Skip to main content
SpringerLink
Log in

Radiotherapy for childhood cancer and subsequent thyroid cancer risk: a systematic review

  • REVIEW
  • Published:
European Journal of Epidemiology Aims and scope Submit manuscript

Abstract

Most of the pooled analyses and reviews reported an association between radiotherapy for childhood cancer and an increased thyroid cancer risk. Up to now this article presents the first systematic literature review on this association combined with a critical assessment of the methodological quality of the included articles. PubMed and Web of Science databases were searched for relevant articles until May 2016. We included peer-reviewed cohort and case–control studies that investigated an association between radiotherapy for childhood cancer and the occurrence of subsequent thyroid cancer. A systematic overview is presented for the included studies. We identified 17 retrospective cohort studies, and four nested case–control studies, representing 100,818 subjects. The age range at first cancer diagnosis was 0–25.2 years. Considerable variability was found regarding study sizes, study design, treatment strategies, dose information, and follow-up periods. 20 of the 21 identified studies showed increased thyroid cancer risks associated with childhood radiation exposure. The large majority showed an increased relative risk or odds ratio confirming the association between radiotherapy and thyroid cancer although the variation in results was large. Additionally to a pooled analysis that has been published recently, we systematically included 17 further studies, which allowed us to cover information from countries that were not covered by large-scale childhood cancer survivor studies. The methodological limitations of existing studies and inconsistencies in findings across studies yielded a large study heterogeneity, which made a detailed comparison of study results difficult. There is a need to strengthen standardisation for reporting.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Bhatti P, Veiga LH, Ronckers CM, et al. Risk of second primary thyroid cancer after radiotherapy for a childhood cancer in a large cohort study: an update from the childhood cancer survivor study. Radiat Res. 2010;174(6):741–52. https://doi.org/10.1667/rr2240.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Haddy N, Andriamboavonjy T, Paoletti C, et al. Thyroid adenomas and carcinomas following radiotherapy for a hemangioma during infancy. Radiother Oncol. 2009;93(2):377–82. https://doi.org/10.1016/j.radonc.2009.05.011.

    Article  PubMed  Google Scholar 

  3. 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):2014–23. https://doi.org/10.1016/s0140-6736(05)66695-0.

    Article  PubMed  Google Scholar 

  4. Ron E, Brenner A. Non-malignant thyroid diseases after a wide range of radiation exposures. Radiat Res. 2010;174(6):877–88. https://doi.org/10.1667/rr1953.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Veiga LH, Holmberg E, Anderson H, et al. Thyroid cancer after childhood exposure to external radiation: an updated pooled analysis of 12 studies. Radiat Res. 2016;185(5):473–84. https://doi.org/10.1667/rr14213.1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. La Vecchia C, Malvezzi M, Bosetti C, et al. Thyroid cancer mortality and incidence: a global overview. Int J Cancer. 2015;136(9):2187–95. https://doi.org/10.1002/ijc.29251.

    Article  CAS  PubMed  Google Scholar 

  7. Mullenders L, Atkinson M, Paretzke H, Sabatier L, Bouffler S. Assessing cancer risks of low-dose radiation. Nat Rev Cancer. 2009;9(8):596–604.

    Article  CAS  PubMed  Google Scholar 

  8. Kumar S. Second malignant neoplasms following radiotherapy. Int J Env Res Public Health. 2012;9(12):4744–59. https://doi.org/10.3390/ijerph9124744.

    Article  Google Scholar 

  9. Furukawa K, Preston D, Funamoto S, et al. Long-term trend of thyroid cancer risk among Japanese atomic-bomb survivors: 60 years after exposure. Int J Cancer. 2013;132(5):1222–6. https://doi.org/10.1002/ijc.27749.

