Download Appendix 5 Notes on Cyclophosphamide Therapy in ILD

Interstitial Lung Disease Guideline
Appendix 5
Notes on Cyclophosphamide Therapy in ILD
NOTES ON CYCLOPHOSPHAMIDE THERAPY IN INTERSTITIAL LUNG DISEASE
Cyclophosphamide therapy is probably the most toxic of the routinely prescribed
immunosuppressive agents. The provision of cyclophosphamide should be in accordance with
locally approved protocols and prescribing guidelines. Intravenous cyclophosphamide therapy
should only be delivered by practitioners appropriately trained in managing extravasations of
chemotherapeutic drugs. These short notes are designed to provide an overview of
cyclophosphamide therapy in the context of inflammatory interstitial lung disease (ILD), most
commonly in association with connective tissue disease or vasculitis and often in combination with
corticosteroid treatment. Cyclophosphamide therapy is not recommended for the treatment of
idiopathic pulmonary fibrosis. Further specific guidance is provided within the disease-specific
sections of the BTS ILD guideline.
Dose and Mode of Delivery
Oral cyclophosphamide is usually given at a dose of up to 2mg/kg/day, with a lower dose in those
over 60 years and those with renal impairment. The length of treatment with oral
cyclophosphamide is dependent upon the underlying disease and the response. In clinical trials of
systemic sclerosis-associated ILD, oral therapy has been continued for up to 1 year1.
Intravenous cyclophosphamide therapy is increasingly favoured over oral therapy due to a
significantly better side-effect profile2. Pulsed intravenous treatment is usually given at a dose of
500-750mg/m2 with adjustments for age and renal function. The dose interval and duration of
treatment is dependent upon the nature of the underlying inflammatory disease. Studies of
intravenous cyclophosphamide in systemic sclerosis associated ILD have generally adopted a 3-4weekly regimen over at least 6 months3-5. This regimen exposes the patient to the drug for a
prolonged period but results in a lower cumulative dose than would be achieved with oral
cyclophosphamide.
Side effects and monitoring
Nausea, vomiting and reversible hair loss are common side effects. Prophylactic anti-emetics
should be prescribed in conjunction with cyclophosphamide therapy.
Bone marrow suppression is the most common serious side-effect and regular full blood count
monitoring is mandatory. The white blood cell nadir usually occurs 10-14 days after an intravenous
pulse. Prophylactic co-trimoxazole therapy to prevent Pneumocystis jiroveci pneumonia has been
shown to be cost effective in patients with Wegener’s granulamatosis6, but there are no
equivalent studies in patients with ILD treated with cyclophosphamide.
Haemorrhagic cystitis and bladder cancer are uncommon but serious side-effects of
cyclophosphamide therapy. The incidence of bladder cancer, after first exposure to
cyclophosphamide and a cumulative dose of 100g, is estimated to be 5% at 10 years and 16% at 15
years7. The risk of bladder complications is reduced by:
1)
co-administration of sodium 2-mercaptoethanesulfonate (Mesna), a regional detoxicant of
active cyclophosphamide metabolites
2)
good hydration
3)
treatment in the early morning to avoid overnight bladder accumulation.
British Thoracic Society, September 2008
Thorax 2008; 63, supplement V
Individuals receiving cumulative doses of cyclophosphamide exceeding 20g should have 3-6
monthly urinalyses, to detect microscopic haematuria, for up to 11 years after cessation of the
drug8.
Reduced and potentially irreversible infertility in males and females treated with
cyclophosphamide is an important consideration. Counselling and support from local fertility
services is mandatory in appropriate cases.
REFERENCES
1)
Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, Arriola E, Silver R, Strange
C, Bolster M, et al., for the Scleroderma Lung Study Research Group Cyclophosphamide versus
placebo in scleroderma lung disease. N Engl J Med 2006;354:2655–2666.
2)
Haubitz M, Schellong S, Göbel U, Schurek HJ, Schaumann D, Koch KM, Brunkhorst R.
Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with
antineutrophil cytoplasmic antibody-associated vasculitis and renal involvement: a prospective,
randomized study. Arthritis Rheum. 1998;41:1835-44.
3)
Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, Roberts C, Desai S, Herrick AL,
McHugh NJ, et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of
corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment
of pulmonary fibrosis in scleroderma. Arthritis Rheum. 2006;54:3962–3970.
4)
Airò P, Danieli E, Rossi M, Frassi M, Cavazzana I, Scarsi M, Grottolo A, Franceschini F,
Zambruni A. Intravenous cyclophosphamide for interstitial lung disease associated to systemic
sclerosis: results with an 18-month long protocol including a maintenance phase. Clin Exp
Rheumatol. 2007;25:293-6
5)
Yiannopoulos G, Pastromas V, Antonopoulos I, Katsiberis G, Kalliolias G, Liossis SN,
Andonopoulos AP. Combination of intravenous pulses of cyclophosphamide and
methylprednizolone in patients with systemic sclerosis and interstitial lung disease. Rheumatol Int.
2007;27:357-61
6)
Chung JB, Armstrong K, Schwartz JS, Albert D. Cost-effectiveness of prophylaxis against
Pneumocystis carinii pneumonia in patients with Wegner's granulomatosis undergoing
immunosuppressive therapy. Arthritis Rheum. 2000;43:1841-8
7)
Vlaovic, P. and M. A. Jewett. Cyclophosphamide-induced bladder cancer. Can.J Urol.
1999;6:745-748.
8)
Talar-Williams C, Hijazi YM, Walther MM, Linehan WM, Hallahan CW, Lubensky I, Kerr GS,
Hoffman GS, Fauci AS, Sneller MC. Cyclophosphamide-induced cystitis and bladder cancer in
patients with Wegener granulomatosis. Ann Intern Med. 1996;124:477-84
British Thoracic Society, September 2008
Thorax 2008; 63, supplement V