1145
5. Jordan VC. Overview from the International Conference on Long-Term Tamoxifen Therapy for Breast Cancer. J Natl Cancer Inst 1992; 84: 231-34. 6. Fendl KC, Zimniski SJ. Role of tamoxifen in the induction of hormone-independent rat mammary tumors. Cancer Res 1992; 52: 235-37. 7. Rutqvist LE, Cedermark B, Glas U, et al. Contralateral primary tumors in breast cancer patients in a randomised trial of adjuvant tamoxifen therapy. J Natl Cancer Inst 1991; 83: 1299-306. 8. Fomander T, Rutqvist LE, Sjoberg HE, et al. Long-term adjuvant tamoxifen in early breast cancer: effect on bone mineral density in postmenopausal women. J Clin Oncol 1990; 8: 1019-24. 9. Love R, Mazees RB, Tormey DC, et al. Bone mineral density in women with breast cancer treated with adjuvant tamoxifen for at least two years. Breast Cancer Res Treat 1988; 12: 279-302. 10. Gotfredson A, Christiansen C, Palshof T. The effect of tamoxifen on bone mineral content in premenopausal women with breast cancer. Cancer 1984; 53: 853-57. 11. Fentiman IS, Caleffi M, Rodin A, et al. Bone mineral content of women receiving tamoxifen for mastalgia. Br J Cancer 1989; 60: 262-64. 12. Powles TJ, Hardy JR, Ashley SE, et al. A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 1989; 60: 126-31. 13. Wolter J, Ryan WG, Subbaiah V, et al. Proc ASCO 1988; 7: 10 (abstr 34). 14. Turken S, Siris E, Seldin D, et al. Effects of tamoxifen on spinal bone density in women with breast cancer. J Natl Cancer Inst 1989; 81: 1086-88. 15. Love R, Mazess RB, Barden HS, Epstein S, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992; 326: 852-56.
The
16. Bush 17.
18.
19. 20.
TL, Fried LP, Barrett-Connor E. Cholesterol, lipoproteins, and coronary heart disease in women. Clin Chem 1988; 34: B60-B70. Rossner S, Wallgren A. Serum lipoproteins and proteins after breast cancer surgery and effects of tamoxifen. Atherosclerosis 1984; 52: 339-46. Love RR, Wiebe DA, Newcomb PA, et al. Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med 1991; 115: 860-64. Bruning PF, Bonfrer JMG, Hart AAM, et al. Tamoxifen, serum lipoproteins and cardiovascular risk. Br J Cancer 1988; 58: 497-99. Noguchi M, Taniya T, Tajiri K, et al. Fatal hyperlipaemia in a case of metastatic breast cancer treated by tamoxifen. Br J Surg 1987; 74: 586-87.
21. FDA Adverse Reaction Reports, 1987-1990. 22. McDonald CC, Stewart HJ. Fatal myocardial infarction in the Scottish Adjuvant Tamoxifen Trial. BMJ 1991; 303: 435-37. 23. Raloff J. Tamoxifen quandary. Science News 1992; 141: 266-69. 24. Testimony of Dr John Toopham before the Oncologic Drugs Advisory Committee of the Food and Drug Administration, June 29, 1990. 25. Ching CK, Smith PG, Long RG. Tamoxifen-associated hepatocellular damage and arganulocytosis. Lancet 1992; 339: 940. 26. Pavlidis NA, Petris C, Briassoulis E, et al. Clear evidence that long-term, low-dose tamoxifen treatment can induce ocular toxicity. Cancer 1992; 69: 2961-64. 27. Hearing on "Breast Cancer Prevention Study: Are Healthy Women Put at Risk by Federal Research?" Oct 22, 1992. Human Resources and Intergovernmental Relations Subcommittee of the Committee on
Government Operations, House of Representatives, One Hundred Second Congress. 28. Shultz MM. From informed consent to patient choice: a new protected interest. Yale Law J 1985; 95: 219-99.
