Impact of Risk-Based Therapy on Late Morbidity and Mortality in Neuroblastoma Survivors: A Report From the Childhood Cancer Survivor Study

Authors

Danielle Novetsky Friedman
Pamela J Goodman
Wendy M Leisenring
Lisa R Diller
Susan L Cohn
Rebecca M Howell
Susan A Smith
Emily S Tonorezos
Suzanne L Wolden
Joseph P Neglia
Kirsten K Ness
Todd M Gibson
Paul C Nathan
Lucie M Turcotte
Brent R Weil
Leslie L Robison
Kevin C Oeffinger
Gregory T Armstrong
Charles A Sklar
Tara O Henderson

Publication Date

6-7-2024

Journal

Journal of the National Cancer Institute

Abstract

Background: Early efforts at risk-adapted therapy for neuroblastoma are predicted to result in differential late effects; the magnitude of these differences has not been well described.

Methods: Late mortality, subsequent malignant neoplasms (SMNs), and severe/life-threatening chronic health conditions (CHCs), graded according to CTCAE v4.03, were assessed among 5-year Childhood Cancer Survivor Study (CCSS) survivors of neuroblastoma diagnosed 1987-1999. Using age, stage at diagnosis, and treatment, survivors were classified into risk groups (low [n = 425]; intermediate [n = 252]; high [n = 245]). Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) of SMNs were compared with matched population controls. Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals for CHC compared with 1029 CCSS siblings.

Results: Among survivors (49.8% male; median age = 21 years, range = 7-42; median follow-up = 19.3 years, range = 5-29.9), 80% with low-risk disease were treated with surgery alone, whereas 79.1% with high-risk disease received surgery, radiation, chemotherapy ± autologous stem cell transplant (ASCT). All-cause mortality was elevated across risk groups (SMRhigh = 27.7 [21.4-35.8]; SMRintermediate = 3.3 [1.7-6.5]; SMRlow = 2.8 [1.7-4.8]). SMN risk was increased among high- and intermediate-risk survivors (SIRhigh = 28.0 [18.5-42.3]; SIRintermediate = 3.7 [1.2-11.3]) but did not differ from the US population for survivors of low-risk disease. Compared with siblings, survivors had an increased risk of grade 3-5 CHCs, particularly among those with high-risk disease (HRhigh = 16.1 [11.2-23.2]; HRintermediate = 6.3 [3.8-10.5]; HRlow = 1.8 [1.1-3.1]).

Conclusion: Survivors of high-risk disease treated in the early days of risk stratification carry a markedly elevated burden of late recurrence, SMN, and organ-related multimorbidity, whereas survivors of low/intermediate-risk disease have a modest risk of late adverse outcomes.

Keywords

Humans, Neuroblastoma, Male, Female, Cancer Survivors, Child, Adolescent, Adult, Young Adult, Neoplasms, Second Primary, Risk Factors, United States, Proportional Hazards Models, Incidence, Child, Preschool

DOI

10.1093/jnci/djae062

PMID

38460547

PMCID

PMC11160496

PubMedCentral® Posted Date

3-9-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes