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Temporal Trends in Treatment and Subsequent Neoplasm Risk Among 5-Year Survivors of Childhood Cancer, 1970-2015

Educational Objective
To learn that some therapies for patients with childhood cancer are associated with an increased risk of subsequent neoplasms.
1 Credit CME
Key Points

Question  Are treatment-era related changes in chemotherapy or radiation therapy doses associated with changes in the risk of subsequent neoplasms over time among survivors of childhood cancer?

Findings  In this longitudinal cohort study of 23 603 survivors of childhood cancer, reductions in therapeutic radiation doses over time were associated with reduced rates of subsequent neoplasms, including subsequent malignancies, nonmelanoma skin cancers, and benign meningiomas.

Meaning  Ongoing efforts to reduce long-term therapeutic toxicity were associated with decreasing subsequent neoplasms among 5-year survivors of childhood cancer.

Abstract

Importance  Cancer treatments are associated with subsequent neoplasms in survivors of childhood cancer. It is unknown whether temporal changes in therapy are associated with changes in subsequent neoplasm risk.

Objective  To quantify the association between temporal changes in treatment dosing and subsequent neoplasm risk.

Design, Setting, and Participants  Retrospective, multicenter cohort study of 5-year cancer survivors diagnosed before age 21 years from pediatric tertiary hospitals in the United States and Canada between 1970-1999, with follow-up through December 2015.

Exposures  Radiation and chemotherapy dose changes over time.

Main Outcomes and Measures  Subsequent neoplasm 15-year cumulative incidence, cumulative burden, and standardized incidence ratios for subsequent malignancies, compared by treatment decade. Multivariable models assessed relative rates (RRs) of subsequent neoplasms by 5-year increments, adjusting for demographic and clinical characteristics. Mediation analyses assessed whether changes in rates of subsequent neoplasms over time were mediated by treatment variable modifications.

Results  Among 23 603 survivors of childhood cancer (mean age at diagnosis, 7.7 years; 46% female) the most common initial diagnoses were acute lymphoblastic leukemia, Hodgkin lymphoma, and astrocytoma. During a mean follow-up of 20.5 years (374 638 person-years at risk), 1639 survivors experienced 3115 subsequent neoplasms, including 1026 malignancies, 233 benign meningiomas, and 1856 nonmelanoma skin cancers. The most common subsequent malignancies were breast and thyroid cancers. Proportions of individuals receiving radiation decreased (77% for 1970s vs 33% for 1990s), as did median dose (30 Gy [interquartile range, 24-44] for 1970s vs 26 Gy [interquartile range, 18-45] for 1990s). Fifteen-year cumulative incidence of subsequent malignancies decreased by decade of diagnosis (2.1% [95% CI, 1.7%-2.4%] for 1970s, 1.7% [95% CI, 1.5%-2.0%] for 1980s, 1.3% [95% CI, 1.1%-1.5%] for 1990s). Reference absolute rates per 1000 person-years were 1.12 (95% CI, 0.84-1.57) for subsequent malignancies, 0.16 (95% CI, 0.06-0.41) for meningiomas, and 1.71 (95% CI, 0.88-3.33) for nonmelanoma skin cancers for survivors with reference characteristics (no chemotherapy, splenectomy, or radiation therapy; male; attained age 28 years). Standardized incidence ratios declined for subsequent malignancies over treatment decades, with advancing attained age. Relative rates declined with each 5-year increment for subsequent malignancies (RR, 0.87 [95% CI, 0.82-0.93]; P < .001), meningiomas (RR, 0.85 [95% CI, 0.75-0.97]; P = .03), and nonmelanoma skin cancers (RR, 0.75 [95% CI, 0.67-0.84]; P < .001). Radiation dose changes were associated with reduced risk for subsequent malignancies, meningiomas, and nonmelanoma skin cancers.

Conclusions and Relevance  Among survivors of childhood cancer, the risk of subsequent malignancies at 15 years after initial cancer diagnosis remained increased for those diagnosed in the 1990s, although the risk was lower compared with those diagnosed in the 1970s. This lower risk was associated with reduction in therapeutic radiation dose.

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Article Information

Corresponding Author: Lucie M. Turcotte, MD, MPH, MS, Division of Pediatric Hematology/Oncology, University of Minnesota, 420 Delaware St SE, MMC 484, Minneapolis, MN 55455 (turc0023@umn.edu).

Author Contributions: Drs Turcotte and Neglia had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Turcotte, Henderson, Leisenring, Armstrong, Robison, Neglia.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Turcotte, Liu, Neglia.

Critical revision of the manuscript for important intellectual content: Yasui, Arnold, Hammond, Howell, Smith, Weathers, Henderson, Gibson, Leisenring, Armstrong, Robison, Neglia.

Statistical analysis: Liu, Yasui, Neglia.

Obtained funding: Armstrong, Robison, Neglia.

Administrative, technical, or material support: Yasui, Hammond, Smith, Weathers, Gibson, Armstrong, Robison, Neglia.

Supervision: Hammond, Leisenring, Armstrong, Neglia.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Arnold reported receiving grants from the National Cancer Institute (NCI). Ms Smith reported receiving a grant from St Jude’s Children’s Research Hospital. Ms Weathers reported receiving a grant from NCI. Dr Henderson reported receiving a grant from Seattle Genetics. Dr Leisenring reported receiving a grant from NCI. No other authors reported disclosures.

Funding/Support: This work was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR000114, B.R. Blazar, principal investigator) and 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).

Role of the Funder/Sponsor: The funders/sponsors of this study had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

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