for clinical trials of tamoxifen for prevention of breast cancer
case
Mammographic screening, modem surgical techniques, radiotherapy, and adjuvant drug treatment have had little impact on mortality from breast cancer. This stark reality has encouraged researchers to look at ways of preventing this common and lethal condition. Hormonal factors are thought to be important in the development of clinical breast cancer from a single malignant cell; tamoxifen may block this process of "endocrine promotion"1 and, if given early enough, may prevent the diseased Tamoxifen has been used since 1971 to treat over 3 million women with breast cancer. The toxicity of this drug is very low and it is effective, but not curative, for metastatic disease. In patients with primary breast cancer, tamoxifen delays relapse and prolongs survival in about 20-30%.3 The frequency of second primary breast cancers in such patients is reduced by about 40%; this observation likewise encourages the idea that administration of tamoxifen could be effective preventive therapy if given before the appearance of the first cancer. So, can tamoxifen prevent breast cancer in healthy women? To answer this key question we at the Royal Marsden Hospital thought it was necessary to undertake a clinical trial with healthy women rather than patients who have had breast cancer. In 1986 we initiated a pilot trial, for which we recruited high-risk women with a strong family history of breast cancer. These women were pre and post menopausal aged between 30 and 70, and they had about a fourfold relative risk of getting breast cancer. Women were randomised to receive tamoxifen 20 mg/day or placebo. Early results indicated good compliance with low subjective toxicity. Safety monitoring showed no evidence of adverse antioestrogenic effects of tamoxifen; potentially beneficial oestrogenic effects included lowering of plasma cholesterol and fibrinogen.4 We have now recruited over 1700 women
and interim analysis of the first 1000 indicates that acute toxicity remains very low (15% hot flushes, 10% irregular menses, 7% vaginal discharge) with a correspondingly high compliance of about 75% at 5 years.5 We can detect no adverse antioestrogenic effects such as an early menopause, vaginal dryness, or loss of libido. Moreover, evidence from adjuvant breast cancer trials indicates that patients taking tamoxifen have a 60% reduction in death from myocardial infarction6 and are significantly protected against postmenopausal bone loss.7 These results seem almost too good to be true-a drug that acts like a mild oestrogen in the body to reduce heart attacks and bone loss, yet drastically interferes with oestrogen promotion of breast cancer. The fact that oestrogen undoubtedly promotes experimental breast cancer and that tamoxifen blocks this process1 raises the possibility that the drug affects cancer cells by a mechanism other than binding to and thereby blocking oestrogenstimulated receptors. This feature could be an important advantage because an effective antioestrogen would probably have adverse effects on bone and the cardiovascular system and would therefore be unacceptable for prevention in healthy women. What about adverse oestrogenic effects on the liver and endometrium? Low doses of oestrogen such as those in oral contraceptives cause hepatomas in rodents although a significant risk in women seems unlikely.8 Oestrogen is believed to act as an endocrine promotor via receptors present in rat liver. Experimentally, tamoxifen has carcinogenic potential. In some strains of rat, but not mouse ADDRESS Breast Unit, Royal Marsden Hospital London and Sutton, Downs Road, Sutton, Surrey SM2 5PT, UK (Dr T J.
Powles, FRCP)
1146
or
hamster, tamoxifen can cause liver cancers at doses as low
mg/kg
ICI
Adducts
data). day (unpublished post-labelling techniques, presumably indicating DNA binding and therefore tamoxifen-induced damage, have been identified in rat and hamster liver after as
5
measured
by
per 32P
short exposure to doses of tamoxifen as low as 1 mg/kg per day.9 However, there are doubts about the correlation of 32P labelling with the risk of malignant disease even in rats,10 let alone in other rodents, mammals, or human beings. There are many uncertainties in extrapolating these experimental data from rats to women. The effect depends on bioavailability, hepatic blood flow, and hepatic metabolism to active genotoxic carcinogens, all of which differ enormously between rat and man. Moreover, the carcinogenic effects of any active metabolites produced in the liver depend on binding affinities to specific proteins, receptors, and DNA and on the potential for DNA repair in the liver, which is likewise very different in rat and man. Finally, an oestrogenic effect of tamoxifen in rat liver may be essential for cancer promotion after genotoxic initiation. More experimental studies are needed to identify the mechanisms of liver carcinogenesis in rats and to explain why this effect seems to be specific for rats. Such data are essential to provide a rational basis for estimation of any human risk. Development of in-vitro techniques designed to imitate metabolism in human liver may help in this respect." Such investigations, in conjunction with clinical research to assess possible DNA damage in human liver and other tissues and careful follow-up for incidence of other cancers in women exposed to tamoxifen, have now been initiated in the UK by the Medical Research Council and the Cancer Research Campaign. Follow-up data for women with primary breast cancer who have received adjuvant tamoxifen are incomplete but nonetheless encouraging. First, despite the fact that millions of women have received tamoxifen, many thousands of whom have survived for more than 10 years, there is no obvious increase in risk of acute leukaemias. Since acute leukaemia is not usually muddled with metastatic breast cancer, this result seems to exclude tamoxifen as a haematological genotoxin. At a dose of 40 mg/day, there is a reported increased risk of endometrial cancer;12 this accords with an unopposed oestrogenic effect of tamoxifen on the postmenopausal uterus.13 At the usual dose of 20 mg/day,14 this increased risk has not been seen although oestrogenic effects on the postmenopausal vagina have been reported. 