PRIMARY OBJECTIVE:
I. Demonstrate a reduction in local failure for patients with large tumors (≥ 8cm) at diagnosis, unfavorable tumor biology, and treated with definitive radiotherapy compared to the historical control of 14.3%.
SECONDARY OBJECTIVES:
I. Report targeted, late grade 3 (G3)+ toxicity at 1 year after completion of radiotherapy for large tumors.
II. To demonstrate non-inferiority of targeted, acute G3+ toxicity of selective dose-escalated and accelerated radiotherapy for Ewing sarcoma compared to historical controls.
III. Report event-free survival (EFS), local control, overall survival (OS) at 2 years after completion of local therapy for large tumors.
IV. Demonstrate the feasibility of real-time circulating tumor deoxyribonucleic acid (ctDNA) analysis to guide treatment decision-making.
CORRELATIVE OBJECTIVES:
I. Report leukopenia rates and compare between pre-defined subgroups.
II. Evaluate chemotherapy delay secondary to local therapy.
III. Explore the predictive and prognostic role of ctDNA in Ewing sarcoma.
IV. Study the predictive and prognostic role of tumor-derived extracellular vesicles (tdEVs) in Ewing sarcoma.
V. Apply ctDNA approaches using fragment size in the setting of Ewing sarcoma.
VI. Investigate the predictive role of positron emission tomography (PET)/computed tomography (CT) and/or magnetic resonance imaging (MRI) in assessing treatment response and apply novel radiomic techniques to maximize this predictive power.
VII. Assess acute G3+ toxicity for patients receiving preoperative or postoperative radiotherapy for the purposes of local control.
VIII. Assess patient-reported outcomes after local therapy, per the Pediatric Quality of Life (PEDSQL) 4.0 generic core instrument or Patient Reported Outcomes Measurement Information System (PROMIS)-29.
IX. Report EFS, local control, OS at 2 year after completion of any local therapy.
OUTLINE: Patients are assigned to 1 of 3 cohorts based on treatment and the size of the tumor at the time of radiotherapy.
COHORT A: Patients with specific high-risk characteristics are assigned to Group 1 and patients with no specific high-risk characteristics are assigned to Group 2:
GROUP 1: Patients may receive standard of care (SOC) chemotherapy every 2 weeks for at least 3 cycles prior to radiotherapy. Patients then undergo hypofractionated or conventional dose-escalated radiotherapy daily, excluding weekends and holidays, for 25-36 treatment fractions in the absence of disease progression or unacceptable toxicity. Patients may also receive consolidation chemotherapy after completion of radiotherapy and/or surgical resection.
GROUP 2: Patients may receive SOC chemotherapy every 2 weeks for at least 3 cycles prior to radiotherapy. Patients then undergo hypofractionated or conventional standard dose radiotherapy daily, excluding weekends and holidays, for 25-31 treatment fractions in the absence of disease progression or unacceptable toxicity. Patients may also receive consolidation chemotherapy after completion of radiotherapy and/or surgical resection.
COHORT B: Patients may receive SOC chemotherapy every 2 weeks for at least 3 cycles prior to radiotherapy. Patients with tumor size < 8cm at diagnosis undergo definitive radiotherapy or surgical resection. Patients may also receive consolidation chemotherapy after completion of definitive radiotherapy or surgical resection.
COHORT C: Patients may receive SOC chemotherapy every 2 weeks for at least 3 cycles prior to radiotherapy. Patients undergo radiotherapy before or after undergoing definitive surgical resection. Patients may also receive consolidation chemotherapy after completion of definitive radiotherapy and surgical resection.
Patients also undergo blood sample collection throughout the study. Additionally, patients may also undergo CT, PET/CT, and MRI with or without CT throughout the study at treating clinician's discretion.
After completion of study treatment, patients are followed up at 1 month and medical records are reviewed for up to 5 years. Patients in Cohort A are also followed at 3, 6, 12 and 24 months after radiotherapy and/or surgical resection. Additionally, patients in Cohort C are followed up at 3 months.
