Skip to main content

Cyclophosphamide Toxicity

Characterising and Avoiding the Problem

Summary

Cyclophosphamide, an orally active alkylating agent, is widely used to treat a variety of malignant and nonmalignant disorders. Although it has some tumour selectivity, it also possesses a wide spectrum of toxicities. The requirement of metabolic activation before cyclophosphamide exerts either its therapeutic or toxic effects is well established, but has not led to effective countermeasures. Clinically, damage to the bladder (haemorrhagic cystitis), immunosuppression (when not desired) and alopecia are the most significant toxicities associated with cyclophosphamide. Cardiotoxicity is also a possibility when very high doses are given. Preventing these toxicities has focused on modifications of the treatment regimens and, in the case of haemorrhagic cystitis, the administration of a drug which is excreted in the urine where it inactivates the bladder-toxic species. As treatment regimens for cancer become more effective in prolonging a patient’s life, and as cyclophosphamide receives increasing use for nonmalignant disorders, the potential for cyclophosphamide-induced cancers, particularly in the bladder, must be recognised. Although the toxicities associated with cyclophosphamide are serious, this agent remains a highly effective drug in many situations. Research on the pathways which play an important role in activating this drug may improve our ability to target particular diseases and decrease unwanted side effects.

This is a preview of subscription content, access via your institution.

References

  • Abdel Karim FW, Ayash RE, Allam C, Salem PA. Pulmonary fibrosis after prolonged treatment with low-dose cyclophosphamide: a case report. Oncology 40: 174–176, 1983

    PubMed  Article  CAS  Google Scholar 

  • Adamson IYR. Drug induced pulmonary fibrosis. Environmental Health Perspectives 55: 25–36, 1984

    PubMed  Article  CAS  Google Scholar 

  • Andre R, Rochant H, Dreyfus B, Duhamel G, Pecheri J. Fibrose interstitielle diffuse du poumon au cours d’une maladie de Hodgkin traitee par des doses élevées d’Endoxan. Bulletin de la Societé Medical L’Hopital Paris 118: 1133–1141, 1967

    CAS  Google Scholar 

  • Andriole GL, Yuan JJ, Catalona WJ. Cystotomy, temporary urinary diversion and bladder packing in the management of severe cyclophosphamide-induced hemorrhagic cystitis. Journal of Urology 143: 1006–1007, 1990

    PubMed  CAS  Google Scholar 

  • Baello EB, Eansberg ME, Ferguson DW, Kugler JW, Gingrich JO, et al. Effect of high-dose cyclophosphamide and total-body irradiation on left ventricular function in adult patients with leukemia undergoing allogenic bone marrow transplantation. Cancer Treatment Reports 70: 1187–1193, 1986

    PubMed  CAS  Google Scholar 

  • Ballow JE, Austin HA, Muenz LR, et al. Effect of treatment on the evaluation of renal abnormalities in lupus nephritis. New England Journal of Medicine 311: 491–495, 1984

    Article  Google Scholar 

  • Beelen DW, Quabeck K, Graeven U, Sayer HG, Mahmoud HK, et al. Acute toxicity and first clinical results of intensive post-induction therapy using a modified busulfan and cyclophosphamide regimen with autologous bone marrow rescue in first remission of acute myeloid leukemia. Blood 74: 1507–1516, 1989

    PubMed  CAS  Google Scholar 

  • Bourscaux F, Brock N. Chemotherapeutic action of a cyclic nitrogen mustard phosphamide ester (B518-ASTA) in experimental tumours in the rat. Nature 181: 931, 1958

    Google Scholar 

  • Buckner CD, Rudolph RH, Fefer A, Clift RA, Epstein RB, et al. High-dose cyclophosphamide therapy for malignant disease: toxicity, tumor response, and the effects of stored autologous marrow. Cancer 29: 357–365, 1972

    Article  Google Scholar 

  • Burke DA, Stoddart JC, Ward MK, Simpson CGB. Fatal pulmonary fibrosis occurring during treatment with cyclophosphamide. British Medical Journal 285: 696, 1982

