Health Outcomes and Quality of Life in a Multi-institutional Prospective Phase II Trial of Proton Radiotherapy for Pediatric Rhabdomyosarcoma

To report clinical outcomes in a prospective phase II pediatric cohort of rhabdomyosarcoma (RMS) treated with proton radiotherapy (PRT) and modern standard VAC-based chemotherapy. The study enrolled patients (<25 years) treated with PRT between 03/2003 - 11/2019 at 2 institutions. CTCAEv3.0, was used to grade adverse effects. Patient/parent reported prospective quality of life inventory (PedsQL) was offered twice during PRT and annually thereafter. PRT and tumor-related characteristics were analyzed with respect to health outcomes, measured from PRT start to the event of interest: log-rank test method to assess clinical variable effect on survival outcome, Fine-Gray competing risks regression for local control (LC), students T-Test for baseline and follow-up (FU) PedsQL scores, and univariate linear regression for clinical characteristics score comparison. One hundred three RMS patients (embryonal/FOX01-, n = 81, 78.6%; alveolar/FOX01+, n = 22, 21.4%), with a median age of 4.2 years (range: 0.1-24.6), had 23.3% low-, 72.8% intermediate- and 3.9% high-risk disease, and were staged according to the Intergroup Rhabdomyosarcoma Study in group I/II (n = 13, 12.6%), III (n = 85, 82.5%) and IV (n = 5, 4.9%). Median total dose delivered was 50.4 GyRBE (range: 36.0-59.4 GyRBE) and median FU was 5.9 years (range: 0.1-14.4). Significant predictors for local failure (LF) were tumor size >5cm (HR 2.61, p = 0.04), and age <2 or >10 vs. 2-10 at PT time (HR 2.6, p = 0.05). 5-year EFS, OS, and LC were 66.5%, 76.2%, and 80.8%, respectively, and 22 (21.4%) died, all from tumor progression. Three (2.9%) patients with embryonal RMS developed a second malignant neoplasm (SMN) (leukemia, pleomorphic adenoma and sarcoma). Excluding recurrences (n = 22), late toxicity (>90 days post-PRT) assessments were available for 69 (85.2%) patients, with no grade 4. Maximum grade late toxicity of 2 and 3 was 30 (43.5%) and 13 (18.8%), respectively. Thirty-six patients had baseline and FU PedsQL data. At baseline the mean total mean core (TCS) and physical and psychosocial summary scores were 67.6, 65.9, and 68.9, increasing over time to 81.9, 89.1, and 78.1 (p = 0.0007, <0.0001 and 0.03, respectively). Patients with tumor sizes ≤5cm reported lower baseline TCS than those >5cm (mean 62.2 vs 77.2; p = 0.04). Alveolar/undifferentiated histology showed higher baseline TCS compared to embryonal (mean 85.6 vs. 64.1; p = 0.02). No clinical variables significantly correlated with long-term TCS. Disease control and SMN are in line with other pediatric RMS proton/photon series. Late toxicity seems favorable compared to photon cohorts. PedsQL scores increased over time.