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Levonorgestrel-releasing intrauterine devices
CORRESPONDENCE
Levonorgestrel-releasing intrauterine devices Sir—F J E Gardner and colleagues (Nov 18, p 1711)1 suggest that the levonorgestrel-releasing intrauterine device has a protective action against the uterine effects of tamoxifen in postmenopausal breast-cancer patients. They described vaginal bleeding relating to the device that persisted for at least 6 months. Vaginal bleeding in post-menopausal breast-cancer tamoxifen-treated patients is associated with a high rate of endometrial disorders, including endometrial cancer.2–4 Gardner and colleagues mention that such bleeding might be associated with proliferative changes of the endometrium, or even endometrial cancer.1 They did hysteroscopic assessments with endometrial sampling before the insertion of the intrauterine device to rule out any pre-existing endometrial disorder. However, patients may develop new endometrial pathologies within the first 12 months of progestative influence induced by the levonorgestrel-releasing intrauterine device.5 Endometrial disorders are more likely to be diagnosed in gynaecologically symptomatic postmenopausal breast-cancer patients who receive tamoxifen treatment, and after a shorter duration of time, than in symptom-free patients.4 Thus, bleeding in women fitted with the levonorgestrel-releasing intrauterine device raises the concern for up to 12 months that possible endometrial disorders should be investigated. Adverse effects of the device should not automatically be assumed. All the patients in Gardner and colleagues’ study had a uniform decidualisation of the endometrium. However, the small number of patients in the study is not enough to reassure us that disorders including endometrial cancer, may not be present. Ilan Cohen Department of Obstetrics and Gynaecology, Sapil Medical Centre, Kfar Saba 44281, Israel (e-mail: [email protected]) 1
2
3
Gardner FJE, Konje JC, Abrams KR, et al. Endometrial protection from tamoxifenstimulated changes by a levonorgestrelreleasing intrauterine system: a randomized controlled trial. Lancet 2000; 356: 1711–17. Gibson LE, Barakat RR, Venkatraman ES. Endometrial changes at dilatation and curettage in breast cancer patients: comparison of tamoxifen users and nonusers. Cancer J 1996; 2: 35–38. Hann LE, Geiss CS, Bach AM, et al. Endometrial thickness in tamoxifen-treated patients: correlation with clinical and pathologic findings. Am J Radiol 1997; 168: 657–61.
THE LANCET • Vol 357 • March 10, 2001
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Cohen I, Perel E. Flex D, et al. Endometrial pathologies in postmenopausal tamoxifen treatment: comparison between gynecologically symptomatic and asymptomatic breast cancer patients. J Clin Pathol 1999; 52: 278–82. Rose PG, Brandewie EV, Abdul-Karim FW. Failure of megestrol acetate to reverse tamoxifen induced endometrial neoplasia: two case reports. Int J Gynecol Cancer 1999; 9: 362–64.
