- Email: [email protected]
Tamoxifen and risk of endometrial cancer
CORRESPONDENCE
progestagens might have harmful orally effects on the breast,3 administered progestagens may have a detrimental effect on the breast,3 orally administered progestagens would not be acceptable to women taking tamoxifen to lower their chance of developing breast cancer. Direct administration of progestagen to the endometrium effectively protects it with little or no systemic effect. Although not licensed for this use, the use of a progestagen or levonorgestrelreleasing intrauteruine system might have protective effects against tamoxifen. If so, many women could continue with tamoxifen, rather than being deprived of the substantial benefits it offers against development of primary breast carcinoma.4 *M J Dickson, T Pandiarajan Department of Obstetrics and Gynaecology, Copeland Offices, Birch Hill Hospital, Rochdale, Lancashire OL12 9QB, UK 1
2
3
4
Bergman L, Beelen MLR, Gallee MPW, et al. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000; 356: 881–87. Ismail SM. Pathology of endometrium treated with tamoxifen. J Clin Pathol 1994; 47: 827–33. Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000; 283: 485–91. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998; 90: 1371–88.
Sir—Liesbeth Bergman and colleagues1 use epidemiological data associated with endometrial cancer to rebut advocates for tamoxifen use in healthy women. Clinical neuropsychological testing is necessary before tamoxifen use in healthy women is recommended. Cognitive deficits are seen when formal neuropsychological testing is done on breast-cancer patients treated with chemotherapy plus tamoxifen or chemotherapy alone.2 Tamoxifen acts as a non-competitive block to the ligated serotonin channel in the central nervous system.3 Subtests that assess memory, executive function, visual perception, and motor dexterity should be highlighted. Visual performance with the starry night task test and motion discrimination using low and high velocity dot kinetogram might document the organic explanation for women’s visual blurring complaints while on tamoxifen. Pamela Kairies 3647 Cedarbrae Lane, San Diego, CA 92106, USA 1
68
Bergman L, Beelen MLR, Gallee MPW, et al. Risk and prognosis of endometrial
2
3
cancer after tamoxifen for breast cancer. Lancet 2000; 356: 881–87. Schagen S, van Dam F, Muller M, Boogerd W, Lindeboom J, Bruning P. Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 1999; 85: 640–50. Allen M, Newland C, Valverde M, Hardy S. Inhibition of ligand-gated cation-selective channels by tamoxifen. Eur J Pharmacol 1998; 354: 261–69.
Sir—Liesbeth Bergman and colleagues1 show risk of endometrial cancer increases with increasing duration of tamoxifen use. More importantly, they show that women who develop endometrial cancer have a worse outlook, less favourable histology, higher stage, and later prescription than previously thought. Although tamoxifen has oestrogenantagonistic effects on breast-cancer cells, it has oestrogen-agonistic activity at other sites, including the endometrium and bone.2 Exposure to unopposed oestrogen increases the risk of endometrial hyperplasia and cancer, and a progestagen is generally added to hormone-replacement therapy to protect the endometrium. The oestrogen-agonistic activity of tamoxifen on the uterus mimics exposure of the endometrium to unopposed oestrogen, It would, therefore, seem sensible to investigate the use of progestagens to protect the endometrium in patients using tamoxifen. Whether progestogens exert a beneficial or harmful effect on the initiation or promotion of breast cancer seems unclear. Progestogens have been used in the treatment of metastatic breast cancer and response rates are similar to that of tamoxifen. However an observational study has suggested that combined oestrogen and progesterone hormone-replacement therapy seems to increase patients’ risks of developing breast cancer compared with oestrogen therapy alone.3 A prospective study on apes might shed more light on this dilemma, suggesting that oestrogenic activity is necessary for progestagens to have a harmful effect on the breast.4 Given the prevalence of breast cancer, it is not surprising that thousands of women in the UK are taking tamoxifen. The Breast Cancer Prevention Trial in the USA5 showed that women with an increased genetic risk of developing breast cancer had a 45% reduction in that risk if they took tamoxifen. If the results of that trial are substantiated, thousands more women will undoubtedly be keen to take tamoxifen. Physicians and patients need clear guidelines as to how best monitor and protect the endometrium from the
unwanted side-effects of tamoxifen, or both. At present, patients are encouraged to report symptoms of vaginal discharge or bleeding. For some this sign may be too late. The medical profession needs to look closely at the risks, benefits, and cost effectiveness of combining progestagens with tamoxifen. If progestagens are beneficial to these patients they may be better delivered to the endometrium locally (eg, the intrauterine levonorgestrel system) to avoid unwanted systemic side-effects. *Fiona Marsh, Martin Mayfield (e-mail: [email protected]) 1
2
3
4
5
Bergman L, Beerlen MLR, Gallee MPW, et al. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000; 356: 881–87. Dixon M, Sainsbury R. Diseases of the Breast, 2nd edn. London: Churchill Livingstone: 147: 1998. Schairer C, Lubin J, Troisi R, et al. Menopausal oestrogen and oestrogenprogesterone replacement therapy and breast cancer risk. JAMA 2000; 238: 485–91. Cline JM, Soderqvist G, Von Shoultz, et al. Effects of conjugated oestrogens, medroxyprogesterone acetate and tamoxifen on the mammary glands of macaques. Breast Cancer Res Treat 1998; 48: 221–29. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel project P-1 study. J Natl Cancer Inst 1998; 90: 1371–88.
