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

Abstract

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.

Keywords: Autologous stem cell therapy; Dinutuximab; MYCN amplification; Photon radiotherapy; Proton radiotherapy; Total body irradiation.

Figure 1.. Survival outcomes and cumulative incidence of local progression for the cohort.

(A) Overall survival (OS), (B) event-free survival (EFS), and (C) cumulative incidence of local progression (CILP) for the entire cohort.

Figure 2.. Representative images from a patient with a marginal recurrence.

(A) Axial CT imaging showing bilateral para-aortic disease at diagnosis. (B) Axial CT imaging showing complete response seen at end-induction imaging. (C) Axial slice of radiation plan showing the 60 cGy isodose line in blue in the area of interest. (D) Axial CT imaging showing para-aortic recurrence at prior site of disease at diagnosis with complete response at end-induction. (E) Representative axial slice of radiation plan. (F) Representative coronal slice of radiation plan. (G) Representative sagittal slice of radiation plan.

Figure 3.. Cumulative incidence of local progression stratified by different factors.

(A) Cumulative incidence of local progression showing five-year rates of 17.5% and 6.5% for patients with MYCN-amplified and non-MYCN-amplified tumors, respectively (Gray’s Test, p=0.007). (B) Cumulative incidence of local progression showing five-year rates of 17.3%, 5.7%, 7.7%, 10.7%, and 27.5% for induction regimens as per 34-DAT, ANBL0532/ANBL02P1, ANBL09P1, ANBL1531/ANBL12P1, and other induction regimen, respectively (p=0.004). (C) Cumulative incidence of local progression showing five-year rates of 19.2%, 7.7%, and 18.2%% for patients receiving no post-consolidation therapy/isotretinoin alone, isotretinoin and anti-GD2 antibody therapy, and other post-consolidation therapy, respectively (Gray’s Test, p=0.034).