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Temporal changes in treatment and late mortality and morbidity in adult survivors of childhood glioma: a report from the Childhood Cancer Survivor Study

Nature Cancer volume 5, pages 590–600 (2024)Cite this article

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Abstract

Pediatric glioma therapy has evolved to delay or eliminate radiation for low-grade tumors. This study examined these temporal changes in therapy with long-term outcomes in adult survivors of childhood glioma. Among 2,501 5-year survivors of glioma in the Childhood Cancer Survivor Study diagnosed 1970–1999, exposure to radiation decreased over time. Survivors from more recent eras were at lower risk of late mortality (≥5 years from diagnosis), severe/disabling/life-threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs). Adjusting for treatment exposure (surgery only, chemotherapy, or any cranial radiation) attenuated this risk (for example, CHCs (1990s versus 1970s), relative risk (95% confidence interval), 0.63 (0.49–0.80) without adjustment versus 0.93 (0.72–1.20) with adjustment). Compared to surgery alone, radiation was associated with greater than four times the risk of late mortality, CHCs and SNs. Evolving therapy, particularly avoidance of cranial radiation, has improved late outcomes for childhood glioma survivors without increased risk for late recurrence.

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Fig. 1: Consort diagram of the cohort.
Fig. 2: Changes in treatment exposures for 5-year survivors of childhood glioma over three decades.
Fig. 3: Cumulative incidence of late mortality among 5-year survivors of childhood glioma by treatment era and treatment exposure.
Fig. 4: Cumulative incidence of chronic health conditions among 5-year survivors of childhood glioma by treatment era and treatment exposure.
Fig. 5: Cumulative incidence of subsequent neoplasm among 5-year survivors of childhood glioma by treatment era and treatment exposure.
Fig. 6: Cumulative incidence of subsequent malignant neoplasm among 5-year survivors of childhood glioma by treatment era and treatment exposure.

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Data availability

The CCSS is a US National Cancer Institute-funded resource (U24 CA55727) to promote and facilitate research among long-term survivors of cancer diagnosed during childhood and adolescence. CCSS data are publicly available on dbGaP at https://www.ncbi.nlm.nih.gov/gap/ through its accession number phs001327.v2.p1. and on the St. Jude Survivorship Portal within the St. Jude Cloud at https://survivorship.stjude.cloud/. In addition, utilization of the CCSS data that leverages the expertise of CCSS Statistical and Survivorship research and resources will be considered on a case-by case basis. For this utilization, a research Application Of Intent followed by an Analysis Concept Proposal must be submitted for evaluation by the CCSS Publications Committee. Users interested in utilizing this resource are encouraged to visit http://ccss.stjude.org. Full analytical data sets associated with CCSS publications since January of 2023 are also available on the St. Jude Survivorship Portal at https://viz.stjude.cloud/community/cancer-survivorship-community~4/publications. Source data are provided with this paper.

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Acknowledgements

This work was supported by the National Cancer Institute (CA55727, G.T. Armstrong, Principal Investigator). Support to St. Jude Children’s Research Hospital also provided by the Cancer Center Support (CORE) grant (CA21765, C. Roberts, Principal Investigator) and the American Lebanese-Syrian Associated Charities (ALSAC).

Author information

Author notes

  1. These authors contributed equally: P. M. K. de Blank, K. R. Lange.

  2. These authors jointly supervised this work: M. F. Okcu, D. C. Bowers.

Authors and Affiliations

  1. The Cure Starts Now Brain Tumor Center, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Peter M. K. de Blank

  2. Division of Pediatric Oncology, Hackensack Meridian Children’s Health, Hackensack, NJ, USA

    Katharine R. Lange

  3. Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Mengqi Xing, Sedigheh Mirzaei Salehabadi & Deokumar Srivastava

  4. Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Tara M. Brinkman, Kirsten K. Ness, Kevin R. Krull & Gregory T. Armstrong

  5. Department of Psychology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Tara M. Brinkman & Kevin R. Krull

  6. Department of Medicine, Duke University, Durham, NC, USA

    Kevin C. Oeffinger

  7. Department of Pediatrics, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN, USA

    Joseph Neglia & Lucie M. Turcotte

  8. Department of Paediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada

    Paul C. Nathan

  9. Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Rebecca Howell

  10. Cancer Prevention and Clinical Statistics Programs, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Wendy Leisenring

  11. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Gregory T. Armstrong

  12. Department of Pediatrics, Baylor College of Medicine, Texas Children’s Cancer and Hematology Centers, Houston, TX, USA

    M. Fatih Okcu

  13. Division of Hematology-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Daniel C. Bowers

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Contributions

P.M.K.d.B., K.R.L., M.F.O. and D.C.B. conceptualized and designed the study. All authors contributed to the collection and assembly of data. Data analysis was provided by M.X., S.M.S. and D.S. P.M.K.d.B., K.R.L., M.F.O., D.C.B., M.X., S.M.S., D.S. and G.T.A. provided data interpretation. P.M.K.d.B. wrote the first draft of the manuscript, and all authors contributed to manuscript editing and revision. All authors approved the final manuscript and are responsible for the final work.

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Correspondence to Peter M. K. de Blank.

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Nature Cancer thanks Rodrigue Allodji, Anna Berghoff, Ryota Tamura and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Table 1 Standardized mortality ratios in 5-year survivors of childhood glioma followed for 15 years
Full size table
Extended Data Table 2 Relative risk of late mortality and chronic health conditions in five-year survivors of childhood glioma by treatment exposure, with and without adjustment for treatment era
Full size table
Extended Data Table 3 Relative risk of late mortality and chronic health conditions in five-year survivors of childhood glioma for specific treatment exposures
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Extended Data Table 4 Relative risk of organ-specific severe, life-threatening or fatal (grade 3–5) chronic health conditions in five-year survivors of childhood glioma
Full size table
Extended Data Table 5 Subsequent malignant neoplasm type and standardized incidence ratio among survivors of pediatric glioma compared to the general United States population, adjusted by sex, age group, and calendar year. Comparator data abstracted from SEER
Full size table
Extended Data Table 6 Subsequent neoplasm in the CNS by treatment exposure
Full size table
Extended Data Table 7 Number and proportion impaired on psychosocial outcome measures
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Extended Data Table 8 Relative risk of late mortality and chronic health conditions in five-year survivors of childhood glioma by treatment era and treatment exposure including immediate (≤1 year from diagnosis) and delayed (>1 year from diagnosis) radiation
Full size table
Extended Data Table 9 List of International Classification of Disease in Oncology (ICD-O) codes used to define glioma cohort in order of frequency
Full size table

Supplementary information

Source data

Source Data Fig. 1

Individual level source data on each cohort member.

Source Data Figs. 2–6

Sheet: Fig. 2: number of patients with treatment exposures by decade. Sheet: Fig. 3a,h: cumulative incidence rate by year from diagnosis. Sheet: Fig. 4a,f: cumulative incidence rate by year from diagnosis. Sheet: Fig. 5a,b: cumulative incidence rate by year from diagnosis. Sheet: Fig. 6a,b: cumulative incidence rate by year from diagnosis.

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de Blank, P.M.K., Lange, K.R., Xing, M. et al. Temporal changes in treatment and late mortality and morbidity in adult survivors of childhood glioma: a report from the Childhood Cancer Survivor Study. Nat Cancer 5, 590–600 (2024). https://doi.org/10.1038/s43018-024-00733-0

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