384 recurrences or deaths had occurred with PEG-IFN--2b versus406 in the observation group (hazard ratio [HR], 0.87; 95% CI, 0.76 to 1.00;P .055); 7-year RFSrate 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.
ConclusionAdjuvant PEG-IFN--2b for stage III melanoma had a positive impact on RFS, which was marginallysignificant and slightly diminished versus the benefit seen at prior follow-up (median, 3.8 years).No significant increase in DMFS or OS was noted in the overall population. Patients with ulceratedmelanoma and lower disease burden had the greatest benefit.
J Clin Oncol 30:3810-3818. 2012 by American Society of Clinical Oncology
INTRODUCTION
In 2011 the US Food and Drug Administrationapproved pegylatedinterferonalfa-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 definitive 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-up of 3.8years.1 EORTC 18991com-
pared adjuvant treatment with PEG-IFN--2b to
observationonlyin 1,256patients withstageIIImel-
anoma. This trial was preceded by the EORTC18952 [High-Dose or Low-Dose Interferon Alfa
Compared With No Further Therapy Following
Surgery in Treating Patients With Stage III Mela-
noma] trial comparing intermediate doses of regular
IFN--2b with observation. It suggested better out-
come forthe25-monthregimen compared with the
13-monthregimenor observation,2 which provided
the rationale for investigating long-term therapy
with PEG-IFN--2b in EORTC 18991.
Stage III disease is heterogeneous, and the
prognosis for patients with microscopic nodes only
JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T
V O LU M E 3 0 N U MB E R 3 1 N O VE M BE R 1 2 0 12
3810 2012 by American Society of Clinical Oncology
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(sentinel node [SN] positive patients) is much better than that ofpatients with palpablelymph nodes.3-5 In ourtrials, we accounted for
this important difference in prognosis by stratifying patients accord-
ing to method of diagnosis: SN staging (microscopic involvementonly: stage III-N1) or gross macroscopic relapse (stage III-N2). Pa-
tients were also stratified 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 stratified 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 modestoverall activity of adjuvant IFNtherapy seen in 25 years of adjuvant
IFN trials. Meta-analyses demonstrate a consistent impact on
recurrence-free survival (RFS) but an inconsistent or marginaleffect on overall survival (OS; 2.8% to 5%).8-10
Wepresent here thematureresultsof EORTC 18991,at a medianfollow-up of 7.6 years. The goals of this analysis were to determinewhethertheRFSbenefitismaintainedatthistimepointandtoidentify
factors predictive of efficacy with adjuvant PEG-IFN--2b therapy.
PATIENTS AND METHODS
PatientsEligible patients were age 18 to 70 years with histologically documented
stageIII melanoma (TxN1-2M0) after complete regional lymphadenectomy.1
Patients were required to have adequate hepatic, renal, and bone marrowfunction. 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 beforerandom assignment. Disease substage was defined as only microscopic, non-palpable nodal involvement (patients identified by SN biopsy), or clinicallypalpable nodal involvement. The protocol was approved by the EORTC pro-tocol review committee and local institutional ethical committees.
Study DesignPatients 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 stratified by disease substage (N1:microscopic vN2: clinically palpable lymph nodes), number of involvedlymph nodes, Breslow thickness of the primary tumor, ulceration of theprimary tumor (presentvabsentvunknown), 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 3g/kg per week SC for the mainte-nance phase (intended treatmentdurationof up to 5 years if patient remainedat an Eastern Cooperative Oncology Groupperformance status[ECOG PS] of0 to 1). Dose adjustments1 were made to manage toxicity and maintain anECOGPS of0 or 1 for each patient.
Efficacy and Toxicity EvaluationThe primary end point was RFS, defined as time from random assign-
ment to any local or regional recurrence, distant metastasis, or death for anyreason. Secondary end points included distant metastasis-free survival(DMFS), defined as timefrom random assignment to anydistantmetastasisordeath for any reason, and OS, defined as time from random assignment to
death. (The primary end point in the original study design, DMFS, waschanged to RFS before any analysis of the trial was conducted on the basis ofregulatory feedback.) For all end points, patients who did not experience thespecified event were censored at date of last contact. Adverse events weregraded according to the National Cancer Institutes Common Toxicity Crite-ria (NCI-CTC) version 2.0.13 Additional details were published earlier.1
Statistical MethodsKaplan-Meier technique was used to estimate survival-type distribu-
tions, and SEs of the estimates were obtained via the Greenwood formula.14The 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 thetreatment comparison wasassumed to be significantat 1%, the 99% CI of theHR was calculated. Efficacy analyses were conductedin the intent-to-treat (ITT) population; toxicity analyses included only thosepatients who participated in the study and had documented adverse events.The cutoff date was fall 2010, and the database (located at EORTC headquar-ters) was frozen in January 2011. SAS 9.2 software (SAS Institute, Cary, NC)was used for statistical analyses.