Sir—After 1 year of treatment in F J E Gardner and colleagues’ trial1 with tamoxifen and levonorgestrel intrauterine device, 41 women had no polyps and six had shrunken fibroids. Of the 52 patients in the control group, polyps developed in four (8%) and fibroids in three (6%), whereas fibroids shrunk in two (4%). Systemic progestin application can prevent endometrial neoplastic changes in tamoxifen-treated patients but may blunt the efficacy of tamoxifen in recurrence prevention. Therefore, local progestin application is a possible alternative. However, the effectiveness of the levonorgestrel intrauterine device must be assessed in the context of cost saving. We saw, in 247 tamoxifen-treated patients with 6-monthly transvaginal ultrasonography for up to 5 years, 14 newly developed polyps, eight hyperplasias, including only three complex atypical hyperplasias, and three endometrial cancers.2 In only these 25 patients could the levonorgestrel intrauterine device be useful for prevention. The price of a device and insertion, in Germany, cost €250 (UK £158) per person. Invasive diagnostics by hysteroscopy and dilation and curettage under general anaesthesia costs €840 (£531) per patient. Outpatient costs are half this amount (€400 [£253]). The treatment costs of tamoxifen-induced endometrial cancer are not included in these calculations, especially since effectiveness of the levonorgestrel intrauterine device in prevention of this disorder is still unclear. R R Barakat and colleagues3 saw in 111 tamoxifen-treated patients who underwent 6-monthly endometrial biopsy for 2 years, four (3·6%) polyps and, one complex, and one simple hyperplasia, which is even lower than our values. For diagnostic procedures, spotting or bloodstained discharge could be the first sign of endometrial cancer,4 but the usefulness of transvaginal ultrasonography will be limited by decidualisation and the device itself. Furthermore, in most patients with a levonorgestrel-releasing intrauterine system, the serum levonorgestrel concentration exceeds 200 pg/mL, and its impact on the effectiveness
of tamoxifen in reduction of recurrences is unsolved. Before fitting of the levonorgestrel intrauterine devices in postmenopausal tamoxifen-treated patients, more patients need to be assessed over a longer period of time. *Bernd Gerber, Toralf Reimer, Annette Krause, Klaus Friese, Heiner Müller Department of Obstetrics and Gynaecology, University of Rostock, 18055 Rostock, Germany (e-mail: [email protected]) 1
2
3
4
5
Gardner FJE, Konje JC, Abrams KR, et al. Endometrial protection from tamoxifenstimulated changes by a levonorgestrelreleasing intrauterine system: a randomised controlled trial. Lancet 2000; 356: 1711–17. Gerber B, Krause A, Müller H, et al. Effects of adjuvant tamoxifen on the endometrium in postmeonpausal women with breast cancer: a prospective long-term study using transvaginal ultrasound. J Clin Oncol 2000; 18: 3464–70. Barakat RR, Gilewski TA, Almadrones L, et al. Effects of adjuvant tamoxifen on the endometrium in women with breast cancer: a prospective study using office endometrial biopsy. J Clin Oncol 2000; 18: 3459–63. Gerber B, Krause A, Müller H, et al. Ultrasonographic detection of asymptomatic endometrial cancer in postmenopausal patients offers no prognostic advantages over symptomatic disease discovered by uterine bleeding. Eur J Cancer 2001; 37: 64–71. Jarvela I, Tekay A, Jouppila P. The effect of a levonorgestrel-releasing intrauterune system on uterine artery blood flow, hormone concentrations and ovarian cyst formation in fertile women. Hum Reprod 1998; 13: 3379–83.
Liposomal amphotericin B Sir—In his Sept 23 news item, A Pirisi,1 erroneously referred to us as having infused 7·5 mg/kg dose of amphotericin in a single injection. This in untrue, since we used liposomal amphotericin B (AmBisome, Nexstar Pharmaceuticals, San Dimas, California, USA), which is a lipid-associated amphotericin B. The daily dose of conventional amphotericin B is 0·5–1·0 mg daily or on alternate days.2 Higher doses are toxic and can result in severe toxic effects, nephrotoxic effects being the most important. Lipidassociated amphotericin B is devoid of such toxic effects, and permits higher daily doses with little or no adverse events. On the issue of failure rate and cost of therapy raised A Bryceson (Dec 2, p 1933),3 he bases his conclusions on a news report of a short presentation. It will be better if we wait for the full publication before making pre-emptive judgments. The relapse rate was 6% and not 10% as he comments. It is up to the manufacturers of the drug to make it available at an affordable price, which is under active consideration of the company. Single-shot therapy has a
801
For personal use only. Reproduce with permission from The Lancet Publishing Group.
