Patterns of recurrence after radiotherapy for high-risk neuroblastoma: Implications for radiation dose and field

Background: Prognosis for patients with high-risk neuroblastoma (HR-NBL) is guarded despite aggressive therapy, and few studies have characterized outcomes after radiotherapy in relation to radiation treatment fields. Methods: Multi-institutional retrospective cohort of 293 patients with HR-NBL who received autologous stem cell transplant (ASCT) and EBRT between 1997–2021. LRR was defined as recurrence at the primary site or within one nodal echelon beyond disease present at diagnosis. Follow-up was defined from the end of EBRT. Event-free survival (EFS) and OS were analyzed by Kaplan-Meier method. Cumulative incidence of locoregional progression (CILP) was analyzed using competing risks of distant-only relapse and death with Gray's test. Results: Median follow-up was 7.0 years (range: 0.01–22.4). Five-year CILP, EFS, and OS were 11.9 %, 65.2 %, and 77.5 %, respectively. Of the 31 patients with LRR and imaging review, 15 (48.4 %) had in-field recurrences (>12 Gy), 6 (19.4 %) had marginal failures (≤12 Gy), and 10 (32.3 %) had both in-field and marginal recurrences. No patients receiving total body irradiation (12 Gy) experienced marginal-only failures (p = 0.069). On multivariable analyses, MYCN amplification had higher risk of LRR (HR: 2.42, 95 % CI: 1.06–5.50, p = 0.035) and post-consolidation isotretinoin and anti-GD2 antibody therapy (HR: 0.42, 95 % CI: 0.19–0.94, p = 0.035) had lower risk of LRR. Conclusions: Despite EBRT, LRR remains a contributor to treatment failure in HR-NBL with approximately half of LRRs including a component of marginal failure. Future prospective studies are needed to explore whether radiation fields and doses should be defined based on molecular features such as MYCN amplification, and/or response to chemotherapy.