Abstract

Background

While the risk of diabetes is increased following radiation exposure to the pancreas among childhood cancer survivors, its association among testicular cancer (TC) survivors has not been investigated.

Methods

Diabetes risk was studied in 2998 1-year TC survivors treated before 50 years of age with orchidectomy with/without radiotherapy between 1976 and 2007. Diabetes incidence was compared with general population rates. Treatment-specific risk of diabetes was assessed using a case–cohort design.

Results

With a median follow-up of 13.4 years, 161 TC survivors were diagnosed with diabetes. Diabetes risk was not increased compared to general population rates (standardised incidence ratios (SIR): 0.9; 95% confidence interval (95% CI): 0.7–1.1). Adjusted for age, para-aortic radiotherapy was associated with a 1.66-fold (95% CI: 1.05–2.62) increased diabetes risk compared to no radiotherapy. The excess hazard increased with 0.31 with every 10 Gy increase in the prescribed radiation dose (95% CI: 0.11–0.51, P = 0.003, adjusted for age and BMI); restricted to irradiated patients the excess hazard increased with 0.33 (95% CI: −0.14 to 0.81, P = 0.169) with every 10 Gy increase in radiation dose.

Conclusion

Compared to surgery only, para-aortic irradiation is associated with increased diabetes risk among TC survivors.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Availability of data and materials:

data were collected at NKI-AVL and are not publicly available.

Additional information

Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

References

  1. 1.

    de Vathaire, F. et al. Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study. Lancet Oncol. 13, 1002–1010 (2012).

  2. 2.

    Meacham, L. R. et al. Diabetes mellitus in long-term survivors of childhood cancer. Increased risk associated with radiation therapy: a report for the childhood cancer survivor study. Arch. Intern. Med. 169, 1381–1388 (2009).

  3. 3.

    Meacham, L. R. et al. Cardiovascular risk factors in adult survivors of pediatric cancer-a report from the childhood cancer survivor study. Cancer Epidemiol. Biomark. Prev. 19, 170–181 (2010).

  4. 4.

    van Nimwegen, F. A. et al. Risk of diabetes mellitus in long-term survivors of Hodgkin lymphoma. J. Clin. Oncol. 32, 3257–3263 (2014).

  5. 5.

    Hauptmann, M. et al. Increased pancreatic cancer risk following radiotherapy for testicular cancer. Br. J. Cancer 115, 901–908 (2016).

  6. 6.

    Haugnes, H. S. et al. Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: a 20-year follow-up study. J. Clin. Oncol. 28, 4649–4657 (2010).

  7. 7.

    Stringhini, S. et al. Socioeconomic status and the 25×25 risk factors as determinants of premature mortality: a multicohort study and meta-analysis of 1.7 million men and women. Lancet 389, 1229–1237 (2017).

  8. 8.

    Grover, S. A., Paquet, S., Levinton, C., Coupal, L. & Zowall, H. Estimating the benefits of modifying risk factors of cardiovascular disease: a comparison of primary vs secondary prevention. Arch. Intern. Med. 158, 655–662 (1998).

  9. 9.

    Conroy, R. M. et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur. Heart J. 24, 987–1003 (2003).

  10. 10.

    van den Belt-Dusebout, A. W. et al. Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J. Clin. Oncol. 24, 467–475 (2006).

  11. 11.

    van den Belt-Dusebout, A. W. et al. Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J. Clin. Oncol. 25, 4370–4378 (2007).

  12. 12.

    Barlow, W. E., Ichikawa, L., Rosner, D. & Izumi, S. Analysis of case-cohort designs. J. Clin. Epidemiol. 52, 1165–1172 (1999).

  13. 13.

    van Leeuwen, F. E. et al. Second cancer risk following testicular cancer: a follow-up study of 1,909 patients. J. Clin. Oncol. 11, 415–424 (1993).

  14. 14.

    Zwaveling, A. & Soebhag, R. Testicular tumors in the Netherlands. Cancer 55, 1612–1617 (1985).

  15. 15.

    Cohn-Cedermark, G., Stahl, O. & Tandstad, T., Swenoteca. Surveillance vs. adjuvant therapy of clinical stage I testicular tumors - a review and the SWENOTECA experience. Andrology 3, 102–110 (2015).

  16. 16.

    Oliver, R. T. et al. Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: a randomised trial. Lancet 366, 293–300 (2005).

  17. 17.

    Schmoll, H. J. et al. European consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG). Ann. Oncol. 15, 1377–1399 (2004).

  18. 18.

    Rutten GEHM, D. G. W. et al. NHG-standaard diabetes mellitus type 2 ((derde herziening)). Huisarts. Wet. 56, 512–525 (2013).

  19. 19.

    Fine, J. A proportional hazards model for the subdistribution of a competing risk. J. Am. Stat. Assoc. 94, 496–509 (1999).

  20. 20.

    Rubin, D. B. Multiple Imputation for Nonresponse in Surveys (John Wiley & Sons, New York, NY, 1987).

  21. 21.

    Oeffinger, K. C. & Sklar, C. A. Abdominal radiation and diabetes: one more piece in the puzzle. Lancet Oncol. 13, 961–962 (2012).

  22. 22.

    Gemici, C. et al. Risk of endocrine pancreatic insufficiency in patients receiving adjuvant chemoradiation for resected gastric cancer. Radiother. Oncol. 107, 195–199 (2013).

  23. 23.

    Du Toit, D. F. et al. The effect of ionizing radiation on the primate pancreas: an endocrine and morphologic study. J. Surg. Oncol. 34, 43–52 (1987).

  24. 24.

    de Haas, E. C. et al. Early development of the metabolic syndrome after chemotherapy for testicular cancer. Annals of oncology: official journal of the European Society for. Med. Oncol. 24, 749–755 (2013).

