Background According to retrospective osteosarcoma series, ABCB1/P-glycoprotein (Pgp) overexpression predicts for poor outcomes. A prospective trial to assess a risk-adapted treatment strategy using mifamurtide in Pgp+ patients was performed. Methods This was a phase 2, multicenter, uncontrolled trial including patients 40 years old or younger with nonmetastatic extremity high-grade osteosarcoma stratified according to Pgp expression. All patients received high-dose methotrexate, doxorubicin, and cisplatin (MAP) preoperatively. In Pgp+ patients, mifamurtide was added postoperatively and combined with MAP for a good histologic response (necrosis >= 90%; good responders [GRs]) or with high-dose ifosfamide (HDIFO) at 3 g/m(2)/d on days 1 to 5 for a histologic response < 90% (poor responders [PRs]). Pgp- patients received MAP postoperatively. After an amendment, the cumulative dose of methotrexate was increased from 60 to 120 g/m(2) (from 5 to 10 courses). The primary end point was event-free survival (EFS). A postamendment analysis was performed. Results In all, 279 patients were recruited, and 194 were included in the postamendment analysis: 70 (36%) were Pgp-, and 124 (64%) were Pgp+. The median follow-up was 51 months. For Pgp+ patients, 5-year EFS after definitive surgery (null hypothesis, 40%) was 69.8% (90% confidence interval [CI], 62.2%-76.2%): 59.8% in PRs and 83.7% in GRs. For Pgp- patients, the 5-year EFS rate was 66.4% (90% CI, 55.6%-75.1%). Conclusions This study showed that adjuvant mifamurtide, combined with HDIFO for a poor response to induction chemotherapy, could improve EFS in Pgp+ patients. Overall, the outcomes compared favorably with previous series. Mifamurtide and HDIFO as salvage chemotherapy are worth further study.

Phase 2 study for nonmetastatic extremity high-grade osteosarcoma in pediatric and adolescent and young adult patients with a risk-adapted strategy based on ABCB1/P-glycoprotein expression: An Italian Sarcoma Group trial (ISG/OS-2) / E. Palmerini, C. Meazza, A. Tamburini, G. Bisogno, V. Ferraresi, S.D. Asaftei, G.M. Milano, L. Coccoli, C. Manzitti, R. Luksch, M. Serra, M. Gambarotti, D.M. Donati, K. Scotlandi, R. Bertulli, C. Favre, A. Longhi, M.E. Abate, S. Perrotta, M. Mascarin, P. D'Angelo, M. Cesari, E.L. Staals, E. Marchesi, E. Carretta, T. Ibrahim, P.G. Casali, P. Picci, F. Fagioli, S. Ferrari. - In: CANCER. - ISSN 0008-543X. - 128:10(2022), pp. 1958-1966. [10.1002/cncr.34131]

Phase 2 study for nonmetastatic extremity high-grade osteosarcoma in pediatric and adolescent and young adult patients with a risk-adapted strategy based on ABCB1/P-glycoprotein expression: An Italian Sarcoma Group trial (ISG/OS-2)

P.G. Casali;
2022

Abstract

Background According to retrospective osteosarcoma series, ABCB1/P-glycoprotein (Pgp) overexpression predicts for poor outcomes. A prospective trial to assess a risk-adapted treatment strategy using mifamurtide in Pgp+ patients was performed. Methods This was a phase 2, multicenter, uncontrolled trial including patients 40 years old or younger with nonmetastatic extremity high-grade osteosarcoma stratified according to Pgp expression. All patients received high-dose methotrexate, doxorubicin, and cisplatin (MAP) preoperatively. In Pgp+ patients, mifamurtide was added postoperatively and combined with MAP for a good histologic response (necrosis >= 90%; good responders [GRs]) or with high-dose ifosfamide (HDIFO) at 3 g/m(2)/d on days 1 to 5 for a histologic response < 90% (poor responders [PRs]). Pgp- patients received MAP postoperatively. After an amendment, the cumulative dose of methotrexate was increased from 60 to 120 g/m(2) (from 5 to 10 courses). The primary end point was event-free survival (EFS). A postamendment analysis was performed. Results In all, 279 patients were recruited, and 194 were included in the postamendment analysis: 70 (36%) were Pgp-, and 124 (64%) were Pgp+. The median follow-up was 51 months. For Pgp+ patients, 5-year EFS after definitive surgery (null hypothesis, 40%) was 69.8% (90% confidence interval [CI], 62.2%-76.2%): 59.8% in PRs and 83.7% in GRs. For Pgp- patients, the 5-year EFS rate was 66.4% (90% CI, 55.6%-75.1%). Conclusions This study showed that adjuvant mifamurtide, combined with HDIFO for a poor response to induction chemotherapy, could improve EFS in Pgp+ patients. Overall, the outcomes compared favorably with previous series. Mifamurtide and HDIFO as salvage chemotherapy are worth further study.
ATP binding cassette subfamily B member 1 (ABCB1); P-glycoprotein; adolescents and young adults (AYAs); chemotherapy; high-grade bone sarcoma; mifamurtide; osteosarcoma; pediatric bone tumors; ATP Binding Cassette Transporter, Subfamily B; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Disease-Free Survival; Extremities; Humans; Ifosfamide; Italy; Methotrexate; Prospective Studies; Retrospective Studies; Treatment Outcome; Young Adult; Bone Neoplasms; Osteosarcoma
Settore MED/06 - Oncologia Medica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/945836
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