15 On this evidence an increased risk of endometrial cancer with 20 mg/day is unlikely, and ultrasound screening or progestagen prevention is not justified. Two liver cancers have been reported in women receiving 40 mg/day 12 but none at 20 mg/day (ICI unpublished data). The duration of treatment and follow-up is short and involves only a few thousand women. Epidemiological studies with many more women, longer follow-up, and accurate distinction between primary hepatomata and metastatic breast cancer are needed to ensure that there is no unacceptable risk. Meanwhile, the clinical evidence does not indicate an increased risk of liver (or any other) cancer. If such a risk should emerge it will be late and probably small and should be considered in the context of a reported 40% reduction in risk of second primary breast cancer already detected in clinical trials.33 What of other side-effects? The possibility of an adverse ocular effect is suggested by reports of a specific type of retinopathy and keratopathy associated with tamoxifen doses of 180 mg daily or more.16 Evidence of retinopathy at lower doses is less convincing: no abnormalties were
controlled trial 17 but Pavlidis et aI18 lately reported typical retinopathy in 4 of 63 patients. The retinopathy is said to be reversible if diagnosed early, so ophthalmic assessment is essential in any woman who manifests visual impairment on treatment. Occasional and sporadic reports of acute liver toxicity and blood dyscrasias19’zo have not indicated an associated increased risk of these conditions attributable to tamoxifen. Similarly, the risk of thromboembolism and thrombophlebitis in association with tamoxifen in women with cancerl is more likely to be related to the disease than to the treatment. Overall, the reported lack of serious long-term sideeffects is reassuring. I believe that the results of our pilot programme, together with safety data from adjuvant tamoxifen trials, indicate that the potential benefits of using tamoxifen in a prevention trial in healthy women with a strong family history of breast cancer far outweigh the potential risks. The arguments against such trials centre mainly on potential unknown risks. On an individual basis, we will never be able to identify those women in whom breast cancer is prevented; at the same time, we will never be able to prove that tamoxifen did not cause a patient’s liver cancer or blindness. Nonetheless, a clinical trial is the only way to identify overall benefit and harm. The issue of risk to healthy women is compounded by that of overtreatment-ie, most women who take tamoxifen would not have developed breast cancer anyway. Overtreatment has always been a part of medical practice: in public health interventions, such as immunisation or water fluoridation, the healthy population at large is exposed to possible hazards for unidentified individual benefits. Similarly, in treatment of primary breast cancer, most patients do not require mastectomy or radiotherapy after excision of the primary cancer, either because they were already cured or because they will die anyway of the disease. Likewise, use of tamoxifen for adjuvant treatment of primary breast cancer is mostly overtreatment, especially for women with good prognosis primary disease, for whom the risk of dying from breast cancer is similar to that of the high-risk women in our prevention programme. With advances in the understanding of the genetic and endocrine basis of breast cancer, it it likely that within the duration of this trial we well be able to better identify those women at risk of the disease, but at the same time we would like to show that we can prevent the disease in these women. Identification is pointless if we can do nothing about it. Prevention studies and genetic and endocrine risk programmes need to progress simultaneously to achieve the goal of preventing breast cancer in women really at risk without having to overtreat the whole population. Finally, in order to address this issue effectively, we have to take into account the magnitude of the problem. I have had the misfortune to look after thousands of women who have died of breast cancer, many in the prime of life. More than half a million women are afflicted with this disease each year and I believe we now have a real opportunity to beat it. Of course, we must be cautious with any intervention in healthy women, and inevitably there are risks, most probably those that we have not even thought of. However, I feel, of all the possible interventions that could be used, tamoxifen is likely to be the safest, the most effective, and the only realistic option in the foreseeable future. I strongly support the proposals for multicentre national tamoxifen trials in middle-aged healthy women with a strong family history of breast cancer. Such trials have already started in the USA and Italy and are under consideration in the UK. detected in
