1550
the UK in late August, 1989. His last contact with potentially schistosoma-infected water was on Aug 24,1989. Trace haematuria was noted and he had eosinophilia (0-84 x 109/1). End-urine specimens were negative for S haematobium ova and an enzymelinked immunosorbent assay (ELISA) for blood schistosomes on Jan 29, 1990, was negative. An intravenous urogram was normal and rectal biopsy and stool microscopy revealed no evidence of S mansoni. While he was waiting for cystoscopy, a second schistosomal ELISA on March 5,1990, was positive at level three. An end-urine sample was negative for S hematobium ova. Cystoscopy on April 23,1990, showed intense infiltration of chronic inflammatory cells and many eosinophils and S haematobium ova. Praziquantel 40 mg/kg was given. By July, 1990, urine showed no red cells and the eosinophil count was normal (0-27 x 109/1). Case 2 (M/21, born in UK, referred by general practitioner in October, 1990, to our unit for tropical screen). He had returned after extensive travel in West Africa in late September, 1990, and his last contact with potentially schistosoma-infested water was Aug 13, 1990. While travelling he had had malaria and amoebic dysentery, and on his return he was treated for giardiasis with metronidazole. There were no red cells in the end-urine sample, so further examination was deemed unnecessary by the microbiology laboratory; no ova were seen in stool. Eosinophils were 0 36 x 109/1 and his schistosomal ELISA was negative on Oct 29,1990, which was 11 weeks after his last possible schistosomal contact. He re-presented in October, 1991, with two episodes of painless terminal haematuria in the preceding spring and summer. Eosinophils were 0 92 x 109/1 and no ova were seen in end-stage urine. A repeat schistosomal ELISA was positive at level three and a rectal biopsy revealed S mansoni ova. Cytoscopy showed sandycoloured mucosa and histological examination of a biopsy specimen revealed S haematobium granuloma. He was treated with praziquantel 40 mg/kg, with resolution of symptoms. Our first patient presented with haematuria 22 weeks after exposure, when a schistosomal ELISA was negative The ELISA became positive 27 weeks after the last possible exposure to S haematobium. The second patient, with combined S haematobium and S mansoni, was seronegative 11weeks after exposure and developed haematuria 9 months after exposure to infected water. The onset of production of S haematobium ova at 10-12 weeks is said to be slower than that for S mansoni, which usually occurs at 7 to 8 weeks, although egg production in S haematobium may start at 30-40 days and in S mansoni at 40-55 days.2,3 In a large UK-based study of over 1500 patients exposed in endemic areas, the sensitivity of the schistosomal ELISA was high, 96% for S mansoni and 92% for S haematobium.4 No mention was made, however, of any variation in the length of seronegative window with different species. Our cases suggest that in the absence of other indicators of schistosomal infection, serology should be repeated if exposure has occurred less than 6 months previously. Regional Infectious Diseases Unit, City Hospital, Edinburgh EH105SB, UK
M. E. JONES R. G. MITCHELL C. L. S. LEEN
1. Kagan IG. Serodiagnosis. In: Strickland GT, ed. Hunter’s tropical medicine Philadelphia: Saunders, 1984: 1005-07. 2. Warren KS. Schistosomiasis. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds Oxford textbok of medicine. Oxford: Oxford Medical Publications, 1987: 5:572. 3. Manson-Bahr PEC, Bell DR. Trematode infections. In: Manson-Bahr PEC, Bell DR eds. Manson’s tropical diseases. London: Bailliere Tindall, 1987: 448-85. 4. Tosswill JHC, Ridley DS. An evaluation of the ELISA for schistosomiasis in a hospital population. Trans R Soc Trop Med Hyg 1986; 80: 435-38.
Nocturnal enuresis SIR,-M. J. M. DeGraff in his personal paper (Oct 17, p 957) about 40 years of nocturnal enuresis records success with the use of desmopressin. We report another such case. A healthy 29-year-old man was admitted unconscious, having had a witnessed grand mal convulsion. He had been taking desmopressin for longstanding nocturnal enuresis, other conventional treatments having failed. He was a regular heavy drinker, and on the night before admission had consumed about 41 (8 pints) of beer. He had been taking twice the recommended dose of
intranasal desmopressin (80 pg at night) for 6 months, which gave good results for his incontinence. On admission plasma sodium was
mmol/1, potassium 4-4 mmol/1, urea 2-5 mmol/1, creatinine 65 umol/1, and creatinine kinase 1562 V/l. Computed tomography of the head was normal. He was treated initially with 500 ml of 1-8% 118
saline followed by fluid restriction, and his clinical state improved rapidly. The day after admission plasma sodium was 131 mmol/1 and consciousness was normal. He was discharged with advice to stop desmopressin and reduce his alcohol intake. Clearly, exceeding the recommended dose of desmopressin coupled with high fluid intake are liable to cause hyponatraemia and fits. The sudden onset of hyponatraemia and water intoxication probably precipitated the convulsion in this case. We therefore recommend that patients are warned not to exceed the recommended dose of desmopressin or to drink heavily when on treatment. Desmopressin should not be used for incontinence secondary to high alcohol consumption. R. C. DAVIS D. S. MORRIS J. E. BRIGGS
Department of Medicine, Royal Shrewsbury Hospital, Shrewsbury, Shropshire SY3 8XF, UK
Prevention of breast
cancer
SiR,—Dr Fugh-Berman and Professor Epstein (Nov 7, p 1143) grossly misrepresent the available evidence on the potential risks and benefits of using tamoxifen in a preventive setting. To dismiss the tamoxifen-associated reduction of contralateral tumours in with breast cancer as being without scientific basis is irrational and defeatist, since the data are the best available, and are women
probably relevant in view of the multistage nature and long latency of breast carcinogenesis. As the first to report a reduction in new contralateral tumours, we have examined the accumulating evidence closely.! These results have now been confirmed by the overview of all available data, in which a 39% reduction was found? Furthermore, no difference was seen in the magnitude of reduction between pre-menopausal and post-menopausal women (Gray R, personal communication), and the same is true for recurrence when all unconfounded trials are examined. In most of these studies tamoxifen was given for 2 years, and again all available evidence points to a larger effect for 5 years of use.
