Characteristics and survival of 4N and non-4N metastatic neuroblastoma across treatment eras: A report from the International Neuroblastoma Risk Group Task Force.

10007 Background: Patients with metastatic neuroblastoma confined to distant lymph nodes (4N) were identified as a subgroup with superior outcomes to those with metastases to other sites. Over the past two decades, outcomes for high-risk neuroblastoma have improved from increasingly effective and intense therapy, while intermediate-risk patients have maintained excellent outcomes with biology and response-based therapy. We aimed to determine if 4N patients remained a favorable subgroup with contemporary therapy. Methods: Patients with International Neuroblastoma Staging System (INSS) stage 4 disease in the International Neuroblastoma Risk Group Data Commons diagnosed between 1990-2020 were evaluated. Those with metastases only to the distant lymph nodes were defined as 4N. All other patients were defined as non-4N. Treatment eras included: 1999 and prior, 2000-2009, 2010 and later which correspond to standardization of multimodal therapy, stem cell transplant, and anti-GD2 immunotherapy for high-risk patients. Differences between 4N and non-4N patients were assessed with chi-square, Wilcoxon rank sum, and t-tests. Five-year Kaplan-Meier estimates of survival with 95% confidence intervals and multivariable Cox proportional hazards modeling were used to evaluate event-free (EFS) and overall (OS) survival. Results: The analytic cohort included 107 4N and 5976 non-4N patients. There were no clinical differences between 4N and non-4N patients apart from unfavorable histology (74.2% [4N] versus 60.1% [non-4N]; p=0.02). 5-year EFS and OS were higher for 4N compared to non-4N patients (p=0.001 and 0.001, respectively). Though survival estimates for 4N were higher in each era, the difference was not statistically significant for patients diagnosed from 2000-2009 nor 2010 and beyond; (1999 and prior: EFS 58.7% (40.9-72.7%) versus 31.8% (29.7-33.9%) p=0.001; OS, 66.2% (48.1-79.3%) versus 37.9% (35.7-40.1%) p=0.002, 2000-2009: EFS, 47.9% (34.0-60.5%) versus 36% (34.1-37.9%) p=0.179; OS, 55.4% (40.7-67.8%) versus 45.1% (43.1-47.1%) p=0.122, and 2010 and later: EFS, 63.6% (29.7-84.5%) versus 42.8% (39.9-45.6%) p=0.178; OS, 71.6% (35.0-89.9%) versus 52.3% (49.2-55.3%) p=0.207. Log-rank calculations may have been underpowered in part due to small sample sizes (n=39, 56, and 12) of each 4N subgroup, respectively. 4N patients had superior EFS (HR=0.48; p=0.0004) and OS (HR=0.49; p=0.0009) in a model which included age, MYCN -amplification status, treatment era, ferritin, and LDH. A sensitivity analysis using only high-risk patients age >18 months yielded similar results. Conclusions: Patients with stage 4N neuroblastoma are a rare subgroup which appears to continue to have favorable outcomes with contemporary therapy. Additional studies to identify opportunities to reduce therapy intensity for this subgroup are warranted.