Local Control for Large Unresectable Intermediate Risk Pediatric Rhabdomyosarcomas

Abstract

<h3>Purpose/Objective(s)</h3> Despite general improvement in progression-free survival (PFS) for non-metastatic pediatric rhabdomyosarcoma (RMS), patients with large, unresectable RMS in unfavorable sites with incomplete response to induction chemotherapy (CT) demonstrated inferior local control (LC) on D9803 and ARST0531. This study provides single-institution data on disease control, patterns of failure, and toxicity following proton therapy for these children at highest risk of local failure. <h3>Materials/Methods</h3> All intermediate-risk group III RMS (IR-RMS) patients ≤21 years old with >5 cm tumors treated on a prospective outcome tracking protocol between April 2007 and June 2021 were included. Patients were excluded if they had paratesticular or orbital tumors, delayed primary excision with gross tumor resection, or complete response to induction CT. Prior to 2013, all patients received ≤50.4 Gy. The cumulative incidence method provided estimates of time-dependent endpoints; the Fine-Gray test statistic assessed the level of statistical significance between predetermined strata of known prognostic factors. <h3>Results</h3> For the 91 patients included, median age at diagnosis was 4.5 years. Most tumors were stage III (84.6%), embryonal/FOX01 fusion negative (68.1%), and located in unfavorable sites (95.6%). Median primary tumor diameter at diagnosis was 7.4 cm (range, 5.2-17.6, including 37% of tumors ≥8 cm). Most patients (75%) received high-dose alkylating CT regimens. Median total dose to PTV2, defined by postinduction CT residual disease, was 50.4 Gy, and 40% received doses between 54 and 59 Gy. All patients underwent proton therapy. With a median follow-up of 7 years (range, 0.7-14.9), 5-year LC, PFS, and overall survival were 74%, 57%, and 66%, respectively. There were 23 in-field recurrences, 3 marginal recurrences, and 17 distant metastases. Significant predictors of improved PFS and OS were age 3-10 at diagnosis and embryonal histology/FOX01 fusion negative status. There were 3 acute grade 3 toxicities (diarrhea, laryngeal edema, and urinary tract obstruction) and 10% started enteral nutrition during radiotherapy due to mucositis. Nineteen patients experienced 23 late toxicities requiring surgical or serious medical intervention, primarily cataracts (n=7), hearing loss (n=5), TIA/stroke (n=3), and dental caries (n=2). No acute or late grade ≥4 toxicities were observed, nor any secondary malignancies. <h3>Conclusion</h3> Compared to historic data, the 74% 5-year LC observed in our cohort suggests that dose escalation of a postinduction tumor volume with proton therapy may partially mitigate negative risk factors in patients with large group III IR-RMS arising in unfavorable sites without increasing major toxicity. This single-institution experience serves as a benchmark and validates ongoing cooperative group pursuits within COG and SIOP to better characterize the therapeutic ratio of radiation dose escalation in children with IR-RMS.