Treatment of Ewing sarcoma family of tumors with a modified P6 protocol in children and adolescents: Analysis of growth signaling pathways expression and clinical outcome.

Abstract

9560 Background: Overall survival (OS) rates of patients with localized Ewing sarcoma family of tumors (ESFT) are >80% when treated with the MSKCC P6 protocol. However, it has been associated with a 5.8% incidence of secondary leukemias. A modified P6 (mP6) protocol with reduced exposure to chemotherapy is presented. The correlation between clinical outcome and the expression of proteins involved in active growth signaling pathways was explored. Methods: Thirty-one newly diagnosed ESFT patients were enrolled onto this phase II, single-arm, non-randomized protocol. A paraffin-embedded tissue array of 45 specimens was stained with the antibodies against c-KIT, AKT, p- AKT, p-mTOR, IGF-1R, IGFBP-3, MAPK, p27KIP1, and p70S6 kinase. Immunohistochemical staining was correlated with patient OS. Results: Twenty-four patients had loco-regional disease and 7 had metastases. The 4-year event-free survival (EFS) rate for patients with localized tumours is 83% and OS is 92%. The 3-year EFS rate for patients with distant metastases is 28% and OS rate is 42%. None of the patients experienced tumour progression before remission. All relapses occurred within 2 years from the end of treatment and local relapses (n=3) happened in patients who did not receive radiation therapy. No secondary malignancies have been observed, median follow-up of 4.3 years. In the univariate analysis only p-mTOR and p27KIP1 showed statistical significance to predict survival. A positive stain for p-mTOR (HR of 4,74 [95% CI (57, 121)]) was significantly (log-rank test, p=0,029) associated with better OS. Also, a positive stain for p27KIP1 (HR 6,87 [95% CI (77, 136)] was significantly (log-rank test, p=0,009) associated with better OS. Multivariate analysis show p-mTOR (HR: 5.57 with 95% CI: 0.7 to 44; p= 0.104) and p27 (HR: 3.2 [95% CI (1.02,10.2)] p=0.047) expression as independent prognostic factors of outcome. Conclusions: In this study, the mP6 protocol produced a complete remission rate of 83% at 4 years in non-metastatic ESFT reducing the risk of secondary malignancies. In our series, p-mTOR and p27KIP1protein overexpression were independently associated with better survival.