    Article  CAS  PubMed  Google Scholar 

  10. Douple EB, Mabuchi K, Cullings HM, et al. Long-term radiation-related health effects in a unique human population: lessons learned from the atomic bomb survivors of Hiroshima and Nagasaki. Disaster Med Public Health Prep. 2011;5(1):S122–33. https://doi.org/10.1001/dmp.2011.21.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Sachs RK, Brenner DJ. Solid tumor risks after high doses of ionizing radiation. Proc Natl Acad Sci USA. 2005;102(37):13040–5. https://doi.org/10.1073/pnas.0506648102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. de Vathaire F, Hardiman C, Shamsaldin A, et al. Thyroid carcinomas after irradiation for a first cancer during childhood. Arch Intern Med. 1999;159(22):2713–9.

    Article  PubMed  Google Scholar 

  13. Prise KM, Schettino G, Folkard M, Held KD. New insights on cell death from radiation exposure. Lancet Oncol. 2005;6(7):520–8. https://doi.org/10.1016/s1470-2045(05)70246-1.

    Article  CAS  PubMed  Google Scholar 

  14. Armenian SH, Landier W, Hudson MM, Robison LL, Bhatia S. Children’s Oncology Group’s 2013 blueprint for research: survivorship and outcomes. Pediatr Blood Cancer. 2013;60(6):1063–8. https://doi.org/10.1002/pbc.24422.

    Article  PubMed  Google Scholar 

  15. Gatta G, Botta L, Rossi S, et al. Childhood cancer survival in Europe 1999-2007: results of EUROCARE-5—a population-based study. Lancet Oncol. 2014;15(1):35–47. https://doi.org/10.1016/s1470-2045(13)70548-5.

    Article  PubMed  Google Scholar 

  16. Berrington de Gonzalez A, Gilbert E, Curtis R, et al. Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose-response relationship. Int J Radiat Oncol Biol Phys. 2013;86(2):224–33. https://doi.org/10.1016/j.ijrobp.2012.09.001.

    Article  PubMed  Google Scholar 

  17. Scholz-Kreisel P, Spix C, Blettner M, et al. Prevalence of cardiovascular late sequelae in long-term survivors of childhood cancer: a systematic review and meta-analysis. Pediatr Blood Cancer. 2017. https://doi.org/10.1002/pbc.26428.

    Article  PubMed  Google Scholar 

  18. 2013 UR. Scientific annex B: effects of radiation exposure of children. New York: United Nations; 2013.

  19. Ron E, Lubin JH, Shore RE, et al. Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies. Radiat Res. 1995;141(3):259–77.

    Article  CAS  PubMed  Google Scholar 

  20. Veiga LH, Lubin JH, Anderson H, et al. A pooled analysis of thyroid cancer incidence following radiotherapy for childhood cancer. Radiat Res. 2012;178(4):365–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lundell M, Hakulinen T, Holm LE. Thyroid cancer after radiotherapy for skin hemangioma in infancy. Radiat Res. 1994;140(3):334–9.

    Article  CAS  PubMed  Google Scholar 

  22. Hayden JA, van der Windt DA, Cartwright JL, Côté P, Bombardier C. Assessing bias in studies of prognostic factors. Ann Intern Med. 2013;158(4):280–6. https://doi.org/10.7326/0003-4819-158-4-201302190-00009.

    Article  PubMed  Google Scholar 

  23. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies. Int J Surg. 2014;12(12):1495–9. https://doi.org/10.1016/j.ijsu.2014.07.013.

    Article  Google Scholar 

  24. Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004;23(9):1351–75. https://doi.org/10.1002/sim.1761.

    Article  PubMed  Google Scholar 

  25. Sankey SS, Weissfeld LA, Fine MJ, Kapoor W. An assessment of the use of the continuity correction for sparse data in meta-analysis. Commun Stat Simul Comput. 1996;25(4):1031–56. https://doi.org/10.1080/03610919608813357.

    Article  Google Scholar 

  26. Svahn-Tapper G, Garwicz S, Anderson H, et al. Radiation dose and relapse are predictors for development of second malignant solid tumors after cancer in childhood and adolescence: a population-based case-control study in the five Nordic countries. Acta Oncol. 2006;45(4):438–48. https://doi.org/10.1080/02841860600658633.

    Article  PubMed  Google Scholar 

  27. Tucker MA, Jones PHM, Boice JD, et al. Therapeutic radiation at a young age is linked to secondary thyroid cancer. Cancer Res. 1991;51(11):2885–8.

