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Aktuelle Überlegungen zur System- und Lokaltherapie beim Ewing-Sarkom

Current considerations regarding systemic and local therapy of Ewing’s sarcoma

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  • Published:
Die Onkologie Aims and scope

Zusammenfassung

Hintergrund

Das Ewing-Sarkom (EWS) ist ein bösartiger Tumor des Knochen- und Weichteilgewebes. Bereits bei der Diagnosestellung weisen 25 % der Patienten Fernmetastasen auf. Die multimodale Therapie setzt sich aus einer chemotherapeutischen Induktionsphase mit darauffolgender chirurgischer und/oder radiotherapeutischer Lokaltherapie und einer anschließenden adjuvanten Chemotherapie zusammen.

Ergebnisse

Bei lokoregionärer Erkrankung wird derzeit eine Kombinationschemotherapie, bestehend aus den Substanzen Ifosfamid, Cyclophosphamid, Doxorubicin, Etoposid, Actinomycin D und Vincristin, als Standard angesehen. Bei ungünstigem histologischen Ansprechen auf eine konventionell dosierte Chemotherapie wird eine hochdosierte Chemotherapie mit Busulfan und Melphalan in Verbindung mit einer Stammzelltransplantation eingesetzt. Die Planung der Lokaltherapie ist geprägt von der Möglichkeit einer makroskopisch vollständigen, En-bloc-Resektion mit tumorfreien Resektionsrändern und der perioperativen Morbidität. Aktuell wird oftmals eine Kombination aus Operation und Bestrahlung der Tumorregion favorisiert. Dabei erfolgt die Bestrahlung unter Einsatz hochkonformaler Techniken, wie z. B. der Protonentherapie, die heute bereits breiter verfügbar ist und mit der vielversprechende Ergebnisse bei der Behandlung des EWS erreicht werden konnten. Im Fall einer Metastasierung kann eine konsequente Lokaltherapie die Behandlungsergebnisse verbessern.

Abstract

Background

Ewing’s sarcoma (EWS) is a malignant tumor of bone and soft tissue. At diagnosis, 25% of patients already present with distant metastases. Multimodal therapy comprises induction chemotherapy, followed by surgical and/or radiotherapeutic local therapy and subsequent adjuvant chemotherapy.

Results

For locoregional disease, combination chemotherapy consisting of ifosfamide, cyclophosphamide, doxorubicin, etoposide, actinomycin D, and vincristine is currently considered standard. In poor responders to induction chemotherapy, high-dose chemotherapy (i.e. with busulfan and melphalan) with stem cell transplantation is given. Local therapy is guided by the ability of a complete, en bloc resection with tumor-free resection margins with acceptable perioperative morbidity. Currently, a combination of surgery and irradiation of the tumor region, including tissue possibly contaminated by the initial biopsy, is often performed. Radiotherapy is delivered using highly conformal techniques, such as proton beam therapy, which is now more widely available and has achieved promising results in the treatment of EWS. In case of metastases at diagnosis, local therapy of distant sites can improve the treatment results.

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Literatur

  1. Andreou D, Hardes J, Gosheger G et al (2015) Interdisciplinary diagnostic and treatment of bone sarcomas of the extremities and trunk. Handchir Mikrochir Plast Chir 47:90–99

    CAS  PubMed  Google Scholar 

  2. Andreou D, Ranft A, Gosheger G et al (2020) Which factors are associated with local control and survival of patients with localized pelvic ewing’s sarcoma? A retrospective analysis of data from the Euro-EWING99 trial. Clin Orthop Relat Res 478:290–302

    Article  PubMed  Google Scholar 

  3. Anonymous (2022) Untersuchung der Tumorheterogenität am Beispiel Fusionsgetriebener Sarkome. https://www.dekade-gegen-krebs.de/de/wir-ueber-uns/aktuelles-aus-der-dekade/_documents/untersuchung-der-tumorheterogenitaet.html?nn=474168. Zugegriffen: 31. Jan. 2022

  4. Attia S, Bolejack V, Ganjoo KN, George S, Agulnik M, Rushing DA, Loggers ET, Livingston MB, Wright JA, Chawla SP, Okuno SH, Reinke DK, Riedel RF, Davis LE, Ryan CW, Maki RG (2017) A phase II trial of regorafenib (REGO) in patients (pts) with advanced Ewing sarcoma and related tumors (EWS) of soft tissue and bone: SARC024 trial results. J Clin Oncol 35:1

