International Study Finds the Best Treatment for Ewing Sarcoma

Ewing sarcoma is a bone cancer that usually affects children and adolescents and is one of the rare tumors. Ewing sarcoma may tend to grow aggressively. At diagnosis, it usually has not developed metastasis, and our conventional treatment approach for Ewing sarcoma in this situation is as follows:

1. before primary treatment, administer neoadjuvant (tumor-shrinking) chemotherapy,
2. provide primary treatments such as radiotherapy or surgery, and
3. then reduce the risk of recurrence with maintenance chemotherapy.

However, in some patients the cancer recurs or becomes resistant to treatment. The question, "What is the optimal chemotherapy regimen for recurrent or treatment-resistant Ewing sarcoma?", has long been on oncology’s agenda. The results of the rEECur trial, conducted for this purpose, were presented on 5 June at the ASCO 2022 annual meeting, and high-dose ifosfamid showed a superior survival advantage over the other three chemotherapy regimens.

Seeking Treatment for Recurrent or Treatment-Resistant Ewing Sarcoma

This international trial is the first randomized head-to-head comparison of commonly used chemotherapy regimens in patients with a rare cancer carrying a high risk of death. These results are expected to change the treatment of Ewing sarcoma globally.

Ewing sarcoma is a very rare cancer of bone and soft tissue affecting children and young adults, particularly in the second decade of life. For example, in England, the annual number of new cases is 3.2 per million people under age 25.

Treatment for Ewing sarcoma varies between cancer centers. Several different chemotherapy regimens are used, all based on single-arm trials, with no consensus about which is best.

This international trial set out to answer the question and compared four different regimens. By forming partnerships, coming together, and recruiting enough patients to identify the optimal treatment even in a very rare patient group, the participating centers were able to resolve a question.

Earlier findings from this trial had shown that ifosfamid improved survival compared with gemsitabin-dosetaksel and also with irinotekan-temozolomid.

The results presented at this meeting compared ifosfamid with the topotekan-siklofosfamid (TC) combination.

rEECur Results

Median overall survival was 15.4 versus 10.5 months, with a 94% probability that ifosfamid was better than TC for overall survival; 1-year overall survival was 55% versus 45%, respectively.  

Median event-free survival was 16.8 months in the 73 patients in the ifosfamid group versus 10.4 months in the 73 patients in the TC group. Six-month event-free survival was 47% versus 37%, respectively. Given the observed data, the probability that ifosfamid was better than TC for event-free survival was 96%.

Better differences in event-free and overall survival were observed particularly in patients younger than 14 compared with those aged 14 and older.

As for side effects, the two groups had similar rates of neutropenic infection, but more severe kidney and brain toxicity was observed with ifosfamid, each occurring in fewer than 10% of patients.

Despite these practice-changing results, the differences between treatments are actually fairly small, and what we really need is better drugs to cure more patients.

The rEEcur trial continues to enroll patients in the ifosfamid group, and a fifth chemotherapy group with karboplatin and etoposid has been added.

Later this year, the researchers also plan to add a new group receiving molecularly targeted drugs.

Important Global Collaboration

The global collaboration behind this trial, which set out to answer important questions about how best to treat a rare disease, is remarkable.

Rare cancers are a truly important concept: if we all work together, we can actually study them and obtain answers.

Pediatricians and oncologists will now be able to discuss the risks and benefits of different regimens more effectively.

Real-World Implications

The invited discussant, Dr. Katherine A. Janeway, is an associate professor of pediatrics at Harvard Medical School and a senior physician in pediatric oncology at Dana-Farber Cancer Institute.

Dr. Janeway illustrated this with a patient diagnosed with Ewing sarcoma at age 19:

The young woman presented with Ewing sarcoma in the pelvis and lung metastasis. She had previously received chemotherapy, had her primary tumor surgically removed, and received radiotherapy to the groin for microscopic disease at the surgical margins, as well as whole-lung radiotherapy.

Her disease recurred 14 months later – she had developed a single lung metastasis, which was surgically removed.

Janeway said, "Before the REEcur trial results, we had very limited evidence to guide pretreatment decisions for a patient like this". She said all four commonly used chemotherapy regimens tested in the trial had been considered for this patient.

"[The patient] received irinotekan-temozolomid along with topotekan-siklofosfamid, the standard treatment for recurrent Ewing sarcoma at my institution because of several retrospective studies showing good objective responses and reasonable progression-free survival", she said. "We generally did not consider high-dose ifosfamid because ifosfamid had been given in the initial preoperative treatment."

But she said high-dose ifosfamid would have been considered as a treatment option if the rEEcur findings had been available.

"I would nevertheless continue to recommend irinotekan and temozolomid as an alternative", she said. "More importantly, I will be able to give her the expected objective response rate, median event-free and overall survival, and toxicities for each treatment option, not only to help her make an informed decision but also to plan for the future."

Janeway said, "Fortunately, more than 10 years have passed and this patient has remained disease-free".

Janeway noted that the rEEcur trial results have the potential not only to benefit patients but also to help future trial design and drug development efforts. Given the poor outcomes even with high-dose ifosfamid, she agreed with the authors that new drugs are needed.

"Recurrent Ewing sarcoma is an aggressive, rapidly progressing disease with a driver that is difficult to target. For the foreseeable future, new drugs will need to be studied together with chemotherapy", she said. She noted that several phase 1 and 2 trials of newer, more targeted agents for Ewing sarcoma are ongoing, but none has been studied in combination with ifosfamid.

Given the rEEcur results, it will be important to consider ifosfamid as "a potential chemotherapy backbone in combination with targeted agents".

Questions That Remain

Janeway said future studies should assess how outcomes with the irinotekan-temozolomid and gemsitabin-dosetaksel chemotherapy combinations compare with those in patients treated with high-dose ifosfamid.

At the same time, it remains unclear whether collaborative, international, multi-arm basket trials such as rEEcur can be conducted in rare cancers after new agents from different industry partners have been studied, and whether researchers can undertake “intercontinental collaborative trials” to capture more.