Bielack, S.

Jost, L.

Jürgens, H.

Paulussen, M.

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Annals of Oncology 19 (Supplement 2): ii97–ii98, 2008doi:10.1093/annonc/mdn103clinical recommendationsEwing’s sarcoma of the bone: ESMO ClinicalRecommendations for diagnosis, treatment and follow-upM. Paulussen1, S. Bielack2, H. Ju¨rgens3 & L. Jost4On behalf of the ESMO Guidelines Working Group*1Department of Pediatric Oncology/Hematology, University Children’s Hospital Basel (UKBB), Basel, Switzerland; 2Department of Pediatric Oncology and Hemaology,Olgahospital, Stuttgart, Germany; 3Department of Pediatric Hematology and Oncology, University Children’s Hospital Mu¨nster, Mu¨nster, Germany; 4Department ofOncology, Kantonsspital, Bruderholz, GermanyincidenceEwing tumors of bone are the second most common primarymalignant bone cancer in children and adolescents, but are alsoseen in adults. The median age at diagnosis is 15 years andthere is a male predilection of 1.5/1. Ewing’s sarcoma (ES)/peripheral neurectodermal tumors (PNETs) are diagnosed inwhite Caucasians at an incidence of 3 per million populationper year, but are very uncommon in African and Asianpopulations.diagnosisThe first symptom is usually pain—often erroneouslyattributed to trauma. Plain radiographs in two planes,complemented by computed tomography (CT) and/ormagnetic resonance imaging (MRI) are indicative ofa malignant tumor. Patients with suggestive findings should bereferred to a center with particular experience in bone sarcomabefore performing a biopsy. The definitive diagnosis is madeby biopsy, providing sufficient material for conventionalhistology and molecular biology (fresh, unfixated material). ES/PNETs are small blue round-cell tumors, PAS- and CD99(MIC2)-positive. Confirmation of diagnosis by a pathologistwith particular expertise in bone tumors is recommended[IV, C]. All ES/PNETs are high-grade tumors. While the degreeof neurological differentiation used to be applied todifferentiate classical ES from PNET, newer molecularbiology studies have shown that all ES/PNETs share a commongene rearrangement involving the EWS gene on chromosome22. In most cases, a reciprocal translocation t(11;22)(q24;q12)is found, but t(21;22)(q22;q12) and others may also be found.staging and risk assessmentBefore biopsy, the description of the local extent of the tumorrequires radiographic and CT/MRI of the entire involved bone,including adjacent joints and soft tissues. For planning of localtherapy, the precise involvement of bone, bone marrow andsoft tissues including the relationship to critical structures likenerves or vessels, must be specified. A chest CT scan is requiredto rule out lung or pleural metastases. The assessment for boneand bone marrow metastases is to include 99mTc bonescintigraphy, to detect osseous metastases, and lightmicroscopic examination of bone marrow aspirates andbiopsies taken at sites distant from the primary tumor. Positronemission tomography (PET) scanning for bone metastases andPCR techniques to investigate for bone marrow metastases aresensitive imaging methods currently under evaluation.Additional appropriate imaging studies and biopsies should betaken from suspicious sites, as the exact staging of the diseasehas impact on treatment and outcome [III, B].About 20% of the patients have ES/PNETs of the pelvicbones, 50% show extremity tumors. ES/PNETs may involve anybone and (less commonly) soft tissues. Twenty to twenty-fivepercent of the patients are diagnosed with metastatic disease(10% lung, 10% bones, 5% combinations or others).With surgery or radiotherapy alone, 5-year survival is <10%.With treatment in current multimodality trials includingchemotherapy, survival approximates to 60–70% in localizedand 20–30% in metastatic disease. Bone metastases confera poorer outcome than lung/pleura metastases (<20% versus20–40% 5-year survival) [IIa, B]. Other known prognosticfactors are tumor