    Article  Google Scholar 

  5. Bedetti B, Wiebe K, Ranft A et al (2015) Local control in Ewing sarcoma of the chest wall: results of the EURO-EWING 99 trial. Ann Surg Oncol 22:2853–2859

    Article  PubMed  Google Scholar 

  6. Bölling T, Dirksen U, Ranft A et al (2009) Radiation toxicity following busulfan/melphalan high-dose chemotherapy in the EURO-EWING-99-trial: review of GPOH data. Strahlenther Onkol 185(2):21–22

    Article  PubMed  Google Scholar 

  7. Bosma SE, Cleven AHG, Dijkstra PDS (2019) Can navigation improve the ability to achieve tumor-free margins in pelvic and sacral primary bone sarcoma resections? A historically controlled study. Clin Orthop Relat Res 477:1548–1559

    Article  PubMed  PubMed Central  Google Scholar 

  8. Bosma SE, Rueten-Budde AJ, Lancia C et al (2019) Individual risk evaluation for local recurrence and distant metastasis in Ewing sarcoma: a multistate model: a multistate model for ewing sarcoma. Pediatr Blood Cancer 66:e27943

    Article  CAS  PubMed  Google Scholar 

  9. Brennan B, Kirton L, Marec-Berard P, Martin-Broto J, Gelderblom H, Gaspar N, Strauss SJ, Urgelles AS, Anderton J, Laurence V, Whelan J, Wheatley K (2020) Comparison of two chemotherapy regimens in Ewing sarcoma (ES): overall and subgroup results of the Euro Ewing 2012 randomized trial (EE2012). J Clin Oncol 38:1

    Article  Google Scholar 

  10. Burgert EO Jr., Nesbit ME, Garnsey LA et al (1990) Multimodal therapy for the management of nonpelvic, localized Ewing’s sarcoma of bone: intergroup study IESS-II. J Clin Oncol 8:1514–1524

    Article  PubMed  Google Scholar 

  11. Chan RC, Sutow WW, Lindberg RD et al (1979) Management and results of localized Ewing’s sarcoma. Cancer 43:1001–1006

    Article  CAS  PubMed  Google Scholar 

  12. Choy E, Butrynski JE, Harmon DC et al (2014) Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy. BMC Cancer 14:813

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Craft AW, Cotterill SJ, Bullimore JA et al (1997) Long-term results from the first UKCCSG Ewing’s tumour study (ET-1). United Kingdom children’s cancer study group (UKCCSG) and the medical research council bone sarcoma working party. Eur J Cancer 33:1061–1069

    Article  CAS  PubMed  Google Scholar 

  14. Delaney TF, Trofimov AV, Engelsman M et al (2005) Advanced-technology radiation therapy in the management of bone and soft tissue sarcomas. Cancer Control 12:27–35

    Article  PubMed  Google Scholar 

  15. Dirksen U, Brennan B, Le Deley MC et al (2019) High-dose chemotherapy compared with standard chemotherapy and lung radiation in ewing sarcoma with pulmonary metastases: results of the European ewing tumour working initiative of national groups, 99 trial and EWING 2008. J Clin Oncol 37:3192–3202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Dirksen U, Bhadri V, Brichard B, Butterfass-Bahloul T, Cyprova S, Faldum A, Gelderblom H, Hardes J, Hauser P, Havemann L, Hjorth L, Juergens H, Kanerva J, Kuehne T, Ladenstein RL, Raciborska A, Rascon J, Timmermann B, Ranft A, Koch R (2020) Efficacy of add-on treosulfan and melphalan high-dose therapy in patients with high-risk metastatic Ewing sarcoma: report from the international Ewing 2008R3 trial. J Clin Oncol 38:1

    Google Scholar 

  17. Dirksen U, Brennan B, Judson IR, Bernstein ML, Gorlick RG, Marina N, Womer RB, Cozic N, Gaspar N, Le Teuff G, Marec-Berard P, Faldum A, Paulussen M, Juergens H, Hjorth L, Wheatley K, Krailo MD, Whelan J, Hawkins DS (2016) Efficacy of busulfan-melphalan high dose chemotherapy consolidation (BuMel) compared to conventional chemotherapy combined with lung irradiation in ewing sarcoma (ES) with primary lung metastases: Results of EURO-EWING 99-R2pulm randomized trial (EE99R2pul). J Clin Oncol 34:1

