Survival and Local Recurrence Risk in Patients with High-Risk Neuroblastoma Treated with Proton Therapy over a 10 Year Interval

Abstract

Patients (pts) with high-risk neuroblastoma (HR-NBL) require radiation (RT) to the primary tumor site (PS); approach is standardized within North American paradigms but remains a subject of global study. Long-term experience using proton therapy (PRT) in this population is lacking. We hypothesized that PRT would be associated with low risk of local recurrence (LR) in a large population of pts with HR-NBL spanning > 10 years. Sequential pts with HR-NBL at a single institution received RT to PS and persistent metastatic sites (MS). Dose to PS after subtotal resection (STR) was reduced from 36 Gy to 21.6 Gy in 2019 based on results from the Children's Oncology Group ANBL0532 trial (Liu K, 2019). Analysis using Kaplan Meier method and log rank test was performed with IRB approval. From 9/2010 - 12/2021, 99 pts with HR-NBL received PS RT during first-line therapy; most [78, (79%)] had adrenal primary tumors and 26 (26%) received MS RT. Median age was 48m at RT (R 11m to 17.5y) and 52 (53%) were female. All pts had multi-agent induction chemotherapy (CT) [+ dinutuximab [12 (13%)] and/ or therapeutic 131MIBG [19 (19%)] and resection of primary tumor prior to RT; 34 (34%) patients had STR with residual disease (RD) on post-op imaging, 65 (66%) had gross total resection (GTR). Dose to PS was 21.6 Gy for 78 (79%) pts and 36 Gy for 21 (21%) based on RD and treatment era; PRT was pencil beam [78 (79%)] or double scattered [22 (22%)], combined with IMRT in 2 (2%). With median FU of 4.2 yrs (R 0.5y - 12y), 80 pts (81%) are alive [66 (67%) disease-free, 14 (14%) with disease], 19 (19%) have died. Progressive disease (PD) occurred in 33 (33%), with median time to PD 24m (R 8-116m); two pts (2%) had isolated LR, 25 (25%) distant PD, and 6 (6%) concurrent LR and distant PD. Risk of LR at 10 years was 8%; absolute risk of any LR was 8% (6/78) in 21.6 Gy cohort and 9% (2/21) in 36 Gy cohort (p = NS). After induction CT, 34 (34%) pts had STR with > 1cm3 RD on axial imaging; 18/ 34 (53%) also had MIBG uptake (MIBG+) at PS. Based on treatment era, 21 pts (62%) after STR received 21.6 Gy + boost to RD (36 Gy), and 13 (38%) 21.6 alone. Of those who received 36 Gy (median FU 5.7y), 2/21 (9.5%) had LR with concurrent distant PD; of those who received 21.6 Gy (median FU 3.2y) 4/13 (31%) had LR (2 with concurrent distant PD and 2 LR only) (p = 0.03). In the 21.6 Gy GTR cohort, 2/65 (3%) had LR + distant PD. Of 8 total patients who experienced LR, 5 had MIBG + RD, 1 MIBG- RD, and 2 GTR. We observed excellent outcomes in 99 pts treated with proton radiotherapy for HR-NBL from 2010 through 2021, with 81% of patients alive and 92% free of LR. Our data suggest that LR is rare after GTR and 21.6 Gy, and uncommon among pts with STR treated with 36 Gy. A small number of pts received 21.6 Gy after STR, however, this experience suggests that a subset of pts with RD may require RT dose > 21.6 Gy. Further work is required to further characterize individual management of PS in pts with HR-NBL with regard to extent of RD and biologic disease features.