The effectiveness of high-dose chemotherapy with autologous hematopoietic stem cell transplantation in the treatment

Background. Ewing sarcoma (EWS) is a second most common pediatric bone tumor. About one quarter of all patients belong to a high-risk group characterized by a poor prognosis. In spite of high-dose chemotherapy (HDCT) with autologous hemopoietic stem cell transplantation (auto-HSCT) being traditionally viewed as a possible option for high-risk patients, there is stills no consensus on indications for this method in EWS patients.

Study objective: to evaluate the HDCT effectiveness and most important prognostic factors in a prospective cohort of high-risk EWS patients. Materials and methods. A total of 73 EWS patients receiving treatment in R.M. Gorbacheva Memorial Institute were included in the study. All patients were characterized by one or several high-risk features: local (primary tumor volume >200 ml, axial localization, poor response to chemotherapy; n = 55; 76 %), primary disseminated disease (n = 58; 80 %), first chemoresponsive relapse (n = 7; 9 %). All patients received a myeloablative consolidation regimen consisting of busulfan 16mg/kg and melphalan 140mg/m². In patients with primary disseminated disease an additional evaluation according to risk scale by R. Ladenstein et al. was performed. Based on risk points all patients were stratified as standard (n = 20), high (n = 26), and ultrahigh risk (n = 12).

Results. The 5-year overall and event-free survivalfor a whole studied cohort were 40 and 37 %, accordingly. In patients with high-risk localized disease the 5-year overall and event-free survival were 48 and 45 %, accordingly. The HDCT regimen was characterized by acceptable toxicity. The main non-hematologic toxicities were infectious complications (n = 61) and gastrointestinal tract mucositis (n = 31). One patient of 76 died due to treatment-related complications. The multivariate analysis revealed the following risk factors: therapy response (hazard ratio (HR) 2.2; p <0.01), bone marrow involvement (HR 5.0; p = 0.01), primary tumor volume (HR 1.9; p = 0.01), and number of bone metastases (HR 2.2; p = 0.05). The risk group determined by R. Ladenstein score was also a good predictor for outcome with only 8 % of ultrahigh risk patients surviving 5 years past auto-HSCT.

Conclusion. HDCT with auto-HSCT may potentially improve treatment results in some high-risk patient subgroups. While risk scale may help to determine patients most likely to benefit from this approach, the outcome in ultrahigh risk patients are still dismal.

1. Delatte O., Zucman J., Plougastel B. et al. Gene fusions with an ETS DNA-binding domain caused by chromosome translocation in human tumors. Nature 1992;359(6391):162— 5. DOI: 10.1038/359162a0.

2. Kim S.K., Park Y.K. Ewing sarcoma: a chronicle of molecular pathogenesis. Hum Pathol 2016;55:91-100. DOI: 10.1016/j.humpath.2016.05.008.

3. Gaspar N., Hawkins D.S., Dirksen U. et al. Ewing sarcoma: current management and future approaches through collaboration. J Clin Oncol 2015;33(27):3036—46. DOI: 10.1200/JCO.2014.59.5256.

4. Karski E.E., McIlvaine E., Segal M.R. et al. Identification of discrete prognostic groups in Ewing sarcoma. Pediatr Blood Cancer 2016;63(1):47—53. DOI: 10.1002/pbc.25709.

5. Ladenstein R., Potschger U., Le Deley M.C. et al. Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING99 trial. J Clin Oncol 2010;28(20):3284—91. DOI: 10.1200/JCO.2009.22.9864.

6. Biermann J.S., Chow W., Reed D.R. et al. NCCN Guidelines Insights: Bone Cancer, Version 2.2017. J Natl Compr Canc Netw 2017;15(2):155—67. DOI: 10.6004/jnccn.2017.0017.

7. Whelan J., Le Deley M.S., Dirksen U. et al. 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 2018;36(31):3110—9. DOI: 10.1200/JCO.2018.78.2516.

8. Dirksen U., Brennan B., Le Deley M.C. et al. 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 2019; JCO1900915. [Epub ahead of print]. DOI: 10.1200/JCO.19.00915.

9. Iukhta T.V., Punanov Y.A., Kazantsev I.V et al. Combined treatment of children and adolescents with Ewing sarcoma family tumors (25 year experience). Voprosy onkologii = Oncology Questions 2015;61(2):233—8. (In Russ.).

