Radiation Therapy Dose Escalation in Unresectable Ewing Sarcoma: Final Results of a Phase 3 Randomized Controlled Trial

Int J Radiat Oncol Biol Phys. 2022 Aug 1;113(5):996-1002. doi: 10.1016/j.ijrobp.2022.04.024. Epub 2022 May 11.

Abstract

Purpose: Our aim was to assess the effect of radiation therapy (RT) dose escalation on outcomes in surgically unresectable Ewing sarcoma (ES)/primitive neuroectodermal tumor (PNET).

Methods and materials: Patients with nonmetastatic unresectable ES/PNET (excluding intracranial/chest wall) receiving vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide chemotherapy, planned for definitive RT, were accrued in this single-institution, open-label, phase 3 randomized controlled trial. Randomization was between standard dose RT (SDRT; 55.8 Gy/31 fractions/5 days a week) versus escalated dose RT (EDRT; 70.2 Gy/39 fractions/5 days a week) with a primary objective of improving local control (LC) by 17% (65%-82%). Secondary outcomes included disease-free survival (DFS), overall survival (OS), and functional outcomes by Musculoskeletal Tumor Society score.

Results: Between April 2005 and December 2015, 95 patients (SDRT 47 and EDRT 48) with a median age of 17 years (interquartile range, 13-23 years) were accrued. The majority of patients were male (59%). Pelvis was the most common site of primary disease (n = 60; 63%). The median largest tumor dimension (9.7 cm) and the median maximum standardized uptake value (8.2) on pretreatment fluorodeoxyglucose positron emission tomography-computed tomography were similar. At a median follow-up of 67 months, the 5-year LC, DFS, and OS for the entire cohort was 62.4%, 41.3%, and 51.9%, respectively. The 5-year LC was significantly better in EDRT compared with SDRT (76.4% vs 49.4%; P = .02). The differences in DFS and OS at 5 years (for EDRT vs SDRT) did not achieve statistical significance (DFS 46.7% vs 31.8%; P = .22 and OS 58.8% vs 45.4%; P = .08). There was a higher incidence of Radiation Therapy Oncology Group grade >2 skin toxic effects (acute) in the EDRT arm (10.4% vs 2.1%; P = .08) with excellent functional outcomes (median Musculoskeletal Tumor Society score = 29) in both arms.

Conclusions: EDRT results in improved LC with good functional outcomes without a significant increase in toxic effects. Radiation dose escalation should be considered for surgically unresectable nonmetastatic ES/PNET.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cyclophosphamide
  • Etoposide
  • Female
  • Humans
  • Ifosfamide
  • Male
  • Neuroectodermal Tumors, Primitive*
  • Sarcoma, Ewing* / drug therapy
  • Sarcoma, Ewing* / pathology
  • Sarcoma, Ewing* / radiotherapy
  • Young Adult

Substances

  • Etoposide
  • Cyclophosphamide
  • Ifosfamide