Viraemia and faecal shedding of HEV in symptom-free carriers Sir—Rakesh Aggarwal and colleagues (Sept 23, p 1081)1 report that hepatitis E virus (HEV) RNA is not detected in stool or serum samples beyond the phase of clinical course and biochemical hepatitis. They conclude that recovered patients are unlikely to serve as reservoirs in HEV-endemic areas. We provide complementary data that may clarify the potential human reservoir of HEV during epidemics. From August, 1999, to November, 1999, we investigated an outbreak of clinical acute hepatitis among Albanian Kosovar refugees returning home to Mitrovica after the withdrawal of the Serbs from Kosovo. This outbreak was spotted early because of the epidemiological and biological collaborations between the Institute of Public Health of Mitrovica and the French Military Health Service. With informed consent, we tested 103 Albanian Kosovars (age 2–50 years [mean 13·6]) and two French members of non-governmental
THE LANCET • Vol 357 • January 6, 2001
For personal use only. Not to be reproduced without permission of The Lancet.
progestagens might have harmful orally effects on the breast,3 administered progestagens may have a detrimental effect on the breast,3 orally administered progestagens would not be acceptable to women taking tamoxifen to lower their chance of developing breast cancer. Direct administration of progestagen to the endometrium effectively protects it with little or no systemic effect. Although not licensed for this use, the use of a progestagen or levonorgestrelreleasing intrauteruine system might have protective effects against tamoxifen. If so, many women could continue with tamoxifen, rather than being deprived of the substantial benefits it offers against development of primary breast carcinoma.4 *M J Dickson, T Pandiarajan Department of Obstetrics and Gynaecology, Copeland Offices, Birch Hill Hospital, Rochdale, Lancashire OL12 9QB, UK 1
2
3
4
Bergman L, Beelen MLR, Gallee MPW, et al. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000; 356: 881–87. Ismail SM. Pathology of endometrium treated with tamoxifen. J Clin Pathol 1994; 47: 827–33. Schairer C, Lubin J, Troisi R, et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000; 283: 485–91. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998; 90: 1371–88.
Sir—Liesbeth Bergman and colleagues1 use epidemiological data associated with endometrial cancer to rebut advocates for tamoxifen use in healthy women. Clinical neuropsychological testing is necessary before tamoxifen use in healthy women is recommended. Cognitive deficits are seen when formal neuropsychological testing is done on breast-cancer patients treated with chemotherapy plus tamoxifen or chemotherapy alone.2 Tamoxifen acts as a non-competitive block to the ligated serotonin channel in the central nervous system.3 Subtests that assess memory, executive function, visual perception, and motor dexterity should be highlighted. Visual performance with the starry night task test and motion discrimination using low and high velocity dot kinetogram might document the organic explanation for women’s visual blurring complaints while on tamoxifen. Pamela Kairies 3647 Cedarbrae Lane, San Diego, CA 92106, USA 1
68
Bergman L, Beelen MLR, Gallee MPW, et al. Risk and prognosis of endometrial
2
3
cancer after tamoxifen for breast cancer. Lancet 2000; 356: 881–87. Schagen S, van Dam F, Muller M, Boogerd W, Lindeboom J, Bruning P. Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma. Cancer 1999; 85: 640–50. Allen M, Newland C, Valverde M, Hardy S. Inhibition of ligand-gated cation-selective channels by tamoxifen. Eur J Pharmacol 1998; 354: 261–69.
