Patterns of Locoregional Relapse after Radiotherapy for High-Risk Neuroblastoma: A Multi-Institutional Study

Abstract

<h3>Purpose/Objective(s)</h3> In high-risk neuroblastoma (HRNBL), locoregional relapse (LRR) is a significant contributor to treatment failure despite intensive multimodal therapy, including radiotherapy (RT). A recent Children's Oncology Group study found no benefit to boost RT for gross residual disease. Thus, we sought to characterize patterns of LRR after RT for patients (pts) with HRNBL. <h3>Materials/Methods</h3> The Institutional Review Boards approved this multi-institutional retrospective cohort study of pts who received ≥1 autologous stem cell transplant (ASCT) and external beam RT for HRNBL from 1997-2021. Pts who progressed prior to ASCT were excluded. LRR was defined as recurrence at the primary site or within one nodal echelon beyond disease present at diagnosis. In-field and marginal recurrences were defined as sites receiving >12 Gy and ≤12 Gy, respectively. Follow-up (FU) was from end of RT. Event-free survival (EFS) and overall survival (OS) were analyzed by Kaplan-Meier method. Cumulative incidence of locoregional progression (CILP) was analyzed using competing risks of distant-only relapse, secondary cancer, and death with Gray's test. <h3>Results</h3> We identified 311 pts with median age at diagnosis of 3.0 years (range: 0.02-28.7). The most common primary site was adrenal/abdominal (n=280, 90.0%). 271 (87.1%), 126 (40.5%) and 240 (77.2%) pts had metastatic disease at diagnosis, <i>MYCN</i> amplification, and unfavorable histology, respectively. 108 pts (34.7%) received proton RT. Of the 167 (53.7%) pts who underwent tandem ASCT, 68 (40.7%) received TBI-based conditioning. No pts received TBI after 2012. Of the 115 (37.0%) pts with subtotal resection (STR), 54 (47.0%) received ≥36 Gy. 202 (65.0%) received post-Consolidation anti-GD2 immunotherapy. Median FU was 6.5 years (range: 0.01-22.4). For the cohort, 5-year CILP, EFS and OS were 10.8%, 66.7% and 78.9%, respectively. After STR, ≥36 Gy did not decrease 5-year CILP (11.8% vs. 13.1%, p=0.80). 5-year CILP was significantly lower for pts receiving immunotherapy (6.4% vs. 21.5%, p<0.001). For pts receiving immunotherapy, 5-year CILP was similar for photon and proton RT (6.1% vs. 6.6%, p=0.78). Of the 29 pts with LRR and imaging for review, 13 (44.8%) were in-field only, 6 (20.7%) were marginal only, and 10 (34.5%) were both in-field and marginal. In pts receiving immunotherapy, 4 LRRs were in-field only, 3 were marginal only, and 4 were both in-field and marginal with 6/7 (85.7%) marginal recurrences occurring at sites of disease present at diagnosis with complete response after induction chemotherapy. <h3>Conclusion</h3> LRR contributes to treatment failure in HRNBL with most occurring in-field. CILP was lower for pts receiving immunotherapy and there was no difference in CILP between photon and proton RT. In pts receiving immunotherapy, approximately 25% of LRRs were marginal only. Future studies are needed to examine the optimal RT fields and dose in the era of anti-GD2 immunotherapy.