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. 2004 May 6;63(10):1307–1311. doi: 10.1136/ard.2003.019125

Urinary bladder cancer in Wegener's granulomatosis: risks and relation to cyclophosphamide

A Knight 1, J Askling 1, F Granath 1, P Sparen 1, A Ekbom 1
PMCID: PMC1754772  PMID: 15130900

Abstract

Objective: To assess and characterise the risk of bladder cancer, and its relation to cyclophosphamide, in patients with Wegener's granulomatosis.

Methods: In the population based, nationwide Swedish Inpatient Register a cohort of 1065 patients with Wegener's granulomatosis, 1969–95, was identified. Through linkage with the Swedish Cancer Register, all subjects in this cohort diagnosed with bladder cancer were identified. Nested within the cohort, a matched case-control study was performed to estimate the association between cyclophosphamide and bladder cancer using odds ratios (ORs) as relative risk. In the cohort the cumulative risk of bladder cancer after Wegener's granulomatosis, and the relative prevalence of a history of bladder cancer at the time of diagnosis of Wegener's granulomatosis, were also estimated.

Results: The median cumulative doses of cyclophosphamide among cases (n = 11) and controls (n = 25) were 113 g and 25 g, respectively. The risk of bladder cancer doubled for every 10 g increment in cyclophosphamide (OR = 2.0, 95% confidence interval (CI) 0.8 to 4.9). Treatment duration longer than 1 year was associated with an eightfold increased risk (OR = 7.7, 95% CI 0.9 to 69). The absolute risk for bladder cancer in the cohort reached 10% 16 years after diagnosis of Wegener's granulomatosis, and a history of bladder cancer was (non-significantly) twice as common as expected at the time of diagnosis of Wegener's granulomatosis.

Conclusion: The results indicate a dose-response relationship between cyclophosphamide and the risk of bladder cancer, high cumulative risks in the entire cohort, and also the possibility of risk factors operating even before Wegener's granulomatosis.

Full Text

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Figure 1.

Figure 1

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 Distribution of the cumulative dose of cyclophosphamide among the 11 cases and their 25 controls in the case-control study nested in a population based cohort of 1065 patients with Wegener's granulomatosis. (Wilcoxon p for difference = 0.01).

Figure 2.

