Study Finds High-Dose Ifosfamide Superior to Other Standard-of-Care Treatments in Recurrent and Primary Refractory Ewing Sarcomas

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Use of high-dose ifosfamide was found to be superior for treating recurrent and primary refractory Ewing sarcomas compared with three other standard-of-care treatments used for the disease, according to research presented by McCabe et al during the Plenary Session at the 2022 ASCO Annual Meeting (Abstract LBA2).

The current 5-year survival rate of recurrent and primary refractory Ewing sarcomas is about 15%. Ewing tumors are uncommon, with about 200 children and teens diagnosed with the disease in the United States each year.

“The rEECur study has, for the first time, accrued randomized data for four widely used chemotherapy regimens and is now accruing data for a fifth regimen. Before the rEECur study, the basis for choosing drugs for patients with relapsed or refractory Ewing sarcoma was weak and lacking randomized trials to inform clinicians or patients about which treatments were most effective and/or most toxic,” said lead author Martin McCabe, MD, PhD, Clinical Senior Lecturer in Pediatric and Adolescent Oncology at the University of Manchester, England.

Study Details

The phase II/III rEECur study is the first trial to provide comparative toxicity and survival data for the four most commonly used chemotherapy regimens in recurrent and primary refractory Ewing sarcomas. The trial randomly assigned patients in Europe, aged 4 to 50 (median age, 19) with recurrent and primary refractory Ewing sarcomas to either topotecan plus cyclophosphamide, irinotecan plus temolozomide, gemcitabine plus docetaxel, or high-dose ifosfamide. The primary outcome was event-free survival in the phase III comparison. Secondary outcomes included reviews of responses by imaging, overall survival, toxicity, and quality of life. At the first and second interim assessments, patients receiving irinotecan plus temolozomide and gemcitabine plus docetaxel had worse objective responses and event-free survival than the other treatments, thereby halting recruitment to both groups. The final assessment was a phase III evaluation of topotecan plus cyclophosphamide vs ifosfamide. Median follow-up was 40 months.

The regimens were chosen because they were the most widely used regimens for recurrent or refractory Ewing sarcoma in Europe at the time the trial was established. These choices were important as some regimens, notably irinotecan plus temolozomide and topotecan plus cyclophosphamide, were being used as the chemotherapy backbone in trials with molecularly targeted agents. 

The study showed that high-dose ifosfamide prolonged median event-free survival by 5.7 months compared with 3.7 months for topotecan plus cyclophosphamide. Median overall survival was 16.8 months for ifosfamide vs 10.4 months for topotecan plus cyclophosphamide. A greater survival difference was observed for patients younger than age 14 than those 14 and older.

In earlier phases of the trial, irinotecan plus temolozomide and gemcitabine plus docetaxel were found to be inferior to ifosfamide, and those enrollment arms were dropped from the trial. Ifosfamide led to more brain and kidney toxicities than topotecan plus cyclophosphamide. Both ifosfamide and topotecan plus cyclophosphamide led to similar febrile neutropenia in 26% and 25% of patients, respectively. Quality-of-life scores favored ifosfamide over topotecan plus cyclophosphamide in children but not in adults.

The trial is continuing to recruit patients to the ifosfamide arm. It has also added a fifth chemotherapy arm that includes carboplatin and an etoposide. The investigators plan to introduce a new arm involving a molecularly targeted therapeutic later this year.

ASCO Perspective

“Data showing the impact of ifosfamide on improved overall survival for patients with recurrent and primary refractory Ewing sarcoma are potentially practice-changing. Prior to this trial, no direct comparison of the most commonly available regimens was available to help guide treatment choices. Findings from the rEECur trial could help physicians talk with patients and their families about the likelihood of response, survival, and toxicity for each regimen available for relapsed Ewing sarcoma based on objective, randomized data,” said Vicki L. Keedy, MD, MSc, an ASCO expert in sarcoma.

Disclosure: The rEECur trial was funded by the Cancer Research UK and European Commission with additional funding from the Aamu Pediatric Cancer Foundation, Australia and New Zealand Children's Hematology and Oncology Group, Australia and New Zealand Sarcoma Association, Canteen, German Cancer Aid, Swiss Pediatric Oncology Group, and the Zoé4life 4life Other Foundation. For full disclosures of the study authors, visit


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