RESULTS
Between October 2000 andAugust 2003, 1,256 patients from 99 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 from theAmericanJoint 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 morethan 70 days between surgery and random assignment, six because of
incorrect staging, one because of additional malignancy, one with
unacceptable concomitant treatment, four with abnormal laboratoryvalues, and five for other reasons.
Figure 1 shows the treatment allocation and follow-up details
by treatment arm. At 12 months after random assignment, 311patients (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.
Efficacy
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 of3.0 years versus 2.2 years for observation. This equates to a 13%
Long-Term Results of Adjuvant PEG-IFN--2b in Stage III Melanoma
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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 theestimated 7-year rate of RFS: 39.1% for PEG-IFN--2b versus 34.6%
for observation. The RFS benefit 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 stratification factors used at random assignment, was of
borderline significance (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(lasufeR
Distant metastases (n = 5))2=n(elbigilenI
)0=n(pu-wollofottsoL
)3=n(rehtO
Allocated to observation (n = 629) Started allocated intervention (n = 613)
Did not receive allocated intervention (n = 16)
)01=n(lasufeR
Distant metastases (n = 0))2=n(elbigilenI
)1=n(pu-wollofottsoL
)3=n(rehtO
)1=n(pu-wollofottsoL
)0=n(ydutsnollitS
Discontinued intervention (n = 626) Distant metastases (n = 186)
)75=n(*rehtO
Death as result of other cause (n = 3)
)822=n(yticixoT)75=n(lasufeR
)3=n(elbigilenI
5-year PEG-IFN--2b (n = 97)
)52=n(pu-wollofottsoL
)0=n(ydutsnollitS
Discontinued intervention (n = 603) Distant metastases (n = 293)
)56=n(*rehtO
Death as result of other cause (n = 3)
)0=n(yticixoT)23=n(lasufeR
)5=n(elbigilenI
5-year observation (n = 206)
Analyzed(n = 627)
Analyzed(n = 629)
)0=n(dedulcxE
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)
Medianyears 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.Pvalue 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
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Analysis stratified by stage and adjusted by all other factors approached
statistical significance (HR, 0.88; 95% CI,0.77to 1.02; P .08).
Results for DMFS in the whole population were consistent with
those for RFS, without reaching statistical significance (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. Theestimated 7-yearDMFS rates were 41.7% and40.0% forthe
treatment and observation arms, respectively.
Overallsurvivalwas not significantlydifferent (P .57)between
thetwo treatmentgroups: theestimated 7-yearOS rate was 47.8% for
PEG-IFN--2b and 46.4% for observation (Table 1; Fig 2C).
Subgroup Analysis
The benefits of PEG-IFN--2b treatment were more pro-
nouncedin patientswithearlier-stage IIImelanoma thanin those with
later-stage disease (Table 2; Fig 3), with stage III-N2 patients having a
worse outcomethanstage III-N1patients, especially in thefirst2 years
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-
-2barm compared with observation, with a median RFSof 6.4years
versus3.7 years; this equates to an improvement of 6.5% in the7-year
RFSrate 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 median DMFS forthe PEG-IFN--2barm was7.8 years
versus 6.1 years for observation, with a 5.3% improvement in the
7-year DMFS rate. Thetreatment difference in OS was not significant
(P .26), with a median OS of 8.2 years for the observation arm and
not yet reached for the PEG-IFN--2b arm. These results were con-
firmed by multivariate analyses. In contrast, in patients with palpable
nodal disease (N2), there wasno evidence of a benefit with PEG-IFN--2b for any end point (Table 2; Fig 4).
Similarly,patientswith tumor involvement limitedto onelymph
node achieved greater reductions in the risk of recurrence (including
death) with PEG-IFN--2btreatment(HR,0.82; 99%CI, 0.62 to1.08;
P .06;medianRFS, 7.1v4.3years),aswellasreductionsintheriskof
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-Meiercurvesforpatients with oneinvolved lymph node showed
that the benefit of PEG-IFN--2b treatment began quite early and was
maintained throughout the study period but decreased thereafter (data
not shown). The7-year rate treatment benefits for this patient subgroupwere 5.2% (RFS), 3.8% (DMFS), and 4.1% (OS; Table 2).