one
1147
REFERENCES
1. Jordan VC. Effect of tamoxifen on initiation and growth of DMBAinduced rat mammary carcinomata. Eur J Cancer 1976; 12: 419-24. 2. Cuzick J, Wang DK, Bulbrook RD. The prevention of breast cancer. Lancet 1986; i: 83-86. 3. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 1992; 339: 1-15. 4. Powles TJ, Hardy JR, Ashley SE, et al. A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 1989; 60: 126-33. 5. Powles TJ, Tillyer CR, Jones AL, et al. Prevention of breast cancer with tamoxifen: an update on the Royal Marsden pilot programme. Eur J Cancer 1990; 26: 680-84. 6. McDonald C, Stewart HJ. Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. BMJ 1991; 303: 435-37. 7. Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992; 326: 852-56. 8. World Health Organisation. Combined oral contraceptives and liver cancer. WHO collaborative study of neoplasia and steroid contraceptives. Int J Cancer 1989; 43: 254-59. 9. Han X, Liehr JG. Induction of covalent DNA adducts in rodents by tamoxifen. Cancer Res 1992; 52: 1360-63. 10. Taningher M, Saccomanno G, Santi L, Grilli S, Parodi S. Quantitative predictability of carcinogenicity of the covalent binding index of
chemical to DNA: comparison of the in vivo and in vitro assays. Environ Health Perspect 1990; 84: 183-92. 11. Crespi CL, Penman BW, Steimal DT, Gelboin HV, Gonzalez FJ. The development of a human cell line stably expressing human CYP3A4: role of metabolic activation of aflatoxin B1 and comparison to CYP1A2 and CYP2A3. Carcinogenesis 1991; 12: 355-59. 12. Fornander T, Rutqvist LE, Cedermark B, et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989; ii: 117-21. 13. Neven P, De Muylder X, Van Belle U, Vanderick G, De Muylder E. Tamoxifen and the uterus and endometrium. Lancet 1989; i: 375. 14. Stewart HJ, Knight GM. Tamoxifen and the uterus and endometrium. Lancet 1989; i: 375-76. 15. Ferrazzi E, Cartei G, Maatarazzo R, Fiorentino M. Oestrogen-like effect of tamoxifen on vaginal epithelium. BMJ 1977; i: 1351-52. 16. Kaiser-Kupfer MI, Lippman ME. Tamoxifen retinopathy. Cancer Treat Rep 1978; 62: 315-20. 17. Longstaff S, Sigurdsson H, O’Keeffe M, et al. A controlled study of the ocular effects of tamoxifen in conventional dosage in the treatment of breast carcinoma. Eur J Cancer Clin Oncol 1989; 25: 1805-08. 18. Pavlidis N, Petris C, Briassoulis E, et al. Clear evidence that long-term low-dose tamoxifen treatment can induce ocular toxicity. Cancer 1992; 69: 2961-64. 19. Blackburn A, Arniel S, Millis R, Rubens R. Tamoxifen and liver damage. BMJ 1984; 289: 288. 20. Ching CK, Smith PG, Long RG. Tamoxifen-associated hepatocellular damage and agranulocytosis. Lancet 1992; 339: 940. 21. Lipton A, Harve H, Hamilton R. Venous thrombosis as a side effect of tamoxifen treatment. Cancer Treat Rep 1984; 68: 887-89.
BOO KSHELF Understanding Steven Lehrer.
Pediatric Heart Sounds
Philadelphia:
Saunders. 1992.
Pp 230
+
audio
cassette.$38.95. ISBN 0-721623875.
Although I am a paediatric cardiologist, I have never really understood paediatric heart sounds. I was bom into the subject in 1980 with an ultrasound machine attached to my right wrist and could not wait to dispense with the guesswork that auscultation seemed to entail. Now I wear my stethoscope only for decoration or to add a touch of old-fashioned authenticity for suspicious parents. The title of this publication seems quaint for the 1990s, at a time when technology has taken over from the stethoscope and a child with a complex heart malformation can be evaluated and surgically treated without the bell ever touching the chest. Bereft of his portable echo machine, Lehrer has put together a package that is ideal for both undergraduates and postgraduates in paediatric training. The reasoning behind children’s heart sounds and murmurs is laid out clearly and Lehrer is obviously a skilled, thoughtful, and experienced auscultator. I recommend especially the chapter on systolic murmurs to many of my consultant paediatric colleagues who remain unable to distinguish a classic innocent murmur from that of a ventricular septal defect. Many children arrive in our clinics having been referred for unnecessary echocardiograms. On several occasions I became concerned that the author had lost touch with modem terminologyeg, endocardial cushion defects are not commonly described as such nowadays, being referred to as atrioventricular septal defects. Also, to talk of surgical pulmonary valvotomy, when the established treatment for pulmonary stenosis for nearly ten years has been a balloon valvuloplasty, seems strange. There is a brief, if slightly naive, overview of some major heart malformations, but this is perfectly suitable for undergraduates.
The tape provides good examples of the different types of heart sounds and murmurs found in children. I was surprised that one of the most common, that of pulmonary stenosis, was not included. However, familiarity with the limited nature of possible diagnoses should dispel the panic often felt by undergraduates-and even, in some instances, postgraduates-when asked to auscultate a child’s heart. Fetal Cardiology, Guy’s Hospital,
LINDSEY ALLAN
London SE1 9RT, UK
Low Molecular
Weight Heparin
Barrowcliffe, E. A. Johnson, D. P. Thomas. Chichester: John Wiley. 1992. Pp 205. 32.50. ISBN 0-471933244. In 1916, a medical student named McLean discovered T. W.
