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)

Cancer. 2022 May 15;128(10):1958-1966. doi: 10.1002/cncr.34131. Epub 2022 Feb 24.

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/m2 /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/m2 (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.

Trial registration: ClinicalTrials.gov NCT01459484.

Keywords: 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.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / therapeutic use
  • Adolescent
  • Adult
  • Antineoplastic Combined Chemotherapy Protocols
  • Bone Neoplasms* / drug therapy
  • Bone Neoplasms* / pathology
  • Bone Neoplasms* / surgery
  • Child
  • Disease-Free Survival
  • Extremities / pathology
  • Humans
  • Ifosfamide
  • Italy
  • Methotrexate
  • Osteosarcoma* / drug therapy
  • Osteosarcoma* / pathology
  • Osteosarcoma* / surgery
  • Prospective Studies
  • Retrospective Studies
  • Treatment Outcome
  • Young Adult

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Ifosfamide
  • Methotrexate

Associated data

  • ClinicalTrials.gov/NCT01459484