In patients with the lowest tumor burden (microscopic nodal in-
volvement of only one node), treatment differences were not significant
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-
provements in4-yearrateswere12.0%,11.8%, and6.9%,respectively,for
these three endpoints, anddifferencesin the7-yearrateswere 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
ksirta.oNnO
PEG-IFN--2b 384 627 349 283 233 94 2Observation 406 629 317 238 205 63 1
Relapse-FreeSurvival(%)
Time (years)
100
80
60
40
20
2 4 6 8 1210
0
P= .33
PEG-IFN--2b
Observation
ksirta.oNnO
PEG-IFN--2b 370 627 385 300 251 98 2Observation 375 629 361 274 238 74 1
DistantMetastases
Free
Survival(%)
Time (years)
100
80
60
40
20
2 4 6 8 1210
0
P= .57
PEG-IFN--2b
Observation
ksirta.oNnO
PEG-IFN--2b 332 627 457 345 290 110 2Observation 336 629 453 331 274 83 2
OverallSurvival(%)
Time (years)
100
80
60
40
20
2 4 6 8 1210
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.
Long-Term Results of Adjuvant PEG-IFN--2b in Stage III Melanoma
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An unplanned analysis was conducted in the subgroup of 186
patientswithmicroscopic 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 2.7v1.7 years; HR, 0.72; 99% CI, 0.46 to 1.13;
P .06), DMFS (median 4.0v2.3 years; HR, 0.65; 99% CI, 0.41 to1.04; P .02), andOS (not reached vmedian 3.6 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 withmicroscopic involvement and unknown ulceration status. In pa-
tients with macroscopic involvement, no significant 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% ofpatients 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%) in thePEG-IFN--2b arm and 23 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).
A total 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
(sevenvsix).
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 nodalinvolvement
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 palpablenodes
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 lymphnode
No. of events/No. ofpatients 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 lymphnode
No. of events/No. ofpatients 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, pegylatedinterferon alfa-2b; RFS, recurrence-free survival.Pvalue given by the Wald test (via a Cox model).Kaplan-Meier estimates along with standard error obtained via the Greenwood formula.
Univariate analysis.Multivariate analysis (Cox model): treatment comparison adjusted for stage (for analyses according to ulceration status), number of positive lymph nodes (all
subgroups butone positive lymph node), sex, and Breslow thickness, as indicated at randomization, and ulceration status, as indicated on the case report forms.
Eggermont et al
3814 2012 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
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0
ksirta.oNnO
PEG-IFN--2b (N1) 143 271 189 156 124 45 1Observation (N1) 161 272 166 130 111 33 0PEG-IFN--2b (N2) 241 356 160 127 109 49 1Observation (N2) 245 357 151 108 94 30 1
Relapse
-FreeSurvival(%)
Time (years)
100
80
60
40
20
2 4 6 8 10
0
ksirta.oNnO
PEG-IFN--2b (N1) 134 271 209 166 134 49 1Observation (N1) 146 272 190 149 128 36 0PEG-IFN--2b (N2) 236 356 176 134 117 49 1
Observation (N2) 229 357 171 125 110 38 1
DistantMetastases
Free
Survival(%)
Time (years)
100
80
60
40
20
2 4 6 8 10
0
PEG-IFN--2b
Observation
PEG-IFN--2b
Observation
ksirta.oNnO
PEG-IFN--2b (N1) 111 271 230 186 157 54 1Observation (N1) 125 272 232 180 150 41 0PEG-IFN--2b (N2) 221 356 227 159 133 56 1Observation (N2) 211 357 221 151 124 42 2
OverallSurvival(%)
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
Relapse-FreeSurvival(%)
Time (years)
100
80
60
40
20
2 4 6 8 10
P= .02
PEG-IFN--2b
Observation
DistantMetastases
Free
Survival(%)
Time (years)
100
80
60
40
20
P= .006
PEG-IFN--2b
ObservationOverallSurvival(%)
Time (years)
100
80
60
40
20
O n No. at risk
PEG-IFN--2b 64 96 54 43 35 11Observation 70 90 41 27 22 6
O n No. at risk
PEG-IFN--2b 58 96 66 47 41 13Observation 67 90 48 30 25 6
O n No. at risk
PEG-IFN--2b 46 96 78 57 51 16Observation 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 Pvalues were calculated by using the log-rank test.
n, number of patients in each arm; PEG-IFN--2b, pegylated interferon alfa-2b.
