Presenter(s)
P. P. Patel1, B. Y. Yeap2, A. Friedmann3, M. Huang3, L. H. Boal4, K. J. Marcus1, H. Elhalawani1, D. A. Haas-Kogan5, D. B. Cameron6, T. I. Yock5, S. M. MacDonald7, and K. X. Liu5; 1Department of Radiation Oncology, Mass General Brigham, Harvard Medical School, Boston, MA, 2Department of Biostatistics, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 3Department of Pediatric Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 4Massachusetts General Hospital, Boston, MA, 5Department of Radiation Oncology, Mass General Brigham, Boston, MA, 6Mass General Brigham, Boston, MA, 7Southwest Florida Proton Center, Estero, FL
Purpose/Objective(s): Radiation therapy (RT) is an important treatment modality for patients with neuroblastoma but contributes to acute and late toxicities. Proton RT (PRT) reduces low dose radiation to normal tissue and may mitigate morbidity. This Phase II study prospectively evaluated acute and late toxicities and outcomes of PRT in pediatric and young adult patients with neuroblastoma.
Materials/Methods: This prospective Phase II trial enrolled patients aged =6 months to =25 years with neuroblastoma. Patients received PRT to the primary site with target volumes following standard Children’s Oncology Group guidelines. RT to metastatic sites was at the discretion of the treating physicians in discussion with patients and families. Toxicities were graded using CTCAE v4.0 and categorized as acute (occurring during RT or =90 days after the completion of RT and resolving within 6 months after completion of RT) or late (occurring >90 days from the completion of RT or any acute toxicities that did not resolve within 6 months). PFS and OS were estimated using Kaplan-Meier methods.
Results: Of the 28 patients enrolled, 11 (39%) were female and 27 had high-risk neuroblastoma. Primary tumors were predominantly abdomen/adrenal (n=25, 89%). MYCN amplification was present in 13 (46%), ALK mutations were present in 5 (18%), and histology was unfavorable in 21 (75%) patients. Median age at diagnosis was 2.8 years (0.6-17.7) and at RT was 3.6 years (1.3-18.2). All patients underwent surgery at the primary site (11 GTR, 17 STR) and received chemotherapy (ANBL12P1, n=2; ANBL0532, n=17; ANBL1531, n=8). Three patients received extended induction, and one patient received chemotherapy as per ANBL1221 for intermediate-risk neuroblastoma refractory to chemotherapy as per ANBL0531. Primary site doses were 36 Gy(RBE) (n=15), 21.6 Gy(RBE) (n=12), and 22.8 Gy(RBE) (n=1); and 6 patients (21%) received RT to metastatic sites. Four patients did not receive high-dose chemotherapy with autologous stem cell transplant (ASCT), while 10 received single and 14 tandem ASCT. Twenty-five patients (89%) received post-consolidation anti-GD2 immunotherapy with cis-retinoic acid, and 7 (25%) received DFMO. Acute grade =3 toxicities were primarily hematologic, including lymphopenia (n=10), neutropenia (n=8), and leukopenia (n=10). Late grade =3 toxicities were rare (n=4), consisting of lymphopenia (n=2), leukopenia (n=1), and hearing impairment (n=1). With median follow-up of 3.7 years (0.3-10.3), one patient developed combined local and distant recurrence, and five developed distant-only relapses. Three-year PFS and OS were 77.2% and 87.6%, respectively.
Conclusion: In this prospective Phase II study, PRT for neuroblastoma demonstrated favorable toxicity profiles and disease control rates. These findings support PRT as a strategy to reduce long-term morbidity without compromising oncologic outcomes and inform future trial design and survivorship care.