Experience of using neoadjuvant three-component chemotherapy (cisplatin, doxorubicin, methotrexate) in young adults with osteosarcoma

Introduction. Modern treatment of osteosarcoma requires multicomponent therapy including pre-surgery chemotherapy. The benefits of such therapy are in vivo evaluation of chemotherapy drug activity and creation of conditions for more effective surgical intervention.

Aim. To analyze the effectiveness of three-component chemotherapy based on a combination of doxorubicin, cisplatin and methotrexate in young adults with osteosarcoma.

Materials and methods. Between 2022 and 2024, 22 patients between the ages of 18 and 42 years (mean age 30 years) with malignant tumors of the bones received treatment at the N.N. Blokhin National Medical Research Center of Oncology. Before the start of chemotherapy, all patients underwent morphological and clinical imaging examinations. The patients received 2 courses of neoadjuvant chemotherapy (doxorubicin + cisplatin + methotrexate) with subsequent surgical treatment stage.

Results. Sixteen patients fully completed neoadjuvant polychemotherapy and local control stage, 12 of them received 2 courses of MAP (doxorubicin + cisplatin + methotrexate) chemotherapy. Complete response was not observed. Stable disease was registered in 1 (8.3 %) patient, partial response in 8 (66.6 %) patients. Tumor control was achieved in 74.9 % of patients. In 3 cases, disease progression was observed. Surgical treatment was performed in 10 (83.3 %) cases, among them 9 (75 %) interventions were organ-sparing. One patient refused surgical treatment and received radical external beam radiotherapy. In 1 (8.3 %) case grade IV therapeutic pathomorphosis was observed, in 3 (25 %) – grade III, in 3 (25 %) – grade II, in 3 (25 %) – grade I, in 2 (16.7 %) cases it was not registerable (disease progression was observed).

Conclusion. During our study we achieved high level of tumor control (74.9 % of cases) but grade III–IV therapeutic pathomorphosis was achieved only in 33.3 % cases. According to our data, peak methotrexate concentration does not affect therapy effectiveness. In the future, it is necessary to include more patients in the study group, analyze recurrence-free and overall survival and compare MAP chemotherapy with standard regimen chemotherapy (cisplatin+ doxorubicin).

1. Raymond A.K., Jaffe N. Osteosarcoma multidisciplinary approach to the management from the pathologist’s perspective. Cancer Treat Res 2009;152:63–84. DOI: 10.1007/978-1-4419-0284-9_4

2. Mirabello L., Troisi R.J., Savage S.A. International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons. Int J Cancer 2009;125(1):229–34. DOI: 10.1002/ijc.24320.

3. Abate M.E., Longhi A., Galletti S. et al. Non-metastatic osteosarcoma of the extremities in children aged 5 years or younger. Pediatr Blood Cancer 2010;55(4):652–4. DOI: 10.1002/pbc.22567

4. Kager L., Zoubek A., Potschger U. et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 2003;21(10):2011–8. DOI: 10.1200/JCO.2003.08.132

5. Pakos E.E., Nearchou A.D., Grimer R.J. et al. Prognostic factors and outcomes for osteosarcoma: an international collaboration. Eur J Cancer 2009;45(13):2367–75. DOI: 10.1016/j.ejca.2009.03.005

6. Cho W.H., Song W.S., Jeon D.G. et al. Differential presentations, clinical courses, and survivals of osteosarcomas of the proximal humerus over other extremity locations. Ann Surg Oncol 2010;17(3):702–8. DOI: 10.1245/s10434-009-0825-6

7. Kaste S.C., Liu T., Billups C.A. et al. Tumor size as a predictor of outcome in pediatric non-metastatic osteosarcoma of the extremity. Pediatr Blood Cancer 2004;43(7):723–8. DOI: 10.1002/pbc.20077

8. Sutow W.W. Combination chemotherapy with Adriamycin (NSC-123127) in primary treatment of osteosarcoma (Part III). Cancer Chemother Rep 1975;6:315–7.

9. Sutow W.W., Gehan E.A., Dyment P.C. et al Multi-drug adjuvant chemotherapy in osteosarcoma: interim report of the Southwest Oncology Group Studies. Cancer Treat Rep 1978;62(2):265–9.

10. Cortez E.P., Holland J.F., Wang J.J. et al. Doxorubicin in disseminated osteosarcoma. JAMA 1972;221(10):1132–7. DOI: 10.1001/jama.221.10.1132

11. Bonnaonna G., Monifardi S., Douglass R.C. et al Phase I and preliminary phase II evaluation of Adriamycin (NSC-123127). Cancer Res 1970;30(10):2572–82.

12. Cortez E.P., Holland J.F., Wang J.J. et al. Chemotherapy of adjuvant osteosarcoma. In: Proceedings of the 24th symposium of the Colston Research Society, April, 1972. London: Butterworths, 1972.

