Abstract
Cyclophosphamide is a powerful immunosuppressive agent that is commonly used clinically to treat neoplastic and inflammatory diseases affecting various sites, including the head and neck. The pharmacology of cyclophosphamide is reviewed with an emphasis on its toxicities and strategies for minimizing therapeutic adverse effects. Principles of therapy are discussed and illustrated by the use of cyclophosphamide in the treatment of Wegener's granulomatosis, a form of systemic vasculitis with prominent head and neck manifestations.
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References
Ataya K, Valeriote FA, Ramahi-Ataya A (1989) Effects of cyclophosphamide on the immature rat ovary. Cancer Res 49: 1660–1664
Austin HA, Klippel JH, Balow JE, LeRiche NGH, Steinberg AD, Plotz PH, Decker JL (1986) Therapy of lupus nephritis: controlled trial of prednisone and cytotoxic drugs. N Engl J Med 314:614–619
Bagley CM, Bostick FW, DeVita VT (1973) Clinical pharmacology of cyclophosphamide. Cancer Res 33:226–233
Baltus JAM, Boersma JW, Hartman AP, Vanderbroucke JP (1983) The occurrence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide: a controlled retrospective study. Ann Rheum Dis 42:368–373
Bermas BL, Hill JA (1995) Effects of immunosuppressive drugs during pregnancy. Arthritis Rheum 38:1722–1732
Boumpas DT, Austin HA, Vaughn EM, Klippel JH, Steinberg AD, Yarboro CH, Balow JE (1992) Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 340:741–745
Boumpas DT, Austin HA, Vaughan EM, Yarboro CH, Klippel JH, Balow JE (1993) Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann Intern Med 119:366–369
Brock N (1967) Pharmacologic characterization of Cyclophosphamide (NSA-26271) and cyclophosphamide metabolites. Cancer Chemother Rep 51:315–325
Buckner CD, Rudolph RH, Fefer A, Clift RA, Epstein RB, Funk DD, Neiman PE, Slichter SJ, Storb R, Thomas ED (1972) High-dose cyclophosphamide therapy for malignant disease: toxicity, tumor response, and the effects of stored autologous marrow. Cancer 29:357–365
Burke DA, Stoddart JC, Ward MK, Simpson CGB (1982) Fatal pulmonary fibrosis occurring during treatment with Cyclophosphamide. BMJ 285:696
Casciato DA, Scott JL (1979) Acute leukemia following prolonged cytotoxic agent therapy. Medicine 58:32–47
Chapman RM (1992) Gonadal toxicity and teratogencity. In: Perry MC (ed) The chemotherapy source book. Williams and Wilkins, Baltimore, pp 710–753
Chapman RM, Sutcliffe SB, Malpas IS (1979) Cytotoxic-induced ovarian failure in women with Hodgkin's disease. JAMA 242:1877–1881
Colvin M, Chabner BA (1990) Alkylating agents. In: Chabner BA, Collins JM (eds) Cancer chemotherapy: principles and practice. Lippincott, Philadelphia, pp 277–313
Colvin M, Hilton J (1981) Pharmacology of cyclophosphamide and metabolites. Cancer Treat Rep 65 [Suppl 3]:89–95
Cooper JAD, White DA, Matthay RA (1986) Drug-induced pulmonary disease. Am Rev Respir Dis 133:321–340
Cox PJ (1979) Cyclophosphamide cystitis — identification of acrolein as the causative agent. Biochem Pharmacol 28:2045–2049
DeFronzo Ra, Colvin OM, Braine H, Robertson GL, Davis PJ (1974) Cyclophosphamide and the kidney. Cancer 33:483–491
Fauci AS, Young KR (1993) Immunoregulatory agents. In: Kelley WN, Harris ED, Ruddy S, Sledge CB (eds) Textbook of rheumatology, 4th edn. Saunders, Philadelphia, pp 797–821
Fauci AS, Dale DC, Balow JE (1976) Glucocorticoid therapy: mechanisms of action and clinical consideratons. Ann Intern Med 84:304–315
Fischer DS (1989) Cancer chemotherapy. In: Lee KJ (ed) Textbook of otolaryngology and head and neck surgery. Elsevier, New York, pp 902–914
Fisher RI, Oken MM (1995) Clinical practice guidelines: nonHodgkin's lymphomas. Cleve Clin J Med 62 [Suppl 1]:6–42
