Skip to main navigation menu Skip to main content Skip to site footer
##common.pageHeaderLogo.altText##

Original article

Vol. 144 No. 4344 (2014)

Cyclophosphamide: As bad as its reputation?

  • Diana Dan
  • Rahel Fischer
  • Sabine Adler
  • Frauke Förger
  • Peter M Villiger
DOI
https://doi.org/10.4414/smw.2014.14030
Cite this as:
Swiss Med Wkly. 2014;144:w14030
Published
19.10.2014

Summary

OBJECTIVES: Despite new treatment modalities, cyclophosphamide (CYC) remains a cornerstone in the treatment of organ or life-threatening vasculitides and connective tissue disorders. We aimed at analysing the short- and long-term side-effects of CYC treatment in patients with systemic autoimmune diseases.

METHODS: Chart review and phone interviews regarding side effects of CYC in patients with systemic autoimmune diseases treated between 1984 and 2011 in a single university centre. Adverse events were stratified according to the “Common Terminology Criteria for Adverse Events” version 4.

RESULTS: A total of 168 patients were included. Cumulative CYC dose was 7.45 g (range 0.5–205 g). Gastro-intestinal side effects were seen in 68 events, hair loss occurred in 38 events. A total of 58 infections were diagnosed in 44/168 patients (26.2%) with 9/44 suffering multiple infections. Severity grading of infections was low in 37/58 cases (63.8%). One CYC-related infection-induced death (0.6%) was registered. Amenorrhoea occurred in 7/92 females (7.6%) with 5/7 remaining irreversible. In females with reversible amenorrhoea, prophylaxis with nafarelin had been administered. Malignancy was registered in 19 patients after 4.7 years (median, range 0.25–22.25) presenting as 4 premalignancies and 18 malignancies, 3 patients suffered 2 premalignancies/malignancies each. Patients with malignancies were older with a higher cumulative CYC dose. Death was registered in 28 patients (16.6%) with 2/28 probably related to CYC.

CONCLUSIONS: Considering the organ or life-threatening conditions which indicate the use of CYC, severe drug-induced health problems were rare. Our data confirm the necessity to follow-up patients long-term for timely diagnosis of malignancies. CYC side-effects do not per se justify prescription of newer drugs or biologic agents in the treatment of autoimmune diseases.