    PubMed  Article  CAS  Google Scholar 

  • Calabresi P, Chabner BA. Chemotherapy of neoplastic diseases. In Gilman et al. (Eds) The pharmacological basis of therapeutics, 8th ed., pp. 1202–1263, MacMillan, New York, 1990

    Google Scholar 

  • Case Records of the Massachusetts General Hospital (Case 26-1972). New England Journal of Medicine 286: 1405-1411, 1972

    Google Scholar 

  • Cazin B, Gorin C, Laprote P, Gallet B, Douay L, et al. Cardiac complications after bone marrow transplantation: a report on a series of 63 consecutive transplantations. Cancer 57: 2061–2069, 1986

    PubMed  Article  CAS  Google Scholar 

  • Chapman RM. Effect of cytotoxic therapy on sexuality and gonadal function. In Perry MC & Yarbro JW (Eds) Toxicity of chemotherapy, pp. 343–363, Grune & Stratton, Orlando, 1984

    Google Scholar 

  • Chaube S, Kurg G, Murphy ML. Teratogenic effects of cyclophosphamide (NSC-26271) in the rat. Cancer Chemotherapy Reports 51: 363–376, 1967

    Google Scholar 

  • Cooper AJD, White DA, Matthay RA. Drug-induced pulmonary disease. American Review of Respiratory Disease 133: 321–340, 1986

    PubMed  CAS  Google Scholar 

  • Cox PJ. Cyclophosphamide cystitis and bladder cancer: a hypothesis. European Journal of Cancer 15: 1071–1072, 1979b

    PubMed  Article  CAS  Google Scholar 

  • Cox PJ. Cyclophosphamide cystitis-identification of acrolein as the causative agent. Biochemical Pharmacology 28: 2045–2049, 1979a

    PubMed  Article  CAS  Google Scholar 

  • Cupps TR. Cyclophosphamide: to pulse or not to pulse? American Journal of Medicine 89: 399–402, 1990

    PubMed  Article  CAS  Google Scholar 

  • DeFronzo RA, Braine H, Colvin M. Water intoxication in man after cyclophosphamide therapy: time course and relation to drug activation. Annals of Internal Medicine 78: 861–869, 1973

    Google Scholar 

  • DeVries CR, Freiha FS. Hemorrhagic cystitis: a review. Journal of Urology 143: 1–7, 1990

    Google Scholar 

  • Dohner VA, Ward HP, Standard RE. Alveolitis during procar-bazine, vincristine and cyclophosphamide therapy. Chest 62: 636–639, 1972

    PubMed  Article  CAS  Google Scholar 

  • Dorr RT, Fritz WL (Eds). Cancer chemotherapy handbook, El-sevier, New York, 1980

    Google Scholar 

  • Efros M, Ahmed T, Choudhury M. Cyclophosphamide-induced hemorrhagic pyelitis and ureteritis associated with cystitis in marrow transplantation. Journal of Urology 144: 1231–1232, 1990

    PubMed  CAS  Google Scholar 

  • Eigner EB, Freiha FS. The fate of the remaining bladder following supravesical diversion. Journal of Urology 144: 31–33, 1990

    PubMed  CAS  Google Scholar 

  • Fairchild WV, Spence CR, Solomon HD, Gangai MP. The incidence of bladder cancer after cyclophosphamide therapy. Journal of Urology 122: 163–164, 1979

    PubMed  CAS  Google Scholar 

  • Forni AM, Koss LG, Geller W. Cytological study of the effect of cyclophosphamide on the epithelium of the urinary bladder in man. Cancer 17: 1348–1355, 1964

    PubMed  Article  CAS  Google Scholar 

  • Gershwin ME, Goetzl EJ, Steinberg AD. Cyclophosphamide: use in practice. Annals of Internal Medicine 80: 531–540, 1974

