Ifosfamide more likely to extend survival than topotecan-cyclophosphamide in Ewing sarcoma
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CHICAGO — In what researchers described as the first randomized controlled trial of chemotherapy in relapsed or refractory Ewing sarcoma, high-dose ifosfamide proved more effective in extending survival than topotecan and cyclophosphamide.
Martin G. McCabe, MD, PhD, clinical senior lecturer in pediatric and adolescent oncology at University of Manchester in the U.K., presented the results of the mutliarm, multistage, adaptive design phase 2/phase 3 rEECUr trial during a press briefing at ASCO Annual Meeting.
Background
Ewing sarcoma mainly affects children and teenagers, with 5-year survival rates of approximately 50% to 60%. Fewer than 15% of patients who experience progression on or after treatment survive 5 years, McCabe said.
Multiple chemotherapy regimens and dosing schedules have been used for these patients.
“Before we opened the rEECur trial in 2014, the evidence was very poor,” he said. “There were no randomized trials, there was no consensus on which was the best regimen to treat patients or which we should use as a chemotherapy backbone to test novel agents.”
The rEECur trial included 451 patients aged 4 to 50 years (median age, 19 years) in Europe with recurrent and primary refractory Ewing sarcoma. Two-thirds of patients had first recurrence, whereas 18% had refractory disease.
Researchers evaluated four treatment regimens: gemcitabine and docetaxel (n = 72); irinotecan and temolozomide (n = 127); topotecan and cyclophosphamide (n = 163); and high-dose (3,000 mg/m2) ifosfamide (n = 82).
EFS served as the primary outcome, with OS, toxicity and quality of life as secondary outcomes.
Median follow-up was 40 months.
Results
The phase 3 comparison of topotecan/cyclophosphamide with ifosfamide showed a 96% probability of longer EFS with ifosfamide. This equated to a median EFS benefit of 2.2 months (5.7 months; 95% CI, 3.8-6.9 vs. 3.5 months; 95% CI, 2.1-5.1) and a 10 percentage-point improvement in 6-month EFS (47%; 95% CI, 35-58 vs. 37%; 95% CI, 26-48).
Researchers also reported a 94% probability of longer OS with ifosfamide. Median OS was 15.4 months (95% CI, 11.3-20.9) with ifosfamide vs. 10.5 months (95% CI, 7.2-15) with topotecan/cyclophosphamide, and 6-month OS rates were 55% (95% CI, 43-66) vs. 45% (95% CI, 33-56).
The benefits of ifosfamide appeared more obvious among children aged younger than 14 years, McCabe said.
Grade 3 to grade 4 adverse events in the topotecan/cyclophosphamide vs. ifosfamide group included febrile neutropenia (26% vs. 25%), infection (8% vs. 14%), vomiting (1% vs. 1%), nausea (0% vs. 3%), diarrhea (1% vs. 1%), encephalopathy (0% vs. 7%) and renal toxicity (0% vs. 8%).
Next steps
The study provides data that can be used to inform patients and develop future studies, McCabe said.
“I should also point out that although we’ve shown that ifosfamide is better than [topotecan/cyclophosphamide], which is better than irinotecan and temolozomide, the differences are quite subtle, and what we actually need is better drugs to cure more patients,” he said.
Perspective
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Ming-Gui Pan, MD
Congratulations to the authors, as this appears to be a well-conducted, informative clinical trial comparing four different treatment regimens for patients with advanced Ewing sarcoma. The main finding that high-dose ifosfamide prolongs EFS and OS compared with three other standard-of-care chemotherapy options for recurrent and primary refractory Ewing sarcoma represents a small step forward for this population of patients. It confirms the value of high-dose ifosfamide in this treatment setting, despite the previous randomized trial by Grier and colleagues, which showed the addition of ifosfamide and etoposide (IE) on top of vincristine sulfate, dactinomycin (actinomycin-D) and cyclophosphamide [VAC] did not improve EFS in metastatic Ewing sarcoma. However, this study is unlikely to change clinical practice in a dramatic fashion.
Although the trial provides high-quality data on the effectiveness of high dose ifosfamide, it mainly reinforces current practices of oncologists treating Ewing sarcoma in the metastatic setting. That is because for metastatic Ewing sarcoma, oncologists already routinely use high-dose ifosfamide-containing regimens such as IE, if not alternating with VAC, likely in a sequential fashion. In addition, I suppose most patients with advanced Ewing sarcoma would go on to receive more than one or two regimens and are likely to be exposed to some of the four regimens that were compared in this trial. We do not have information at this time about the percent of patients in each arm who received the sequential therapies.
This research serves as an important reminder for oncologists not to skip high-dose ifosfamide and to regularly evaluate it as part of a patient’s treatment plan. The findings may also reassure patients with metastatic Ewing sarcoma who currently receive treatment with high-dose ifosfamide.
Additional future research could test combining high-dose ifosfamide with a tyrosine kinase inhibitor or checkpoint inhibitor in this setting.
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McCabe MG, et al. Abstract LBA2. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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