risk of recurrence and survival after relapse in patients with ewing sarcoma

Pediatr Blood Cancer 2011;57:549–553

Risk of Recurrence and Survival After Relapse in Patients With Ewing Sarcoma

Martin Stahl, MD,1 Andreas Ranft,1 Michael Paulussen, MD,2 Tobias Bolling, MD,3 Volker Vieth, MD,4

Stefan Bielack, MD,5 Irene Gortitz, MD,6 Gabriele Braun-Munzinger,1 Jendrik Hardes, MD,7

Heribert Jurgens, MD,1 and Uta Dirksen, MD1*

INTRODUCTION

The outcome after an initial diagnosis of Ewing sarcoma in

patients with localized disease has been significantly and steadily

improved up to 75% over the last years [1–3]. This success

has been attributed to multimodal treatment including multiagent

chemotherapy, surgery, and radiotherapy [1,2,4,5].

By contrast, endeavors to improve survival in high-risk

patients with primary disseminated disease have been without

success so far. In these patients, 5-year overall survival remains

at a low level of 13%–30% despite the introduction of high-dose

chemotherapeutic approaches [6]. Detailed analysis identified

relevant prognostic factors in this group of patients: age, tumor

volume,number,andsiteofmetastases. Inpatientswithdisseminated

disease the unfavorable prognosis may be improved by consistent

local treatment [7,8].

In conclusion, there is still a considerable rate of recurrent

disease in patientswithEwing sarcoma.About 30%–40%ofpatients

with a localized primary and 60%–80% of patients with primary

disseminated disease sustain a relapse [9].

Survival following relapse is 20%, and despite the introduction

of new therapeutic agents including high-dose chemotherapy, all

attempts to improve the prognosis have not been successful [10–16].

Recent analyses on Ewing sarcoma relapse focus on a putative

association between outcome and treatment given [17–20]. The

present study analyzes a group of patients who received highly

heterogeneous treatment and thus provides no valid information

on this aspect. The value of various therapeutic regimens will not

be subject of this paper.

We present our analysis on risk of recurrence and survival after

relapse in a large cohort of 714 patients. All patients were initially

treatedwithin theGPOHCESS81,CESS86,orEICESS92trials.We

aimed at a detailed analysis of clinically relevant factors in a large

cohort of patients with relapsed Ewing sarcoma in order to discover

relevant prognostic parameters. Our vision was to get solid data

amenable to providing a relevant risk score as a useful guideline

for future follow-up programs and clinical trials in relapsed patients.

The analysis aims to identify the prognostic relevance of type of

relapse and time to recurrence.

PATIENTS AND METHODS

Between 1980 and 1998, 1,549 patients with histologically

proven Ewing sarcoma of bone or soft tissue were registered into

three consecutiveGPOH trials, i.e.,CESS81,CESS86, andEICESS

92. The trials were approved by the appropriate ethics committees.

All patients and/or their legal representatives gave informed consent

to treatment as well as data storage and analysis according to

the appropriate guidelines. Details of the treatment regimens

including agents, dosage, routes, and schedules of chemotherapy

administration, the dose and schedule of radiotherapy, and the extent

of surgery given for local control were described elsewhere [1,21–

24]. The present analysis includes data from the time of enrollment

into the respective trial until July2010when thedatabasewas frozen.

Background. The prognosis in patients with relapsed Ewing sar-coma is unfavorable.Our investigation identifies factors predicting forthe outcome following relapse. Procedure. We analyzed type ofrelapse, time to relapse and overall survival after relapse (OSr) in714 patientswith first recurrence. All patients had been treatedwithinthe Cooperative Ewing Sarcoma Studies (CESS) 81 or 86, or the Euro-pean Intergroup CESS (EICESS 92). OSr time was calculated fromdiagnosis of first relapse to last follow-up or death. Results. Medianfollow-up time from diagnosis of primary disease was 2.2 years(mean ¼ 4.0; range: 0.2–24.9). Relapse siteswere local in 15%, com-binedlocalandsystemicin12%,andsystemic in73%.Amongpatientswith a localized primary tumor, 20% relapsed locally, while 12%