    CAS  PubMed  Google Scholar 

  28. Finke I, Scholz-Kreisel P, Hennewig U, Blettner M, Spix C. Radiotherapy and subsequent thyroid cancer in German childhood cancer survivors: a nested case-control study. Radiat Oncol. 2015;10:219. https://doi.org/10.1186/s13014-015-0521-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Broniscer A, Ke W, Fuller CE, Wu J, Gajjar A, Kun LE. Second neoplasms in pediatric patients with primary central nervous system tumors: the St. Jude Children’s Research Hospital experience. Cancer. 2004;100(10):2246–52. https://doi.org/10.1002/cncr.20253.

    Article  PubMed  Google Scholar 

  30. Navid F, Billups C, Liu T, Krasin MJ, Rodriguez-Galindo C. Second cancers in patients with the Ewing sarcoma family of tumours. Eur J Cancer. 2008;44(7):983–91. https://doi.org/10.1016/j.ejca.2008.02.027.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Nygaard R, Garwicz S, Haldorsen T, et al. Second malignant neoplasms in patients treated for childhood leukemia: a population-based cohort study from the Nordic countries. Acta Paediatr. 1991;80(12):1220–8. https://doi.org/10.1111/j.1651-2227.1991.tb11812.x.

    Article  CAS  Google Scholar 

  32. Bhatia S, Sather HN, Pabustan OB, Trigg ME, Gaynon PS, Robison LL. Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983. Blood. 2002;99(12):4257–64.

    Article  CAS  PubMed  Google Scholar 

  33. Bhatia S, Yasui Y, Robison LL, et al. 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):4386–94. https://doi.org/10.1200/jco.2003.11.059.

    Article  PubMed  Google Scholar 

  34. Chow EJ, Friedman DL, Stovall M, et al. Risk of thyroid dysfunction and subsequent thyroid cancer among survivors of acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer. 2009;53(3):432–7. https://doi.org/10.1002/pbc.22082.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Inskip PD, Curtis RE. New malignancies following childhood cancer in the United States, 1973–2002. Int J Cancer. 2007;121(10):2233–40. https://doi.org/10.1002/ijc.22827.

    Article  CAS  PubMed  Google Scholar 

  36. Lee JS, DuBois SG, Coccia PF, Bleyer A, Olin RL, Goldsby RE. Increased risk of second malignant neoplasms in adolescents and young adults with cancer. Cancer. 2016;122(1):116–23. https://doi.org/10.1002/cncr.29685.

    Article  PubMed  Google Scholar 

  37. Metayer C, Lynch CF, Clarke EA, et al. Second cancers among long-term survivors of Hodgkin’s disease diagnosed in childhood and adolescence. J Clin Oncol. 2000;18(12):2435–43. https://doi.org/10.1200/jco.2000.18.12.2435.

    Article  CAS  PubMed  Google Scholar 

  38. Rose J, Wertheim BC, Guerrero MA. Radiation treatment of patients with primary pediatric malignancies: risk of developing thyroid cancer as a secondary malignancy. Am J Surg. 2012;204(6):881–6. https://doi.org/10.1016/j.amjsurg.2012.07.030 (discussion 6–7).

    Article  PubMed  Google Scholar 

  39. Socie G, Curtis RE, Deeg HJ, et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol. 2000;18(2):348–57. https://doi.org/10.1200/jco.2000.18.2.348.

    Article  CAS  PubMed  Google Scholar 

  40. Rubino C, Adjadj E, Guerin S, et al. Long-term risk of second malignant neoplasms after neuroblastoma in childhood: role of treatment. Int J Cancer. 2003;107(5):791–6. https://doi.org/10.1002/ijc.11455.

    Article  CAS  PubMed  Google Scholar 

  41. Dorffel W, Riepenhausenl M, Luders H, Bramswig J, Schellong G. Secondary malignancies following treatment for Hodgkin’s lymphoma in childhood and adolescence. Dtsch Arztebl Int. 2015;112(18):320–7. https://doi.org/10.3238/arztebl.2015.0320.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Cohen A, Rovelli A, van Lint MT, et al. Secondary thyroid carcinoma after allogeneic bone marrow transplantation during childhood. Bone Marrow Transplant. 2001;28(12):1125–8. https://doi.org/10.1038/sj.bmt.1703290.