    PubMed  CAS  Google Scholar 

  • Gould VE, Miller J. Sclerosing alveolitis induced by cyclophosphamide. American Journal of Pathology 81: 513–528, 1975

    PubMed  CAS  Google Scholar 

  • Grinberg-Funes D, Sheldon C, Weiss M. The use of prostaglandin F2alpha for the prophylaxis of cyclophosphamide induced cystitis in rats. Journal of Urology 144: 1500–1504, 1990

    PubMed  CAS  Google Scholar 

  • Gurtoo HL, Hipkens JH, Sharma SD. Role of glutathione metabolism dependent toxicity and chemotherapy of cyclophosphamide. Cancer Research 41: 3584–3591, 1981

    PubMed  CAS  Google Scholar 

  • Hakkinen PJ, Whiteley JW, Witschi HP. Hyperoxia, but not thoracic X-radiation, potentiates bleomycin and cyclophosphamide-induced lung damage in mice. American Review of Respiratory Disease 126: 281–285, 1982

    PubMed  CAS  Google Scholar 

  • Hoffman GS, Leavitt RY, Fleisher TA, Minor JR, Fauci AS. Treatment of Wegener’s granulomatosis with intermittent high-dose intravenous cyclophosphamide. American Journal of Medicine 89: 403–410, 1990

    PubMed  Article  CAS  Google Scholar 

  • Hopkins HA, Betsill WL, Hobson AS, Looney WB. Cyclophosphamide induced cardiomyopathy in the rat. Cancer Treatment Reports 66: 1521–1527, 1982

    PubMed  CAS  Google Scholar 

  • Horn M, Phebus C, Blatt J. Cancer chemotherapy after solid organ transplantation. Cancer 66: 1468–1471, 1990

    PubMed  Article  CAS  Google Scholar 

  • Johnson WW, Meadows DC. Urinary-bladder fibrosis and telangiectasia associated with long term cyclophosphamide therapy. New England Journal of Medicine 284: 290–294, 1971

    PubMed  Article  CAS  Google Scholar 

  • Karnofsky DA. Late effects of immunosuppressive anticancer drugs. Federation Proceedings 26: 925–932, 1967

    PubMed  CAS  Google Scholar 

  • Kaye CM. Biosynthesis of mercapturic acids from allyl alcohol, allyl esters and acrolein. Biochemical Journal 134: 1093–1101, 1973

    PubMed  CAS  Google Scholar 

  • Kehrer JP, Klein-Szanto AJP, Sorensen EMB, Pearlman R, Rosner MH. Enhanced acute lung damage following corticosteroid treatment. American Review of Respiratory Disease 130: 256–261, 1984

    PubMed  CAS  Google Scholar 

  • Koss LG. A light and electron microscopic study of the effect of a single dose of cyclophosphamide on various organs in the rat. Laboratory Investigation 16: 44–65, 1967

    PubMed  CAS  Google Scholar 

  • Lawrence HJ, Simone J, Aur JA. Cyclophosphamide-induced hemorrhagic cystitis in children with leukemia. Cancer 36: 1572–1576, 1975

    PubMed  Article  CAS  Google Scholar 

  • Lazo JS, Hoyt DG. The molecular basis of interstitial pulmonary fibrosis by antineoplastic agents. Cancer Treatment Reviews 17: 165–167, 1990

    PubMed  Article  CAS  Google Scholar 

  • Lee Y-CC, Kehrer JP. Increased pulmonary collagen syntheses in mice treated with cyclophosphamide. Drug and Chemical Toxicology 8: 503–512, 1985

    PubMed  Article  CAS  Google Scholar 

  • Lemmers MJ, Barry JM. Denovo carcinoma of the lower urinary tract in renal allograft recipients. Journal of Urology 144: 1233–1235, 1990

    PubMed  CAS  Google Scholar 

  • Levine LA. Kranc DM. Evaluation of carboprost tromethamine in the treatment of cyclophosphamide-induced hemorrhagic cystitis. Cancer 66: 242–245, 1990