showed combined and 68% systemic relapse. When the primarydisease was disseminated, 82% developed systemic, 13% combined,and 5% local relapse. Five-year OSr was 0.13 (SE ¼ 0.01). Outcomefollowing local relapse,witha5-year survival rateof 0.24 (P < 0.001),was superior to outcomeafter systemic or combined recurrence. Five-yearOSrwas0.07 (SE ¼ 0.01) inpatientswho relapsed0–2years afterthe diagnosis of primary disease, as compared to a 5-year OSr of 0.29(SE ¼ 0.03) when relapse occurred later. Conclusions. 5-year OSr inEwingsarcomaispoor (<0.2).Prognostically favorable factorsare: lateonset (>2 years) and strictly localized relapse. Pediatr Blood Cancer2011;57:549–553. � 2011 Wiley-Liss, Inc.

Key words: Ewing sarcoma; recurrence; risk factors; prognosis

1Department of Pediatric Hematology and Oncology, University Hos-

pital Munster, Munster, Germany; 2Department of Pediatric Oncology/

Hematology, University Witten-Herdecke, Vestic Children’s Hospital,

Datteln, Germany; 3Department of Radiotherapy and Radiation Oncol-

ogy, University Hospital Munster, Munster, Germany; 4Department of

Clinical Radiology, University Hospital Munster, Munster, Germany;5Department of Pediatric Oncology, Hematology, and Immunology,

Klinikum Stuttgart, Children’s Hospital, Stuttgart, Germany; 6Depart-

ment of Pediatric Hematology and Oncology, University Children’s

Hospital Hamburg, Hamburg, Germany; 7Department of Orthopedics,

Munster, University Hospital Munster, Munster, Germany

Grant sponsor: Deutsche Krebshilfe; Grant numbers: 50-2551-Ju3, 50-

2551-Ju4, DKH- 108128; Grant sponsor: Federal Ministry of Education

and Research Germany; Grant sponsor: BMBF (TranSaRNet); Grant

sponsor:DeutschesZentrumfurLuft-undRaumfahrte.V;Grantnumber:

01GM0869; Grant sponsor: EuroBoNet; Grant sponsor: EU-

Framework 6.

Conflict of Interest Statement:The authors havenoconflicts of interest to

disclose.

*Correspondence to:Prof.Dr.UtaDirksen,MD,DepartmentofPediatric

Hematology and Oncology, University Hospital Munster, Albert-

Schweitzer-Strasse 33, 48149 Munster, Germany.

E-mail: [email protected]

Received 29 September 2010; Accepted 27 December 2010

� 2011 Wiley-Liss, Inc.DOI 10.1002/pbc.23040Published online 25 March 2011 in Wiley Online Library(wileyonlinelibrary.com).

Relapse was confirmed by imaging including technetium

scintigraphy and/or positron emission scan and/or whole body

MRI in all cases, and confirmation of relapse by biopsy was

recommended in ambiguous cases. Patients with progression of

disease under therapy were excluded from the analysis. Complete

data sets were available in 714 patients with relapse (Fig. 1).

Relapse was classified in three groups: local (local recurrence

alone), combined (local and synchronal distant recurrence), and

systemic (distant recurrence only).

Statistical analyses of overall survival after relapse (OSr) were

performed using the Kaplan–Meier method [25]. OSr time was

calculated from diagnosis of first relapse to last follow-up or death.

Univariate comparisons between groups of patients and statistical

significancewere done by log-rank test.Multivariate test procedures

applied Cox and logistic regression analyses [26–28]. Frequencies

were compared using theChi-square or log-rank test, as appropriate.

RESULTS

Patient Characteristics

38.5%of the patients were female, and 61.5%,male. Themedian

age at diagnosis was 15.8 years (range: 0.2–57.7) and the median

follow-up time was 2.2 years (mean ¼ 4.0; range: 0.2–24.9) from

initialdiagnosis.Allpatients receivedchemotherapyaccordingto the

appropriate trial, 80.7%were given radiotherapy, and 62.4% under-

went surgery.

Type of Recurrence

Weanalyzed714patientswithfirst recurrenceofEwing sarcoma;

465 patients (65%) had primary localized, 249 patients (35%),

primary disseminated disease.

The predominant type of recurrence was systemic relapse

(n ¼ 521), which was seen in 73% of the total group, followed by

local (n ¼ 104; 15%) and combined relapse (n ¼ 89; 12%). The site

of systemic relapsewas pulmonary in 35%of the cases, bone in 29%

and multisystem or other in 36%. Systemic relapse occurred more

often in patients with primary disseminated disease (82%) than in

patients with primary localized disease (68%; P < 0.001). Strictly

localized relapse was mainly observed in patients with primary

localized disease andwas rare in patients with primary disseminated

disease (20% versus 5%; P < 0.001, Fig. 2).

Time to Recurrence

Seventy-twopercentoffirst relapsesoccurredwithin2years from

initial diagnosis, 86% within 3 years, and 94% within 5 years. The

median time to relapse was 501 days from the initial diagnosis.

Patients with primary disseminated disease relapsed significantly

earlier, with a median time to relapse of 434 days, than patients with

localized disease where the median time to relapse was 563 days

(P < 0.001). Systemic bone relapse and combined relapse were

diagnosed earlier, after median intervals of 460 and 432 days from

initial diagnosis, respectively, while other types of relapse were

diagnosed significantly later: multisystem, 516 days; systemic lung,

533 days; local, 595 days (P < 0.001).

Survival After Relapse

The 1-year OSr was 0.43 (SE ¼ 0.02), 5-year OSr, 0.13

(SE ¼ 0.01), and 10-year OSr, 0.09 (SE ¼ 0.01). Patients who

relapsed early after the primary diagnosis had a significantly poorer

outcome. Among patients who relapsed within the first 2 years after

primary diagnosis, 1-year OSr was 0.28 (SE ¼ 0.02), 2-year OSr,

0.12 (SE ¼ 0.01) and 5-year OSr, 0.07 (SE ¼ 0.01). By contrast,

patients who were in remission for more than two years after the

first diagnosis of Ewing sarcoma achieved 1-, 2-, and 5-year OSr

rates of 0.82 (SE ¼ 0.03), 0.54 (SE ¼ 0.04), and 0.29 (SE ¼ 0.03).

A longer relapse-free interval from primary diagnosis (exceeding 3

Fig.1. Cohortofrelapsedpatientsaccordingtoinitial stageofdiseaseat

diagnosis (localized or disseminated), time to relapse (before or after 2

years after initial diagnosis), and type of relapse (local, systemic, or

combined relapse).

Fig. 2. This figure shows the type of recurrence in 714 patients. The

columns represent either the entire group pf patients or patients with

localized disease at diagnosis of metastatic disease at diagnosis. Total

number and percent of the type of relapse are given. The different type of

relapse are illustrated in different colors (n ¼ 714/%).

550 Stahl et al.

Pediatr Blood Cancer DOI 10.1002/pbc

years) had no additional impact on survival (1-yearOSr: 0.81; 2-year

OSr: 0.56; 5-year OSr: 0.30, Fig. 3).

The type of relapse, i.e., local, systemic, or combined, had a

significant impact on survival (P < 0.001). Patients with local

relapse had a superior outcome with an OSr of 0.58 (SE ¼ 0.05)

at1year,0.39(SE ¼ 0.05)at2years,and0.24(SE ¼ 0.04)at5years,

while systemic relapse was associated with an unfavorable OSr of

0.43 (SE ¼ 0.01) at 1 year, 0.23 (SE ¼ 0.02) at 2 years, and 0.12

(SE ¼ 0.02) at 5 years. The least favorable outcomewas observed in

patientswith combined relapsewhereOSrwas0.24 (SE ¼ 0.05) at 1

year, 0.06 (SE ¼ 0.03) at 2 years, and 0.04 (SE ¼ 0.02) at 5 years.