    Article  Google Scholar 

  18. Dirksen U, Ranft A, Baumhoer D, van den Berg H, Brichard B, Eich HT, Gelderblom H, Hardes J, Hartmann W, Juergens H, Kollar A, Kruseova J, Kuehne T, Ladenstein RL, Leithner A, Streitbuerger A, Timmermann B, Tunn PU, Adreou D (2021) Association of treatment delays with an unfavorable outcome in patients with localized Ewing sarcoma: a retrospective analysis of data from the GPOH Euro‑E.W.I.N.G. 99 trial. J Clin Oncol 39:1

    Article  Google Scholar 

  19. Dubois S, Buxton A, Laack N, Randall L, Chen H, Seibel N, Terezakis S, Hill-Kayser C, Hayes-Jordan A, Reid J, Teot L, Rakheja D et al (2019) Randomized phase 3 trial of ganitumab added to interval compressed chemotherapy for patients with newly diagnosed metastatic ewing sarcoma: a report from the children’s oncology group (cog). Connective Tissue Oncology Society (CTOS),

    Google Scholar 

  20. Dunst J, Schuck A (2004) Role of radiotherapy in Ewing tumors. Pediatr Blood Cancer 42:465–470

    Article  PubMed  Google Scholar 

  21. Elghazawy H, Nasr A, Zaky I et al (2020) Whole lung irradiation for completely responding pulmonary metastases in pediatric Ewing sarcoma. Future Oncol 16:1043–1051

    Article  CAS  PubMed  Google Scholar 

  22. Enneking WF, Dunham WK (1978) Resection and reconstruction for primary neoplasms involving the innominate bone. J Bone Joint Surg Am 60:731–746

    Article  CAS  PubMed  Google Scholar 

  23. Evans RG, Nesbit ME, Gehan EA et al (1991) Multimodal therapy for the management of localized Ewing’s sarcoma of pelvic and sacral bones: a report from the second intergroup study. J Clin Oncol 9:1173–1180

    Article  CAS  PubMed  Google Scholar 

  24. Federico SM, Pappo AS, Sahr N et al (2020) A phase I trial of talazoparib and irinotecan with and without temozolomide in children and young adults with recurrent or refractory solid malignancies. Eur J Cancer 137:204–213

    Article  CAS  PubMed  Google Scholar 

  25. Foulon S, Brennan B, Gaspar N et al (2016) Can postoperative radiotherapy be omitted in localised standard-risk Ewing sarcoma? An observational study of the Euro‑E.W.I.N.G group. Eur J Cancer 61:128–136

    Article  PubMed  Google Scholar 

  26. Gaspar N, Hawkins DS, Dirksen U et al (2015) Ewing sarcoma: current management and future approaches through collaboration. J Clin Oncol 33:3036–3046

    Article  CAS  PubMed  Google Scholar 

  27. Gerrand C, Bate J, Seddon B et al (2020) Seeking international consensus on approaches to primary tumour treatment in Ewing sarcoma. Clin Sarcoma Res 10:21

    Article  PubMed  PubMed Central  Google Scholar 

  28. Granowetter L, Womer R, Devidas M et al (2009) Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a children’s oncology group study. J Clin Oncol 27:2536–2541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Grier HE, Krailo MD, Tarbell NJ et al (2003) Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 348:694–701

    Article  CAS  PubMed  Google Scholar 

  30. Grünewald TGP, Cidre-Aranaz F, Surdez D et al (2018) Ewing sarcoma. Nat Rev Dis Primers 4:5

    Article  PubMed  Google Scholar 

  31. Guenther LM, Dharia NV, Ross L et al (2019) A combination CDK4/6 and IGF1R inhibitor strategy for Ewing sarcoma. Clin Cancer Res 25:1343–1357

    Article  CAS  PubMed  Google Scholar 

  32. Haeusler J, Ranft A, Boelling T et al (2010) The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES). Cancer 116:443–450