    CAS  Google Scholar 

  • Levine LA. Richie JP. Urological complications of cyclophosphamide. Journal of Urology 141: 1063–1069, 1989

    CAS  Google Scholar 

  • Mark GJ, Lehimgar-zadeh A, Ragsdale BD. Cyclophosphamide pneumonitis. Thorax 33: 89–93, 1978

    PubMed  Article  CAS  Google Scholar 

  • Mathé G. Prevention of chemotherapy complications: time, toxicity, pharmacokinetic, pharmacodynamic and logistic factors. In Mathé and Oldham (Eds) Complications of cancer chemotherapy, pp. 124–139, Springer-Verlag, New York, 1974

    Chapter  Google Scholar 

  • Maxwell I. Reversible pulmonary edema following cyclophosphamide treatment. Journal of the American Medical Association 229: 137–138, 1974

    PubMed  Article  CAS  Google Scholar 

  • McDougal WS, Cramer SF, Miller R. Invasive carcinoma of the renal pelvis following cyclophosphamide therapy for nonmalignant disease. Cancer 48: 691–695, 1981

    PubMed  Article  CAS  Google Scholar 

  • Mills BA, Roberts RW. Cyclophosphamide-induced cardiomyopathy: a report of two cases and review of the English literature. Cancer 43: 2223–2226, 1979

    PubMed  Article  CAS  Google Scholar 

  • Mitchell EP, Schein PS. Gastrointestinal toxicity of chemotherapeutic agents. In Yarbro et al. (Eds) Toxicity of chemotherapy, pp. 269–295, Grune & Stratton, New York, 1984

    Google Scholar 

  • Newell DR, Gore ME. Toxicity of alkylating agents: clinical characteristics and pharmacokinetic determinants. In Powis G & Hacker MP (Eds) Toxicity of anticancer drugs, pp. 44–62, Pergamon Press, New York, 1991

    Google Scholar 

  • O’Connell TX, Berenbaum MC. Cardiac and pulmonary effects of high doses of cyclophosphamide and isophosphamide. Cancer Research 34: 1586–1591, 1974

    PubMed  Google Scholar 

  • Patel AR, Shah PC, Rhee HL, Sassoon H, Rao KP. Cyclophosphamide therapy and interstitial pulmonary fibrosis. Cancer 38: 1542–1549, 1976

    PubMed  Article  CAS  Google Scholar 

  • Patel JM, Block ER, Hood CI. Biochemical indices of cyclophosphamide-induced lung toxicity. Toxicology and Applied Pharmacology 76: 128–138, 1984

    PubMed  Article  CAS  Google Scholar 

  • Patel JM. Metabolism and pulmonary toxicity of cyclophosphamide. Pharmacology and Therapeutics 47: 137–146, 1990

    PubMed  Article  CAS  Google Scholar 

  • Pearlman CK. Cystitis due to cytoxan-Case report. Journal of Urology 95: 713–715, 1966

    PubMed  CAS  Google Scholar 

  • Pesce A, Cassuto JP, Joyner MV, Path MRC, DuJardin P, et al. Scalp tourniquet in the prevention of chemotherapy-induced alopecia. New England Journal of Medicine 298: 1204–1205, 1978

    PubMed  CAS  Google Scholar 

  • Phillips FS, Sternberg SS, Cronin AP, Vidal PM. Cyclophosphamide and urinary bladder toxicity. Cancer Research 21: 1577–1589, 1961

    Google Scholar 

  • Plotz PH, Klippel JH, Decker JL, et al. Bladder complications in patients receiving cyclophosphamide for systemic lupus erythematosus or rheumatoid arthritis. Annals of Internal Medicine 91: 221–223, 1979

    PubMed  CAS  Google Scholar 

  • Plowchalk DR, Mattison DR. Phosphoramide mustard is responsible for the ovarian toxicity of cyclophosphamide. Toxicology and Applied Pharmacology 107: 472–481, 1991