Considering that systemic and combined relapse both include dis-

semination to distant sites, we determined which patients with

systemic relapse had a more favorable outcome than patients with

combined relapse (P < 0.001, Fig. 4).

Adetailedanalysisof521patientswithsystemicrelapseshoweda

significant relationship between site of systemic relapse and out-

come.Relapse in the lung, as compared to other sites, was associated

with a significantly better outcome; the proportion of pulmonary

relapse thus determined outcome results for the entire group of

patients with systemic relapse. By contrast, patients with bone or

multisystem relapse showedanoutcomecomparable to patientswith

combined relapse. Thus, the site of systemic relapse did have a

significant impact on survival (Fig. 5).

The univariate results given above were confirmed by a

multivariate Cox analysis which included the factors time to

relapse (�2 years; >2 years) and site of relapse (local, bone, lung,

multisystem, and combined; Table I).

We found early relapse within 2 years from initial diagnosis

(risk ratio (RR): 2.95; 95% CI 2.44–3.57, P < 0.001) to predict

for poor prognosis; we found that combined (RR: 2.62, 95%

CI 1.93–3.56, P < 0.001), systemic bone (RR: 1.70; 95% CI

1.30–2.24, P < 0.001) and multisystem relapse (RR: 2.08, 95%

CI 1.60–2.71, P < 0.001) were confirmed as prognostically poor.

DISCUSSION

Relapse in Ewing sarcoma is associated with a critical prognosis

and therefore represents a challenge for health care providers. Even

though significant advances have been made in the treatment of

primary Ewing sarcoma, therapeutic approaches tend to fail when

appliedsecondlineevenwhennovelagentsare includedthatwerenot

used first line [14–16]. Recent approaches focusing on novel mol-

ecular targets as monoclonal antibodies to the insulin-like growth

factor receptor failed, at least when used in a monotherapeutic

approach [11,29]. Therefore, in relapsed Ewing sarcoma ongoing

efforts towardan improvementof theprognosis isurgentlyneeded. In

our investigation we focused on putative prognostic factors by

Fig. 3. Survival after relapse according to time to relapse (n ¼ 714;

P < 0.001). OSr ¼ overall survival. n ¼ number of patients.

Fig. 4. Survival after relapse according to type of relapse (n ¼ 714;


Fig. 5. Survival according to type of systemic relapse (n ¼ 521;


TABLE I. Survival After Relapse: Multivariate Analysis

RR 95% CI P

Time to relapse

Early (< ¼ 2y) 2.95 2.44–3.57 <0.001

Type of relapse (P < 0.001)

Local 1 — —

Lung 1.30 0.99–1.69 ¼0.056

Bone 1.70 1.30–2.24 <0.001

Multisystem 2.08 1.60–2.71 <0.001

Combined 2.62 1.93–3.56 <0.001

Risk Factors in Relapsed Ewing Sarcoma 551


analyzing clinical data of a large cohort of patients. We analyzed

the data of 714 patients with Ewing sarcoma treated within the

CESS 81, CESS 86, and EICESS 92 trials. We focused our analysis

on the impact of time to relapse and type of relapse on the prognosis.

The patients had not been included into a prospective clinical trial

suitable to provide solid data on the value of therapeutic approaches

and the cohort analyzed was highly heterogeneous regarding

systemic treatment. Consequently, we did not include the analysis

on chemotherapy for relapsed disease in the data presented in this

manuscript.

The analysis regarding outcome in this high-risk group of

patients not only identified several prognostic factors but also

revealed a relationship between primary presentation and

presentation at relapse. Our results support some previously

published data, but also point to important additional novel aspects.