size or volume, serum lactate dehydrogenase(LDH) levels, axial localization or older age (>15 years). Undertreatment, poor histological response to preoperativechemotherapy, and incomplete or no surgery for local therapyare further adverse prognostic factors [IIa, B].treatment planAs ES/PNETs are rare cancers, and their management iscomplex, the accepted standard is treatment in specializedcenters and in the framework of co-operative trials.localized diseaseMultimodal approaches within clinical trials, employingcombination chemotherapy and surgery and/or radiotherapy,have raised 5-year survival rates from <10% to >60%. All*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L.Taddei 4, CH-6962 Viganello-Lugano, SwitzerlandApproved by the ESMO Guidelines Working Group: August 2002, last update January2008. This publication supercedes the previously published version—Ann Oncol 2007;18 (Suppl 2): ii79–ii80.Conflict of interest: the authors have reported no conflicts of interest.ª 2008 European Society for Medical Oncologycurrent trials employ three to six cycles of initial chemotherapyafter biopsy, followed by local therapy and another six to tencycles of chemotherapy usually applied at 3-week intervals.Treatment duration is thus 8–12 months. Agents consideredmost active include doxorubicin, cyclophosphamide,ifosfamide, vincristine, dactinomycin and etoposide. Virtuallyall active protocols are based on four- to six-drug combinationsof these substances. The protocols that have proved to be mosteffective include at least one alkylating agent (ifosfamide orcyclophosphamide) and doxorubicin [Ib, A]. Theincorporation of ifosfamide and etoposide into the treatmentregimen significantly improved the outcome for patients withnon-metastatic ES/PNETs in a randomized trial.Despite lively debate, complete surgery, where feasible, isregarded as the best modality of local control. Radiotherapyshould be applied if complete surgery is impossible, and shouldbe discussed where histological response in the surgicalspecimen was poor (i.e. >10% viable tumor cells) [IV, C]. Inone large series it was found that incomplete surgery followedby radiotherapy was not superior to radiotherapy alone.Radiotherapy is applied at doses of 40–45 Gy for microscopicresidues and 50–60 Gy for macroscopic disease [III, B].metastatic and recurrent diseaseOutside specific clinical trials, patients with metastatic diseaseought to receive therapy similar to that given for localizeddisease, with appropriate local treatment of metastases,commonly applied as radiotherapy. Several non-randomizedtrials have assessed the value of more intensive, time-compressed or high-dose chemotherapy approaches, followedby autologous stem-cell rescue, but evidence of benefit, e.g.resulting from randomized trials, is still lacking [III, B]. Theiruse may be justifiable in selected patients with isolated lungmetastases on an individual basis. In patients with lungmetastases, the resection of residual metastases afterchemotherapy, and whole lung irradiation may confera survival advantage [III, B]. Patients with bone or bonemarrow metastases and patients with recurrent disease still farepoorly, with 5-year survival rates of £20%.The only prognostic factor identified in relapse seems to betime to relapse: patients relapsing later than 2 years from initialdiagnosis have a better outcome [III, B]. Chemotherapy regimensin relapse situations are not standardized and are commonlybased on alkylating agents (cyclophosphamide, ifosfamide) incombination with topoisomerase inhibitors (etoposide,topotecan). Doxorubicin therapy is usually no longer feasible dueto previously achieved cumulative doses [III, B].response evaluationThe best radiological method used for local staging should berepeated after palliative or neoadjuvant chemotherapy and afterdefinitive local therapy. MRI may provide the most accurateevaluation of response. In case of neoadjuvant