A large multi-center trial comparing four regimens commonly used to treat recurrent and refractory Ewing sarcoma-a rare cancer mostly of children, teens, and young adults-found that high-dose ifosfamide was slightly superior in prolonging life than the other three chemotherapeutic agents in the trial.
Results of this study, dubbed the rEECur trial-presented during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting-now provides a fact-based platform upon which pediatricians and oncologists can better inform patients and their families about treatment risks and benefits available now for this disease (Abstract LBA2). Prior to this study, objective data needed to guide physicians and families about the best therapies to combat recurrent and refractory Ewing sarcoma was sketchy at best, the researchers said.
"Before we opened the rEECur trial in 2014, the evidence was very poor. There were no randomized trials [and] there was no consensus on which was the best regimen to treat patients or which we should use as a chemotherapy background to test novel agents," said Martin McCabe, MD, PhD, Clinical Senior Lecturer in Pediatric and Adolescent Oncology at the University of Manchester in England, who presented findings during an ASCO press briefing. "This is the first-ever randomized control trial of chemotherapy in this disease setting."
Vicki Keedy, MD, Clinical Director of the Sarcoma Program at Vanderbilt University in Nashville, added the results were "potentially practice-changing."
"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 Keedy, who did not take part of this study.
Research Findings
Ewing sarcoma is a rare cancer of bone and soft tissues that predominantly strikes about 200 children, teens, and young adults per year in the United States, particularly during the second decade of life. Five-year overall survival (OS) for the disease is roughly 50-60 percent, but for patients whose disease has either progressed after initial treatment or recurred, 5-year median survival is under 15 percent.
As is the case with many rare tumors, randomized studies comparing multiple treatment regimens have been difficult to conduct for Ewing sarcoma, beyond a few trials performed in isolated settings. To overcome this hurdle, about 8 years ago, an international collaboration from Europe, Australia, New Zealand, and elsewhere came together in a Phase II/III trial to assess treatment regimens commonly used to treat recurrent or primary refractory Ewing sarcoma.
Some 451 patients, ages 4-50, with recurrent and primary refractory Ewing sarcoma were recruited into the trial and randomly assigned to four arms: topotecan plus cyclophosphamide, irinotecan plus temozolomide, gemcitabine plus docetaxel, or high-dose ifosfamide.
The primary outcome was event-free survival (EFS), defined as the length of time after the primary treatment in the trial ends and the patient remains free of cancer progression. Secondary outcomes included OS, toxicity, and EFS. The study was designed as a multi-arm, multi-stage, adaptive, simultaneous Phase II/III trial with Bayesian analysis.
"This trial design is an extremely economical way for studying multiple regimens in as few patients as quickly as possible," McCabe said.
Early analyses showed that patients on two of the regimens-irinotecan plus temozolomide and gemcitabine plus docetaxel-had worse objective responses and EFS than the other two treatments. Given these early findings, the researchers decided to drop those arms from the trial. Final assessment was based on a Phase III evaluation of topotecan plus cyclophosphamide versus ifosfamide, with a median follow-up of 40 months.
Results showed that EFS was 5.7 months for patients treated with ifosfamide compared to 3.7 months for topotecan plus cyclophosphamide (95% CI: 2.1-5.1). Median OS was 16.8 months for patients treated with ifosfamide versus 10.4 months for topotecan plus cyclophosphamide. At 1 year, about 55 percent of the patients who received ifosfamide were alive versus 45 percent of patients on topotecan plus cyclophosphamide.
Both regimens were similar in terms of neutrophilic infection, but ifosfamide caused more severe renal and brain toxicity than the topotecan regimen. Frequency of these adverse events in both arms was less than 10 percent. McCabe added that results showed that the benefits of ifosfamide were better among children under age 14.
Given the rarity of the disease, McCabe said the research team agreed that a 70 percent probability that one arm was better than another would be sufficient to identify this regimen as a standard in future trials. Based on analyses of the observed data, the research team concluded there was a 96 percent probability that the ifosfamide regimen was better than topotecan for EFS, and a 94 percent probability that the ifosfamide regimen was superior to topotecan for OS.
Ifosfamide works by adding an alkyl group to DNA, leading to an eventual breaking of DNA strands, limiting the ability of cancer cells to multiply and survive. Though the trial clearly demonstrated that the ifosfamide regimen was superior to the topotecan combination, the differences were "quite subtle," McCabe said. "What we actually need is better drugs to cure more patients."
As for next steps, McCabe said additional patients will be recruited for the ifosfamide arm of the trial; a fifth chemotherapy also will be added that includes carboplatin and an etoposide, an agent which can damage DNA. The investigators also plan to add another arm later this year that includes a molecularly targeted agent.
Warren Froelich is a contributing writer.