Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group

Abstract

Purpose: Chemotherapy with alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide cycles and primary tumor treatment with surgery and/or radiation therapy constitute the usual approach to localized Ewing sarcoma in North America. We tested whether chemotherapy intensification through interval compression could improve outcome.

Patients and methods: This was a prospective, randomized controlled trial for patients younger than 50 years old with newly diagnosed localized extradural Ewing sarcoma. Patients assigned to standard and intensified treatment were to begin chemotherapy cycles every 21 and 14 days, respectively, provided an absolute neutrophil count greater than 750×10(6)/L and a platelet count greater than 75×10(9)/L. Patients received vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1.2 g/m2) alternating with ifosfamide (9 g/m2) and etoposide (500 mg/m2) for 14 cycles, with filgrastim (5 mg/kg per day; maximum, 300 mg) between cycles. Primary tumor treatment (surgery, radiation, or both) was to begin at week 13 (after four cycles in the standard arm and six cycles in the intensified arm). The primary end point was event-free survival (EFS). The study is registered at ClinicalTrials.gov (identifier: NCT00006734).

Results: Five hundred eighty-seven patients were enrolled and randomly assigned, and 568 patients were eligible, with 284 patients in each regimen. For all cycles, the median cycle interval for standard treatment was 21 days (mean, 22.45 days); for intensified treatment, the median interval was 15 days (mean, 17.29 days). EFS at a median of 5 years was 65% in the standard arm and 73% in the intensified arm (P=.048). The toxicity of the regimens was similar.

Conclusion: For localized Ewing sarcoma, chemotherapy administered every 2 weeks is more effective than chemotherapy administered every 3 weeks, with no increase in toxicity.

Fig 1.

Design of the study. Regimen A was the control regimen, and regimen B was the experimental (intensified) regimen. Cycles of vincristine-doxorubicin-cyclophosphamide alternated with cycles of ifosfamide-etoposide. CPM, cyclophosphamide (1,200 mg/m² on day 1 of each cycle); Dox, doxorubicin (37.5 mg/m² on days 1 and 2 of each cycle; cumulative dose, 375 mg/m² for all patients); ETOP, etoposide (100 mg/m² on days 1 through 5 of each cycle); IFOS, ifosfamide (1,800 mg/m² on days 1 through 5 of each cycle); VCR, vincristine (1.5 mg/m² [maximum, 2 mg] on day 1 of each cycle); Q2W, every 2 weeks; Q3W, every 3 weeks.

Fig 2.

CONSORT diagram. Patients who experienced a relapse, second malignant neoplasm (SMN), or death before the last contact date were counted as having an event. LC, local control; RT, radiation therapy; SX, surgery.

Fig 3.

Kaplan-Meier plots of treatment outcome. (A) Event-free survival (EFS) according to the assigned treatment regimen. (B) Overall survival (OS) by regimen. (C) EFS and (D) OS, respectively, for the four strata, pooling the treatment regimens.