Fugh-Berman and Epstein’s discussion of tamoxifen’s action on bone density and lipid profiles ignores basic principles about statistical power. Most of the bone studies were too short or too small to be able to detect important differences, and in many cases were designed to examine the possibility of a large bone loss from an anti-oestrogenic effect. Only one study had more than 20 postmenopausal women with pretreatment and post-treatment measurements, and it showed a clear protective effect in the lumbar spine.3 Likewise, the 10-30% reductions in low-density lipoprotein cholesterol were large and consistent, whereas the changes in high-density lipoprotein cholesterol were small and not above the basic level. Similar lipid changes due to oestrogen replacement therapy have led to convincing reductions in cardiovascular mortality.4 Fugh-Berman and Epstein mistakenly refer to a five-fold excess of endometrial cancer in women receiving 20 mg daily tamoxifen. The excess to which they refer is taken from a compilation including the Stockholm trial, which used 40 mg daily, and only this trial showed a large excess. When trials of 20 mg daily only are included, .
no excess
is apparent.
However, because of tamoxifen’s weak
oestrogenic activity a small excess might be anticipated, and this will be monitored closely. These cancers are rarely fatal, in sharp contradistinction to breast cancer. If Fugh-Berman and Epstein are prepared to ignore the substantial data on breast cancer suppression in rats and mice, how can they champion the far more tenuous rat data on liver tumours? Notifications of severe adverse effects in patients receiving tamoxifen are remarkably rare, in view of the more than 5 million women-years of use. In particular, the few cases of hepatic failure and hepatobiliary complications are unimpressive, especially since many of these women would also have received cytotoxic chemotherapy. We do not propose that tamoxifen is completely safe and should
1551
be routinely available as a prophylactic. The point of current trials is to obtain information to make an informed assessment of risks and benefits. Evidence weighs strongly in favour of benefits, which could be much larger than the minimum detectable 30% reduction of incidence which determined sample size; it also suggests a net positive balance for other outcomes, which again could be sizeable. No one is obliged to join these trials; to argue against them in the face of such strongly favourable evidence is to promote ignorance and deny women a choice on a matter of great personal concern. now
Imperial Cancer Research
JACK CUZICK,
Fund
Lincoln’s Inn Fields, London WC2A 3PX, UK
Chairman, UKCCCR Working Party Tamoxifen Prevention Trial
MICHAEL BAUM, Marsden London SW3
Royal
Chairman, UK Breast Cancer Trials
Hospital,
Co-ordinating Committee
1. Cuzick J, Baum M. Tamoxifen and contralateral breast cancer. Lancet 1985; i: 282. 2. Early Breast Cancer Trialists Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 1992; 339: 1-15; 71-85. 3. Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in post menopausal women with breast cancer. N Engl J Med 1992; 326: 852-56. 4. Henderson BE, Paganini-Hill A, Ross RK. Estrogen replacement therapy and protection from acute myocardial infarction. Am J Obstet Gynecol 1988; 159: 312-17.
SiR,—On behalf of
a centre
participating
Breast Cancer Prevention Trial of the that all the arguments put forward
in the Tamoxifen
NSABP, I would point out by Dr Fugh-Berman and
Professor
Epstein were addressed exhaustively in the discussions leading up to this trial. The consent form used describes any potential toxicities explicitly, and it is the choice of the potential candidate whether to participate or not. So far, over 70 women in Calgary have chosen to enter the trial. The Fugh-Berman and Epstein article read well enough until the last paragraph, when we were startled to see the statement "to accord risk factors the status of diseases is to obscure the difference between well and ill". The implication here is that patients with breast cancer are all ill. This statement made us wonder whether these workers were familiar with looking after patients with breast cancer. Patients with primary breast cancer are not ill; they are well-and, after appropriate treatment, about 50% may be regarded as cured. These women work, participate in sports (mostly skiing and horse-riding in our part of the world), sometimes have babies, and enjoy a full life. They usually attend follow-up clinics that are termed well-woman breast clinics. We cannot identify which of these well women are at risk of recurrence and death, but clinical trials have shown that the risk of death can be much reduced by tamoxifen. These women have risk factors for recurrence that are accorded the status of diseases and are treated with tamoxifen, despite the fact that they are well. The clinical results of tamoxifen therapy after surgery with or without radiation for primary breast cancer mentioned above have encouraged us to extend these useful results further by undertaking a trial of tamoxifen to test whether we can prevent the disease in well women at risk of developing the disease before the clinical cancer can be palpated or diagnosed with mammography. How do Fugh-Berman and Epstein propose to distinguish between well women who may never get breast cancer and well women who are cured of their breast cancers and who are unnecessarily receiving tamoxifen or, for that matter, adjuvant
chemotherapy? Southern Alberta Cancer Programme, Tom Baker Cancer Centre, Calgary, Alberta, Canada T2N 4N2
A. H. G. PATERSON
SIR,—The Lancet has published opposing views on the value of tamoxifen; Dr Fugh-Berman and Professor Epstein against and Dr Powles in favour of its prophylactic use for breast cancer. Most of the effects of tamoxifen have been related to both its oestrogenic and anti-oestrogenic properties. We are interested in this issue because of possible side-effects on the genital tract. Abnormal vaginal bleeding on tamoxifen is a recognised side-effect. However, there is great variation in pathological type of endometrial disease in