13. Middleman E., Luce L., Frei E. Clinical trials with Adriamycin. Cancer 1971;28(4):844–50. DOI: 10.1002/1097-0142(1971)28:43.0.co;2-9

14. Smith M.A., Ungerleider R.S., Horowitz M.E. et al. Influence of doxorubicin dose intensity on response and outcome for patients with osteogenic sarcoma and Ewing’s sarcoma. J Nat Cancer Inst 1991;83(20):1460–70. DOI: 10.1093/jnci/83.20.1460

15. Nitschke R., Starling K.A., Vats T. et al. Cis-diamminedichloroplatinum II (NSC119875) In: Childhood malignancies. A Southwest Oncology Group study. Med Pediatr Oncol 1978;4(2):127–32. DOI: 10.1002/mpo.2950040208

16. Ochs J.J., Freeman A.I., Douglass H.O. Jr et al. Cis-diamminedichloroplatinum (II) in advanced osteogenic sarcoma. Cancer Treat Rep 1978;62(2):239–45.

17. Pratt C.B., Champion J.E., Senzer N. et al. Treatment of unresectable or metastatic osteosarcoma with cisplatin or cisplatin – doxorubicin. Cancer 1985;56(8):1930–3. DOI: 10.1002/1097-0142(19851015)56:83.0.co;2-u

18. Jaffe N., Knapp J., Chuang V.P. et al. Osteosarcoma intra-arterial treatment of the primary tumor with cis-diamminedichloroplatinum-II (CDP). Angiographic, pathologic and pharmacologic studies. Cancer 1983;51(3):402–7. DOI: 10.1002/1097-0142(19830201)51:33.0.co;2-p

19. Jaffe N., Raymond A.K., Ayala A. et al. Effect of cumulative courses of intra-arterial cis- diamminedichloroplatinum II on the primary tumor in osteosarcoma. Cancer 1989;63(1):63–8. DOI: 10.1002/1097-0142(19890101)63:13.0.co;2-o

20. Petrilli A.S., de Camargo B., Filho V.O. et al. Results of the Brazilian Osteosarcoma Treatment Group Studies III and IV: prognostic factors and impact on survival. J Clin Oncol 2006;24(7):1161–8. DOI: 10.1200/JCO.2005.03.5352

21. Jaffe N. Recent advances in the chemotherapy of osteogenic sarcoma. Cancer 1972;30(6):1627–31. DOI: 10.1002/1097-0142(197212)30:63.0.co;2-h

22. Skipper H.E., Schabel F.M., Wilcox W.S. Experimental evaluation of potential anticancer agents. XIV Further study of certain basic concepts underlying chemotherapy of leukemia. Cancer Chemother Rep 1964;35:1–28.

23. Laster W.R. Jr, Mayo J.G., Simpson-Herrin L. et al. Success and failure in the treatment of solid tumors. II. Kinetic parameters and “cell cure” of moderately advanced carcinoma. Cancer Chemother Rep 1969;53(3):169–88.

24. Schabel F.M. Jr. Concepts for systemic treatment of micro-metastases. Cancer 1975;35(1):15–24. DOI: 10.1002/1097-0142(197501)35:13.0.co;2-w

25. Jaffe N. Progress report on high-dose methotrexate (NSC-740) with citrovorum rescue in the treatment of metastatic bone tumor. Cancer Chemother Rep 1974;58(2):275–80.

26. Jaffe N., Traggis D. Toxicity of high-dose methotrexate (NSC-740) and citrovorum factor (NSC-3590) in osteogenic sarcoma. Cancer Chemother Rep 1975;6(1):31–6. DOI: 10.1002/1097-0142(197701)39:13.0.co;2-t

27. Jaffe N., Traggis D., Cassady J.R. et al. Multidisciplinary treatment for macrometastatic osteogenic sarcoma. Br Med J 1976;2(6043):1039–41. DOI: 10.1136/bmj.2.6043.1039

28. Frei E. III, Jaffe N., Tattersall M.H.N. et al. New approaches to cancer chemotherapy with methotrexate. N Engl J Med 1975;292(16):846–51. DOI: 10.1056/NEJM197504172921607

29. Pratt C., Shanks E., Hustu O. et al. Adjuvant multiple drug chemotherapy for osteosarcoma of the extremity. Cancer 1977;39(1):51–7. DOI: 10.1002/1097-0142(197701)39:13.0.co;2-t

30. Rosen G., Tefft M., Martinez A. et al. Combination chemotherapy and radiation therapy in the treatment of metastatic osteosarcoma. Cancer 1975;35(3):622–30. DOI: 10.1002/1097-0142(197503)35: 33.0.co;2-c

31. Meyers P.A., Schwartz C.L., Krailo M. et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate J Clin Oncol 2005;23(9):2004–11. DOI: 10.1200/JCO.2005.06.031

32. Meyers P.A., Schwartz C.L., Krailo M.D. et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival – a report from the Children’s Oncology Group J Clin Oncol 2008;26(4):633–8. DOI: 10.1200/JCO.2008.14.0095

33. Whelan J.S., Bielack S.S., Marina N. et al. EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment. Ann Oncol 2015;26(2):407–14. DOI: 10.1093/annonc/mdu526

34. Smeland S., Muller C., Alvegard T.A. et al. Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders. Eur J Cancer 2003;39(4):488–94. DOI: 10.1016/s0959-8049(02)00747-5