Fox DA, McCune WJ (1994) Immunosuppressive drug therapy of systemic lupus erythematosus. Rheum Dis Clin North Am 20:265–299
Fraiser LH, Kanekal S, Kehrer JP (1991) Cyclophosphamide toxicity: characterizing and avoiding the problem. Drugs 42:781–795
Ginsberg SJ, Comis RL (1984) The pulmonary toxicity of antineoplastic agents. In: Perry MC, Yarbro JW (eds) Toxicity of chemotherapy. Grune and Stratton, Orlando, pp 227–268
Godeau B, Coutant-Perronne V, Huong DLT, Guillevin L, Magadur G, Bandt M de, Dellion S, Rossert J, Rostoker G, Piette J-C, Schaeffer A (1994)Pneumocystis carinii pneumonia in the course of connective tissue disease: report of 34 cases. J Rheumatol 21:246–251
Greenberg LH, Tanaka KR (1964) Congenital abnormalities probably induced by cyclophosphamide. JAMA 188:423–426
Grunwald HW, Rosner F (1979) Acute leukemia and immunosuppressive drug use: review of patients undergoing immunosuppressive therapy for non-neoplastic disease. Ann Intern Med 139:461–466
Harmenberg J, Hoglund M, Hellstrom-Lindberg E (1994) Gand GM-CSF in oncology and oncological haematology. Eur J Haematol 52:1–28
Haynes BF (1992) Glucocorticosteroid therapy. In: Wyngaarden JB, Smith LH, Bennett JC (eds) Cecil textbook of medicine, 19th edn. Saunders, Philadelphia, pp 104–108
Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, Rottem M, Fauci AS (1992) Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 116:488–498
Jarrousse B, Guillevin L, Bindi P, Hachulla E, Leclerc P, Nilson B, Remy P, Rossert J, Jacquot C (1993) Increased risk ofPneumocystis carinii pneumonia in patients with Wegener's granulomatosis. Clin Exp Rheumatol 11:615–621
Kahl LE (1994) Herpes zoster infections in systemic lupus erythematosus: risk factors and outcome. J Rheumatol 21:84–86
Kantarjian HM, Keating MJ (1987) Therapy-related leukemia and myelodysplastic syndrome. Semin Oncol 14:435–443
Khandekar JD (1991) Chemotherapy of head and neck cancer. In: Ballenger JJ (ed) Diseases of the nose, throat, ear, head, and neck. Lea and Febiger, Philadelphia, pp 753–766
Koren G, Beatty K, Seto A, Einarson TR, Lishner M (1992) The effects of impaired liver function on the elimination of antineoplastic agents. Ann Pharmacother 26:363–371
Koyama H, Wada T, Nishizawa Y, Iwanaga T, Aoki Y, Terasawa T, Kosaki G, Yamamoto T, Wada A (1977) Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer. Cancer 39:1403–1409
Langford CA, McCallum RM (1995) Idiopathic vasculitis. In: Belch JJF, Zurier RB (eds) Connective tissue diseases. Chapman and Hall, London, pp 179–217
Langford CA, Sneller MC, Hallahan C, Hoffman GS, Kammerer WA, Talar-Williams C, Fauci AS, Lebovics RS (1995) Clinical features and therapeutic management of subglottic stenosis in patients with Wegener's granulomatosis. Arthritis Rheum [Suppl] 38:53–90
Mills BA, Roberts RW (1979) Cyclophosphamide-induced cardiomyopathy: a report of 2 cases and review of the English literature. Cancer 43:2223–2226
Mitchell EP, Schein PS (1992) Gastrointestinal toxicity of chemotherapeutic agents. In: Perry MC (ed) The chemotherapy source book. Williams and Wilkins, Baltimore, pp 620–634
Morgan MC, Matteson E, Dunne R, Brown M, Fox DA, McCune WJ (1990) Complication of intravenous cyclophosphamide: association of infections with high doses of prednisone in lupus patients. Arthritis Rheum 33 [Suppl 5]:R27
Mouridsen HT, Jacobsen E (1975) Pharmacokinetics of Cyclophosphamide in renal failure. Acta Pharmacol Toxicol 36:409–414
Newell DR, Gore ME (1991) Toxicity of alkylating agents: clinical characteristics and pharmacokinetic determinants. In: Powis G, Hacker MP (eds) The toxicity of anticancer drugs. Pergamon, New York, pp 44–62
