Cyclophosphamide treatment of systemic lupus erythematosus: risk of bladder cancer exceeds benefit

R W Elliott, D M Essenhigh, A R Morley
1982 BMJ (Clinical Research Edition)  
Twelve patients with cirrhosis (nine men, three women) aged 21-72 years, who were admitted consecutively with bleeding oesophageal varices, were studied three days after the bleeding had stopped. Three of these patients were studied again one month later. The study was approved by the hospital ethics committee. Wedged and free hepatic venous pressure were measured using a Cordis Cobra II torque-controlled balloon catheter, French gauge 7 (Cordis Corporation, Miami, USA), as described by
more » ... n et al.3 Pressures were also recorded in the right atrium, and in the inferior vena cava within the liver and above and below it. Measurements were made with a Hewlett-Packard 1280 series physiologic pressure transducer linked to a Hewlett-Packard blood-pressure module 78205A. After the patient was settled three recordings of wedged and free hepatic venous pressures were taken over 10 minutes. Cimetidine 200 mg was then given intravenously, and after 10 minutes three more readings of wedged and free hepatic venous pressures were taken over the next 10 minutes. The figure shows the gradients between wedged and free hepatic venous pressures in each patient before and 10 minutes after 200 mg cimetidine given intravenously. There was no significant difference between the means of the pressure gradients before (16-8 ± SD 4-2 mm Hg) and after cimetidine (16-1±3-1 mm Hg). 26 *0 24 22 * *0 0 20-* 18-Gradient between pressures (mm Hg) 16 * _ -14 8 12 * 10 8 0 Before After 10 rTinutes Effect of 200 mg cimetidine given intravenously on gradient between wedged and free hepatic venous pressures, using average of three readings. (*, A, C =Patients studied twice one month apart.) Comment In this study of patients with cirrhosis 200 mg cimetidine given intravenously did not reduce portal hypertension as measured by the gradient between wedged and free hepatic venous pressures. The dose of cimetidine used is unlikely to have been insufficient to produce a reduction in portal pressure, since the same dose saturates H,receptors in the systemic circulation within minutes.4 This largely removes the proposed rationale for long-term use of cimetidine to prevent recurrent variceal haemorrhage. Prospective trials of cimetidine prophylaxis are likely to be disappointing. As cimetidine does not affect portal pressure in patients with cirrhosis it probably does not reduce splanchnic blood flow. The possibility that it causes simultaneous vasoconstriction in the portal system to maintain portal pressure is highly unlikely. The original report' that cimetidine reduces blood flow to the liver in normal subjects has itself been challenged. In that study hepatic blood flow was measured by clearance of indocyanine green and the reduction after cimetidine interpreted as indicating decreased liver blood flow. The reduction in indocyanine green clearance after cimetidine may, however, have been caused not only by a decrease in blood flow to the liver but also by a decrease in extraction of indocyanine green. Such a decrease in extraction of indocyanine green after cimetidine has been shown in two patients with liver disease, in whom hepatic blood flow apparently increased.5 This provides further support for our conclusion that cimetidine does not have any effect on portal hypertension in patients with cirrhosis and so is unlikely to be beneficial in preventing recurrent bleeding from gastrooesophageal varices. Feely J, Wilkinson GR, Wood AJJ. Reduction of liver blood flow and propranolol metabolism by cimetidine. N EnglJ Med 1981;304:692-5. 2 Lebrec D, Novel 0, Bernvav J, Bouygues M, Rueff B, Benhamou J-P. Propranolol in prevention of recurrent gastrointestinal bleeding in cirrhotic patients. Lancet 1981 ;i :920-1. 3Groszmann R, Glickman M, Blei A, Storer E, Conn HO. Wedged and free hepatic venous pressure measured with a balloon catheter. Gastroenterology 1979 ;76 :254-8. Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG A K BURROUGHS, MB, MRCP, honorary clinical lecturer R WALT, MB, MRcP, medical registrar A DUNK, MB, MRCP, medical registrar W JENKINS, MA, MRCP, lecturer in medicine S SHERLOCK, DBE, FRcP, professor of medicine S MACKIE, DMRD, senior registrar in radiology R DICK, FRCR, FRACR, consultant radiologist Cyclophosphamide treatment of systemic lupus erythematosus: risk of bladder cancer exceeds benefit Systemic lupus erythematosus has a variable clinical course, making assessment of treatment difficult. In association with steroids cyclophosphamide has been used to treat the disease for at least 20 years. Cyclophosphamide is claimed to reduce the dose of steroids required but is extremely toxic. We report on two women who developed bladder cancer after prolonged treatment with cyclophosphamide. Case 1-A 28-year-old woman developed systemic lupus erythematosus in 1969 after exposure to sunlight. Symptoms included rash, haemolytic anaemia, and proteinuria. Renal biopsy specimens showed proliferative glomerulonephritis. Treatment was started with steroids and with cyclophosphamide 50-100 mg daily, which was given intermittently for six years. In 1981 she presented with symptoms of urinary tract infection. Cultures were sterile. Intravenous urography disclosed a bladder tumour: biopsy specimens showed poorly differentiated keratinising squamous-cell carcinoma with extensive haemorrhage and necrosis. A short course of deep x-ray treatment was followed by total cystectomy and transplantation of ureters into an ileal conduit. Kidney function remained normal with no evidence of recurrence of the systemic lupus erythematosus. Case 2-A 45-year-old woman presented in 1969 with a five-year history of respiratory symptoms, bilateral pleural effusions, and moderate proteinuria and lupus erythematosus cells on testing. She was three months pregnant. Renal biopsy specimen's showed proliferative glomerulonephritis. She underwent hysterotomy and tubal ligation. Prednisone 50 mg and cyclophosphamide 100 mg daily were started: both were reduced to maintenance dosage but when they were stopped joint swelling recurred. In 1976, while taking 20 mg cyclophosphamide and 7-5 mg prednisone, she developed left loin pain. Intravenous urography showed a dilated left ureter and calices due to obstruction by bladder tumour. Investigations showed poorly differentiated transitional-cell carcinoma infiltrating muscle. She underwent deep x-ray treatment, total cystectomy, and transplantation of ureters into an ileal conduit. Renal function was normal. Four years after this operation she developed an exacerbation of systemic lupus erythematosus after exposure to sunlight. She responded satisfactorily to steroids alone.
doi:10.1136/bmj.284.6323.1160 fatcat:anc232r6sjaj5mal6xpisreclu