[Skip to Content]
[Skip to Content Landing]

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.


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.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

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.

Mertens  AC, Liu  Q, Neglia  JP,  et al.  Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study.  J Natl Cancer Inst. 2008;100(19):1368-1379.PubMedGoogle ScholarCrossref
Hudson  MM, Mertens  AC, Yasui  Y,  et al; Childhood Cancer Survivor Study Investigators.  Health status of adult long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.  JAMA. 2003;290(12):1583-1592.PubMedGoogle ScholarCrossref
Kurt  BA, Nolan  VG, Ness  KK,  et al.  Hospitalization rates among survivors of childhood cancer in the Childhood Cancer Survivor Study cohort.  Pediatr Blood Cancer. 2012;59(1):126-132.PubMedGoogle ScholarCrossref
Armstrong  GT, Chen  Y, Yasui  Y,  et al.  Reduction in late mortality among 5-year survivors of childhood cancer.  N Engl J Med. 2016;374(9):833-842.PubMedGoogle ScholarCrossref
Robison  LL, Armstrong  GT, Boice  JD,  et al.  The Childhood Cancer Survivor Study: a National Cancer Institute-supported resource for outcome and intervention research.  J Clin Oncol. 2009;27(14):2308-2318.PubMedGoogle ScholarCrossref
Bhatia  S, Armenian  SH, Armstrong  GT,  et al.  Collaborative research in childhood cancer survivorship: the current landscape.  J Clin Oncol. 2015;33(27):3055-3064.PubMedGoogle ScholarCrossref
Friedman  DL, Whitton  J, Leisenring  W,  et al.  Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study.  J Natl Cancer Inst. 2010;102(14):1083-1095.PubMedGoogle ScholarCrossref
Garwicz  S, Anderson  H, Olsen  JH,  et al; Nordic Society for Pediatric Hematology and Oncology, Association of the Nordic Cancer Registries.  Second malignant neoplasms after cancer in childhood and adolescence: a population-based case-control study in the 5 Nordic countries.  Int J Cancer. 2000;88(4):672-678.PubMedGoogle ScholarCrossref
Jenkinson  HC, Hawkins  MM, Stiller  CA, Winter  DL, Marsden  HB, Stevens  MC.  Long-term population-based risks of second malignant neoplasms after childhood cancer in Britain.  Br J Cancer. 2004;91(11):1905-1910.PubMedGoogle ScholarCrossref
Armstrong  GT, Stovall  M, Robison  LL.  Long-term effects of radiation exposure among adult survivors of childhood cancer: results from the Childhood Cancer Survivor Study.  Radiat Res. 2010;174(6):840-850.PubMedGoogle ScholarCrossref
Borgmann  A, Zinn  C, Hartmann  R,  et al; ALL-REZ BFM Study Group.  Secondary malignant neoplasms after intensive treatment of relapsed acute lymphoblastic leukaemia in childhood.  Eur J Cancer. 2008;44(2):257-268.PubMedGoogle ScholarCrossref
Kim  SH, Shin  KH, Seok  SO,  et al.  Secondary malignant neoplasms after osteosarcoma: early onset and cumulative alkylating agent dose dependency.  Ann Surg Oncol. 2015;22(3):859-865.PubMedGoogle ScholarCrossref
Pole  JD, Gu  LY, Kirsh  V, Greenberg  ML, Nathan  PC.  Subsequent malignant neoplasms in a population-based cohort of pediatric cancer patients: a focus on the first 5 years.  Cancer Epidemiol Biomarkers Prev. 2015;24(10):1585-1592.PubMedGoogle ScholarCrossref
Hudson  MM, Neglia  JP, Woods  WG,  et al.  Lessons from the past: opportunities to improve childhood cancer survivor care through outcomes investigations of historical therapeutic approaches for pediatric hematological malignancies.  Pediatr Blood Cancer. 2012;58(3):334-343.PubMedGoogle ScholarCrossref
Green  DM, Kun  LE, Matthay  KK,  et al.  Relevance of historical therapeutic approaches to the contemporary treatment of pediatric solid tumors.  Pediatr Blood Cancer. 2013;60(7):1083-1094.PubMedGoogle ScholarCrossref
Leisenring  WM, Mertens  AC, Armstrong  GT,  et al.  Pediatric cancer survivorship research: experience of the Childhood Cancer Survivor Study.  J Clin Oncol. 2009;27(14):2319-2327.PubMedGoogle ScholarCrossref
Fritz  AG.  International Classification of Diseases for Oncology: ICD-O. Geneva, Switzerland: World Health Organization; 2000.