patients with breast cancer on tamoxifen. The frequency of uterine polyps and endometrial hyperplasia have been correlated with the cumulative dose of tamoxifen.l Endocervical and endometrial cytology among tamoxifen users showed nuclear hyperplasia, though without cellular atypia; there was also a tendency towards increased endometrial thickness (Rayter G, et al, unpublished). Tamoxifen seems to have a proliferative effect on the endometrium. The notion that tamoxifen increases the frequency of endometrial cancer is based on work in animals and small uncontrolled case studies in patients with breast cancer. We would like to draw attention to another possible mechanism of the oestrogenic properties in patients with breast cancer treated with tamoxifen. Tamoxifen competes with oestrogen at receptor bindings sites but this anti-oestrogenic effect differs in various end organs. There is epidemiological evidence that upper body fat distribution (android obesity) is a risk factor for breast and for endometrial cancer.2,3 Patients with breast cancer and this type of fat distribution have an increased number of oestrogen receptors in breast cancer tissue.2,4 A subset of women with breast cancer who have high numbers of oestrogen receptors and are therefore selected for tamoxifen treatment may have an inherent risk for endometrial carcinoma. In this group of patients tamoxifen would not be expected to prevent endometrial carcinoma. It may therefore not always be logical to extrapolate tamoxifen data on end-organ response in patients with breast cancer to healthy women who are using the drug prophylactically. Selection bias is unlikely in pilot trials such as the double-blind trial underway at the Royal Marsden. Routine transvaginal scanning estimating endometrial thickness, uterine growth, and ovarian morphology in conjunction with histopathological appearances will reveal the true extent of the oestrogenic potential of tamoxifen on the genital tract. Departments of Gynaecological Oncology and Histopathology, St Bartholomew’s Hospital, London EC1A 7BE, UK
PATRICK NEVEN DAVID G. LOWE JOHN H. SHEPHERD
1. De
Muylder X, Neven P, De Somer M, et al. Endometrial lesions in patients undergoing tamoxifen therapy. Int J Gynecol Obstet 1991; 36: 127-30 2. Shapira DV, Kumar NB, Lyman GH, et al. Obesity and body fat distribution and breast cancer prognosis. Cancer 1991; 67: 523-28. 3. Shapira DV, Kumar NB, Lyman GH, et al. Upper-body fat distribution and endometrial cancer risk. JAMA 1991; 266: 1808-11. 4. Giuffrida D, Lupo L, La Porta GA, et al. Relation between steroid receptor status and body weight in breast cancer patients. Eur J Cancer 1992; 28: 112-15.
SiR,—The viewpoints of Dr Fugh-Berman and Professor and of Dr Powles provide powerful, but specialist, arguments for and against trials of tamoxifen for the prevention of breast cancer. They are unlikely to help women invited to take part in such trials, since they provide no direct comparisons. I suggest that it is possible to produce a risk-benefit analysis of greater value to
Epstein,
such
women.
According to the protocol for the British trial, 40 cases of breast expected among the in the trial. Half the women will receive a placebo; for those receiving tamoxifen, the trialists expect a 33 % reduction in cases of breast cancer. So the expected benefit is the prevention of 6-6 (range: 0 [no prevention] to 20 [total prevention]) breast cancers per 10 000 woman-years of tamoxifen exposure. Risks of tamoxifen, which involve a magnitude of harm similar to that of breast cancer, include death, blindness, and life-threatening illness from liver or bone-marrow disease of endometrial carcinoma. Five deaths, 16 cases of hepatic disease, and 15 cases of blood dyscrasia in UK women are known to the Committee on Safety of Medicines (CSM).l The rate at which side-effects are reported to the CSM is usually between one quarter and one third of the true incidence; on the assumption that, in this instance, reporting has been better and half the tamoxifen-related cases have been reported, there would have been 72 major side-effects of the above types. There are few case-histories of disabling retinopathy and keratopathy, or of blindness, in the UK;2,3 they suggest a total of 4 such cases so far. Total exposure to tamoxifen in the UK is not known. Powles suggests 3 million women world wide have received this drug. The cancer
women
per 10 000 woman-years would be
1552
UK has about one-twelfth of the developed world’s population, who would be the main users of tamoxifen. Let us assume, therefore, that 250 000 women in the UK have received tamoxifen and that, on average, they took it for 2 years. Total exposure to tamoxifen in the UK would then be 500 000 woman-years, which gives a rate for the risks discussed above of 1 ’5 per 10 000 years. The frequency of endometrial carcinoma in all women taking tamoxifen is five times higher than in contols, but in women receiving only 20 mg tamoxifen each day, the relative risk is 2.25.4 The annual incidence of endometrial carcinoma in England and Wales in women over the age of 45 is 33-5 per 100 000.5 Taking tamoxifen at low dose therefore increases the incidence of endometrial carcinoma by 4-2 cases per 10 000 woman-years. The total number of major tamoxifen-related side-effects seems thus to be 5-7 per 10 000 woman-years, range 1 8-107, obtained by altering the assumptions made within reasonable limits. So the expected benefits, and the major risks, of low-dose tamoxifen are of the same order of magnitude. There are also less severe side-effects, of course, which contribute to about 5% of women abandoning treatment, and to 25% abandoning Powles’ pilot study of
prevention. This, surely,
is the sort of information that prospective trial could understand and use, particularly when warned that the chance of any individual woman having a cancer prevented by taking part in the trial is less than 1%. Ethics committees should insist that researchers who run large-scale trials should both perform such risk-benefit analysis, when possible, and provide the results to all potential recruits. entrants
Bulletin of Medical Ethics, London N5 1LA, UK
R. H. NICHOLSON
Ching CK, Smith PG, Long RG. Tamoxifen-associated hepatocellular damage and agranulocytosis. Lancet 1992; 339: 940. 2. Bentley CR, Davies G, Aclimandos WA. Tamoxifen retinopathy: a rare but serious complication. BMJ 1992; 304: 495-96. 3. Griffiths MF. Tamoxifen retinopathy at low dosage. Am J Ophthalmol 1987; 104: 1.
