Association Between Participation in Clinical Trials and Overall Survival Among Children With Intermediate- or High-risk Neuroblastoma.

Importance: Participants in clinical trials may experience benefits associated with new therapeutic strategies as well as tight adherence to best supportive care practices. Objectives: To investigate whether participation in a clinical trial is associated with improved survival among children with neuroblastoma and investigate potential recruitment bias of patients in clinical trials. Design, Setting, and Participants: This cohort study included pediatric patients with intermediate- or high-risk neuroblastoma in North American studies who were included in the International Neuroblastoma Risk Group Data Commons and who received a diagnosis between January 1, 1991, and March 1, 2020. Exposure: Enrollment in a clinical trial. Main Outcomes and Measures: Event-free survival and overall survival (OS) of patients with intermediate- or high-risk neuroblastoma enrolled in an up-front Children's Oncology Group (COG) clinical trial vs a biology study alone were analyzed using log-rank tests and Cox proportional hazards regression models. The racial/ethnic composition and the demographic characteristics of the patients in both groups were compared. Results: The cohort included 3058 children with intermediate-risk neuroblastoma (1533 boys [50.1%]; mean [SD] age, 10.7 [14.7] months) and 6029 children with high-risk neuroblastoma (3493 boys [57.9%]; mean [SD] age, 45.8 [37.4] months) who were enrolled in a Children's Oncology Group or legacy group neuroblastoma biology study between 1991 and 2020. A total of 1513 patients with intermediate-risk neuroblastoma (49.5%) and 2473 patients with high-risk neuroblastoma (41.0%) were also enrolled in a clinical trial, for a cohort total of 3986 of 9087 children (43.9%) enrolled in a clinical trial. The prevalence of prognostic markers for the clinical trial and non-clinical trial cohorts differed, although representation of patients from racial/ethnic minority groups was similar in both cohorts. Among patients with intermediate-risk neuroblastoma, OS was higher among those who participated in a clinical trial compared with those enrolled only in a biology study (OS, 95% [95% CI, 94%-96%] vs 91% [95% CI, 89%-94%]; P = .01). Among patients with high-risk neuroblastoma, participation in a clinical trial was not associated with OS (OS, 38% [95% CI, 35%-41%] in the clinical trial group vs 41% [95% CI, 38%-44%] in the biology study group; P = .23). Conclusions and Relevance: Approximately 44% of patients in this large cohort of patients with neuroblastoma were enrolled in up-front clinical trials. Compared with children not enrolled in clinical trials, a higher prevalence of favorable prognostic markers was identified among patients with intermediate-risk neuroblastoma enrolled in clinical trials, and unfavorable features were more prevalent among patients with high-risk neuroblastoma enrolled in clinical trials. No evidence of recruitment bias according to race/ethnicity was observed. Participation in a clinical trial was not associated with OS in this cohort, likely reflecting the common practice of treating nontrial participants with therapeutic and supportive care regimens used in a previous therapeutic trial.

Nervous system: Embryonal tumors: Neuroblastoma.

Neuroblastoma is a clinically heterogenous pediatric cancer of the sympathetic nervous system that originates from neural crest cells. It is the most common extracranial solid tumor in childhood and prognosis ranges from spontaneous tumor regression to aggressive disease resistant to multimodal therapy. Prognosis depends on patient characteristics and tumor biology that determine risk classification. Advancements in therapy reductions are merited for low- and intermediate-risk neuroblastoma patients, who generally have excellent outcomes. Of the patients with high-risk disease, only 50% achieve long-term survival, and therapeutic advancements are needed. Over the past several decades, genomic features such as germline mutations, somatic genetic aberrations, chromosome copy number, transcriptomics, and epigenetics have proven to contribute to the pathogenesis of neuroblastoma. The primary predisposition genes in familial neuroblastoma are ALK and PHOX2B. Sporadic neuroblastoma arises with complex pathogenesis, but chromosomal abnormalities and single-nucleotide polymorphisms have been identified to cooperatively lead to oncogenesis. These advances have led to new therapeutic approaches with the potential to improve outcomes for children with neuroblastoma.