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Addition of Vincristine, Topotecan, and Cyclophosphamide to Five-Drug Interval-Compressed Chemotherapy for Ewing Sarcoma


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As reported in the Journal of Clinical Oncology by Leavey et al, the phase III Children’s Oncology Group AEWS1031 trial showed no improvement in event-free or overall survival with the addition of vincristine, topotecan, and cyclophosphamide (VTC) to standard five-drug interval-compressed chemotherapy in previously untreated patients with nonmetastatic Ewing sarcoma. However, estimated survival rates were the highest reported to date in this setting.

Study Details

The multicenter trial included 629 eligible patients (median age = 13 years, range = 0–34 years, 83% < 18 years). They were randomly assigned between November 2010 and January 2016 to receive standard 5-drug interval-compressed chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC) and ifosfamide and etoposide (IE) for 17 cycles (standard group, n = 309) or 5 cycles of VTC within the 17 cycles of chemotherapy (experimental group, n = 320).

All patients received 6 cycles of induction therapy (12 weeks) and 11 cycles of consolidation therapy (22 weeks). The standard group received five cycles of VDC, four cycles of vincristine and cyclophosphamide (VC), and eight cycles of IE. In addition to five cycles of VTC, the experimental group received five cycles of VDC and seven cycles of IE.

The primary outcome measures were event-free and overall survival. Data were current through September 2020.

While VTC added to five-drug interval-compressed chemotherapy did not improve survival, these outcomes represent the best survival estimates to date for patients with previously untreated nonmetastatic Ewing sarcoma.
— Leavey et al

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Key Findings

Among all patients, estimated 5-year event-free survival and overall survival were 78% (95% confidence interval [CI] = 75%–81%) and 87% (95% CI = 84%–90%), respectively.

Event-free survival at 5 years was 79% (95% CI = 74%–83%) in the experimental group vs 78% (95% CI = 72%–82%) in the standard group (hazard ratio [HR] = 0.86, 95% CI = 0.62–1.2, P = .192).

Overall survival at 5 years was 88% (95% CI = 84%–91%) in the experimental group vs 86% (95% CI = 82%–90%) in the standard group (HR = 0.81, 95% CI = 0.54–1.2, P = .159).

For event-free survival among all patients, no significant associations with age or primary site of disease were observed; 5-year rates were 75%, 78%, and 85% among patients with pelvic, nonpelvic bone, and extraosseous primary tumors, respectively, and 79% and 75% among patients aged <18 and ≥ 18 years, respectively. Tumor volume ≥ 200 mL vs < 200 mL was associated with poorer event-free survival, with 5-year rates of 71% vs 81% (HR = 1.63, 95% CI = 1.16–2.31, P = .005).

For overall survival among all patients, no significant association with primary site of disease was observed, with 5-year rates of 87%, 85%, and 92% among patients with pelvic, nonpelvic bone, and extraosseous primary sites. Age ≥ 18 years was associated with poorer overall survival vs age < 18 years, with 5-year rates of 78% vs 89% (HR = 1.84, 95% CI = 1.15–2.96, P = .00993).

The investigators concluded, “While VTC added to five-drug interval-compressed chemotherapy did not improve survival, these outcomes represent the best survival estimates to date for patients with previously untreated nonmetastatic Ewing sarcoma.”

Patrick J. Leavey, MD, of the University of Texas Southwestern Medical Center, Dallas, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by grants from the National Clinical Trials Network and St. Baldrick’s Foundation. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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