35. Ferrari S., Ruggieri P., Cefalo G. et al. Neoadjuvant chemotherapy with methotrexate, cisplatin, and doxorubicin with or without ifosfamide in nonmetastatic osteosarcoma of the extremity: an Italian sarcoma group trial ISG/OS-1. J Clin Oncol 2012;30(17):2112–8. DOI: 10.1200/JCO.2011.38.4420

36. Fuchs N., Bielack S.S., Epler D. et al. Long-term results of the cooperative German-Austrian-Swiss osteosarcoma study group’s protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann Oncol 1998;9(8):893–9. DOI: 10.1023/a:1008391103132

37. Bielack S.S., Kempf-Bielack B., Delling G. et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 2002;20(3):776–90. DOI: 10.1200/JCO.2002.20.3.776

38. Janeway K.A., Barkauskas D.A., Krailo M.D. et al. Outcome for adolescent and young adult patients with osteosarcoma: a report from the Children’s Oncology Group. Cancer 2012;118(18):4597–605. DOI: 10.1002/cncr.27414

39. Whelan J.S., Jinks R.C., McTiernan A. et al. Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials. Ann Oncol 2012;23(6):1607–16. DOI: 10.1093/annonc/mdr491

40. Angelini A., Mavrogenis A.F., Trovarelli G. et al. Telangiectatic osteosarcoma: a review of 87 cases. J Cancer Res Clin Oncol 2016;142(10):2197–207. DOI: 10.1007/s00432-016-2210-8

41. Bacci G., Picci P., Ferrari S. et al. Primary chemotherapy and delayed surgery for non-metastatic telangiectatic osteosarcoma of the extremities. Results in 28 patients. Eur J Cancer 1994;30A(5):620–6. DOI: 10.1016/0959-8049(94)90532-0

42. Marina N.M., Smeland S., Bielack S.S. et al. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol 2016;17(10):1396–408. DOI: 10.1016/S1470-2045(16)30214-5

43. Bielack S., Jurgens H., Jundt G. et al. Osteosarcoma: the COSS experience. Cancer Treat Res 2009;152:289–308. DOI: 10.1007/978-1-4419-0284-9_15

44. Boye K., Del Prever A.B., Eriksson M. et al. High-dose chemotherapy with stem cell rescue in the primary treatment of metastatic and pelvic osteosarcoma: final results of the ISG/SSG II study. Pediatr Blood Cancer 2014;61(5):840–5. DOI: 10.1002/pbc.24868

45. Bacci G., Longhi A., Versari M. et al. Prognostic factors for osteosarcoma of the extremity treated with neoadjuvant chemotherapy: 15-year experience in 789 patients treated at a single institution. Cancer 2006;106(5):1154–61. DOI: 10.1002/cncr.21724

46. Hauben E.I., Weeden S., Pringle J. et al. Does the histological subtype of high-grade central osteosarcoma influence the response to treatment with chemotherapy and does it affect overall survival? A study on 570 patients of two consecutive trials of the European Osteosarcoma Intergroup. Eur J Cancer 2002;38(9):1218–25. DOI: 10.1016/s0959-8049(02)00037-0

47. Bacci G., Picci P., Ruggieri P. et al. Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of the extremities. The Istituto Rizzoli Experience in 127 patients treated preoperatively with intravenous methotrexate (high versus moderate doses) and intraarterial cisplatin. Cancer 1990;65(11):2539. DOI: 10.1002/1097-0142(19900601)65:113.0.co;2-m

48. Graf N., Winkler K., Betlemovic M. et al. Methotrexate pharmacokinetics and prognosis in osteosarcoma. J Clin Oncol 1994;12(7):1443. DOI: 10.1200/JCO.1994.12.7.1443

49. Bacci G., Ferrari S., Delepine N. et al. Predictive factors of histologic response to primary chemotherapy in osteosarcoma of the extremity: study of 272 patients preoperatively treated with high-dose methotrexate, doxorubicin, and cisplatin. J Clin Oncol 1998;16(2):658. DOI: 10.1200/JCO.1998.16.2.658

50. Li .Z., Ma X., Wang Z. et al. A meta-analysis of theefficacy and safety of first-line chemotherapeutic agents for osteosarcoma. Adv Clin Exp Med 2024;33(5):445–54. DOI: 10.17219/acem/170098

51. Bramwell V.H., Burgers M., Sneath R. et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol 1992;10(10):1579–91. DOI: 10.1200/JCO.1992.10.10.1579

52. Bielack S.S., Smeland S., Whelan J.S. et al. Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable highgrade osteosarcoma and good histologic response to preoperative MAP: First results of the EURAMOS-1 good response randomized controlled trial. J Clin Oncol 2015;33(20):2279–87. DOI: 10.1200/JCO.2014.60.0734

53. Senerchia A.A., Macedo C.R., Ferman S. et al. Results of a randomized, prospective clinical trial evaluating metronomic chemotherapy in nonmetastatic patients with high-grade, operable osteosarcomas of the extremities: a report from the Latin American Group of Osteosarcoma Treatment. Cancer 2017;123(6):1003–10. DOI: 10.1002/cncr.30411