185-86. 4.
Nayfield SG, Karp JE, Ford LG, et al. Potential role of tamoxifen in prevention of breast cancer. Natl Cancer Inst 1991; 83: 1450-59. J C, Waterhouse J, Mack T, et al. Cancer incidence in five continents, vol V: IARC Scientific Publication no 88. Lyon: IARC, 1987.
5. Muir
Rigors and bronchospasm with urokinase after streptokinase SIR,-We report an unexpectedly high frequency of rigors and bronchospasm in a small group of patients given urokinase as a thrombolytic agent in acute myocardial infarction. After the presentation of results in the I SI S-3 3 triall at the meeting of the American College of Cardiology in March, 1991, we continued a policy of using streptokinase as the thrombolytic agent of choice in patients with no prior exposure because of the favourable price (NZ$360 per treatment). We were persuaded by evidence that second use of this drug, at least within 1-4 years, was likely to be prejudiced by the presence of antibodies in a substantial number of patients .2 However, we were inhibited in the use of the only other registered agent in New Zealand, recombinant tissue plasminogen activator, by its price (NZ$1890 per treatment). We found evidence for the efficacy3,4 of urokinase in this situation and a lack of antigenic effects5-7 with no reports of cross-reactivity with streptokinase. We negotiated with Abbott Pharmaceuticals a supply at a favourable price (under section 29 of the New Zealand Health Act) for named patients. This use was approved by the ethics committee of the Wellington Area Health Board, and a consent form was devised to explain to patients the reason for our choice of drug. Between October, 1991, and July, 1992, six patients with apparent recurrent myocardial infarction previously treated with streptokinase and deemed suitable for further thrombolytic therapy agreed to receive urokinase at 1 5MU infused over 30 min. Two of these patients tolerated the infusion without problems but four had rigors, and two of these also had bronchospasm (table). None of the patients had any history of asthma, atopy, or allergic reaction. All recovered fully rapidly, but after the second case of bronchospasm, we felt it was no longer ethically justified to continue the practice.
PATIENTS DETAILS
The supplying company and the New Zealand adverse drug reaction authority were notified. Rigors and other anaphylactoid reactions occur as a response to foreign protein and, because urokinase is a natural human protein, were not expected here.4 We have been informed by Abbott that there have been several reports in the USA of rigors (but not bronchospasm), which are thought to be due to a change in manufacturing process, but the specific cause has not yet been identified. Reports of such reactions to urokinase generally show a low frequency of such side-effects.4 The difference in our series was previous use of streptokinase. Cardiology Department, Wellington Area Health Board, Private Bag 31907, Lower Hutt, New Zealand
PHILLIP MATSIS STEWART MANN
1. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs amstreplase and of aspirin plus heparin vs aspirin alone among 41 299 cases of suspected acute myocardial infarction. Lancet 1992; 339: 753-70. 2. Jalihar S, Moms GK. Antistreptokinase titres after intravenous streptokinase. Lancet 1990; 335: 184-85. 3. Wall TC, Phillips HR, Stack RS, et al. Results of high dose intravenous urokinase for acute myocardial infarction. Am J Cardiol 1990; 65: 124-31. 4. Mathey DG, Schofer J, Sheehan FH, et al. Intravenous urokinase in acute myocardial infarction. Am J Cardiol 1985; 55: 878-82. 5. Bell W, Black EB, DeMets D, et al. Urokinase/streptokinase embolism trial. JAMA 1974; 229: 1606-13. 6. Walsh P, Stengle JM, Sherry S. Urokinase pulmonary embolism trial. Circulation 1969; 39: 153-56. 7. Volgesang G, Bell W. Treatment of pulmonary embolism and deep vein thrombosis with thrombolytic therapy, Clin Chest Med 1984; 5: 487-94.
