Are We Underdosing Patients With Ewing Sarcoma?

Busulfan and melphalan may improve event-free survival (EFS) and overall survival (OS) when given after vincristine, ifosfamide, doxorubicin, and etoposide induction in patients with high-risk, localized Ewing sarcoma, found a new study published in the Journal of Clinical Oncology.

Jeremy Whelan, MD, of the University College Hospital in London, and colleagues conducted a randomized study to investigate whether consolidation high-dose chemotherapy improved survival in patients with localized Ewing sarcoma at a high risk for relapse. A total of 240 patients aged 50 years or younger who had a poor a histologic response (≥ 10% viable cells) after receiving vincristine, ifosfamide, doxorubicin, and etoposide (6 courses) were included. Patients were required to have a tumor volume at diagnosis of ≥ 200 mL if unresected, initially resected, or resected after radiotherapy. The median age was 17.1 years, and 78% entered the trial because of poor histologic response after chemotherapy alone.

The researchers hoped that busulfan and melphalan would result in at least a 15% improvement in the 3-year EFS (hazard ratio [HR], 0.60). Between 2000 and 2015, patients were randomly assigned to either busulfan and melphalan (n = 122) or 7 courses of standard chemotherapy including vincristine, dactinomycin, and ifosfamide (n = 118).

After a median follow-up of 7.8 years, a significant decrease in the risk of an event in the busulfan and melphalan arm was observed. In an intent-to-treat analysis, the researchers found that the risk of an event was significantly decreased (HR, 0.64) with busulfan and melphalan compared with standard chemotherapy. The same was true for EFS: the 3-year EFS was 69.0% vs 56.7% (standard therapy), and the 8-year EFS was 60.7% vs 47.1% (standard therapy).

When the investigators looked at OS, there was also a trend favoring busulfan and melphalan (HR, 0.63). The 3-year OS was 78.0% vs 72.2% (standard therapy), and the 8-year OS was 64.5% vs 55.6% (standard therapy). The authors noted that two patients died from busulfan- and melphalan-related toxicity, and one patient died after standard chemotherapy. In addition, significantly more patients in the busulfan and melphalan arm experienced severe acute toxicities compared with standard therapy.

“For the patient population they studied, what they showed was very impressive,” Aaron Sugalski, DO, an associate professor of pediatrics in the Division of Hematology/Oncology at UT Health San Antonio, San Antonio, Texas, told Cancer Network. However, he noted an important difference in chemotherapy in the United States vs Europe. “We use a different approach with our chemotherapy regimens. We need to use this type of research to further improve our outcomes, so this is an important study in that way,” Sugalski said.