Our data, in agreement with Leavey et al. [30] who analyzed 262

relapsed patients treated according to the Children’s Oncology

Group protocols between 1988 and 2000, confirm the importance

of time to relapse as a prognostic factor. Furthermore, we report a

similar 5-year OSr rate (13% versus 12%) and outcome of patients

with late relapse more than 2 years after primary diagnosis (29%

versus30)or early relapse less than twoyears after primarydiagnosis

(7% versus 7%). In this cohort of patients wewere able to conduct a

detailed analysis on the type of relapse and the correlation

between the time to relapse and the type of recurrence. The main

findings of our analyses may be summarized focusing on the time to

relapse, the type of relapse and the time to relapse and type of relapse

combined. Over 80% of the recurrences occurred within 3 years

from diagnosis. Our data showed a significantly poorer prognosis in

patientswithearlycompared toa later relapse.Theprognosticcut-off

in our analyses was 24months after diagnosis. This is in accordance

with data reported for smaller cohorts [9,17,18,30,31]. The

analysis of a large cohort such as the one reviewed here provided

the opportunity to identify additional prognostic factors. Patients

with Ewing sarcoma disseminated at the time of primary diagnosis

tended to have systemic recurrences, while in patients with primary

localized Ewing sarcoma local recurrence was more common.

The reason for this difference in relapse pattern is not easily attribu-

table to the treatment given.While localized relapse in patients with

a single localized lesion at the time of diagnosis might be blamed

on poor local control, the very low prevalence of local relapse in

primarydisseminateddisease,wherequiteoftennolocalcontrolatall

is achieved, seems to contradict this argument [8,31].Whether or not

biological factors play a role in these patients might be a question

for ancillary studies. Distant bone and combined relapses occurred

significantly earlier than local relapses. One might speculate

that tumor-related and/or patient-related factors may render the

Ewing sarcoma cells prone to spread to distant sites and to develop

secondary systemic disease.

The multivariate analyses show that the site of the relapse is a

prognostic factor itself: Local relapse is the type of relapse with a

superiorprognosis.Thisresult is tosomeextent incontradictiontothe

report of Shankar et al. [17] who reviewed a smaller cohort of

64 relapsed patients and described that the site of relapse had no

influence on the final outcome. The discrepancy might be due to

the smaller patient number or to other factors like selection bias due

to different first line treatment, or success of local treatment

in relapse. Bielack et al. [32] have reported that in osteosarcoma

obtaining a complete surgical remission is the most important

prognostic factor for survival even in a second or higher relapse.

Combined relapse is associated with a poor prognosis [30].

Reasons may be the early occurrence as an independent prognostic

factor and the dissemination as a second factor. It is well known

that patients with primary pulmonary metastases fare better than

patients with extrapulmonary metastases [33–36]. Our results

suggest a better prognosis in patients diagnosed for pulmonary

metastases only at the time of relapse compared to patients with

extrapulmonary lesions.

Even though the present analysis is based on a large number

of patients with Ewing sarcoma and a long observation period,

retrospective analyses always have certain limitations. A selection

bias, incomplete, or ambiguous data, patient-, disease-, or treatment-

related factors not recorded, may taint such analyses among

other factors.

In conclusion, both the time to relapse and the type of relapse

are relevant predicting factors concerning the prognosis in a

Ewing sarcoma relapse. Relapse occurring later than 2 years after

primary diagnosis and local relapse in particular are favorable

predictors.

The overall prognosis after relapse remains unfavorable. Besides

the urgent need of the development of novel second line treatments,

our data implicate that prevention from early and most unfavorable

relapse may be feasible by modifying first line regimens. From our

data it is most reasonable to expect relapse in the first 2 years

after diagnosis. Thus, in patients with high-risk disease, prolonged

treatment, and/or introduction of novel agents could be of benefit.

The prognostic factors identified in our analysis may have an impact

on the development of novel treatment strategies and serve as a basis

for comparison.

ACKNOWLEDGMENT

This work was supported by Deutsche Krebshilfe: 50-2551-Ju3

and 50-2551-Ju4, DKH- 108128 and by Federal Ministry of

EducationandResearchGermany,BMBF(TranSaRNet),Deutsches

Zentrum fur Luft- und Raumfahrt e.V 01GM0869, EuroBoNet,

EU-Framework 6. The authors like to thank Regina Kloss and the

Ewing trial staff Munster for their kind support.

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Risk Factors in Relapsed Ewing Sarcoma 553


risk of recurrence and survival after relapse in patients with ewing sarcoma

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