Figure 2

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 Cumulative incidence of bladder cancer by time since first discharge for Wegener's granulomatosis.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ansher A. F., Melton J. W., 3rd, Sliwinski A. J. Bladder malignancy in a patient receiving low dose cyclophosphamide for treatment of rheumatoid arthritis. Arthritis Rheum. 1983 Jun;26(6):804–805. doi: 10.1002/art.1780260618. [DOI] [PubMed] [Google Scholar]
  2. Baker G. L., Kahl L. E., Zee B. C., Stolzer B. L., Agarwal A. K., Medsger T. A., Jr Malignancy following treatment of rheumatoid arthritis with cyclophosphamide. Long-term case-control follow-up study. Am J Med. 1987 Jul;83(1):1–9. doi: 10.1016/0002-9343(87)90490-6. [DOI] [PubMed] [Google Scholar]
  3. Beauparlant P., Papp K., Haraoui B. The incidence of cancer associated with the treatment of rheumatoid arthritis. Semin Arthritis Rheum. 1999 Dec;29(3):148–158. doi: 10.1016/s0049-0172(99)80026-2. [DOI] [PubMed] [Google Scholar]
  4. Brandau S., Böhle A. Bladder cancer. I. Molecular and genetic basis of carcinogenesis. Eur Urol. 2001 May;39(5):491–497. doi: 10.1159/000052494. [DOI] [PubMed] [Google Scholar]
  5. Breslow N. E., Day N. E. Statistical methods in cancer research. Volume II--The design and analysis of cohort studies. IARC Sci Publ. 1987;(82):1–406. [PubMed] [Google Scholar]
  6. Cox P. J. Cyclophosphamide cystitis--identification of acrolein as the causative agent. Biochem Pharmacol. 1979 Jul 1;28(13):2045–2049. doi: 10.1016/0006-2952(79)90222-3. [DOI] [PubMed] [Google Scholar]
  7. De Ridder D., van Poppel H., Demonty L., D'Hooghe B., Gonsette R., Carton H., Baert L. Bladder cancer in patients with multiple sclerosis treated with cyclophosphamide. J Urol. 1998 Jun;159(6):1881–1884. doi: 10.1016/S0022-5347(01)63185-9. [DOI] [PubMed] [Google Scholar]
  8. Fauci A. S., Haynes B. F., Katz P., Wolff S. M. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med. 1983 Jan;98(1):76–85. doi: 10.7326/0003-4819-98-1-76. [DOI] [PubMed] [Google Scholar]
  9. Fernandes E. T., Manivel J. C., Reddy P. K., Ercole C. J. Cyclophosphamide associated bladder cancer--a highly aggressive disease: analysis of 12 cases. J Urol. 1996 Dec;156(6):1931–1933. [PubMed] [Google Scholar]
  10. Hoffman G. S., Kerr G. S., Leavitt R. Y., Hallahan C. W., Lebovics R. S., Travis W. D., Rottem M., Fauci A. S. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992 Mar 15;116(6):488–498. doi: 10.7326/0003-4819-116-6-488. [DOI] [PubMed] [Google Scholar]
  11. Jayne David, Rasmussen Niels, Andrassy Konrad, Bacon Paul, Tervaert Jan Willem Cohen, Dadoniené Jolanta, Ekstrand Agneta, Gaskin Gill, Gregorini Gina, de Groot Kirsten. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003 Jul 3;349(1):36–44. doi: 10.1056/NEJMoa020286. [DOI] [PubMed] [Google Scholar]
  12. Khan M. A., Travis L. B., Lynch C. F., Soini Y., Hruszkewycz A. M., Delgado R. M., Holowaty E. J., van Leeuwen F. E., Glimelius B., Stovall M. p53 mutations in cyclophosphamide-associated bladder cancer. Cancer Epidemiol Biomarkers Prev. 1998 May;7(5):397–403. [PubMed] [Google Scholar]
  13. Knight Ann, Askling Johan, Ekbom Anders. Cancer incidence in a population-based cohort of patients with Wegener's granulomatosis. Int J Cancer. 2002 Jul 1;100(1):82–85. doi: 10.1002/ijc.10444. [DOI] [PubMed] [Google Scholar]
  14. Mattsson B., Wallgren A. Completeness of the Swedish Cancer Register. Non-notified cancer cases recorded on death certificates in 1978. Acta Radiol Oncol. 1984;23(5):305–313. doi: 10.3109/02841868409136026. [DOI] [PubMed] [Google Scholar]
  15. Mellemkjaer L., Andersen V., Linet M. S., Gridley G., Hoover R., Olsen J. H. Non-Hodgkin's lymphoma and other cancers among a cohort of patients with systemic lupus erythematosus. Arthritis Rheum. 1997 Apr;40(4):761–768. doi: 10.1002/art.1780400424. [DOI] [PubMed] [Google Scholar]
  16. Pedersen-Bjergaard J., Ersbøll J., Hansen V. L., Sørensen B. L., Christoffersen K., Hou-Jensen K., Nissen N. I., Knudsen J. B., Hansen M. M. Carcinoma of the urinary bladder after treatment with cyclophosphamide for non-Hodgkin's lymphoma. N Engl J Med. 1988 Apr 21;318(16):1028–1032. doi: 10.1056/NEJM198804213181604. [DOI] [PubMed] [Google Scholar]
  17. Plotz P. H., Klippel J. H., Decker J. L., Grauman D., Wolff B., Brown B. C., Rutt G. Bladder complications in patients receiving cyclophosphamide for systemic lupus erythematosus or rheumatoid arthritis. Ann Intern Med. 1979 Aug;91(2):221–223. doi: 10.7326/0003-4819-91-2-221. [DOI] [PubMed] [Google Scholar]
  18. Radis C. D., Kahl L. E., Baker G. L., Wasko M. C., Cash J. M., Gallatin A., Stolzer B. L., Agarwal A. K., Medsger T. A., Jr, Kwoh C. K. Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis. A 20-year followup study. Arthritis Rheum. 1995 Aug;38(8):1120–1127. doi: 10.1002/art.1780380815. [DOI] [PubMed] [Google Scholar]
  19. Stillwell T. J., Benson R. C., Jr, DeRemee R. A., McDonald T. J., Weiland L. H. Cyclophosphamide-induced bladder toxicity in Wegener's granulomatosis. Arthritis Rheum. 1988 Apr;31(4):465–470. doi: 10.1002/art.1780310402. [DOI] [PubMed] [Google Scholar]
  20. Talar-Williams C., Hijazi Y. M., Walther M. M., Linehan W. M., Hallahan C. W., Lubensky I., Kerr G. S., Hoffman G. S., Fauci A. S., Sneller M. C. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med. 1996 Mar 1;124(5):477–484. doi: 10.7326/0003-4819-124-5-199603010-00003. [DOI] [PubMed] [Google Scholar]
  21. Tatsis E., Reinhold-Keller E., Steindorf K., Feller A. C., Gross W. L. Wegener's granulomatosis associated with renal cell carcinoma. Arthritis Rheum. 1999 Apr;42(4):751–756. doi: 10.1002/1529-0131(199904)42:4<751::AID-ANR19>3.0.CO;2-D. [DOI] [PubMed] [Google Scholar]
  22. Travis L. B., Curtis R. E., Glimelius B., Holowaty E. J., Van Leeuwen F. E., Lynch C. F., Hagenbeek A., Stovall M., Banks P. M., Adami J. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma. J Natl Cancer Inst. 1995 Apr 5;87(7):524–530. doi: 10.1093/jnci/87.7.524. [DOI] [PubMed] [Google Scholar]

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