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Ifosfamide May Be Treatment of Choice for Some People with Ewing Sarcoma, Trial Shows

, by NCI Staff

MRI scans showing a large Ewing sarcoma tumor in the fibula of a 10-year-old boy (A) and the lower leg after surgery to remove the tumor (B).

Credit: Curr Oncol. Oct 2021. DOI: 10.3390/curroncol28050299. CC BY 4.0.

New findings from a large clinical trial could help doctors and patients select treatments for relapsed or treatment-resistant Ewing sarcoma, a rare cancer that forms in bone and the soft tissue surrounding bone.

The trial included people with Ewing sarcoma whose tumors did not shrink in response to their initial treatment or came back after that treatment. In the study, patients who received the chemotherapy drug ifosfamide (Ifex) lived about 5 months longer than those who received a combination of two other chemotherapy drugs, topotecan and cyclophosphamide.

The new findings are from the first randomized phase 3 clinical trial to compare commonly used chemotherapy regimens for recurrent Ewing sarcoma.

Such trials have been challenging to conduct in part because of the rarity of the disease, which occurs most often in adolescents and young adults. In the United States, for example, about 200 people are diagnosed with the disease each year.

In the trial, patients with Ewing sarcoma that had recurred or stopped responding to treatment who received high doses of ifosfamide lived for a median of 15.4 months, versus 10.5 months for those who received topotecan plus cyclophosphamide, according to results from the rEECur study. The findings were reported at the American Society of Clinical Oncology (ASCO) annual meeting on June 5.

“Before the rEECur study, the basis for choosing drugs for patients with relapsed or refractory Ewing sarcoma was weak,” said Martin McCabe, M.D., Ph.D., of the University of Manchester in the United Kingdom, who presented the results at the meeting.

With the new results, doctors will have objective data from a randomized trial to use when talking with their patients about which treatments are most effective and/or have the worst side effects, he noted. 

Dr. McCabe and his colleagues have evaluated four chemotherapy regimens over the course of the study, which began as a phase 2 trial. The current study, which is now a larger phase 3 trial, is still recruiting patients and has been collecting data on another regimen, carboplatin plus etoposide. 

“This is an important and ambitious study,” said Christine Heske, M.D., a sarcoma researcher in NCI’s Pediatric Oncology Branch who was not involved in the trial. “The study attempted to define the most effective regimen for recurrent Ewing sarcoma and has provided some useful data.”

A potential new treatment option for some patients

When the trial began, in 2014, participants were randomly assigned to receive one of four treatment regimens: topotecan plus cyclophosphamide, irinotecan plus temozolomide, gemcitabine plus docetaxel, or high-dose ifosfamide.

During this part of the study, the patient groups receiving irinotecan plus temozolomide and gemcitabine plus docetaxel had lower tumor response rates than other patients, according to findings reported in 2020. The researchers stopped recruiting patients to these treatment groups.

More research is needed to better understand how high-dose ifosfamide compares with irinotecan plus temozolomide and with gemcitabine plus docetaxel, according to Dr. Heske.

She predicted, however, that doctors would now consider offering high-dose ifosfamide to patients with recurrent or treatment-resistant Ewing sarcoma.

Cancer Research UK, the European Commission, and the University of Birmingham are sponsoring the trial.

An international effort in a rare disease

Most patients who have Ewing sarcoma that has not spread from its original location in the body respond well to chemotherapy.

But for patients whose cancer does not respond to therapy or has come back after initial treatment, the chance of survival is low. The rEECur study is focusing on this group of patients.

The data presented at the ASCO meeting was based on 146 patients in the phase 3 part of the study, who ranged in age from 4 to 49.

The researchers assessed overall survival as well as event-free survival, which is the amount of time after treatment begins that the patient is free of the cancer.

At a median follow-up of 40 months, patients treated with ifosfamide had a median event-free survival of 5.7 months, compared with 3.7 months for patients who received topotecan plus cyclophosphamide.

Both treatments led to similar rates of febrile neutropenia, a condition that involves fever and a lower-than-normal number of white blood cells called neutrophils. The condition occurred in about 25% of patients in both groups.

Ifosfamide was associated with serious side effects in the brain, such as encephalopathy, and the kidneys, such as acute kidney disease, although these were reported in less than 10% of patients. Patients in the ifosfamide group were more likely than other patients to discontinue treatment due to side effects.

Building on new findings

During a discussion of the study results at the ASCO annual meeting, Dr. McCabe said that differences in survival among the chemotherapy regimens were modest and that new treatments for the disease are needed.

“Clearly, we need to do much better,” agreed Katherine Janeway, M.D., who treats patients with Ewing sarcoma at the Dana-Farber Cancer Institute and discussed the rEECur study at the meeting.

The abnormal protein driving Ewing sarcoma in about 90% of patients—the EWS/FLI1 fusion protein—has been challenging to target with a drug, Dr. Janeway noted. Doctors have relied on chemotherapy because newer treatments, such as immunotherapy, have not been shown to be effective against the disease, she added.

But research conducted by the Fusion Oncoproteins in Childhood Cancers (FusOnC2) consortium, which is supported by the Cancer Moonshot, could reveal ways to overcome this challenge.

“We’re excited about some of the science emerging from the Cancer Moonshot,” Dr. Janeway said. Meanwhile, potential new treatments for Ewing sarcoma, including some targeted therapies, are being evaluated in clinical trials.

The rEECur results could help researchers conducting clinical trials select chemotherapy regimens to use as “a backbone” in combination with targeted therapies, according to Dr. Heske.

“Several new agents are currently in clinical testing or soon will be,” she said. “I think we may see some of these drugs added to an ifosfamide backbone.”

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