heparin whilst searching for a coagulant in livers of various animal species. Since then, heparin, a sulphated glycosaminoglycan that is extracted from bovine and porcine lung or intestine, has become a familiar anticoagulant. It is effective in the prevention and treatment of venous thrombosis and pulmonary embolism, the prevention of mural thrombosis after myocardial infarction, the treatment of patients with unstable angina and acute myocardial infarction, and the prevention of coronary artery reocclusion after thrombolysis. From the mid-1970s onwards, research suggested that heparin fractions of low molecular weight might have advantages over standard heparin in anticoagulant regimens. The authors of this book, who are at the forefront of research into the development of low-molecular-weight heparin, recount their story well, from early physicochemical investigations in vitro, through extensive
5. Jordan VC. Overview from the International Conference on Long-Term Tamoxifen Therapy for Breast Cancer. J Natl Cancer Inst 1992; 84: 231-34. 6. Fendl KC, Zimniski SJ. Role of tamoxifen in the induction of hormone-independent rat mammary tumors. Cancer Res 1992; 52: 235-37. 7. Rutqvist LE, Cedermark B, Glas U, et al. Contralateral primary tumors in breast cancer patients in a randomised trial of adjuvant tamoxifen therapy. J Natl Cancer Inst 1991; 83: 1299-306. 8. Fomander T, Rutqvist LE, Sjoberg HE, et al. Long-term adjuvant tamoxifen in early breast cancer: effect on bone mineral density in postmenopausal women. J Clin Oncol 1990; 8: 1019-24. 9. Love R, Mazees RB, Tormey DC, et al. Bone mineral density in women with breast cancer treated with adjuvant tamoxifen for at least two years. Breast Cancer Res Treat 1988; 12: 279-302. 10. Gotfredson A, Christiansen C, Palshof T. The effect of tamoxifen on bone mineral content in premenopausal women with breast cancer. Cancer 1984; 53: 853-57. 11. Fentiman IS, Caleffi M, Rodin A, et al. Bone mineral content of women receiving tamoxifen for mastalgia. Br J Cancer 1989; 60: 262-64. 12. Powles TJ, Hardy JR, Ashley SE, et al. A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 1989; 60: 126-31. 13. Wolter J, Ryan WG, Subbaiah V, et al. Proc ASCO 1988; 7: 10 (abstr 34). 14. Turken S, Siris E, Seldin D, et al. Effects of tamoxifen on spinal bone density in women with breast cancer. J Natl Cancer Inst 1989; 81: 1086-88. 15. Love R, Mazess RB, Barden HS, Epstein S, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992; 326: 852-56.
The
16. Bush 17.
18.
19. 20.
TL, Fried LP, Barrett-Connor E. Cholesterol, lipoproteins, and coronary heart disease in women. Clin Chem 1988; 34: B60-B70. Rossner S, Wallgren A. Serum lipoproteins and proteins after breast cancer surgery and effects of tamoxifen. Atherosclerosis 1984; 52: 339-46. Love RR, Wiebe DA, Newcomb PA, et al. Effects of tamoxifen on cardiovascular risk factors in postmenopausal women. Ann Intern Med 1991; 115: 860-64. Bruning PF, Bonfrer JMG, Hart AAM, et al. Tamoxifen, serum lipoproteins and cardiovascular risk. Br J Cancer 1988; 58: 497-99. Noguchi M, Taniya T, Tajiri K, et al. Fatal hyperlipaemia in a case of metastatic breast cancer treated by tamoxifen. Br J Surg 1987; 74: 586-87.
21. FDA Adverse Reaction Reports, 1987-1990. 22. McDonald CC, Stewart HJ. Fatal myocardial infarction in the Scottish Adjuvant Tamoxifen Trial. BMJ 1991; 303: 435-37. 23. Raloff J. Tamoxifen quandary. Science News 1992; 141: 266-69. 24. Testimony of Dr John Toopham before the Oncologic Drugs Advisory Committee of the Food and Drug Administration, June 29, 1990. 25. Ching CK, Smith PG, Long RG. Tamoxifen-associated hepatocellular damage and arganulocytosis. Lancet 1992; 339: 940. 26. Pavlidis NA, Petris C, Briassoulis E, et al. Clear evidence that long-term, low-dose tamoxifen treatment can induce ocular toxicity. Cancer 1992; 69: 2961-64. 27. Hearing on "Breast Cancer Prevention Study: Are Healthy Women Put at Risk by Federal Research?" Oct 22, 1992. Human Resources and Intergovernmental Relations Subcommittee of the Committee on
Government Operations, House of Representatives, One Hundred Second Congress. 28. Shultz MM. From informed consent to patient choice: a new protected interest. Yale Law J 1985; 95: 219-99.
for clinical trials of tamoxifen for prevention of breast cancer
case
Mammographic screening, modem surgical techniques, radiotherapy, and adjuvant drug treatment have had little impact on mortality from breast cancer. This stark reality has encouraged researchers to look at ways of preventing this common and lethal condition. Hormonal factors are thought to be important in the development of clinical breast cancer from a single malignant cell; tamoxifen may block this process of "endocrine promotion"1 and, if given early enough, may prevent the diseased Tamoxifen has been used since 1971 to treat over 3 million women with breast cancer. The toxicity of this drug is very low and it is effective, but not curative, for metastatic disease. In patients with primary breast cancer, tamoxifen delays relapse and prolongs survival in about 20-30%.3 The frequency of second primary breast cancers in such patients is reduced by about 40%; this observation likewise encourages the idea that administration of tamoxifen could be effective preventive therapy if given before the appearance of the first cancer. So, can tamoxifen prevent breast cancer in healthy women? To answer this key question we at the Royal Marsden Hospital thought it was necessary to undertake a clinical trial with healthy women rather than patients who have had breast cancer. In 1986 we initiated a pilot trial, for which we recruited high-risk women with a strong family history of breast cancer. These women were pre and post menopausal aged between 30 and 70, and they had about a fourfold relative risk of getting breast cancer. Women were randomised to receive tamoxifen 20 mg/day or placebo. Early results indicated good compliance with low subjective toxicity. Safety monitoring showed no evidence of adverse antioestrogenic effects of tamoxifen; potentially beneficial oestrogenic effects included lowering of plasma cholesterol and fibrinogen.4 We have now recruited over 1700 women
and interim analysis of the first 1000 indicates that acute toxicity remains very low (15% hot flushes, 10% irregular menses, 7% vaginal discharge) with a correspondingly high compliance of about 75% at 5 years.5 We can detect no adverse antioestrogenic effects such as an early menopause, vaginal dryness, or loss of libido. Moreover, evidence from adjuvant breast cancer trials indicates that patients taking tamoxifen have a 60% reduction in death from myocardial infarction6 and are significantly protected against postmenopausal bone loss.7 These results seem almost too good to be true-a drug that acts like a mild oestrogen in the body to reduce heart attacks and bone loss, yet drastically interferes with oestrogen promotion of breast cancer. The fact that oestrogen undoubtedly promotes experimental breast cancer and that tamoxifen blocks this process1 raises the possibility that the drug affects cancer cells by a mechanism other than binding to and thereby blocking oestrogenstimulated receptors. This feature could be an important advantage because an effective antioestrogen would probably have adverse effects on bone and the cardiovascular system and would therefore be unacceptable for prevention in healthy women. What about adverse oestrogenic effects on the liver and endometrium? Low doses of oestrogen such as those in oral contraceptives cause hepatomas in rodents although a significant risk in women seems unlikely.8 Oestrogen is believed to act as an endocrine promotor via receptors present in rat liver. Experimentally, tamoxifen has carcinogenic potential. In some strains of rat, but not mouse ADDRESS Breast Unit, Royal Marsden Hospital London and Sutton, Downs Road, Sutton, Surrey SM2 5PT, UK (Dr T J.
Powles, FRCP)
1146
or
hamster, tamoxifen can cause liver cancers at doses as low
mg/kg
ICI
Adducts
data). day (unpublished post-labelling techniques, presumably indicating DNA binding and therefore tamoxifen-induced damage, have been identified in rat and hamster liver after as
5
measured
by
per 32P
short exposure to doses of tamoxifen as low as 1 mg/kg per day.9 However, there are doubts about the correlation of 32P labelling with the risk of malignant disease even in rats,10 let alone in other rodents, mammals, or human beings. There are many uncertainties in extrapolating these experimental data from rats to women. The effect depends on bioavailability, hepatic blood flow, and hepatic metabolism to active genotoxic carcinogens, all of which differ enormously between rat and man. Moreover, the carcinogenic effects of any active metabolites produced in the liver depend on binding affinities to specific proteins, receptors, and DNA and on the potential for DNA repair in the liver, which is likewise very different in rat and man. Finally, an oestrogenic effect of tamoxifen in rat liver may be essential for cancer promotion after genotoxic initiation. More experimental studies are needed to identify the mechanisms of liver carcinogenesis in rats and to explain why this effect seems to be specific for rats. Such data are essential to provide a rational basis for estimation of any human risk. Development of in-vitro techniques designed to imitate metabolism in human liver may help in this respect." Such investigations, in conjunction with clinical research to assess possible DNA damage in human liver and other tissues and careful follow-up for incidence of other cancers in women exposed to tamoxifen, have now been initiated in the UK by the Medical Research Council and the Cancer Research Campaign. Follow-up data for women with primary breast cancer who have received adjuvant tamoxifen are incomplete but nonetheless encouraging. First, despite the fact that millions of women have received tamoxifen, many thousands of whom have survived for more than 10 years, there is no obvious increase in risk of acute leukaemias. Since acute leukaemia is not usually muddled with metastatic breast cancer, this result seems to exclude tamoxifen as a haematological genotoxin. At a dose of 40 mg/day, there is a reported increased risk of endometrial cancer;12 this accords with an unopposed oestrogenic effect of tamoxifen on the postmenopausal uterus.13 At the usual dose of 20 mg/day,14 this increased risk has not been seen although oestrogenic effects on the postmenopausal vagina have been reported. 15 On this evidence an increased risk of endometrial cancer with 20 mg/day is unlikely, and ultrasound screening or progestagen prevention is not justified. Two liver cancers have been reported in women receiving 40 mg/day 12 but none at 20 mg/day (ICI unpublished data). The duration of treatment and follow-up is short and involves only a few thousand women. Epidemiological studies with many more women, longer follow-up, and accurate distinction between primary hepatomata and metastatic breast cancer are needed to ensure that there is no unacceptable risk. Meanwhile, the clinical evidence does not indicate an increased risk of liver (or any other) cancer. If such a risk should emerge it will be late and probably small and should be considered in the context of a reported 40% reduction in risk of second primary breast cancer already detected in clinical trials.33 What of other side-effects? The possibility of an adverse ocular effect is suggested by reports of a specific type of retinopathy and keratopathy associated with tamoxifen doses of 180 mg daily or more.16 Evidence of retinopathy at lower doses is less convincing: no abnormalties were
controlled trial 17 but Pavlidis et aI18 lately reported typical retinopathy in 4 of 63 patients. The retinopathy is said to be reversible if diagnosed early, so ophthalmic assessment is essential in any woman who manifests visual impairment on treatment. Occasional and sporadic reports of acute liver toxicity and blood dyscrasias19’zo have not indicated an associated increased risk of these conditions attributable to tamoxifen. Similarly, the risk of thromboembolism and thrombophlebitis in association with tamoxifen in women with cancerl is more likely to be related to the disease than to the treatment. Overall, the reported lack of serious long-term sideeffects is reassuring. I believe that the results of our pilot programme, together with safety data from adjuvant tamoxifen trials, indicate that the potential benefits of using tamoxifen in a prevention trial in healthy women with a strong family history of breast cancer far outweigh the potential risks. The arguments against such trials centre mainly on potential unknown risks. On an individual basis, we will never be able to identify those women in whom breast cancer is prevented; at the same time, we will never be able to prove that tamoxifen did not cause a patient’s liver cancer or blindness. Nonetheless, a clinical trial is the only way to identify overall benefit and harm. The issue of risk to healthy women is compounded by that of overtreatment-ie, most women who take tamoxifen would not have developed breast cancer anyway. Overtreatment has always been a part of medical practice: in public health interventions, such as immunisation or water fluoridation, the healthy population at large is exposed to possible hazards for unidentified individual benefits. Similarly, in treatment of primary breast cancer, most patients do not require mastectomy or radiotherapy after excision of the primary cancer, either because they were already cured or because they will die anyway of the disease. Likewise, use of tamoxifen for adjuvant treatment of primary breast cancer is mostly overtreatment, especially for women with good prognosis primary disease, for whom the risk of dying from breast cancer is similar to that of the high-risk women in our prevention programme. With advances in the understanding of the genetic and endocrine basis of breast cancer, it it likely that within the duration of this trial we well be able to better identify those women at risk of the disease, but at the same time we would like to show that we can prevent the disease in these women. Identification is pointless if we can do nothing about it. Prevention studies and genetic and endocrine risk programmes need to progress simultaneously to achieve the goal of preventing breast cancer in women really at risk without having to overtreat the whole population. Finally, in order to address this issue effectively, we have to take into account the magnitude of the problem. I have had the misfortune to look after thousands of women who have died of breast cancer, many in the prime of life. More than half a million women are afflicted with this disease each year and I believe we now have a real opportunity to beat it. Of course, we must be cautious with any intervention in healthy women, and inevitably there are risks, most probably those that we have not even thought of. However, I feel, of all the possible interventions that could be used, tamoxifen is likely to be the safest, the most effective, and the only realistic option in the foreseeable future. I strongly support the proposals for multicentre national tamoxifen trials in middle-aged healthy women with a strong family history of breast cancer. Such trials have already started in the USA and Italy and are under consideration in the UK. detected in
one
1147
REFERENCES
1. Jordan VC. Effect of tamoxifen on initiation and growth of DMBAinduced rat mammary carcinomata. Eur J Cancer 1976; 12: 419-24. 2. Cuzick J, Wang DK, Bulbrook RD. The prevention of breast cancer. Lancet 1986; i: 83-86. 3. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 1992; 339: 1-15. 4. Powles TJ, Hardy JR, Ashley SE, et al. A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer. Br J Cancer 1989; 60: 126-33. 5. Powles TJ, Tillyer CR, Jones AL, et al. Prevention of breast cancer with tamoxifen: an update on the Royal Marsden pilot programme. Eur J Cancer 1990; 26: 680-84. 6. McDonald C, Stewart HJ. Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial. BMJ 1991; 303: 435-37. 7. Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992; 326: 852-56. 8. World Health Organisation. Combined oral contraceptives and liver cancer. WHO collaborative study of neoplasia and steroid contraceptives. Int J Cancer 1989; 43: 254-59. 9. Han X, Liehr JG. Induction of covalent DNA adducts in rodents by tamoxifen. Cancer Res 1992; 52: 1360-63. 10. Taningher M, Saccomanno G, Santi L, Grilli S, Parodi S. Quantitative predictability of carcinogenicity of the covalent binding index of
chemical to DNA: comparison of the in vivo and in vitro assays. Environ Health Perspect 1990; 84: 183-92. 11. Crespi CL, Penman BW, Steimal DT, Gelboin HV, Gonzalez FJ. The development of a human cell line stably expressing human CYP3A4: role of metabolic activation of aflatoxin B1 and comparison to CYP1A2 and CYP2A3. Carcinogenesis 1991; 12: 355-59. 12. Fornander T, Rutqvist LE, Cedermark B, et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989; ii: 117-21. 13. Neven P, De Muylder X, Van Belle U, Vanderick G, De Muylder E. Tamoxifen and the uterus and endometrium. Lancet 1989; i: 375. 14. Stewart HJ, Knight GM. Tamoxifen and the uterus and endometrium. Lancet 1989; i: 375-76. 15. Ferrazzi E, Cartei G, Maatarazzo R, Fiorentino M. Oestrogen-like effect of tamoxifen on vaginal epithelium. BMJ 1977; i: 1351-52. 16. Kaiser-Kupfer MI, Lippman ME. Tamoxifen retinopathy. Cancer Treat Rep 1978; 62: 315-20. 17. Longstaff S, Sigurdsson H, O’Keeffe M, et al. A controlled study of the ocular effects of tamoxifen in conventional dosage in the treatment of breast carcinoma. Eur J Cancer Clin Oncol 1989; 25: 1805-08. 18. Pavlidis N, Petris C, Briassoulis E, et al. Clear evidence that long-term low-dose tamoxifen treatment can induce ocular toxicity. Cancer 1992; 69: 2961-64. 19. Blackburn A, Arniel S, Millis R, Rubens R. Tamoxifen and liver damage. BMJ 1984; 289: 288. 20. Ching CK, Smith PG, Long RG. Tamoxifen-associated hepatocellular damage and agranulocytosis. Lancet 1992; 339: 940. 21. Lipton A, Harve H, Hamilton R. Venous thrombosis as a side effect of tamoxifen treatment. Cancer Treat Rep 1984; 68: 887-89.
BOO KSHELF Understanding Steven Lehrer.
Pediatric Heart Sounds
Philadelphia:
Saunders. 1992.
Pp 230
+
audio
cassette.$38.95. ISBN 0-721623875.
Although I am a paediatric cardiologist, I have never really understood paediatric heart sounds. I was bom into the subject in 1980 with an ultrasound machine attached to my right wrist and could not wait to dispense with the guesswork that auscultation seemed to entail. Now I wear my stethoscope only for decoration or to add a touch of old-fashioned authenticity for suspicious parents. The title of this publication seems quaint for the 1990s, at a time when technology has taken over from the stethoscope and a child with a complex heart malformation can be evaluated and surgically treated without the bell ever touching the chest. Bereft of his portable echo machine, Lehrer has put together a package that is ideal for both undergraduates and postgraduates in paediatric training. The reasoning behind children’s heart sounds and murmurs is laid out clearly and Lehrer is obviously a skilled, thoughtful, and experienced auscultator. I recommend especially the chapter on systolic murmurs to many of my consultant paediatric colleagues who remain unable to distinguish a classic innocent murmur from that of a ventricular septal defect. Many children arrive in our clinics having been referred for unnecessary echocardiograms. On several occasions I became concerned that the author had lost touch with modem terminologyeg, endocardial cushion defects are not commonly described as such nowadays, being referred to as atrioventricular septal defects. Also, to talk of surgical pulmonary valvotomy, when the established treatment for pulmonary stenosis for nearly ten years has been a balloon valvuloplasty, seems strange. There is a brief, if slightly naive, overview of some major heart malformations, but this is perfectly suitable for undergraduates.
The tape provides good examples of the different types of heart sounds and murmurs found in children. I was surprised that one of the most common, that of pulmonary stenosis, was not included. However, familiarity with the limited nature of possible diagnoses should dispel the panic often felt by undergraduates-and even, in some instances, postgraduates-when asked to auscultate a child’s heart. Fetal Cardiology, Guy’s Hospital,
LINDSEY ALLAN
London SE1 9RT, UK
Low Molecular
Weight Heparin
Barrowcliffe, E. A. Johnson, D. P. Thomas. Chichester: John Wiley. 1992. Pp 205. 32.50. ISBN 0-471933244. In 1916, a medical student named McLean discovered T. W.
heparin whilst searching for a coagulant in livers of various animal species. Since then, heparin, a sulphated glycosaminoglycan that is extracted from bovine and porcine lung or intestine, has become a familiar anticoagulant. It is effective in the prevention and treatment of venous thrombosis and pulmonary embolism, the prevention of mural thrombosis after myocardial infarction, the treatment of patients with unstable angina and acute myocardial infarction, and the prevention of coronary artery reocclusion after thrombolysis. From the mid-1970s onwards, research suggested that heparin fractions of low molecular weight might have advantages over standard heparin in anticoagulant regimens. The authors of this book, who are at the forefront of research into the development of low-molecular-weight heparin, recount their story well, from early physicochemical investigations in vitro, through extensive