Robison  LL, Mertens  AC, Boice  JD,  et al.  Study design and cohort characteristics of the Childhood Cancer Survivor Study: a multi-institutional collaborative project.  Med Pediatr Oncol. 2002;38(4):229-239.PubMedGoogle ScholarCrossref
Green  DM, Nolan  VG, Goodman  PJ,  et al.  The cyclophosphamide equivalent dose as an approach for quantifying alkylating agent exposure: a report from the Childhood Cancer Survivor Study.  Pediatr Blood Cancer. 2014;61(1):53-67.PubMedGoogle ScholarCrossref
Dong  H, Robison  LL, Leisenring  WM, Martin  LJ, Armstrong  GT, Yasui  Y.  Estimating the burden of recurrent events in the presence of competing risks: the method of mean cumulative count.  Am J Epidemiol. 2015;181(7):532-540.PubMedGoogle ScholarCrossref
Bhakta  N, Liu  Q, Yeo  F,  et al.  Cumulative burden of cardiovascular morbidity in paediatric, adolescent, and young adult survivors of Hodgkin’s lymphoma: an analysis from the St Jude Lifetime Cohort Study.  Lancet Oncol. 2016;17(9):1325-1334.PubMedGoogle ScholarCrossref
Surveillance, Epidemiology, and End Results Program (SEER), National Cancer Institute (NCI). SEER Cancer Statistics Review (CSR), 1975-2012. NCI website. https://seer.cancer.gov/archive/csr/1975_2012/. Accessed January 27, 2017.
Baron  RM, Kenny  DA.  The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations.  J Pers Soc Psychol. 1986;51(6):1173-1182.PubMedGoogle ScholarCrossref
Hayes  AF.  Introduction to Mediation, Moderation, and Conditional Process Analysis: A Regression-Based Approach. New York, NY: Guilford Press; 2013.
MacKinnon  DP, Fairchild  AJ, Fritz  MS.  Mediation analysis.  Annu Rev Psychol. 2007;58:593-614.PubMedGoogle ScholarCrossref
Armstrong  GT, Liu  W, Leisenring  W,  et al.  Occurrence of multiple subsequent neoplasms in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.  J Clin Oncol. 2011;29(22):3056-3064.PubMedGoogle ScholarCrossref
Inskip  PD, Robison  LL, Stovall  M,  et al.  Radiation dose and breast cancer risk in the Childhood Cancer Survivor Study.  J Clin Oncol. 2009;27(24):3901-3907.PubMedGoogle ScholarCrossref
Sigurdson  AJ, Ronckers  CM, Mertens  AC,  et al.  Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study.  Lancet. 2005;365(9476):2014-2023.PubMedGoogle ScholarCrossref
Pui  CH, Campana  D, Pei  D,  et al.  Treating childhood acute lymphoblastic leukemia without cranial irradiation.  N Engl J Med. 2009;360(26):2730-2741.PubMedGoogle ScholarCrossref
Green  DM, Hyland  A, Barcos  MP,  et al.  Second malignant neoplasms after treatment for Hodgkin’s disease in childhood or adolescence.  J Clin Oncol. 2000;18(7):1492-1499.PubMedGoogle Scholar
Omer  B, Kadan-Lottick  NS, Roberts  KB,  et al.  Patterns of subsequent malignancies after Hodgkin lymphoma in children and adults.  Br J Haematol. 2012;158(5):615-625.PubMedGoogle ScholarCrossref
Bhatia  S, Robison  LL, Oberlin  O,  et al.  Breast cancer and other second neoplasms after childhood Hodgkin’s disease.  N Engl J Med. 1996;334(12):745-751.PubMedGoogle ScholarCrossref
Bhatia  S, Yasui  Y, Robison  LL,  et al; Late Effects Study Group.  High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin’s disease: report from the Late Effects Study Group.  J Clin Oncol. 2003;21(23):4386-4394.PubMedGoogle ScholarCrossref
Schaapveld  M, Aleman  BM, van Eggermond  AM,  et al.  Second cancer risk up to 40 years after treatment for Hodgkin’s lymphoma.  N Engl J Med. 2015;373(26):2499-2511.PubMedGoogle ScholarCrossref
Reulen  RC, Frobisher  C, Winter  DL,  et al; British Childhood Cancer Survivor Study Steering Group.  Long-term risks of subsequent primary neoplasms among survivors of childhood cancer.  JAMA. 2011;305(22):2311-2319.PubMedGoogle ScholarCrossref
Olsen  JH, Möller  T, Anderson  H,  et al.  Lifelong cancer incidence in 47,697 patients treated for childhood cancer in the Nordic countries.  J Natl Cancer Inst. 2009;101(11):806-813.PubMedGoogle ScholarCrossref
Turcotte  LM, Whitton  JA, Friedman  DL,  et al.  Risk of subsequent neoplasms during the fifth and sixth decades of life in the Childhood Cancer Survivor Study cohort.  J Clin Oncol. 2015;33(31):3568-3575.PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience

Lookup An Activity


My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
State Requirements