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Treatment-related differences in cardiovascular risk factors in long-term survivors of testicular cancer

  • T. Wethal
  • J. Kjekshus
  • J. Røislien
  • T. Ueland
  • A. K. Andreassen
  • R. Wergeland
  • P. Aukrust
  • S. D. Fosså
Article

Abstract

Objective

Treatment in testicular cancer survivors (TCSs) may be followed by cardiovascular disorders. We have examined whether today’s three treatment modalities are assicated with a biochemical cardiovascular risk profile.

Materials and methods

In this cross sectional study serum inflammatory markers, atherogenic lipoproteins and gonadal hormones were measured in 589 orchiectomized TCSs who have been treated 5–20 years previously. There were 140 patients treated by surgery alone (SURG), 231 who had had infradiaphragmatic radiotherapy alone (RAD), and 218 who had chemotherapy with or without additional surgery (CHEM).

Results

(1) The RAD group had higher levels of high-sensitivity C-reactive protein and soluble CD40 ligand compared to the SURG group. (2) The CHEM group had lower levels of high density lipoprotein cholesterol and an increased apolipoprotein B/apolipoprotein A-1 ratio than the SURG group. The prevalence of metabolic syndrome was higher in the CHEM group than in the SURG group. (3) Hypogonadism was significantly more prevalent in the CHEM than in the SURG group.

Conclusion

Treatment for TC was related to long-term biochemical cardiovascular risk factors by different pathways: Radiation treatment is followed by elevated serum markers of chronic inflammation and endothelial dysfunction, whereas chemotherapy is followed by the development of atherogenic lipid changes and of the metabolic syndrome. This study provides justification for a prospective study of the impact of these treatment modalities on cardiovascular risk in testical cancer survivors. In the interim testicular cancer survivors should monitor cardiovascular risk over time.

Keywords

Endothelial inflammation Metabolic syndrome Hypogonadism 

Notes

Acknowledgements

The Norwegian Foundation for Health and Rehabilitation. Norwegian Cancer Society. The study is part of Norwegian Urological Cancer Group. Study III. The Nord-Trøndelag Health Study (HUNT Study), a collaboration between the HUNT Research Center, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Verdal, is acknowledged.