Long-Term Results of Adjuvant PEG-IFN--2b in Stage III Melanoma
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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 inthe ITT population across all strata, which approached but did not
reach statistical significance (P .055). There was no survival
benefit, however. The RFS benefit seen in the ITT population wasdriven 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, itwasnecessary to reduce dosing to maintain patientsat an ECOG PS of
0 to 1 as much as possible. Discontinuation because of toxicity oc-
curred mainlyduring year1. Thereafter,only 12%of patients droppedout 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
comparedwith 16.3 monthsfor theITT population and9 monthsfor
the N2 group (patients who have a high relapse rate in year 1).
Our study suggests that patients with lower disease burden (ie,
SN-positivepatients [stageIII-N1])benefited morefrom therapywith
PEG-IFN--2b than those with greater disease burden, and patientswith ulcerated melanoma had the greatest benefit. Moreover, both
lower tumor stage and ulceration were predictive factors forresponse
to PEG-IFN--2b.This is consistent with ourpreviousEORTC 18952
trial of IFN--2b and was confirmed by the meta-analysis of EORTC
trials 18991 and 18952.7 It is noteworthy that in this patient popula-
tion(ie, SN-positive patientswithan ulcerated primary tumor), there
is a significant impact on RFS, DMFS, and OS, indicating true IFN
sensitivity and IFN benefit. Although this subgroup analysis was not
preplanned,thematuredatafrom thislong-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 lymphnode
No. of events/No. ofpatients 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 lymphnode
No. of events/No. ofpatients 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
No. of events/No. ofpatients 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
No. of events/No. ofpatients 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 (asindicated 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, pegylatedinterferon alfa-2b; RFS, recurrence-free survival.Pvalue given by the Wald test (via a Cox model).
Kaplan-Meier estimates along with standard error obtained via the Greenwood formula.Univariate analysis.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 reportforms.
Eggermont et al
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mediansurvival (8yearsinthePEG-IFN--2barmv3.7yearsinthe
observation arm; Fig 4). However, neither DMFS nor OS benefit was
observed with this treatmentregimen in N2 patientswith bulky nodal
disease (comparable to AJCC stage IIIB).
Adjuvant treatment with PEG-IFN--2b is more convenient
than treatment with regular IFN because it requires only one weekly
self-administered SC injection. The mostfrequently observedadverse
effects were fatigue, liver enzyme disturbances, and depression thatdid not worsen over time compared with standard IFN.1,2 This is
illustratedbyadiscontinuationrateof25%inthefirstyearfollowedby
lowsubsequent discontinuationrates dueto toxicity of 5.5%, 2%, 1%,
and 3.5% in years 2, 3, 4, and 5, respectively.
Palpable nodal disease may be more aggressive from the onset
or may become more aggressive through acquisition of mutations.
For the same Breslow thickness, an ulcerated primary melanoma is
associated with significantly 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 profile,16 (2) SNs asso-
ciated with ulcerated primaries are severely immunosuppressed,17
and (3) ulceratedand nonulcerated primarieshave distinct stromalresponses.18 Concordant with our findings is the recently pub-
lished analysis of the Sunbelt adjuvant IFN trial19 in patients with
SN-positive stage III disease, in which only patients with an ulcer-
ated primary tumor benefited 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 findings of a much reduced effect of PEG-
IFN in stage III-N2 melanoma.
