International Study on Optimizing Treatment for Patients with Ewing Sarcoma

Ewing sarcoma is a rare, malignant tumor that most commonly affects the bones and, less frequently, soft tissues (muscles, fat, connective tissue). It can occur at any age but primarily affects children and adolescents and likely arises from precursor cells known as mesenchymal stem cells. The tumor often grows in the pelvis or the long bones of the legs and presents with symptoms such as pain, swelling, or fever. Diagnosis is made through imaging (X-rays, magnetic resonance imaging, computed tomography), a tissue sample (biopsy), and genetic testing to detect characteristic changes. By the time of diagnosis, tumor cells have often already spread through the bloodstream to other parts of the body, where they can form tumor foci (metastases) if left untreated. Therefore, further tests are conducted for staging, with patients with metastases classified as high-risk (HR) and patients without metastases classified as standard-risk (SR).

The standard treatment for Ewing sarcoma begins with chemotherapy (induction phase) to shrink the tumor and combat micrometastases (tumor foci that are not yet visible). This is followed by local therapy, either surgery to remove the tumor or radiation therapy, and sometimes a combination of both. This depends on the tumor’s location, size, and response to the previous treatment. After local therapy, chemotherapy is continued (consolidation) to destroy any remaining cancer cells and reduce the risk of recurrence. For high-risk patients (those with metastases), treatment is similar, but usually involves more intensive chemotherapy and, in some cases, additional radiation therapy to the metastases. As part of the chemotherapy regimen, the standard induction phase consists of a combination of vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE) for a total of 9 cycles. The consolidation phase consists of an additional 5 cycles of these two combinations, also administered alternately. However, doxorubicin is omitted in this phase. An additional drug used in this study is vinorelbine, a chemotherapeutic agent from the same class as vincristine that is already approved. It is already part of maintenance therapy for other diseases. Maintenance therapy is administered after completion of tumor treatment and is intended to destroy any remaining cancer cells and reduce the risk of relapse. For Ewing sarcomas, there is currently no maintenance therapy as part of the standard of care.

The goal of the iEuroEwing study is, on the one hand, to evaluate the efficacy and safety of different radiation therapy doses and, on the other hand, to measure the effect of additional maintenance therapy with vinorelbine and cyclophosphamide. To this end, patients in the standard-risk group who are scheduled to receive radiation therapy will first be randomly assigned to one of four groups, with each group receiving a different radiation dose (54 Gy, 59.4 Gy, 63 Gy, and 68.4 Gy). All of these doses are standard doses for the treatment of Ewing sarcoma and are already in use; however, this study will conduct a systematic comparison. The exact course of radiation therapy depends on the progression of the disease. The study is open-label, meaning that patients and medical staff know which group they are in. After completion of treatment, all patients will be randomly assigned to two groups. All patients whose disease has completely resolved (complete remission) are eligible to participate in this part of the study, regardless of whether they received radiation therapy in the first part. Patients in the standard-of-care arm complete treatment according to the current standard of care following the completion of the 3-phase treatment (induction, local therapy, consolidation). Patients in the experimental arm of the study receive additional maintenance therapy with the approved medications vinorelbine and cyclophosphamide for a duration of 6 months. The medications are taken in tablet form, so hospitalization is generally not required. Assignment to either arm is open. Follow-up as part of the study lasts for up to 3 years.

Women and men between the ages of 2 and 49 with Ewing sarcoma are eligible to participate in the study. Before enrolling in the study, patients must not have received more than one cycle of chemotherapy.