    PubMed  Article  CAS  Google Scholar 

  • Primack A. Amelioration of cyclophosphamide-induced cystitis. Journal of the National Cancer Institute 47: 223–227, 1971

    PubMed  CAS  Google Scholar 

  • Rodin AE, Haggard ME, Travis LB. Lung changes and chemotherapeutic agents in childhood. American Journal of Diseases in Children 120: 337–340, 1970

    CAS  Google Scholar 

  • Rubin JS, Rubin RT. Cyclophosphamide hemorrhagic cystitis. Journal of Urology 96: 313–316, 1966

    PubMed  CAS  Google Scholar 

  • Santos GW, Sensenbrenner L, Burke PJ, Colvin M, Ownen Jr AH, et al. Marrow transplantation in man following cyclophosphamide. Transplantation Proceedings 3: 400–404, 1971

    PubMed  CAS  Google Scholar 

  • Sen RP, Walsh TE, Fisher W, Brock N. Pulmonary complications of combination therapy with cyclophosphamide and predni- sone. Chest 99: 143–146, 1991

    PubMed  Article  CAS  Google Scholar 

  • Siemann DW, Macler L, Penney DP. Cyclophosphamide-induced pulmonary toxicity. British Journal of Cancer 53 (Suppl. VII): 343–346, 1986

    CAS  Google Scholar 

  • Smith RD, Kehrer JP. Cooxidation of cyclophosphamide as an alternative pathway for its bioactivation and lung toxicity. Cancer Research 51: 542–548, 1991

    PubMed  CAS  Google Scholar 

  • Spector IJ, Zimbler H, Ross JS. Cyclophosphamide and interstitial pneumonitis. Journal of the American Medical Association 243: 1133, 1980

    PubMed  Article  CAS  Google Scholar 

  • Spector IJ, Zimbler H, Ross JS. Early onset of cyclophosphamide-induced interstitial pneumonitis. Journal of the American Medical Association 242: 2852–2853, 1979

    PubMed  Article  CAS  Google Scholar 

  • Stella F, Battistelli S, Marcheggiani F, De Santis M, Giardini C, et al. Urothelial cell changes due to busulfan and cyclophosphamide treatment in bone marrow transplantation. Acta Cytologica 34: 885–890, 1990

    PubMed  CAS  Google Scholar 

  • Stillwell TJ, Benson RC. Cyclophosphamide-induced hemorrhagic cystitis. Cancer 61: 451–457, 1988

    PubMed  Article  CAS  Google Scholar 

  • Thrasher JB, Miller GJ, Wettlaufer JN. Bladder leiomyosarcoma following cyclophosphamide therapy for lupus nephritis. Journal of Urology 143: 119–121, 1990

    PubMed  CAS  Google Scholar 

  • Tokaz LK, Von Hoff DD. The cardiotoxicity of anticancer agents. In Yarbro et al. (Eds) Toxicity of chemotherapy, pp. 199–226, Grune & Station Inc, New York, 1984

    Google Scholar 

  • Toledo TM, Harper RC, Mosser RH. Fetal effects during cyclophosphamide and irradiation therapy. Annals of Internal Medicine 74: 87–91, 1971

    PubMed  CAS  Google Scholar 

  • Topilow AA, Rothenberg SP, Cottrell TS. Interstitial pneumonia after prolonged treatment with cyclophosphamide. American Review of Respiratory Disease 108: 114–117, 1973

    PubMed  CAS  Google Scholar 

  • Ziegler JL, Morrow RH, Fass L, et al. Treatment of Burkitt’s tumor with cyclophosphamide. Cancer 26: 474–484, 1970

    PubMed  Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Fraiser, L.H., Kanekal, S. & Kehrer, J.P. Cyclophosphamide Toxicity. Drugs 42, 781–795 (1991). https://doi.org/10.2165/00003495-199142050-00005

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-199142050-00005

Keywords

  • Cyclophosphamide
  • Cystitis
  • Acrolein
  • Pulmonary Toxicity
  • Mesna