Sir—Liesbeth Bergman and colleagues1 show risk of endometrial cancer increases with increasing duration of tamoxifen use. More importantly, they show that women who develop endometrial cancer have a worse outlook, less favourable histology, higher stage, and later prescription than previously thought. Although tamoxifen has oestrogenantagonistic effects on breast-cancer cells, it has oestrogen-agonistic activity at other sites, including the endometrium and bone.2 Exposure to unopposed oestrogen increases the risk of endometrial hyperplasia and cancer, and a progestagen is generally added to hormone-replacement therapy to protect the endometrium. The oestrogen-agonistic activity of tamoxifen on the uterus mimics exposure of the endometrium to unopposed oestrogen, It would, therefore, seem sensible to investigate the use of progestagens to protect the endometrium in patients using tamoxifen. Whether progestogens exert a beneficial or harmful effect on the initiation or promotion of breast cancer seems unclear. Progestogens have been used in the treatment of metastatic breast cancer and response rates are similar to that of tamoxifen. However an observational study has suggested that combined oestrogen and progesterone hormone-replacement therapy seems to increase patients’ risks of developing breast cancer compared with oestrogen therapy alone.3 A prospective study on apes might shed more light on this dilemma, suggesting that oestrogenic activity is necessary for progestagens to have a harmful effect on the breast.4 Given the prevalence of breast cancer, it is not surprising that thousands of women in the UK are taking tamoxifen. The Breast Cancer Prevention Trial in the USA5 showed that women with an increased genetic risk of developing breast cancer had a 45% reduction in that risk if they took tamoxifen. If the results of that trial are substantiated, thousands more women will undoubtedly be keen to take tamoxifen. Physicians and patients need clear guidelines as to how best monitor and protect the endometrium from the
unwanted side-effects of tamoxifen, or both. At present, patients are encouraged to report symptoms of vaginal discharge or bleeding. For some this sign may be too late. The medical profession needs to look closely at the risks, benefits, and cost effectiveness of combining progestagens with tamoxifen. If progestagens are beneficial to these patients they may be better delivered to the endometrium locally (eg, the intrauterine levonorgestrel system) to avoid unwanted systemic side-effects. *Fiona Marsh, Martin Mayfield (e-mail: [email protected]) 1
2
3
4
5
Bergman L, Beerlen MLR, Gallee MPW, et al. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 2000; 356: 881–87. Dixon M, Sainsbury R. Diseases of the Breast, 2nd edn. London: Churchill Livingstone: 147: 1998. Schairer C, Lubin J, Troisi R, et al. Menopausal oestrogen and oestrogenprogesterone replacement therapy and breast cancer risk. JAMA 2000; 238: 485–91. Cline JM, Soderqvist G, Von Shoultz, et al. Effects of conjugated oestrogens, medroxyprogesterone acetate and tamoxifen on the mammary glands of macaques. Breast Cancer Res Treat 1998; 48: 221–29. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel project P-1 study. J Natl Cancer Inst 1998; 90: 1371–88.
Viraemia and faecal shedding of HEV in symptom-free carriers Sir—Rakesh Aggarwal and colleagues (Sept 23, p 1081)1 report that hepatitis E virus (HEV) RNA is not detected in stool or serum samples beyond the phase of clinical course and biochemical hepatitis. They conclude that recovered patients are unlikely to serve as reservoirs in HEV-endemic areas. We provide complementary data that may clarify the potential human reservoir of HEV during epidemics. From August, 1999, to November, 1999, we investigated an outbreak of clinical acute hepatitis among Albanian Kosovar refugees returning home to Mitrovica after the withdrawal of the Serbs from Kosovo. This outbreak was spotted early because of the epidemiological and biological collaborations between the Institute of Public Health of Mitrovica and the French Military Health Service. With informed consent, we tested 103 Albanian Kosovars (age 2–50 years [mean 13·6]) and two French members of non-governmental
THE LANCET • Vol 357 • January 6, 2001
For personal use only. Not to be reproduced without permission of The Lancet.