    Article  PubMed  Google Scholar 

  33. Hesla AC, Papakonstantinou A, Tsagkozis P (2021) Current status of management and outcome for patients with ewing sarcoma. Cancers 13(6):1202. https://doi.org/10.3390/cancers13061202

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hesla AC, Tsagozis P, Jebsen N et al (2016) mproved prognosis for patients with Ewing sarcoma in the sacrum compared with the innominate bones: the Scandinavian sarcoma group experience. J Bone Joint Surg Am 98:199–210

    Article  PubMed  Google Scholar 

  35. Italiano A, Mir O, Mathoulin-Pelissier S et al (2020) Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial. Lancet Oncol 21:446–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Keole S, Ashman JB, Daniels TB (2014) Proton therapy for sarcomas. Cancer J 20:409–414

    Article  CAS  PubMed  Google Scholar 

  37. Ladenstein R, Potschger U, Le Deley MC et al (2010) Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 28:3284–3291

    Article  CAS  PubMed  Google Scholar 

  38. Laskar S, Sinha S, Chatterjee A, Khanna NR, Puri A, Gulia A, Nayak P, Vora T, Chinnaswamy G, Prasad M, Juvekar S, Desai S, Janu A, Rangarajan V, Purandare N, Shah S, Rekhi B, Jambhekar N, Muckaden MA, Kurkure P (2019) Radiotherapy dose escalation in unresectable ewing’s sarcoma/PNET: final results of a phase III randomized controlled trial. Int J Radiat Oncol Biol Phys. https://doi.org/10.1016/j.ijrobp.2019.06.504

    Article  Google Scholar 

  39. Le Deley MC, Paulussen M, Lewis I et al (2014) Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol 32:2440–2448

    Article  CAS  PubMed  Google Scholar 

  40. Leavey PJ, Laack NN, Krailo MD et al (2021) Phase III trial adding vincristine-topotecan-cyclophosphamide to the initial treatment of patients with nonmetastatic ewing sarcoma: a children’s oncology group report. J Clin Oncol 39:4029–4038

    Article  CAS  PubMed  Google Scholar 

  41. Ludwig JA, Meyers PA, Dirksen U (2021) Ewing’s sarcoma. N Engl J Med 384:1476

    Article  PubMed  Google Scholar 

  42. Luksch R, Tienghi A, Hall KS et al (2012) Primary metastatic Ewing’s family tumors: results of the Italian sarcoma group and Scandinavian sarcoma group ISG/SSG IV study including myeloablative chemotherapy and total-lung irradiation. Ann Oncol 23:2970–2976

    Article  CAS  PubMed  Google Scholar 

  43. Mounessi FS, Lehrich P, Haverkamp U et al (2013) Pelvic Ewing sarcomas. Three-dimensional conformal vs. intensity-modulated radiotherapy. Strahlenther Onkol 189:308–314

    Article  CAS  PubMed  Google Scholar 

  44. Pappo AS, Dirksen U (2018) Rhabdomyosarcoma, Ewing sarcoma, and other round cell sarcomas. J Clin Oncol 36:168–179

    Article  CAS  PubMed  Google Scholar 

  45. Paulino AC, Nguyen TX, Mai WY et al (2007) Dose response and local control using radiotherapy in non-metastatic Ewing sarcoma. Pediatr Blood Cancer 49:145–148

    Article  PubMed  Google Scholar 

  46. Paulussen M, Craft AW, Lewis I et al (2008) Results of the EICESS-92 study: two randomized trials of Ewing’s sarcoma treatment—cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients. J Clin Oncol 26:4385–4393

    Article  CAS  PubMed  Google Scholar 

  47. Rao A, Chen Q, Ermoian R et al (2017) Practice patterns of palliative radiation therapy in pediatric oncology patients in an international pediatric research consortium: Rao et al. Pediatr Blood Cancer 64:e26589

    Article  CAS  Google Scholar 

  48. Sankar S, Theisen ER, Bearss J et al (2014) Reversible LSD1 inhibition interferes with global EWS/ETS transcriptional activity and impedes Ewing sarcoma tumor growth. Clin Cancer Res 20:4584–4597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Schuck A, Ahrens S, Paulussen M et al (2003) 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 55:168–177

    Article  PubMed  Google Scholar 

  50. Scobioala S, Ranft A, Wolters H et al (2018) Impact of whole lung irradiation on survival outcome in patients with lung relapsed Ewing sarcoma. Int J Radiat Oncol Biol Phys 102:584–592

    Article  PubMed  Google Scholar 

  51. Seddon BM, Cassoni AM, Galloway MJ et al (2005) Fatal radiation myelopathy after high-dose busulfan and melphalan chemotherapy and radiotherapy for Ewing’s sarcoma: a review of the literature and implications for practice. Clin Oncol 17:385–390

    Article  CAS  Google Scholar 

  52. Strauss SJ, Frezza AM, Abecassis N et al (2021) Bone sarcomas: ESMO-EURACAN-GENTURIS-ERN PaedCan clinical practice guideline for diagnosis, treatment and follow-up. Ann Oncol 32:1520–1536

    Article  CAS  PubMed  Google Scholar 

  53. Su Z, Indelicato DJ, Mailhot RB et al (2020) Impact of different treatment techniques for pediatric Ewing sarcoma of the chest wall: IMRT, 3DCPT, and IMPT with/without beam aperture. J Appl Clin Med Phys 21:100–107

    Article  PubMed  PubMed Central  Google Scholar 

  54. Talleur AC, Navid F, Spunt SL et al (2016) Limited margin radiation therapy for children and young adults with Ewing sarcoma achieves high rates of local tumor control. Int J Radiat Oncol Biol Phys 96:119–126

    Article  PubMed  PubMed Central  Google Scholar 

  55. Toretsky JA, Gorlick R (2010) IGF-1R targeted treatment of sarcoma. Lancet Oncol 11:105–106

    Article  PubMed  Google Scholar 

  56. Wexler LH, Delaney TF, Tsokos M et al (1996) Ifosfamide and etoposide plus vincristine, doxorubicin, and cyclophosphamide for newly diagnosed Ewing’s sarcoma family of tumors. Cancer 78:901–911

    Article  CAS  PubMed  Google Scholar 

  57. Whelan J, Le Deley MC, Dirksen U et al (2018) High-dose chemotherapy and blood autologous stem-cell rescue compared with standard chemotherapy in localized high-risk ewing sarcoma: results of Euro‑E.W.I.N.G.99 and Ewing-2008. J Clin Oncol 36:Jco2018782516

    Article  Google Scholar 

  58. Womer RB, West DC, Krailo MD et al (2012) Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the children’s oncology group. J Clin Oncol 30:4148–4154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zöllner SK, Amatruda JF, Bauer S et al (2021) Ewing sarcoma-diagnosis, treatment, clinical challenges and future perspectives. J Clin Med 10(8):1685

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Zöllner SK, Selvanathan SP, Graham GT et al (2017) Inhibition of the oncogenic fusion protein EWS-FLI1 causes G(2)-M cell cycle arrest and enhanced vincristine sensitivity in Ewing’s sarcoma. Sci Signal 10(499):eaam8429. https://doi.org/10.1126/scisignal.aam8429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Klinik für Partikeltherapie, Universitätsklinikum Essen, Westdeutsches Protonentherapiezentrum Essen (WPE), Westdeutsches Tumorzentrum (WTZ), Deutsches Konsortium für Translationale Krebsforschung (DKTK), Hufelandstr. 55, 45147, Essen, Deutschland

    Beate Timmermann

  2. Abteilung für Tumororthopädie und Sarkomchirurgie, Helios Klinikum Bad Saarow, Sarkomzentrum Berlin-Brandenburg, Bad Saarow, Deutschland

    D. Andreou

  3. Klinik für Kinderheilkunde III, Universitätsklinikum Essen, Westdeutsches Tumorzentrum (WTZ), Deutsches Konsortium für Translationale Krebsforschung (DKTK), Essen, Deutschland

    U. Dirksen

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  1. Beate Timmermann
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Correspondence to Beate Timmermann.

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B. Timmermann, D. Andreou und U. Dirksen geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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Timmermann, B., Andreou, D. & Dirksen, U. Aktuelle Überlegungen zur System- und Lokaltherapie beim Ewing-Sarkom. Onkologie 28, 563–571 (2022). https://doi.org/10.1007/s00761-022-01128-5

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