References

  1. 1.
    Barter, P. J., Nicholls, S., Rye, K. A., Anantharamaiah, G. M., Navab, M., & Fogelman, A. M. (2004). Antiinflammatory properties of HDL. Circulation Research, 95, 764–772.PubMedCrossRefGoogle Scholar
  2. 2.
    Basavaraju, S. R., & Easterly, C. E. (2002). Pathophysiological effects of radiation on atherosclerosis development and progression, and the incidence of cardiovascular complications. Medical Physics, 29, 2391–2403.PubMedCrossRefGoogle Scholar
  3. 3.
    Beckman, J. A., Thakore, A., Kalinowski, B. H., Harris, J. R., & Creager M. A. (2001). Radiation therapy impairs endothelium-dependent vasodilation in humans. Journal of the American College of Cardiology, 37, 761–765.PubMedCrossRefGoogle Scholar
  4. 4.
    Dirix, L. Y., Libura, M., Libura, J., Vermeulen, P. B., De Bruijn, E. A., & van Oosterom, A. T. (1997). In vitro toxicity studies with mitomycins and bleomycin on endothelial cells. Anticancer Drugs, 8, 859–868.PubMedCrossRefGoogle Scholar
  5. 5.
    Eliopoulos, A. G., & Young, L. S. (2004) The role of the CD40 pathway in the pathogenesis and treatment of cancer. Current Opinion in Pharmacology, 4, 360–367.PubMedCrossRefGoogle Scholar
  6. 6.
    English, K. M., Mandour, O., Steeds, R. P., Diver, M. J., Jones, T. H., & Channer, K. S. (2000). Men with coronary artery disease have lower levels of androgens than men with normal coronary angiograms. European Heart Journal, 21, 890–894.PubMedCrossRefGoogle Scholar
  7. 7.
    Erlinger, T. P., Platz, E. A., Rifai, N., & Helzlsouer, K. J. (2004). C-reactive protein and the risk of incident colorectal cancer. JAMA, 291, 585–590.PubMedCrossRefGoogle Scholar
  8. 8.
    Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2001). JAMA, 285, 2486–2497.Google Scholar
  9. 9.
    Hanks, G. E., Peters, T., & Owen, J. (1992) Seminoma of the testis: long-term beneficial and deleterious results of radiation. International Journal of Radiation Oncology, Biology, Physics, 24, 913–919.PubMedGoogle Scholar
  10. 10.
    Haugnes, H. S., Aass, N., Fossa, S. D., Dahl, O., Klepp, O., Wist, E. A., et al. (2007) Components of the metabolic syndrome in long-term survivors of testicular cancer. Annals of Oncology, 18, 241–248.Google Scholar
  11. 11.
    Holm, T., Aukrust, P., Andreassen, A. K., Ueland, T., Brosstad, F., Froland, S. S., et al. (2000). Peripheral endothelial dysfunction in heart transplant recipients: Possible role of proinflammatory cytokines. Clinical Transplantation, 14, 218–225.PubMedCrossRefGoogle Scholar
  12. 12.
    Huddart, R. A., Norman, A., Shahidi, M., Horwich, A., Coward, D., Nicholls, J., et al. (2003). Cardiovascular disease as a long-term complication of treatment for testicular cancer. Journal of Clinical Oncology, 21, 1513–1523.PubMedCrossRefGoogle Scholar
  13. 13.
    Jurado, J., & Thompson, P. D. (2005). Prevention of coronary artery disease in cancer patients. Pediatr. Blood Cancer, 44, 620–624.PubMedCrossRefGoogle Scholar
  14. 14.
    Kahn, R., Buse, J., Ferrannini, E., & Stern, M. (2005). The metabolic syndrome: Time for critical appraisal. Joint statement from the American Diabetes Association for the Study of Diabetes. Diabetes Care, 28, 2289–2304.PubMedCrossRefGoogle Scholar
  15. 15.
    Laaksonen, D. E., Niskanen, L., Punnonen, K., Nyyssonen, K., Tuomainen, T. P., Salonen, R., et al. (2003). Sex hormones, inflammation and the metabolic syndrome: A population-based study. European Journal of Endocrinology, 149, 601–608.PubMedCrossRefGoogle Scholar
  16. 16.
    Meinardi, M. T., Gietema, J. A., van Veldhuisen. D. J., van der Graaf, W. T. A., de Vries, E. G. E., & Sleijfer, D. T. (2000). Long-term chemotherapy-related cardiovascular morbidity. Cancer Treatment Reviews, 26, 429–447.PubMedCrossRefGoogle Scholar
  17. 17.
    Myers, R. H., Montgomery, D. C., & Vining, G. G. (2002). Generalized linear models: With applications in engineering and the sciences. Wiley series in probability and statistics. The Family of Generalized Linear Models (pp. 169–71). New York: Wiley.Google Scholar
  18. 18.
    Nord, C., Bjoro, T., Ellingsen, D., Mykletun, A., Dahl, O., Klepp, O., et al. (2003). Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer. European Urology, 44, 322–328.PubMedCrossRefGoogle Scholar
  19. 19.
    Nuver, J., Smit, A. J., Sleijfer, D. T., van Gessel, A. I., van Roon, A. M., van der Meer, J., et al. (2004). Microalbuminuria, decreased fibrinolysis, and inflammation as early signs of atherosclerosis in long-term survivors of disseminated testicular cancer. European Journal of Cancer, 40, 701–706.PubMedCrossRefGoogle Scholar
  20. 20.
    Nuver, J., Smit, A. J., van der Meer, J., van den Berg, M. P., van der Graaf, W. T. A., Meinardi, M. T., et al. (2005a). Acute chemotherapy-induced cardiovascular changes in patients with testicular cancer. Journal of Clinical Oncology, 23, 9130–9137.PubMedCrossRefGoogle Scholar