Erwinase-induced pancreatitis SIR,-Acute pancreatitis occurs in about 3% of children after administration of Escherichia coli derived L-asparaginase for acute lymphoblastic leukaemia (ALL).l,2 Erwinase, a commercially available enzyme from Erurinia chrysanthemi, has been introduced with the claim of less severe treatment-related toxicity.3 Pancreatitis among Erwinase-treated ALL patients has not been reported to the
WHO adverse drug event registry, Swedish National Medical Product Agency (M. Wadelius, Lakemedal Suerket, Uppsala), and the Regulatory Administration in the UK (D. Musgrave, Porton Products). We report this event in a previously healthy 11-year-old girl with intermediate risk pre-B ALL (French-American-British Ll/L2) with 46 XX, t(4;5) +ring chromosome. Remission in our patient was achieved by systemic vincristine, doxorubicin, prednisolone, and prophylactic intrathecal methotrexate. Severe epigastric pain occurred on the 9th day during scheduled consolidation with erwinase, administered as an intravenous bolus daily at 30 000 IUjm2. Vomiting, fatigue, and increasing pain necessitated introduction of a nasogastric tube and spinal anaesthesia for 5 days. Increased serum amylase 25-8 U jl was detected at onset of pain; enzyme was 50-7 U/1 on the next day and returned to normal (1 -2-5-0) U/1) within a week. Insulin for 3 days controlled the emerging hyperglycaemia, which peaked at 25.8 mmol/1. A day after onset, a swollen pancreas was seen by ultrasound. Parenteral fluid replacement was given for 3 days to
the UK in late August, 1989. His last contact with potentially schistosoma-infected water was on Aug 24,1989. Trace haematuria was noted and he had eosinophilia (0-84 x 109/1). End-urine specimens were negative for S haematobium ova and an enzymelinked immunosorbent assay (ELISA) for blood schistosomes on Jan 29, 1990, was negative. An intravenous urogram was normal and rectal biopsy and stool microscopy revealed no evidence of S mansoni. While he was waiting for cystoscopy, a second schistosomal ELISA on March 5,1990, was positive at level three. An end-urine sample was negative for S hematobium ova. Cystoscopy on April 23,1990, showed intense infiltration of chronic inflammatory cells and many eosinophils and S haematobium ova. Praziquantel 40 mg/kg was given. By July, 1990, urine showed no red cells and the eosinophil count was normal (0-27 x 109/1). Case 2 (M/21, born in UK, referred by general practitioner in October, 1990, to our unit for tropical screen). He had returned after extensive travel in West Africa in late September, 1990, and his last contact with potentially schistosoma-infested water was Aug 13, 1990. While travelling he had had malaria and amoebic dysentery, and on his return he was treated for giardiasis with metronidazole. There were no red cells in the end-urine sample, so further examination was deemed unnecessary by the microbiology laboratory; no ova were seen in stool. Eosinophils were 0 36 x 109/1 and his schistosomal ELISA was negative on Oct 29,1990, which was 11 weeks after his last possible schistosomal contact. He re-presented in October, 1991, with two episodes of painless terminal haematuria in the preceding spring and summer. Eosinophils were 0 92 x 109/1 and no ova were seen in end-stage urine. A repeat schistosomal ELISA was positive at level three and a rectal biopsy revealed S mansoni ova. Cytoscopy showed sandycoloured mucosa and histological examination of a biopsy specimen revealed S haematobium granuloma. He was treated with praziquantel 40 mg/kg, with resolution of symptoms. Our first patient presented with haematuria 22 weeks after exposure, when a schistosomal ELISA was negative The ELISA became positive 27 weeks after the last possible exposure to S haematobium. The second patient, with combined S haematobium and S mansoni, was seronegative 11weeks after exposure and developed haematuria 9 months after exposure to infected water. The onset of production of S haematobium ova at 10-12 weeks is said to be slower than that for S mansoni, which usually occurs at 7 to 8 weeks, although egg production in S haematobium may start at 30-40 days and in S mansoni at 40-55 days.2,3 In a large UK-based study of over 1500 patients exposed in endemic areas, the sensitivity of the schistosomal ELISA was high, 96% for S mansoni and 92% for S haematobium.4 No mention was made, however, of any variation in the length of seronegative window with different species. Our cases suggest that in the absence of other indicators of schistosomal infection, serology should be repeated if exposure has occurred less than 6 months previously. Regional Infectious Diseases Unit, City Hospital, Edinburgh EH105SB, UK
M. E. JONES R. G. MITCHELL C. L. S. LEEN
1. Kagan IG. Serodiagnosis. In: Strickland GT, ed. Hunter’s tropical medicine Philadelphia: Saunders, 1984: 1005-07. 2. Warren KS. Schistosomiasis. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds Oxford textbok of medicine. Oxford: Oxford Medical Publications, 1987: 5:572. 3. Manson-Bahr PEC, Bell DR. Trematode infections. In: Manson-Bahr PEC, Bell DR eds. Manson’s tropical diseases. London: Bailliere Tindall, 1987: 448-85. 4. Tosswill JHC, Ridley DS. An evaluation of the ELISA for schistosomiasis in a hospital population. Trans R Soc Trop Med Hyg 1986; 80: 435-38.
Nocturnal enuresis SIR,-M. J. M. DeGraff in his personal paper (Oct 17, p 957) about 40 years of nocturnal enuresis records success with the use of desmopressin. We report another such case. A healthy 29-year-old man was admitted unconscious, having had a witnessed grand mal convulsion. He had been taking desmopressin for longstanding nocturnal enuresis, other conventional treatments having failed. He was a regular heavy drinker, and on the night before admission had consumed about 41 (8 pints) of beer. He had been taking twice the recommended dose of
intranasal desmopressin (80 pg at night) for 6 months, which gave good results for his incontinence. On admission plasma sodium was
mmol/1, potassium 4-4 mmol/1, urea 2-5 mmol/1, creatinine 65 umol/1, and creatinine kinase 1562 V/l. Computed tomography of the head was normal. He was treated initially with 500 ml of 1-8% 118
saline followed by fluid restriction, and his clinical state improved rapidly. The day after admission plasma sodium was 131 mmol/1 and consciousness was normal. He was discharged with advice to stop desmopressin and reduce his alcohol intake. Clearly, exceeding the recommended dose of desmopressin coupled with high fluid intake are liable to cause hyponatraemia and fits. The sudden onset of hyponatraemia and water intoxication probably precipitated the convulsion in this case. We therefore recommend that patients are warned not to exceed the recommended dose of desmopressin or to drink heavily when on treatment. Desmopressin should not be used for incontinence secondary to high alcohol consumption. R. C. DAVIS D. S. MORRIS J. E. BRIGGS
Department of Medicine, Royal Shrewsbury Hospital, Shrewsbury, Shropshire SY3 8XF, UK
Prevention of breast
cancer
SiR,—Dr Fugh-Berman and Professor Epstein (Nov 7, p 1143) grossly misrepresent the available evidence on the potential risks and benefits of using tamoxifen in a preventive setting. To dismiss the tamoxifen-associated reduction of contralateral tumours in with breast cancer as being without scientific basis is irrational and defeatist, since the data are the best available, and are women
probably relevant in view of the multistage nature and long latency of breast carcinogenesis. As the first to report a reduction in new contralateral tumours, we have examined the accumulating evidence closely.! These results have now been confirmed by the overview of all available data, in which a 39% reduction was found? Furthermore, no difference was seen in the magnitude of reduction between pre-menopausal and post-menopausal women (Gray R, personal communication), and the same is true for recurrence when all unconfounded trials are examined. In most of these studies tamoxifen was given for 2 years, and again all available evidence points to a larger effect for 5 years of use.
