PURPOSE: Conventional osteosarcoma is an orphan disease. Current treatment approaches include combining a three drug chemotherapy schedule and surgery. The 3- and 5-year event-free survival (EFS) in localized disease is roughly 65 and 60%, respectively. The registration study of mifamurtide reported survival benefit, but some methodological controversies have been insufficient for FDA market authorization in contrast to EMA. METHODS: prospective single centre survival analysis of a mifamurtide addition to conventional therapy in 23 patients over a 5.5 year enrolment period is reported and compared to a historical control of 26 patient with localized disease. Bias arising from observational methodology was addressed using Landmark analysis and time-dependent Cox models. Blood count dynamics were analysed during the treatment. RESULTS: The adverse event profile was as expected with no dose limiting toxicities. There were no local relapses observed, one patient died in the first complete remission due to doxorubicin cardiotoxicity, one patient had pulmonary metastatic relapse. The observed 3- and 5-year EFS was 87.4% (CI 72.4-100%) and 87.4% (CI 72.4-100%), progression free survival (PFS) was 92.9% (CI 80.3-100%) and 92.9% (CI 80.3-100%), overall survival was 94.1% (CI 83.6-100) and 80.7% (CI 58.3-100), respectively. Comparison to the historical control showed statistically significant better PFS for mifamurtide patients (Landmark analysis; p = 0.044). Risk of progression was 5-times lower for the mifamurtide group (Cox model; HR 0.21, p = 0.136). Only subtle differences in lymphocyte counts were observed across treatment. CONCLUSION: the PFS benefit of mifamurtide is reported herein. The addition of mifamurtide could be considered as a best treatment option for localized osteosarcoma.

Department of Orthopaedics St Annés University Hospital Brno and School of Medicine Masaryk University Pekarska 53 Brno 613 00 Czech Republic

Department of Paediatric Oncology University Hospital Brno and School of Medicine Masaryk University Cernopolni 9 Brno 613 00 Czech Republic

Department of Pathology St Anne's University Hospital Brno and School of Medicine Masaryk University Pekarska 53 Brno 613 00 Czech Republic

Department of Pathology University Hospital Brno and School of Medicine Masaryk University Jihlavska 20 Brno 625 00 Czech Republic

International Clinical Research Centre St Anne's University Hospital Brno Pekarska 53 Brno 656 91 Czech Republic

Zobrazit více v PubMed

Ottaviani G., Jaffe N. The epidemiology of osteosarcoma. Cancer Treat. Res. 2009;152:3–13. doi: 10.1007/978-1-4419-0284-9_1. PubMed DOI

Kager L., Pötschger U., Bielack S. Review of mifamurtide in the treatment of patients with osteosarcoma. Ther. Clin. Risk Manage. 2010;6:279–286. doi: 10.2147/tcrm.s5688. PubMed DOI PMC

Kansara M., Teng M.W., Smyth M.J., Thomas D.M. Transitional biology of Osteosarcoma. Nat. Rev. 2014;14:722–735. doi: 10.1038/nrc383. PubMed DOI

Chou A.J., Kleinerman E.S., Krailo M.D., Chen Z., Betcher D.L., Healey J.H., 3rd Conrad E.U., Nieder M.L., Weiner M.A., Wells R.J., Womer R.B., Meyers P.A. Children's Oncology Group. Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: a report from the Children's Oncology Group. Cancer. 2009;115:5339–5348. doi: 10.1002/cncr.24566. PubMed DOI PMC

Fisher L.D., Lin D.Y. Time-dependent covariates in the Cox proportional-hazards regression model. Annu. Rev. Public Health. 1999;20:145–157. doi: 10.1146/annurev.publhealth.20.1.145. PubMed DOI

Anderson J.R., Cain K.C., Gelber R.D. Analysis of survival by tumor response. J. Clin. Oncol. 1983;1:710–719. PubMed

Singer J.D., Willett J.B. Oxford University Press; 2003. Applied Longitudinal Data Analysis: Modeling Change and Event Occurrence.

T. Therneau. A Package for Survival Analysis in S_. version 2.38, https://CRAN.R-project.org/package=survival. 2015.

J. Pinheiro, D. Bates, S. DebRoy, D. Sarkar and R Core Team. _nlme: Linear and Nonlinear Mixed Effects Models_. R package version 3.1-139, https://CRAN.R-project.org/package=nlme. 2019.

R Development Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, http://www.R-project.org. 2008.

Smeland S., Bielack S.S., Whelan J., Bernstein M., Hogendoorn P., Krailo M.D., Gorlick R., Janeway K.A., Ingleby F.C., Anninga J., Antal I., Arndt C., Brown K.L.B., Butterfass-Bahloul T., Calaminus G., Capra M., Dhooge C., Eriksson M., Flanagan A.M., Friedel G., Gebhardt M.C., Gelderblom H., Goldsby R., Grier H.E., Grimer R., Hawkins D.S., Hecker-Nolting S., Hall K.S., Isakoff M.S., Jovic G., Kühne T., Kager L., von Kalle T., Kabickova E., Lang S., Lau C.C., Leavey P.J., Lessnick S.L., Mascarenhas L., Mayer-Steinacker R., Meyers P.A., Nagarajan R., Randall R.L., Reichardt P., Renard M., Rechnitzer C., Schwartz C.L., Strauss S., Teot L., Timmermann B., Sydes M.R., Marina N., Survival and prognosis with osteosarcoma: outcomes in more than patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort. Eur. J. Cancer. 2019;109:36–50. doi: 10.1016/j.ejca.2018.11.027. PubMed DOI PMC

Tacyildiz N., Incesoy O.S., Unal E., Berber M., Dincaslan H., Yavus G. The Efficiency and toxicity of mifamurtide in childhood osteosarcoma. J. Pediatr. Hematol. Oncol. 2018;40:e373–e376. doi: 10.1097/mph.0000000000001236. PubMed DOI

Brard C., Piperno-Neumann S., Delaye J. Sarcome-13/OS2016 trial protocol: a multicentre, randomised, open-label, phase II trial of mifamurtide combined with postoperative chemotherapy for patients with newly diagnosed high-risk osteosarcoma. BMJ Open. 2019;9 doi: 10.1136/bmjopen-2018-025877. PubMed DOI PMC

Meyers P.A., Chou A.J. Muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) in the treatment of osteosarcoma. Adv. Exp. Med. Biol. 2014;804:307–321. doi: 10.1007/978-3-319-04843-7_17. PubMed DOI

Anderson P.M., Meyers P., Kleinerman E., Venkatakrishnan K., Hughes D.P., Herzog C., Huh W., Sutphin R., Vyas Y.M., Shen V., Warwick A., Yeager N., Oliva C., Wang B., Liu Y., Chou A. Mifamurtide in metastatic and recurrent osteosarcoma: A patient access study with pharmacokinetic, pharmacodynamic, and safety assessments. Pediatr. Blood Cancer. 2014;61:238–244. doi: 10.1002/pbc.24686. PubMed DOI PMC