Ifosfamide Induces ‘Subtle’ Survival Improvement Over Hycamtin-Cyclophosphamide Combo in Ewing Sarcoma

Patients with Ewing sarcoma, a rare type of bone or soft tissue cancer, derived a small benefit from treatment with the chemotherapy ifosfamide over the combination of Hycamtin (topotecan) and cyclophosphamide.

Findings from the phase 2/3 rEECur trial — which were presented at the 2022 American Society of Clinical Oncology Annual Meeting — demonstrated that at a median follow-up of 40 months, patients treated with ifosfamide experienced a median event-free survival (time after treatment stops where a patient remains free of the cancer returning or the onset of certain symptoms, such as bone pain) of 5.7 months compared with 3.5 months for patients who received the Hycamtin plus cyclophosphamide combination.

The six-month event-free survival rates were 47% and 37%, respectively.

Additionally, patients who received ifosfamide achieved a median overall survival (time a patient is alive until death from any cause) of 15.4 months compared with 10.5 among patients treated with Hycamtin plus cyclophosphamide. The one-year overall survival rates were 55% and 45%, respectively.

“Given the observed data, there is a 96% probability that ifosfamide is better than topotecan plus cyclophosphamide for (event-free survival),” Martin McCabe, a clinical senior lecturer at the University of Manchester in England, said during a presentation of the data. “(However), the numbers (of patients) beyond six months are extremely small. There was a 94% probability that ifosfamide is better than topotecan plus cyclophosphamide for (overall survival). Again, (there are) very small numbers (of patients) beyond about two years. The benefits of ifosfamide over topotecan plus cyclophosphamide were more obvious in children than in adolescents and adults.”

Patients enrolled onto the rEECur trial were randomly assigned to receive Hycamtin plus cyclophosphamide (163 patients), irinotecan plus temozolomide (127 patients), gemcitabine and docetaxel (72 patients), or ifosfamide (83 patients). The phase 3 comparison between ifosfamide and Hycamtin plus cyclophosphamide reported in the presentation included 73 patients in both treatment groups.

he median age of patients in the trial was 19 years (range, 4 to 49). Most patients had first recurrent disease (66%) and 18% had refractory disease. Seventy percent of patients had bone as their initial disease site. Sites of progression included pleuropulmonary metastases (disease that has spread to an organ in the chest cavity) only (34%), primary site only (15%), and other metastatic (51%).

Measuring event-free survival was the main goal of the study. The investigators also aimed to analyze overall survival, toxicity and quality of life.

In terms of safety, both ifosfamide and Hycamtin plus cyclophosphamide caused similar rates of neutropenic infection (infection caused by a decrease in white blood cells). Ifosfamide caused more severe kidney toxicity and brain toxicity compared with the combination therapy, however both were observed in less than 10% of patients. Common serious or severe side effects for Hycamtin plus cyclophosphamide versus ifosfamide, respectively, included, but were not limited to, vomiting (1% vs. 1%), nausea (0% vs 3%), diarrhea (1% vs 1%) and kidney toxicity (0% vs 8%).

“This is the first ever randomized, controlled trial of chemotherapy in this disease setting,” McCabe concluded. “Importantly, we now have data both to inform patients and to develop future studies. The differences (between these regimens) are quite subtle. What we actually need are better drugs to cure more patients.”

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