Fugh-Berman and Epstein’s discussion of tamoxifen’s action on bone density and lipid profiles ignores basic principles about statistical power. Most of the bone studies were too short or too small to be able to detect important differences, and in many cases were designed to examine the possibility of a large bone loss from an anti-oestrogenic effect. Only one study had more than 20 postmenopausal women with pretreatment and post-treatment measurements, and it showed a clear protective effect in the lumbar spine.3 Likewise, the 10-30% reductions in low-density lipoprotein cholesterol were large and consistent, whereas the changes in high-density lipoprotein cholesterol were small and not above the basic level. Similar lipid changes due to oestrogen replacement therapy have led to convincing reductions in cardiovascular mortality.4 Fugh-Berman and Epstein mistakenly refer to a five-fold excess of endometrial cancer in women receiving 20 mg daily tamoxifen. The excess to which they refer is taken from a compilation including the Stockholm trial, which used 40 mg daily, and only this trial showed a large excess. When trials of 20 mg daily only are included, .
no excess
is apparent.
However, because of tamoxifen’s weak
oestrogenic activity a small excess might be anticipated, and this will be monitored closely. These cancers are rarely fatal, in sharp contradistinction to breast cancer. If Fugh-Berman and Epstein are prepared to ignore the substantial data on breast cancer suppression in rats and mice, how can they champion the far more tenuous rat data on liver tumours? Notifications of severe adverse effects in patients receiving tamoxifen are remarkably rare, in view of the more than 5 million women-years of use. In particular, the few cases of hepatic failure and hepatobiliary complications are unimpressive, especially since many of these women would also have received cytotoxic chemotherapy. We do not propose that tamoxifen is completely safe and should
1551
be routinely available as a prophylactic. The point of current trials is to obtain information to make an informed assessment of risks and benefits. Evidence weighs strongly in favour of benefits, which could be much larger than the minimum detectable 30% reduction of incidence which determined sample size; it also suggests a net positive balance for other outcomes, which again could be sizeable. No one is obliged to join these trials; to argue against them in the face of such strongly favourable evidence is to promote ignorance and deny women a choice on a matter of great personal concern. now
Imperial Cancer Research
JACK CUZICK,
Fund
Lincoln’s Inn Fields, London WC2A 3PX, UK
Chairman, UKCCCR Working Party Tamoxifen Prevention Trial
MICHAEL BAUM, Marsden London SW3
Royal
Chairman, UK Breast Cancer Trials
Hospital,
Co-ordinating Committee
1. Cuzick J, Baum M. Tamoxifen and contralateral breast cancer. Lancet 1985; i: 282. 2. Early Breast Cancer Trialists Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 1992; 339: 1-15; 71-85. 3. Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in post menopausal women with breast cancer. N Engl J Med 1992; 326: 852-56. 4. Henderson BE, Paganini-Hill A, Ross RK. Estrogen replacement therapy and protection from acute myocardial infarction. Am J Obstet Gynecol 1988; 159: 312-17.
SiR,—On behalf of
a centre
participating
Breast Cancer Prevention Trial of the that all the arguments put forward
in the Tamoxifen
NSABP, I would point out by Dr Fugh-Berman and
Professor
Epstein were addressed exhaustively in the discussions leading up to this trial. The consent form used describes any potential toxicities explicitly, and it is the choice of the potential candidate whether to participate or not. So far, over 70 women in Calgary have chosen to enter the trial. The Fugh-Berman and Epstein article read well enough until the last paragraph, when we were startled to see the statement "to accord risk factors the status of diseases is to obscure the difference between well and ill". The implication here is that patients with breast cancer are all ill. This statement made us wonder whether these workers were familiar with looking after patients with breast cancer. Patients with primary breast cancer are not ill; they are well-and, after appropriate treatment, about 50% may be regarded as cured. These women work, participate in sports (mostly skiing and horse-riding in our part of the world), sometimes have babies, and enjoy a full life. They usually attend follow-up clinics that are termed well-woman breast clinics. We cannot identify which of these well women are at risk of recurrence and death, but clinical trials have shown that the risk of death can be much reduced by tamoxifen. These women have risk factors for recurrence that are accorded the status of diseases and are treated with tamoxifen, despite the fact that they are well. The clinical results of tamoxifen therapy after surgery with or without radiation for primary breast cancer mentioned above have encouraged us to extend these useful results further by undertaking a trial of tamoxifen to test whether we can prevent the disease in well women at risk of developing the disease before the clinical cancer can be palpated or diagnosed with mammography. How do Fugh-Berman and Epstein propose to distinguish between well women who may never get breast cancer and well women who are cured of their breast cancers and who are unnecessarily receiving tamoxifen or, for that matter, adjuvant
chemotherapy? Southern Alberta Cancer Programme, Tom Baker Cancer Centre, Calgary, Alberta, Canada T2N 4N2
A. H. G. PATERSON
SIR,—The Lancet has published opposing views on the value of tamoxifen; Dr Fugh-Berman and Professor Epstein against and Dr Powles in favour of its prophylactic use for breast cancer. Most of the effects of tamoxifen have been related to both its oestrogenic and anti-oestrogenic properties. We are interested in this issue because of possible side-effects on the genital tract. Abnormal vaginal bleeding on tamoxifen is a recognised side-effect. However, there is great variation in pathological type of endometrial disease in
patients with breast cancer on tamoxifen. The frequency of uterine polyps and endometrial hyperplasia have been correlated with the cumulative dose of tamoxifen.l Endocervical and endometrial cytology among tamoxifen users showed nuclear hyperplasia, though without cellular atypia; there was also a tendency towards increased endometrial thickness (Rayter G, et al, unpublished). Tamoxifen seems to have a proliferative effect on the endometrium. The notion that tamoxifen increases the frequency of endometrial cancer is based on work in animals and small uncontrolled case studies in patients with breast cancer. We would like to draw attention to another possible mechanism of the oestrogenic properties in patients with breast cancer treated with tamoxifen. Tamoxifen competes with oestrogen at receptor bindings sites but this anti-oestrogenic effect differs in various end organs. There is epidemiological evidence that upper body fat distribution (android obesity) is a risk factor for breast and for endometrial cancer.2,3 Patients with breast cancer and this type of fat distribution have an increased number of oestrogen receptors in breast cancer tissue.2,4 A subset of women with breast cancer who have high numbers of oestrogen receptors and are therefore selected for tamoxifen treatment may have an inherent risk for endometrial carcinoma. In this group of patients tamoxifen would not be expected to prevent endometrial carcinoma. It may therefore not always be logical to extrapolate tamoxifen data on end-organ response in patients with breast cancer to healthy women who are using the drug prophylactically. Selection bias is unlikely in pilot trials such as the double-blind trial underway at the Royal Marsden. Routine transvaginal scanning estimating endometrial thickness, uterine growth, and ovarian morphology in conjunction with histopathological appearances will reveal the true extent of the oestrogenic potential of tamoxifen on the genital tract. Departments of Gynaecological Oncology and Histopathology, St Bartholomew’s Hospital, London EC1A 7BE, UK
PATRICK NEVEN DAVID G. LOWE JOHN H. SHEPHERD
1. De
Muylder X, Neven P, De Somer M, et al. Endometrial lesions in patients undergoing tamoxifen therapy. Int J Gynecol Obstet 1991; 36: 127-30 2. Shapira DV, Kumar NB, Lyman GH, et al. Obesity and body fat distribution and breast cancer prognosis. Cancer 1991; 67: 523-28. 3. Shapira DV, Kumar NB, Lyman GH, et al. Upper-body fat distribution and endometrial cancer risk. JAMA 1991; 266: 1808-11. 4. Giuffrida D, Lupo L, La Porta GA, et al. Relation between steroid receptor status and body weight in breast cancer patients. Eur J Cancer 1992; 28: 112-15.
SiR,—The viewpoints of Dr Fugh-Berman and Professor and of Dr Powles provide powerful, but specialist, arguments for and against trials of tamoxifen for the prevention of breast cancer. They are unlikely to help women invited to take part in such trials, since they provide no direct comparisons. I suggest that it is possible to produce a risk-benefit analysis of greater value to
Epstein,
such
women.
According to the protocol for the British trial, 40 cases of breast expected among the in the trial. Half the women will receive a placebo; for those receiving tamoxifen, the trialists expect a 33 % reduction in cases of breast cancer. So the expected benefit is the prevention of 6-6 (range: 0 [no prevention] to 20 [total prevention]) breast cancers per 10 000 woman-years of tamoxifen exposure. Risks of tamoxifen, which involve a magnitude of harm similar to that of breast cancer, include death, blindness, and life-threatening illness from liver or bone-marrow disease of endometrial carcinoma. Five deaths, 16 cases of hepatic disease, and 15 cases of blood dyscrasia in UK women are known to the Committee on Safety of Medicines (CSM).l The rate at which side-effects are reported to the CSM is usually between one quarter and one third of the true incidence; on the assumption that, in this instance, reporting has been better and half the tamoxifen-related cases have been reported, there would have been 72 major side-effects of the above types. There are few case-histories of disabling retinopathy and keratopathy, or of blindness, in the UK;2,3 they suggest a total of 4 such cases so far. Total exposure to tamoxifen in the UK is not known. Powles suggests 3 million women world wide have received this drug. The cancer
women
per 10 000 woman-years would be
1552
UK has about one-twelfth of the developed world’s population, who would be the main users of tamoxifen. Let us assume, therefore, that 250 000 women in the UK have received tamoxifen and that, on average, they took it for 2 years. Total exposure to tamoxifen in the UK would then be 500 000 woman-years, which gives a rate for the risks discussed above of 1 ’5 per 10 000 years. The frequency of endometrial carcinoma in all women taking tamoxifen is five times higher than in contols, but in women receiving only 20 mg tamoxifen each day, the relative risk is 2.25.4 The annual incidence of endometrial carcinoma in England and Wales in women over the age of 45 is 33-5 per 100 000.5 Taking tamoxifen at low dose therefore increases the incidence of endometrial carcinoma by 4-2 cases per 10 000 woman-years. The total number of major tamoxifen-related side-effects seems thus to be 5-7 per 10 000 woman-years, range 1 8-107, obtained by altering the assumptions made within reasonable limits. So the expected benefits, and the major risks, of low-dose tamoxifen are of the same order of magnitude. There are also less severe side-effects, of course, which contribute to about 5% of women abandoning treatment, and to 25% abandoning Powles’ pilot study of
prevention. This, surely,
is the sort of information that prospective trial could understand and use, particularly when warned that the chance of any individual woman having a cancer prevented by taking part in the trial is less than 1%. Ethics committees should insist that researchers who run large-scale trials should both perform such risk-benefit analysis, when possible, and provide the results to all potential recruits. entrants
Bulletin of Medical Ethics, London N5 1LA, UK
R. H. NICHOLSON
Ching CK, Smith PG, Long RG. Tamoxifen-associated hepatocellular damage and agranulocytosis. Lancet 1992; 339: 940. 2. Bentley CR, Davies G, Aclimandos WA. Tamoxifen retinopathy: a rare but serious complication. BMJ 1992; 304: 495-96. 3. Griffiths MF. Tamoxifen retinopathy at low dosage. Am J Ophthalmol 1987; 104: 1.