Thehypothesis that lowerstageandulceration arecrucial predictive
factors for IFN sensitivity will be prospectively evaluated in the EORTC
18081 trialcomparingPEG-IFNandobservationin1,200stageIIpatients
with primary ulcerated melanoma. If the efficacy of PEG-IFN in this
populationconfirmsthedataobservedinSN-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 profiles have been reported as potential predictive
factors for adjuvant IFN treatment,21 but confirmation 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 benefit in patients with lower tumor burden
and ulcerated primaries.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST
Although all authors completed the disclosure declaration, the followingauthor(s) and/or an authors immediate family member(s) indicated afinancial or other interest that is relevant to the subject matter underconsideration in this article. Certain relationships marked with a U arethose for which no compensation was received; those relationships markedwith a C were compensated. For a detailed description of the disclosurecategories, or for more information about ASCOs conflict of interest policy,
please refer to the Author Disclosure Declaration and the Disclosures ofPotential Conflicts of Interest section in Information for Contributors.Employment or Leadership Position: None Consultant or AdvisoryRole:Alexander M.M. Eggermont, MSD (C), Roche (C), Bristol-MyersSquibb (C), GlaxoSmithKline (C); Alessandro Testori, Bristol-MyersSquibb (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:NoneHonoraria: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 PharmaResearch Funding:Reinhard Dummer, MSD; Dirk Schadendorf, MerckExpert Testimony:NoneOther Remuneration:Alessandro Testori, travel expenses fromONCOVISION, IGEA
AUTHOR CONTRIBUTIONS
Conception and design:Alexander M.M. Eggermont, Stefan Suciu,Alessandro Testori, Francois Sales, Alan Spatz, Ulrich Keilholz
Administrative support:Gaetan de Schaetzen, Ulrich KeilholzProvision of study materials or patients: Alexander M.M. Eggermont,Alessandro Testori, Mario Santinami, Wim H.J. Kruit, Jeremy Marsden,Cornelis J.A. Punt, Francois Sales, Reinhard Dummer, Caroline Robert,Dirk Schadendorf, Poulam M. Patel, Alan Spatz, Ulrich KeilholzCollection and assembly of data: Stefan Suciu, Mario Santinami, WimH.J. Kruit , Jeremy Marsden, Cornelis J.A. Punt, Francois Sales, ReinhardDummer, Caroline Robert, Dirk Schadendorf, Poulam M. Patel, Gaetande Schaetzen, Alan Spatz, Ulrich KeilholzData analysis and interpretation:Alexander M.M. Eggermont, StefanSuciu, Cornelis J.A. Punt, Poulam M. Patel, Gaetan de Schaetzen,Ulrich KeilholzManuscript writing:All authorsFinal approval of manuscript: All authors
REFERENCES
1. Eggermont AM, Suciu S, Santinami M, et al:
Adjuvant therapy with pegylated interferon alfa-2b
versus observation alone in resected stage III mela-
noma: Final results of EORTC 18991, a randomised
phase III trial. Lancet 372:117-126, 2008
2. Eggermont AM, Suciu S, MacKie R, 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 366:
1189-1196, 2005
3. Balch CM, Gershenwald JE, Soong SJ, et al:
Final version of 2009 AJCC melanoma staging and
classification. J Clin Oncol 27:6199-6206, 2009
4. Balch CM, Gershenwald JE, Soong SJ, et al:
Multivariate analysis of prognostic factors among
2,313 patients with stage III melanoma: Comparison
of nodal micrometastases versus macrometasta-
ses. J Clin Oncol 28:2452-2459, 2010
5. van der Ploeg AP, van Akkooi AC, Rut-
kowski P, et al: Prognosis in patients with sentinel
node-positive melanoma is accurately defined by
the combined Rotterdam tumor load and Dewar
topography criteria. J Clin Oncol 29:2206-2214,
2011
6. Balch CM, Murad TM, Soong SJ, et al: A
multifactorial analysis of melanoma: Prognostic his-
topathological features comparing Clarks and
Breslows staging methods. Ann Surg 188:732-742,
1978
7. Eggermont AM, Suciu S, Testori A, et al: Ulcer-
ation and stage are predictive of interferon efficacy in
melanoma: Results of the phase III adjuvant trials
EORTC 18952 and EORTC 18991. Eur J Cancer 48:
218-225, 2012
8. Wheatley K, Ives NJ, Lorigan P: Does adjuvant
vaccine therapy really have activity in malignant mela-
noma? J Clin Oncol 25:4693, 2007; author reply 4693-
4695
Long-Term Results of Adjuvant PEG-IFN--2b in Stage III Melanoma
www.jco.org 2012 by American Society of Clinical Oncology 3817
Downloaded from jco.ascopubs.org on September 17, 2014. For personal use only. No other uses without permission.Copyright 2012 American Society of Clinical Oncology. All rights reserved.
-
8/11/2019 JCO-2012-Interferon- pegilado en melanomas.pdf
9/9
9. Wheatley K, Ives N, Hancock B, et al: Does
adjuvant interferon-alpha for high-risk melanoma
provide a worthwhile benefit? A meta-analysis of
the randomised trials. Cancer Treat Rev 29:241-252,
2003
10. Mocellin S, Pasquali S, Rossi CR, et al: Inter-
feron alpha adjuvant therapy in patients with high-risk
melanoma: A systematic review and meta-analysis.