    Article  CAS  PubMed  Google Scholar 

  43. de Vathaire F, Francois P, Schlumberger M, et al. Epidemiological evidence for a common mechanism for neuroblastoma and differentiated thyroid tumour. Br J Cancer. 1992;65(3):425–8.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8(5):336–41. https://doi.org/10.1016/j.ijsu.2010.02.007.

    Article  PubMed  Google Scholar 

  45. Higgins J, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration; 2011.

  46. Freycon C, Berger C, Casagranda L, et al. Effets tardifs de la radiothérapie pour un cancer dans l’enfance traité entre 1987 et 1992 en région Auvergne-Rhône-Alpes: résultats de l’étude SALTO. Rev Oncol Hématol Pédiatr. 2016;4(4):210–21. https://doi.org/10.1016/j.oncohp.2016.10.002.

    Article  Google Scholar 

  47. Baskar R, Lee KA, Yeo R, Yeoh KW. Cancer and radiation therapy: current advances and future directions. Int J Med Sci. 2012;9(3):193–9. https://doi.org/10.7150/ijms.3635.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Bhide SA, Nutting CM. Recent advances in radiotherapy. BMC Med. 2010;8(1):25. https://doi.org/10.1186/1741-7015-8-25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lubin JH, Adams MJ, Shore R, et al. Thyroid cancer following childhood low dose radiation exposure: a pooled analysis of nine cohorts. J Clin Endocrinol Metab. 2017. https://doi.org/10.1210/jc.2016-3529.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the Deutsche Krebshilfe (German Cancer Aid) for supporting this work (Award Number: 70111916). The content of this publication is solely the responsibility of the authors.

Author information

Authors and Affiliations

  1. Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Centre of the Johannes Gutenberg University Mainz, 55101, Mainz, Germany

    Eva Lorenz, Peter Scholz-Kreisel, Dan Baaken, Roman Pokora & Maria Blettner

  2. Infectious Disease Epidemiology, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Straße 74, 20359, Hamburg, Germany

    Eva Lorenz

Authors
  1. Eva Lorenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Scholz-Kreisel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dan Baaken
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roman Pokora
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria Blettner
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MB, PSK and RP wrote the grant application and laid down the overall principles of the study, and advised on conceptual issues. EL compiled the search. EL, PSK, and DB screened titles, abstracts and full-text articles for inclusion, and completed the quality and risk of bias assessment. EL led the review process, the analysis and the writing. All authors read, edited and approved the final manuscript.

Corresponding author

Correspondence to Eva Lorenz.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (XLSX 14 kb)

Appendices

Appendix

See Tables 3, 4, 5 and 6.

Table 3 Descriptive summary characteristics of cohort studies on radiotherapy and secondary thyroid cancer risk included in the systematic review
Full size table
Table 4 Descriptive summary characteristics of nested case–control studies on radiotherapy and secondary thyroid cancer risk included in the systematic review
Full size table
Table 5 Information on performed analyses and statistical models used in the cohort studies included in the systematic review
Full size table
Table 6 Information on performed analyses and statistical models used in the nested case–control studies included in the systematic review
Full size table

PubMed and Web of Science search strategy conducted on May 20th, 2016

(Child OR Child* OR Pediatric OR Adolescent OR Infant) AND (cancer OR neoplasm OR tumor OR malignancy OR hemangioma) AND (radiation therapy OR irradiation OR radiation treatment OR radiotherapy) AND ((Second OR subsequent OR secondary OR second primary) AND (Thyroid Neoplasm OR Thyroid Cancer)).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lorenz, E., Scholz-Kreisel, P., Baaken, D. et al. Radiotherapy for childhood cancer and subsequent thyroid cancer risk: a systematic review. Eur J Epidemiol 33, 1139–1162 (2018). https://doi.org/10.1007/s10654-018-0467-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10654-018-0467-8

Keywords

Search

Navigation