10. Linn P.P., Jaffe N., Herzog C.E. et al. Chemotherapy response is an important predictor of local recurrence in Ewing sarcoma. Cancer 2007;109(3):603—11. DOI: 10.1002/cncr.22412.

11. Hanafy E., Al Jabri A., Gadelkarim G. et al. Tumor histopathological response to neoadjuvant chemotherapy in childhood solid malignancies: is it still impressive? J Investig Med 2018;66(2):289—97. DOI: 10.1136/jim-2017-000531.

12. Duarte R.F., Labopin M., Bader P. et al. Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2019. Bone Marrow Transplant 2019;54(10):1525—52. DOI: 10.1038/s41409-019-0516-2.

13. Majhail N.S., Farnia S.H., Carpenter P.A. et al. Indications for autologous and allogeneic hematopoietic cell transplantation: Guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2015;21(11):1863—9. DOI: 10.1016/j.bbmt.2015.07.032.

14. Casali P.G., Bielack S., Abecassis N. et al. Bone sarcomas: ESMO-PaedCan-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29(Suppl 4):iv79—95. DOI: 10.1093/annonc/mdy310.

15. Ivanova N.M., Aleinikova O.V., Mentkevich G.L. et al. High-dose chemotherapy with autologous hematopoietic stem cell transplantation in patients with high-risk Ewing sarcoma. Detskaya onkologiya = Pediatric Oncology 2003;3:26-31. (In Russ.).

16. Nisichenko O.A., Dzampaev A.Z., Nisichenko D.V. et al. Treatment of children with Ewing sarcoma of pelvis. East European Sarcoma Study Group experience. Onkopediatriya = Oncopediatrics 2015;2(3):313—14. (In Russ.).

17. Cherny N.L., Sullivan R., Dafni U. et al. A standardized, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: The European Society for Medical Oncology Magnitude of Clinical Benefit Scale. Ann Oncol 2015;26(8):1547—73. DOI: 10.1093/annonc/mdv249.

18. 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(1):168—77. DOI: 10.1016/s0360-3016(02)03797-5.

19. Bolling T., Dirksen U., Ranft A. et al. Radiation toxicity following busulfan/ melphalan high-dose chemotherapy in the EURO-EWING-99-trial: Review of GPOH data. Stralenther Onkol 2009;185(Suppl 2):21—2. DOI: 10.1007/s00066-009-1009-9.

20. Juergens H., Ranft A., Paulssen M. et al. Treosulfan-based high-dose chemotherapy with autologous stem cell transplantation in high-risk Ewing sarcoma. J Clin Oncol 2009;27(15_Suppl):10546. DOI: 10.1200/jco.2009.27.

21. Luksch R., Tienghi A., Hall K.S. et al. 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 2012;23(11):2970—6. DOI: 10.1093/annonc/mds117.

22. Skinner R., Mulder R.L., Kremer L.C. et al. Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer survivors: A report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium. Lancet Oncol 2017;18(2):e75—90. DOI: 10.1016/S1470-2045(17)30026-8.

23. Van Dorp W., Mulder R.L., Kremer L.C. et al. Recommendations for premature ovarian insufficiency surveillance for female survivors of childhood, adolescent, and young adult cancer: a report from the international late effects of childhood cancer guideline harmonization group in collaboration with the PanCareSurFup consortium. J Clin Oncol 2016;34(28):3440—50. DOI: 10.1200/JCO.2015.64.3288.

24. Rasper M., Jabar S., Ranft A. et al. The value of high-dose chemotherapy in patients with first relapsed Ewing sarcoma. Pediatr Blood Cancer 2014;61(8):1382—6. DOI: 10.1002/pbc.25042.

25. Burdach S., Thiel U., Schoniger M. et al. Total body MRI-governed involved compartment irradiation combined with high-dose chemotherapy and stem cell rescue improves long-term survival in Ewing tumor patients with multiple primary bone metastases. Bone Marrow Transplant 2010;45(3):483—9. DOI: 10.1038/bmt.2009.184.

26. Thiel U., Wawer A., von Luettichau I. et al. Bone marrow involvement identifies a subgroup of advanced Ewing sarcoma patients with fatal outcome irrespective of therapy in contrast to curable patients with multiple bone metastases but unaffected marrow. Oncotarget 2016;7(43):70957—68. DOI: 10.18632/oncotarget.10938.