J Natl Cancer Inst 102:493-501, 2010
11. Pocock SJ, Simon R: Sequential treatment as-
signment with balancing for prognostic factors in the
controlled clinical trial. Biometrics 31:103-115, 1975
12. Freedman LS, White SJ: On the use of Po-
cock and Simons method for balancing treatment
numbers over prognostic factors in the controlled
clinical trial. Biometrics 32:691-694, 1976
13. Cancer Therapy EvaluationProgram,NationalCan-
cer Institute: Common Toxicity Criteria, Version 2.0.
1999. http://ctep.cancer.gov/protocolDevelopment/
electronic_applications/docs/ctcv20_4-30-992.pdf
14. Kalbfleisch JD, Prentice RL: The Statistical
Analysis of Failure Time Data (ed 2). Hoboken, NJ,
John Wiley & Sons, 2002
15. Lin DY, Wei LJ, Ying Z: Checking the Cox
model with cumulative sums of martingale-based
residuals. Biometrika 80:557-572, 1993
16. Winnepenninckx V, Lazar V, Michiels S, et al:
Gene expression profiling of primary cutaneous mel-
anoma and clinical outcome. J Natl Cancer Inst
98:472-482, 2006
17. Elliott B, Scolyer RA, Suciu S, et al: Long-term
protective effect of mature DC-LAMP dendritic cell
accumulation in sentinel lymph nodes containing mi-
crometastatic melanoma. Clin Cancer Res 13:3825-
3830, 2007
18. Spatz A, Cook MG, Elder DE, et al: Interob-
server reproducibility of ulceration assessment in
primary cutaneous melanomas. Eur J Cancer 39:
1861-1865, 2003
19. McMasters KM, Edwards MJ, Ross MI, et al:
Ulceration as a predictive marker for response to
adjuvant interferon therapy in melanoma. Ann Surg
252:460-465, 2010; discussion 465-466
20. Hansson J, Aamdal S, Bastholt L, et al: Two
different durations of adjuvant therapy with
intermediate-dose interferon alfa-2b in patients with
high-risk melanoma (Nordic IFN trial): A randomised
phase 3 trial. Lancet Oncol 12:144-152, 2011
21. Yurkovetsky ZR, Kirkwood JM, Edington HD,
et al: Multiplex analysis of serum cytokines in mel-
anoma patients treated with interferon-alpha2b. Clin
Cancer Res 13:2422-2428, 2007
22. Gogas H, Ioannovich J, Dafni U, et al: Prognos-
tic significance of autoimmunity during treatment of
melanoma with interferon. N Engl J Med354:709-718,
200623. Bouwhuis MG, ten Hagen TL, Eggermont
AM: Immunologic functions as prognostic indicators
in melanoma. Mol Oncol 5:183-189, 2011
24. Bouwhuis MG, Suciu S, Collette S, et al:
Autoimmune antibodies and recurrence-free interval
in melanoma patients treated with adjuvant inter-
feron. J Natl Cancer Inst 101:869-877, 2009
25. Bouwhuis MG, Suciu S, Testori A, et al:
Phase III trial comparing adjuvant treatment with
pegylated interferon Alfa-2b versus observation:
Prognostic significance of autoantibodies
EORTC 18991. J Clin Oncol 28:2460-2466, 2010
Affiliations
Alexander M.M. Eggermont and Caroline Robert, Institut de Cancerologie Gustave Roussy, Villejuif, France; Stefan Suciu and Gaetan deSchaetzen, EuropeanOrganisation for Researchand Treatment of Cancer Headquarters; Francois Sales, InstitutJules Bordet, Brussels, Belgium;
Alessandro Testori, Istituto Europeo di Oncologia; Mario Santinami, Istituto Nazionale dei Tumori, Milan, Italy; Wim H.J. Kruit, Erasmus
University MedicalCenter, Rotterdam;Cornelis J.A.Punt, Academic MedicalCenter,Amsterdam,theNetherlands; JeremyMarsden,UniversityHospital Birmingham, Birmingham; Poulam M. Patel, Nottingham University, 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.
Eggermont et al
3818 2012 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
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http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcv20_4-30-992.pdfhttp://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcv20_4-30-992.pdfhttp://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcv20_4-30-992.pdfhttp://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf