Cancer Chemotherapy and Pharmacology

, Volume 59, Issue 5, pp 643–650

Histological changes in bladders of patients submitted to ifosfamide chemotherapy even with mesna prophylaxis

  • Marcos Venício Alves Lima
  • Francisco Valdeci Ferreira
  • Francisco Yuri Bulcão Macedo
  • Gerly Anne de Castro Brito
  • Ronaldo Albuquerque Ribeiro
Original Article



Hemorrhagic cystitis (HC) is a limiting side effect of chemotherapy with ifosfamide (IFS). Mesna is the drug of choice for prevention of HC. In this study, we analyzed cystoscopic and histological changes present in bladders of patients using IFS with mesna prophylaxis.


Thirty-three patients selected for IFS plus three doses of mesna chemotherapy regime were assigned at random to two groups: Group I or reference group consisted of 18 patients yet untreated. Group II consisted of 15 patients in whom urinalysis and cystoscopy plus vesical biopsy were performed only 24 h after receiving the last dose of IFS. The cystoscopic and histological findings were used as parameters for evaluating the results. For the former the criterion adopted was macroscopic vesical changes in accordance with Gray’s criteria. Histological analyses were performed by evaluation method especially adapted to this study.


Even under treatment with three doses of mesna, 66.7% of patients presented cystoscopic alterations and 100% showed bladder mucosa microscopic alterations such as edema, exocytosis, and hemorrhage.


The standard protocol used for prevention of IFS-induced HC with three doses of mesna does not completely prevent bladder damage. The histopathological criteria used in this study for observation of inflammatory events allowed staging the intensity of IFS-induced urothelial and mucosal injury.


Ifosfamide Hemorrhagic cystitis Mesna Histopathology 


  1. 1.
    Brade WP, Herdrich K, Varini M (1985) Ifosfamide—pharmacology, safety and therapeutic potential. Cancer Treat Rev 12:1PubMedCrossRefGoogle Scholar
  2. 2.
    Brock N, Pohl J (1983) The development of mesna for regional detoxification. Cancer Treat Rev 10:33–43PubMedCrossRefGoogle Scholar
  3. 3.
    Burket H (1983) Clinical overview of mesna. Cancer Treat Rev 10(Suppl A):175–181CrossRefGoogle Scholar
  4. 4.
    Cox PJ (1979) Cyclophosphamide cystitis—identification of acrolein as the causative agent. Biochem Pharmacol 28:2045–2049PubMedCrossRefGoogle Scholar
  5. 5.
    Dechant KL, Brogden RN, Pilkington T, Faulds D (1991) Ifosfamide/Mesna. A review of its antineoplastic activity, pharmacokinetic properties and therapeutic efficacy in cancer. Drugs 42:428–467PubMedCrossRefGoogle Scholar
  6. 6.
    Etlik O, Tomur A, Deveci S, Piskin I, Pekcan M (1997) Comparison of uroprotective efficacy of Mesna and HBO treatments in cyclophosphamide-induced hemorrhagic cystitis. J Urol 158:2296–2299PubMedCrossRefGoogle Scholar
  7. 7.
    Foad BSI, Hess EV (1976) Urinary bladder complications with cyclophosphamide therapy. Arch Intern Med 136:616–619PubMedCrossRefGoogle Scholar
  8. 8.
    Gomes TNA, Santos CC, Souza-Filho MVP, Cunha FQ, Ribeiro RA (1995) Participation of TNF-α and IL-1 in the pathogenesis of cyclophosphamide-induced hemorrhagic cystitis. Braz J Med Biol Res 28:1103–1108PubMedGoogle Scholar
  9. 9.
    Hensley ML, Schuchter ML, Lindley C, Meropol NJ et al (1999) American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. J Clin Oncol 17:3333–3355PubMedGoogle Scholar
  10. 10.
    Higgs D, Nagy C, Einhorn LH (1989) Ifosfamide: a clinical review. Semin Oncol Nurs 5:70–77PubMedCrossRefGoogle Scholar
  11. 11.
    Hu VY, Malley S, Dattilio A, Folsom SB, Zvara P, Vizzard MA (2003) COX-2 and prostanoid expression in micturition pathways after cyclophosphamide-induced cystitis in the rat. Am J Physiol Regul Integr Comp Physiol 284:574–585Google Scholar
  12. 12.
    Gray KJ, Engelmann UH, Johnson EH, Fishman IJ (1986) Evaluation of misoprostol cytoprotection of the bladder with cyclophosphamide (Cytoxan) therapy. J Urol 133:497–500Google Scholar
  13. 13.
    Katz A, Epelman S, Anelli A et al (1995) A prospective randomized evaluation of three schedules of mesna administration in patients receiving an ifosfamide-containing chemotherapy regimen: sustained efficiency and simplified administration. J Cancer Res Clin Oncol 121:128–131PubMedCrossRefGoogle Scholar
  14. 14.
    Mace JR, Keohan ML, Bernardy H, Junge K, Niebch G et al (2003) Crossover randomized comparison of intravenous versus intravenous/oral mesna in soft tissue sarcoma treated with high-dose ifosfamide. Clin Cancer Res 9:5829–5834PubMedGoogle Scholar
  15. 15.
    Morais MM, Belarmino-Filho JN, Brito GAC, Ribeiro RA (1999) Pharmacological and histopathological study of cyclophosphamide-induced hemorrhagic cystitis—comparison of the effects of dexamethasone and Mesna. Braz J Med Biol Res 32:1211–1215PubMedCrossRefGoogle Scholar
  16. 16.
    Pyeritz R, Droller MJ, Bender WL, Saral R (1978) An approach to control of massive hemorrhage in cyclophosphamide-induced cystitis by intravenous vasopressin: a case report. J Urol 120:253–254PubMedGoogle Scholar
  17. 17.
    Ratliff TR, Willians RD (1998) Hemorrhagic cystitis, chemotherapy, and bladder toxicity. J Urol 159:1044PubMedCrossRefGoogle Scholar
  18. 18.
    Ribeiro RA, Freitas HC, Campos MC et al (2002) Tumor necrosis factor-α and interleukin-1β mediate the production of nitric oxide involved in the pathogenesis of ifosfamide induced hemorrhagic cystitis in mice. J Urol 150:2229–2234Google Scholar
  19. 19.
    Shepherd JD, Pringle LE, Barnett MJ, Klingemann HG, Reece DE, Phillips GL (1991) Mesna versus hyperhydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation. J Clin Oncol 11:2016–2020Google Scholar
  20. 20.
    Souza-Filho MVP, Lima MVA, Pompeu MML, Ballejo G, Cunha FQ, Ribeiro RA (1997) Involvement of nitric oxide in the pathogenesis of cyclophosphamide-induced hemorrhagic cystitis. Am J Pathol 150:247–256Google Scholar
  21. 21.
    Theman H, Oberdorf E, Brock N, Pohl J (1987) Electron microscopic investigations of cyclophosphamide-induced lesions of the urinary bladder of the rat and their prevention by mesna. Urol Int 42:37–43CrossRefGoogle Scholar
  22. 22.
    Vieira MM, Brito GA, Belarmino-Filho JN, Macedo FY, Nery EA, Cunha FQ, Ribeiro RA (2003) Use of dexamethasone with mesna for the prevention of ifosfamide-induced hemorrhagic cystitis. Int J Urol 10(11):595–602PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Marcos Venício Alves Lima
    • 1
  • Francisco Valdeci Ferreira
    • 2
  • Francisco Yuri Bulcão Macedo
    • 3
  • Gerly Anne de Castro Brito
    • 4
  • Ronaldo Albuquerque Ribeiro
    • 3
    • 5
    • 6
  1. 1.Department of Surgery, Division of UrologyCancer Institute of CearáFortalezaBrazil
  2. 2.Department of PathologyCancer Institute of CearáFortalezaBrazil
  3. 3.Department of Physiology and Pharmacology, Faculty of MedicineUniversidade Federal do CearáFortalezaBrazil
  4. 4.Department of Morphology, Faculty of MedicineUniversidade Federal do CearáFortalezaBrazil
  5. 5.Department of Clinical OncologyCancer Institute of CearáFortalezaBrazil
  6. 6.Centro de Biomedicina, Faculdade de MedicinaUniversidade Federal do CearáFortalezaBrazil

Personalised recommendations