Patel JM (1990) Metabolism and pulmonary toxicity of Cyclophosphamide. Pharmacol Ther 47:137–146
Pedersen-Bjergaard J, Ersboll J, Sorensen HM, Keiding N, Larsen SO, Philip P, Larsen MS, Schultz H, Nissen NI (1985) Risk of acute nonlymphocytic leukemia and preleukemia in patients treated with cyclophosphamide for non-Hodgkin's lymphomas. Ann Intern Med 103:195–200
Plotz PH, Klippel JH, Decker JL, Grauman D, Wolff B, Brown BC, Rutt G (1979) Bladder complications in patients receiving cyclophosphamide for systemic lupus erythematosus or rheumatoid arthritis. Ann Intern Med 91:221–223
Porges AJ, Beattie SL, Ritchlin C, Kimberly RP, Christian CL (1992) Patients with systemic lupus erythematosus at risk forPneumocystis carinii pneumonia. J Rheumatol 19:1191–1194
Radis CD, Kahl LE, Baker GL, Wasko MCM, Cash JM, Gallatin A, Stolzer BL, Agarwal AK, Medsger TA, Kwoh CK (1995) Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis: a 20-year follow-up study. Arthritis Rheum 38:1120–1127
Roubenoff R, Hoyt J, Petri M, Hochberg MC, Hellmann DB (1988) Effects of antiinflammatory and immunosuppressive drugs on pregnancy and fertility. Semin Arthritis Rheum 18:88–110
Santos GW, Sensenbrenner LL, Burke PJ, Colvin M, Owens AH, Bias WB, Slavin RE (1971) Marrow transplantation in man following cyclophsophamide. Transplant Proc 3:400–404
Sen RP, Walsh TE, Fisher W, Brock N (1991) Pulmonary complications of combination therapy with cyclophosphamide and prednisone. Chest 99:143–146
Shepherd JD, Pringle LE, Barnett MJ, Klingemann H-G, Reece DE, Phillips GL (1991) Mesna versus hyperhydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation. J Clin Oncol 9:2016–2020
Sneller MC, Hoffman GS, Talar-Williams C, Kerr GS, Hallahan CW, Fauci AS (1995) An analysis of forty-two Wegener's granulomatosis patients treated with methotrexate and prednisone. Arthritis Rheum 38:608–613
Spector JI, Zimbler H, Ross JS (1979) Early-onset cyclophosphamide-induced interstitial pneumonitis. JAMA 242:2852–2854
Steele TH, Serpick AA, Block JB (1973)Antidiuretic response to cyclophosphamide in man. J Pharmacol Exp Ther 185:245–253
Stewart KA, Mazanec DJ (1992) Pulse intravenous cyclophosphamide for kidney disease in relapsing polychondritis. J Rheumatol 19:498–500
Stillwell TJ, Benson RC (1988) Cyclophosphamide-induced hemorrhagic cystitis. Cancer 61:451–457
Struck RF, Alberts DS, Horne K, Phillips JG, Peng Y-M, Roe DJ (1987) Plasma pharmacokinetics of cyclophosphamide and its cytotoxic metabolites after intravenous versus oral administration in a randomized, crossover trial. Cancer Res 47:2723–2726
Talar-Williams C, Hijazi TM, Walther MM, Linehan WM, Hallahan CW, Lubensky I, Kerr GS, Hoffman GS, Fauci AS, Sneller MC (1996) Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med 124:477–484
Tokaz LK, Von Hoff DD (1984) The cardiotoxicity of the anticancer drugs. In: Perry MC, Yarbro JW (eds) Toxicity of chemotherapy. Grune and Stratton, Orlando, pp 199–226
Toledo TM, Harper RC, Moser RH (1971) Fetal effects during cyclophosphamide and irradiation therapy. Ann Intern Med 74:87–91
Trasler JM, Hales BF, Robaire B (1985) Paternal cyclophosphamide treatment of rats causes fetal loss and malformations without affecting male fertility. Nature 316:144–146
Zemlickis D, Lishner M, Erlich R, Koren G (1993) Teratogenicity and carinogenicity in a twin exposed in utero to cyclophosphamide. Teratog Carcinog Mutagen 13:139–143
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Langford, C.A. Complications of cyclophosphamide therapy. Eur Arch Otorhinolaryngol 254, 65–72 (1997). https://doi.org/10.1007/BF01526181
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DOI: https://doi.org/10.1007/BF01526181