References

  1. Charles P, Bienvenu B, Bonnotte B, Gobert P, Godmer P, Hachulla E, et al. French Vasculitis Study Group. Presse Med. 2013;42(10):1317–30.
  2. Clowse ME, Chow SC, Hoffman GS, Merkel PA, Spiera RF, Davis JC Jr, et al. WGET Research Group. Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener's). Arthritis Care Res (Hoboken). 2011;63(12):1777–81. doi: 10.1002/acr.20605.
  3. Le Guenno G, Mahr A, Pagnoux C, Dhote R, Guillevin L. French Vasculitis Study Group. Incidence and predictors of urotoxic adverse events in cyclophosphamide-treated patients with systemic necrotizing vasculitides. Arthritis Rheum. 2011;63(5):1435–45. doi: 10.1002/art.30296.
  4. Talar-Williams C, Hijazi YM, Walther MM, Linehan WM, Hallahan CW, Lubensky I, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med. 1996;124(5):477–84.
  5. Bryant BM, Jarman M, Ford HT, Smith IE. Prevention of isophosphamide-induced urothelial toxicity with 2–mercaptoethane sulphonate sodium (mesnum) in patients with advanced carcinoma. Lancet. 1980;2(8196):657–9.
  6. Henes JC, Henes M, von Wolff M, Schmalzing M, Kötter I, Lawrenz B. Fertility preservation in women with vasculitis: experiences from the FertiPROTEKT network. Clin Exp Rheumatol. 2012;30(1 Suppl 70):S53–6. Epub 2012 May 10.
  7. Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. N Engl J Med. 2000;343(16):1156–62.
  8. National Cancer Institute – Common terminology criteria for adverse events – Version 4 – National Cancer Institute 2009
  9. Houssiau FA, Vasconcelos C, D’Cruz D, et al Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide – Arthritis Rheum. 2002;46:2121–31.
  10. Graus F, Keime-Guibert F, Rene R, Benyahia B, Ribalta T, Ascaso C, et al. Anti Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain. 2001;124:1138–48.
  11. Jones RB, Tervaert JW, Hauser T, Lugmani R, Morgan MD, Peh CA, et al. European Vasculitis Study Group. Rituximab versus cyclosphosphamide in ACNA-associated renal vasculitis. N Engl J Med. 2010;363(3):211–20.
  12. Martin F, Lauwerys B, Lefèbvre C, Devogelaer JP, Houssiau FA. Side-effects of intravenous cyclophosphamide pulse therapy. Lupus. 1997;6(3):254–7.
  13. Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, et al. Mysler E, Sánchez-Guerrero J, Solomons N, Wofsy D; Aspreva Lupus Management Study Group. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009;20(5):1103–12. doi: 10.1681/ASN.2008101028. Epub 2009 Apr 15.
  14. Harward LE, Mitchell K, Pieper C, Copland S, Criscione-Schreiber LG, Clowse ME. The impact of cyclophosphamide on menstruation and pregnancy in women with rheumatologic disease. Lupus. 2013;22(1):81–6. doi: 10.1177/0961203312468624.
  15. Baba S, Katsumata Y, Kawaguchi Y, Gono T, Sugiura T, Kanno T, et al. Association between low-dose pulsed intravenous cyclophosphamide therapy and amenorrhea in patients with systemic lupus erythematosus: a case-control study. BMC Womens Health. 2011;11:28.
  16. Huong DL, Amoura Z, Duhaut P, Sbai A, Costedoat N, Wechsler B, et al. Risk of ovarian failure and fertility after intravenous cyclophosphamide. A study in 84 patients. J Rheumatol. 2002;29(12):2571–6.
  17. Henes JC, Henes M, von Wolff M, Schmalzing M, Kötter I, Lawrenz B. Fertility preservation in women with vasculitis: experiences from the FertiPROTEKT network. Clin Exp Rheumatol. 2012;30(1 Suppl 70):S53–6. Epub 2012 May 10.
  18. Elgindy EA, El-Haieg DO, Khorshid OM, Ismail EI, Abdelgawad M, Sallam HN, et al. Gonadatrophin suppression to prevent chemotherapy-induced ovarian damage: a randomized controlled trial. Obstet Gynecol. 2013;121(1):78–86. doi: http://10.1097/AOG.0b013e31827374e2.
  19. Marder W, McCune WJ, Wang L, Wing JJ, Fisseha S, McConnell DS, et al. Adjunctive GnRH-a treatment attenuates depletion of ovarian reserve associated with cyclophosphamide therapy in premenopausal SLE patients. Gynecol Endocrinol. 2012;28(8):624–7. doi: 10.3109/09513590.2011.650752. Epub 2012 Feb 2.
  20. McGregor JG, Hogan SL, Hu Y, Jennette CE, Falk RJ, Nachman PH. Glucocorticoids and relapse and infection rates in anti-neutrophil cytoplasmic antibody disease. Clin J Am Soc Nephrol. 2012;7(2):240–7. doi: 10.2215/CJN.05610611. Epub 2011 Dec 1.
  21. Noël V, Lortholary O, Casassus P, Cohen P, Généreau T, André MH, et al. Risk factors and prognostic influence of infection in a single cohort of 87 adults with systemic lupus erythematosus. Ann Rheum Dis. 2001;60(12):1141–4.
  22. Mahr A, Heijl C, Le Guenno G, Faurschou M. ANCA-associated vasculitis and malignancy: current evidence for cause and consequence relationships. Best Pract Res Clin Rheumatol. 2013;27(1):45–56. doi: 10.1016/j.berh.2012.12.003.
  23. Faurschou M, Sorensen IJ, Mellemkjaer L, Loft AG, Thomsen BS, Tvede N, et al. Malignancies in Wegener's granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J Rheumatol. 2008;35(1):100–5. Epub 2007 Oct 15.
  24. Heijl C, Harper L, Flossmann O, Stücker I, Scott DG, Watts RA, et al; European Vasculitis Study Group (EUVAS). Incidence of malignancy in patients treated for antineutrophil cytoplasm antibody-associated vasculitis: follow-up data from European Vasculitis Study Group clinical trials. Ann Rheum Dis. 2011;70(8):1415–21. doi: 10.1136/ard.2010.145250. Epub 2011 May 25.

Most read articles by the same author(s)