  21. 21.
    Nuver, J., Smit, A. J., Wolffenbuttel, B. H., Sluiter, W. J., Hoekstra, H. J., Sleijfer, D. T., et al. (2005b). The metabolic syndrome and disturbance in hormone levels in long-term survivors of disseminated testicular cancer. Journal of Clinical Oncology, 23, 3718–3725.PubMedCrossRefGoogle Scholar
  22. 22.
    Pearson, T. A., Mensah, G. A., Alexander, R. W., Anderson, J. L., Cannon, R. O. 3rd, Criqui, M., et al. (2003). Markers of inflammation and cardiovascular disease: Application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Society. Circulation, 107, 499–511.PubMedCrossRefGoogle Scholar
  23. 23.
    Ridker, P. M., Rifai, N., Rose, L., Buring, J. E., & Cook, N. R. (2002). Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. New England journal of medicine, 347, 1557–1565.PubMedCrossRefGoogle Scholar
  24. 24.
    Rutter, M. K., Meigs, J. B., Sullivan, L. M., D’Agostino, R. B. Sr., & Wilson, P. W. (2004). C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation, 110, 380–385.PubMedCrossRefGoogle Scholar
  25. 25.
    Sagstuen, H., Aass, N., Fossa, S. D., Dahl, O., Klepp, O., Wist, E. A., et al. (2005). Blood pressure and body mass index in long-term survivors of testicular cancer. Journal of Clinical Oncology, 23, 4980–4990.PubMedCrossRefGoogle Scholar
  26. 26.
    Schonbeck, U., Varo, N., Libby, P., Buring, J., & Ridker, P. M. (2001). Soluble CD40L and cardiovascular risk in women. Circulation, 104, 2266–2268.PubMedGoogle Scholar
  27. 27.
    Tak, P. P., & Firestein, G. S. (2001). NF-kB: a key role in inflammatory diseases. Journal of Clinical Investigation, 107, 7–11.PubMedCrossRefGoogle Scholar
  28. 28.
    Testis. Incidence. Counties. Survival. Cancer Registry of Norway; Institute of Population-based Cancer Research, 2001 (Accessed November 15, 2005, at http://www.kreftregisteret.no/frame.htm?forekomst_og_overlevelse_2001/testis/incidence.htm).
  29. 29.
    Thorsen, L., Nystad, W., Stigum, H., Dahl, O., Klepp, O., Bremnes, R. M., et al. (2005). The association between self-reported physical activity and prevalence of depression and anxiety disorder in long-term survivors of testicular cancer and men in a general population sample. Support Care Cancer, 13, 637–646.PubMedCrossRefGoogle Scholar
  30. 30.
    Ubbink, J. B., Vermaak, W. J. H., & Bissbort, S. (1991). Rapid high-performance liquid chromatography assay for total homocysteine levels in human serum. Journal of chromatography, 565, 441–446.PubMedCrossRefGoogle Scholar
  31. 31.
    van den Belt-Dusebout, A. W., Nuver, J., de Wit, R., Gietema, J. A., & ten Bokkel Huinink, W. W., (2006). Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. Journal of Clinical Oncology, 24, 467–475.PubMedCrossRefGoogle Scholar
  32. 32.
    Vermeulen, A., Verdonck, L., & Kaufman, J. M. (1999). A critical evaluation of simple methods for the estimation of free testosterone in serum. Journal of Clinical Endocrinology and Metabolism, 84, 3666–3672.PubMedCrossRefGoogle Scholar
  33. 33.
    Wallace, A. M., McMahon, A. D., Packard, C. J., Kelly, A., Shepherd, J., Gaw, A., et al. (2001). Plasma leptin and the risk of cardiovascular disease in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation, 104, 3052–3056.PubMedGoogle Scholar
  34. 34.
    Whincup, P. H., Danesh, J., Walker, M., Lennon, L., Thomson, A., Appleby, P., et al. (2002). von Willebrand factor and coronary heart disease. Prospective study and meta-analysis. European Heart Journal, 23, 1764–1770.PubMedCrossRefGoogle Scholar
  35. 35.
    Wirehn, A. B., Tornberg, S., & Carstensen, J. (2005). Serum cholesterol and testicular cancer incidence in 45 000 men followed for 25 years. British Journal of Cancer, 92, 1785–1786.PubMedCrossRefGoogle Scholar
  36. 36.
    Zagars, G. K., Ballo, M. T., Lee, A. K., & Strom, S. S. (2004). Mortality after cure of testicular seminoma. Journal of Clinical Oncology, 22, 640–647.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • T. Wethal
    • 1
  • J. Kjekshus
    • 1
  • J. Røislien
    • 2
  • T. Ueland
    • 3
  • A. K. Andreassen
    • 7
  • R. Wergeland
    • 4
  • P. Aukrust
    • 3
    • 5
  • S. D. Fosså
    • 6
  1. 1.Department of Cardiology, Faculty Division RikshospitaletUniversity of OsloOsloNorway
  2. 2.Section of BiostatisticsRikshospitalet-Radiumhospitalet Medical CentreOsloNorway
  3. 3.Research Institute for Internal Medicine, Faculty Division RikshospitaletUniversity of OsloOsloNorway
  4. 4.Department of Medical BiochemistryRikshospitalet-Radiumhospitalet Medical CentreOsloNorway
  5. 5.Section of Clinical Immunology and Infectious DiseasesRikshospitalet-Radiumhospitalet Medical CentreOsloNorway
  6. 6.Department of Clinical Cancer ResearchRikshospitalet-Radiumhospitalet Medical CentreOsloNorway
  7. 7.Department of CardiologyRikshospitalet-Radiumhospitalet Medical CentreOsloNorway

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