Patterns of Failure in Pediatric Rhabdomyosarcoma After Proton Therapy

Purpose

To report on the patterns of failure in children with rhabdomyosarcoma treated with proton therapy.

Patients and Methods

Between February 2007 and November 2013, 66 children with a median age of 4.1 years (range, 0.6-15.3 years) diagnosed with nonmetastatic rhabdomyosarcoma were treated with proton therapy. Clinical target volume 1 was defined as the prechemotherapy tumor plus a 1-cm anatomically constrained margin. Clinical target volume 2 was defined as the postchemotherapy tumor (or tumor bed) plus a 0.5-cm anatomically constrained margin, further expanded to encompass potential pathways of spread, including soft tissue infiltrated with tumor at diagnosis.

Results

Of the 66 children, 11 developed locally progressive disease at a median of 16 months (range, 14-32 months), for an actuarial 2-year local control rate of 88%. Among the children who progressed, median age and tumor size at diagnosis were 6.7 years (range, 0.6-16 years) and 6 cm (range, 2-8 cm), respectively. Of the recurrences, 64% and 36% were embryonal and alveolar, respectively. Disease progression was observed in 7 (64%) parameningeal, 2 (18%) head and neck (other), and 2 (18%) bladder/prostate subsites. At diagnosis, 8 of 11 patients who developed a recurrence were Intergroup Rhabdomyosarcoma Study stage 3, and all 11 were group III. Of the relapses, 100% (11 of 11) were confirmed as in-field within the composite 95% isodose line. One of the 11 patients (9%) developed a new simultaneous regional nodal recurrence outside of the previously treated radiation field.

Conclusion

Early data suggest that the sharp dosimetric gradient associated with proton therapy is not associated with an increased risk of marginal failure. Routine use of a 0.5- to 1-cm clinical target volume 1/2 margin with highly conformal proton therapy does not compromise local control in children diagnosed with rhabdomyosarcoma with unfavorable risk features.

Introduction

Soft tissue sarcomas comprise approximately 9% of all childhood malignancies (1). Of this diverse group of tumors, rhabdomyosarcomas account for 5% of pediatric malignancies, with embryonal (75%) and alveolar (16%) as the 2 major histologic subtypes (2). In the treatment of rhabdomyosarcoma, local failure is a major cause of morbidity and mortality, despite significant improvements in survival over the last few decades, with recurrence rates reported at 15% to 37% 3, 4, 5. Obtaining local control with radiation therapy is critical to advancing survival rates because most treatment failures in children and adolescents with nonmetastatic disease involve a component of local disease progression 6, 7, 8, 9, 10, 11. When local therapy is intensified to improve local control, however, young patients risk acquiring various developmental, hearing, visual, vascular, and cognitive deficits because of treatment toxicity (12).

Advancements in radiotherapeutic techniques, such as intensity modulated radiation therapy (IMRT) and daily image guidance, have allowed for increasingly conformal treatments and opportunities to reduce margins by mitigating treatment uncertainties and lessening the adverse exposure of normal tissue to radiation 5, 11, 13. In pediatric and adult sarcomas, proton therapy can mediate the exposure of healthy tissue to radiation and maintain adequate target volume coverage. Modeling studies and single-institutional series have demonstrated that, compared with conventional radiation therapy plans, proton beam therapy plans can decrease the radiation dose to critical normal structures without compromising disease outcomes of local control, failure-free survival, and overall survival, thereby offering the prospect of dose escalation to reduce recurrence rates 12, 14, 15, 16, 17, 18, 19. As with other conformal radiation therapies like IMRT, proton therapy introduces a concern for the increased risk of “marginal misses” 11, 20. In conformal radiation therapy, reducing toxicity has also been possible through the systematic reduction of the clinical target volume (CTV) margin 13, 21. Herein we report patterns of failure in children treated with proton therapy using limited margins for rhabdomyosarcoma at our institution.