  25. 25.

    Traish, A. M., Saad, F. & Guay, A. The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance. J. Androl. 30, 23–32 (2009).

  26. 26.

    Selvin, E. et al. Androgens and diabetes in men: results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care 30, 234–238 (2007).

  27. 27.

    Tandstad, T. et al. Treatment of stage I seminoma, with one course of adjuvant carboplatin or surveillance, risk-adapted recommendations implementing patient autonomy: a report from the Swedish and Norwegian Testicular Cancer Group (SWENOTECA). Ann. Oncol. 27, 1299–1304 (2016).

  28. 28.

    Aparicio, J. et al. Risk-adapted management for patients with clinical stage I seminoma: the Second Spanish Germ Cell Cancer Cooperative Group study. J. Clin. Oncol. 23, 8717–8723 (2005).

  29. 29.

    Mead, G. M. et al. Randomized trials in 2466 patients with stage I seminoma: patterns of relapse and follow-up. J. Natl Cancer Inst. 103, 241–249 (2011).

Download references

Acknowledgements

We would like to thank M.J. Nielen from the Netherlands Institute for Public Health Research for providing incidence data on diabetes for the general Dutch population. In addition, we thank T. Bootsma, M. Berkhof, S. Fase, and K. Kooijman (Netherlands Cancer Institute, Amsterdam, the Netherlands) for collecting data from the medical records and all participating general practitioners for completing questionnaires. This work was supported by the Dutch Cancer Society, grant number KWF-2011-5209.

Author information

Affiliations

  1. Department of Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    • Harmke J. Groot
    • , Alexandra W. van den Belt-Dusebout
    • , Flora E. van Leeuwen
    •  & Michael Schaapveld
  2. Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands

    • Jourik A. Gietema
  3. Department of Radiation Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    • Berthe M. P. Aleman
  4. Department of Radiation Oncology, Erasmus Medical Center Cancer Institute, ‘s-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands

    • Luca Incrocci
  5. Department of Medical Oncology, Erasmus Medical Center Cancer Institute, ‘s-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands

    • Ronald de Wit
  6. Department of Urology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands

    • J. Alfred Witjes
  7. Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands

    • Gerard Groenewegen
  8. Department of Radiation Oncology, Dr. Bernard Verbeeten Institute, Brugstraat 10, 5042 SB, Tilburg, The Netherlands

    • Peter de Brouwer
  9. Department of Radiation Oncology, VU University Medical Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    • Otto W. M. Meijer
  10. Department of Radiation Oncology, Amsterdam Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands

    • Maarten C. C. M. Hulshof
  11. Department of Radiotherapy, Catharina Hospital, Michelangelolaan 2, 5623 EJ, Eindhoven Eindhoven, The Netherlands

    • Hetty A. van den Berg
  12. Department of Medical Oncology, Jeroen Bosch Hospital, Den Bosch, Henri Dunantstraat 1, 5223 GZ, ‘s-Hertogenbosch, The Netherlands

    • Tineke J. Smilde
  13. Department of Radiotherapy, MAASTRO-clinic, Dr. Tanslaan 12, 6229 ET, Maastricht, The Netherlands

    • Ben G. L. Vanneste
  14. Department of Medical Oncology, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX, Maastricht, The Netherlands

    • Maureen J. Aarts
  15. Department of Radiation Oncology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands

    • Alphonsus C. M. van den Bergh
  16. Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    • J. Martijn Kerst
  17. Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands

    • Sjoukje Lubberts
  18. Department of Biostatistics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    • Katarzina Jóźwiak
  19. Department of Urology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    • Simon Horenblas

Authors

  1. Search for Harmke J. Groot in:

  2. Search for Jourik A. Gietema in:

  3. Search for Berthe M. P. Aleman in:

  4. Search for Luca Incrocci in:

  5. Search for Ronald de Wit in:

  6. Search for J. Alfred Witjes in:

  7. Search for Gerard Groenewegen in:

  8. Search for Peter de Brouwer in:

  9. Search for Otto W. M. Meijer in:

  10. Search for Maarten C. C. M. Hulshof in:

  11. Search for Hetty A. van den Berg in:

  12. Search for Tineke J. Smilde in:

  13. Search for Ben G. L. Vanneste in:

  14. Search for Maureen J. Aarts in:

  15. Search for Alphonsus C. M. van den Bergh in:

  16. Search for J. Martijn Kerst in:

  17. Search for Alexandra W. van den Belt-Dusebout in:

  18. Search for Sjoukje Lubberts in:

  19. Search for Katarzina Jóźwiak in:

  20. Search for Simon Horenblas in:

  21. Search for Flora E. van Leeuwen in:

  22. Search for Michael Schaapveld in:

Contributions

Conception and design: H.J.G., M.S., F.E.v.L.

Provision of study materials or patients: B.M.P.A., A.W.v.d.B.-D., L.I., R.d.W., J.A.W., A.C.M.v.d.B., G.G., P.d.B., H.A.v.d.B., M.C.C.M.H., O.W.M.M., T.J.S., M.J.A., B.G.L.V., S.H., J.M.K., J.A.G., F.E.v.L.

Collection and assembly of data: H.J.G, M.S., A.v.d. B.-D., S.L., F.E.v.L.

Data analysis and interpretation: H.J.G., M.S., F.E.v.L., K.J.

Manuscript writing and final approval of manuscript: All authors.

Competing interests

The authors declare no competing interests.

Ethics approval

The study protocol was submitted to the Institutional Review Board of the Netherlands Cancer Institute, which waived the requirement for individual patient consent. STROBE statement All data are presented in accordance with STROBE guidelines.

Note:

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Corresponding author

Correspondence to Michael Schaapveld.

Electronic supplementary material

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/s41416-018-0248-x