185-86. 4.
Nayfield SG, Karp JE, Ford LG, et al. Potential role of tamoxifen in prevention of breast cancer. Natl Cancer Inst 1991; 83: 1450-59. J C, Waterhouse J, Mack T, et al. Cancer incidence in five continents, vol V: IARC Scientific Publication no 88. Lyon: IARC, 1987.
5. Muir
Rigors and bronchospasm with urokinase after streptokinase SIR,-We report an unexpectedly high frequency of rigors and bronchospasm in a small group of patients given urokinase as a thrombolytic agent in acute myocardial infarction. After the presentation of results in the I SI S-3 3 triall at the meeting of the American College of Cardiology in March, 1991, we continued a policy of using streptokinase as the thrombolytic agent of choice in patients with no prior exposure because of the favourable price (NZ$360 per treatment). We were persuaded by evidence that second use of this drug, at least within 1-4 years, was likely to be prejudiced by the presence of antibodies in a substantial number of patients .2 However, we were inhibited in the use of the only other registered agent in New Zealand, recombinant tissue plasminogen activator, by its price (NZ$1890 per treatment). We found evidence for the efficacy3,4 of urokinase in this situation and a lack of antigenic effects5-7 with no reports of cross-reactivity with streptokinase. We negotiated with Abbott Pharmaceuticals a supply at a favourable price (under section 29 of the New Zealand Health Act) for named patients. This use was approved by the ethics committee of the Wellington Area Health Board, and a consent form was devised to explain to patients the reason for our choice of drug. Between October, 1991, and July, 1992, six patients with apparent recurrent myocardial infarction previously treated with streptokinase and deemed suitable for further thrombolytic therapy agreed to receive urokinase at 1 5MU infused over 30 min. Two of these patients tolerated the infusion without problems but four had rigors, and two of these also had bronchospasm (table). None of the patients had any history of asthma, atopy, or allergic reaction. All recovered fully rapidly, but after the second case of bronchospasm, we felt it was no longer ethically justified to continue the practice.
PATIENTS DETAILS
The supplying company and the New Zealand adverse drug reaction authority were notified. Rigors and other anaphylactoid reactions occur as a response to foreign protein and, because urokinase is a natural human protein, were not expected here.4 We have been informed by Abbott that there have been several reports in the USA of rigors (but not bronchospasm), which are thought to be due to a change in manufacturing process, but the specific cause has not yet been identified. Reports of such reactions to urokinase generally show a low frequency of such side-effects.4 The difference in our series was previous use of streptokinase. Cardiology Department, Wellington Area Health Board, Private Bag 31907, Lower Hutt, New Zealand
PHILLIP MATSIS STEWART MANN
1. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs amstreplase and of aspirin plus heparin vs aspirin alone among 41 299 cases of suspected acute myocardial infarction. Lancet 1992; 339: 753-70. 2. Jalihar S, Moms GK. Antistreptokinase titres after intravenous streptokinase. Lancet 1990; 335: 184-85. 3. Wall TC, Phillips HR, Stack RS, et al. Results of high dose intravenous urokinase for acute myocardial infarction. Am J Cardiol 1990; 65: 124-31. 4. Mathey DG, Schofer J, Sheehan FH, et al. Intravenous urokinase in acute myocardial infarction. Am J Cardiol 1985; 55: 878-82. 5. Bell W, Black EB, DeMets D, et al. Urokinase/streptokinase embolism trial. JAMA 1974; 229: 1606-13. 6. Walsh P, Stengle JM, Sherry S. Urokinase pulmonary embolism trial. Circulation 1969; 39: 153-56. 7. Volgesang G, Bell W. Treatment of pulmonary embolism and deep vein thrombosis with thrombolytic therapy, Clin Chest Med 1984; 5: 487-94.
Erwinase-induced pancreatitis SIR,-Acute pancreatitis occurs in about 3% of children after administration of Escherichia coli derived L-asparaginase for acute lymphoblastic leukaemia (ALL).l,2 Erwinase, a commercially available enzyme from Erurinia chrysanthemi, has been introduced with the claim of less severe treatment-related toxicity.3 Pancreatitis among Erwinase-treated ALL patients has not been reported to the
WHO adverse drug event registry, Swedish National Medical Product Agency (M. Wadelius, Lakemedal Suerket, Uppsala), and the Regulatory Administration in the UK (D. Musgrave, Porton Products). We report this event in a previously healthy 11-year-old girl with intermediate risk pre-B ALL (French-American-British Ll/L2) with 46 XX, t(4;5) +ring chromosome. Remission in our patient was achieved by systemic vincristine, doxorubicin, prednisolone, and prophylactic intrathecal methotrexate. Severe epigastric pain occurred on the 9th day during scheduled consolidation with erwinase, administered as an intravenous bolus daily at 30 000 IUjm2. Vomiting, fatigue, and increasing pain necessitated introduction of a nasogastric tube and spinal anaesthesia for 5 days. Increased serum amylase 25-8 U jl was detected at onset of pain; enzyme was 50-7 U/1 on the next day and returned to normal (1 -2-5-0) U/1) within a week. Insulin for 3 days controlled the emerging hyperglycaemia, which peaked at 25.8 mmol/1. A day after onset, a swollen pancreas was seen by ultrasound. Parenteral fluid replacement was given for 3 days to
