Will High-Dose Ifosfamide Become the Go-To Therapy in Recurrent Ewing Sarcoma?

CHICAGO — High-dose ifosfamide proved more effective at prolonging event-free survival (EFS) and overall survival (OS) than topotecan plus cyclophosphamide in relapsed/refractory Ewing sarcoma, according to the rEECur trial.

The phase II/III trial compared the four most commonly used regimens at the time in Europe (recruitment started in 2014), specifically:

• Topotecan and cyclophosphamide (TC)
• Irinotecan (Campto) and temozolomide
• Gemcitabine (Gemzar) and docetaxel
• High-dose ifosfamide (3000 mg/m²)

Treatment with ifosfamide led to a median EFS of 5.7 months (95% CI 3.8, 6.9) versus a median EFS of 3.5 months (95% CI 2.1, 5.1), according to Martin McCabe, PhD, of the University of Manchester in England.

Patients treated with ifosfamide had a median OS of 15.4 months versus 10.4 months with TC, he said in a presentation at the American Society of Clinical Oncology (ASCO) annual meeting. He also reported at an ASCO press conference that at 1-year, 55% of the patients on ifosfamide were alive versus 45% of the patients on TC.

“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 [carboplatin-etoposide],” McCabe said. “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.”

However, he also cautioned that the “differences between the best performing arms in rEECur are relatively modest. New, more effective drugs are needed to cure more patients.”

Vicki Keedy, MD, of Vanderbilt University in Nashville, said the trial data “are potentially practice changing…Prior to this trial, no direct comparison of the most commonly available regimens were 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,” Keedy, who was not involved in the study, told MedPage Today.

Ewing tumors are rare; about 200 children and teens are diagnosed with the disease in the U.S. each year, according to the American Cancer Society. Keedy said that 70% to 80% of patients with Ewing sarcoma will respond favorably to initial treatment of surgery and a chemotherapy regimen, and that response can last 7 to 10 months. The current study discusses how to treat the remaining patients who relapse or don’t respond to initial therapy, she noted, adding that even among those who relapse, about 15% can achieve a cure.

“Given the rarity of the disease, in the phase III comparison, we judged a 70% probability that one arm was better than another would be sufficient to take that arm forward as the standard arm in future trials,” the authors explained.

The trial recruited patients diagnosed with recurrent or refractory Ewing’s sarcoma (median age 19 years). At the first and second interim assessments, patients receiving irinotecan-temozolomide and gemcitabine-docetaxel had worse objective responses and EFS versus the other treatments so those regiments were halted, McCabe noted. Median follow-up for the current trial regimen was 40 months. Other survival outcomes in rEECur were reported at the 2020 ASCO meeting.

McCabe and colleagues offered several take-home messages from the study: Benefits of ifosfamide over TC “were more obvious in children than in adolescents and adults”; both regimens resulted in similar rates of neutropenic infection (<10% of patients), with ifosfamide causing more severe kidney toxicity and brain toxicity versus TC; and “We can use these data to design future studies based on evidence rather than supposition.”