chemotherapyhistologic response should be evaluated in the resectionspecimen. The proportion of viable tumor cells providesprognostic information and may guide the use of furthertherapy including radiotherapy in localized disease.follow-upMost relapses occur in the first 3 years of follow-up; laterelapses have rarely been observed even after 15 years or longer.Beside the detection of relapse, long-term sequelae of treatmentare the main concern in long-term follow-up. Impaired renalfunction may be observed early in follow-up, but cardiac orpulmonary damage may become apparent later. Secondarycancers may arise in irradiated sites. Secondary leukemia,particularly acute myeloid leukemia, may rarely be observedindependent of previous irradiation as early as 2–5 years aftertreatment [III, B]. Follow-up intervals should be 2–3 monthsduring the first 3 years, 6 months until 5 years and at least onceyearly thereafter. Follow-up is more specifically detailed inconcurrent clinical trial manuals, e.g. EURO-E.W.I.NG. 99.noteLevels of evidence [I–V] and grades of recommendation [A–D]as used by the American Society of Clinical Oncology aregiven in square brackets. Statements without grading wereconsidered justified standard clinical practice by the expertsand the ESMO faculty.literature1. Bacci G, Ferrari S, Bertoni F et al. Prognostic factors in nonmetastatic Ewing’ssarcoma of bone treated with adjuvant chemotherapy: Analysis of 359 patients atthe Istituto Ortopedico Rizzoli. J Clin Oncol 2000; 18: 4–11.2. Bernstein ML, Devidas M, Lafreniere D et al. Intensive therapy with growth factorsupport for patients with Ewing tumor metastatic at diagnosis: Pediatric OncologyGroup/Children’s Cancer Group Phase II Study 9457—a report from theChildren’s Oncology Group. J Clin Oncol 2006; 24: 152–159.3. Pinkerton CR, Bataillard A, Guillo S et al. Treatment strategies for metastaticEwing’s sarcoma. Eur J Cancer 2001; 37: 1338–1344.4. Cotterill SJ, Ahrens S, Paulussen M et al. Prognostic factors in Ewing’s tumor ofbone: analysis of 975 patients from the European Intergroup Cooperative Ewing’sSarcoma Study Group. J Clin Oncol 2000; 18: 3108–3114.5. Nesbit ME Jr, Gehan EA, Burgert EO et al. Multimodal therapy for themanagement of primary, nonmetastatic Ewing’s sarcoma of bone: a long-term follow-up of the first intergroup study. J Clin Oncol 1990; 8: 1664–1674.6. Burgert EO Jr, Nesbit ME, Garnsey LA et al. Multimodal therapy for themanagement of nonpelvic, localized Ewing’s sarcoma of bone: intergroup studyIESS-II. J Clin Oncol 1990; 8: 1514–1524.7. Grier HE, Krailo MD, Tarbell NJ et al. Addition of ifosfamide and etoposide tostandard chemotherapy for Ewing’s sarcoma and primitive neuroectodermaltumor of bone. N Engl J Med 2003; 348: 694–701.8. Schuck A, Ahrens S, Paulussen M et al. Local therapy in localized Ewing tumors:results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials.Int J Radiat Oncol Biol Phys 2003; 55: 168–177.9. Bacci G, Forni C, Longhi A et al. Long-term outcome for patients with non-metastatic Ewing’s sarcoma treated with adjuvant and neoadjuvantchemotherapies. 402 patients treated at Rizzoli between 1972 and 1992. EurJ Cancer 2004; 40: 73–83.10. Paulussen M, Ahrens S, Craft AW. Ewing’s tumors with primary lung metastases.Survival analysis of 114 (European Intergroup) Cooperative Ewing’s SarcomaStudy patients. J Clin Oncol 1998; 16: 3044–3052.11. Cangir A, Vietti TJ, Gehan EA et al. Ewing’s sarcoma metastatic at diagnosis.Results and comparisons of two intergroup Ewing’s sarcoma studies. Cancer1990; 66: 887–893.12. EURO-E.W.I.N.G. 99 treatment manual. http://euro-ewing.klinikum.uni-muenster.de/ (last accessed 2007-03-14).clinical recommendations Annals of Oncologyii98 | ESMO Guidelines Working Group Volume 19 | Supplement 2 | May 2008

Ewing's sarcoma of the bone: ESMO Clinical Recommendations for diagnosis, treatment and follow-up

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