Levonorgestrel-releasing intrauterine devices Sir—F J E Gardner and colleagues (Nov 18, p 1711)1 suggest that the levonorgestrel-releasing intrauterine device has a protective action against the uterine effects of tamoxifen in postmenopausal breast-cancer patients. They described vaginal bleeding relating to the device that persisted for at least 6 months. Vaginal bleeding in post-menopausal breast-cancer tamoxifen-treated patients is associated with a high rate of endometrial disorders, including endometrial cancer.2–4 Gardner and colleagues mention that such bleeding might be associated with proliferative changes of the endometrium, or even endometrial cancer.1 They did hysteroscopic assessments with endometrial sampling before the insertion of the intrauterine device to rule out any pre-existing endometrial disorder. However, patients may develop new endometrial pathologies within the first 12 months of progestative influence induced by the levonorgestrel-releasing intrauterine device.5 Endometrial disorders are more likely to be diagnosed in gynaecologically symptomatic postmenopausal breast-cancer patients who receive tamoxifen treatment, and after a shorter duration of time, than in symptom-free patients.4 Thus, bleeding in women fitted with the levonorgestrel-releasing intrauterine device raises the concern for up to 12 months that possible endometrial disorders should be investigated. Adverse effects of the device should not automatically be assumed. All the patients in Gardner and colleagues’ study had a uniform decidualisation of the endometrium. However, the small number of patients in the study is not enough to reassure us that disorders including endometrial cancer, may not be present. Ilan Cohen Department of Obstetrics and Gynaecology, Sapil Medical Centre, Kfar Saba 44281, Israel (e-mail: [email protected]) 1
2
3
Gardner FJE, Konje JC, Abrams KR, et al. Endometrial protection from tamoxifenstimulated changes by a levonorgestrelreleasing intrauterine system: a randomized controlled trial. Lancet 2000; 356: 1711–17. Gibson LE, Barakat RR, Venkatraman ES. Endometrial changes at dilatation and curettage in breast cancer patients: comparison of tamoxifen users and nonusers. Cancer J 1996; 2: 35–38. Hann LE, Geiss CS, Bach AM, et al. Endometrial thickness in tamoxifen-treated patients: correlation with clinical and pathologic findings. Am J Radiol 1997; 168: 657–61.
THE LANCET • Vol 357 • March 10, 2001
4
5
Cohen I, Perel E. Flex D, et al. Endometrial pathologies in postmenopausal tamoxifen treatment: comparison between gynecologically symptomatic and asymptomatic breast cancer patients. J Clin Pathol 1999; 52: 278–82. Rose PG, Brandewie EV, Abdul-Karim FW. Failure of megestrol acetate to reverse tamoxifen induced endometrial neoplasia: two case reports. Int J Gynecol Cancer 1999; 9: 362–64.
Sir—After 1 year of treatment in F J E Gardner and colleagues’ trial1 with tamoxifen and levonorgestrel intrauterine device, 41 women had no polyps and six had shrunken fibroids. Of the 52 patients in the control group, polyps developed in four (8%) and fibroids in three (6%), whereas fibroids shrunk in two (4%). Systemic progestin application can prevent endometrial neoplastic changes in tamoxifen-treated patients but may blunt the efficacy of tamoxifen in recurrence prevention. Therefore, local progestin application is a possible alternative. However, the effectiveness of the levonorgestrel intrauterine device must be assessed in the context of cost saving. We saw, in 247 tamoxifen-treated patients with 6-monthly transvaginal ultrasonography for up to 5 years, 14 newly developed polyps, eight hyperplasias, including only three complex atypical hyperplasias, and three endometrial cancers.2 In only these 25 patients could the levonorgestrel intrauterine device be useful for prevention. The price of a device and insertion, in Germany, cost €250 (UK £158) per person. Invasive diagnostics by hysteroscopy and dilation and curettage under general anaesthesia costs €840 (£531) per patient. Outpatient costs are half this amount (€400 [£253]). The treatment costs of tamoxifen-induced endometrial cancer are not included in these calculations, especially since effectiveness of the levonorgestrel intrauterine device in prevention of this disorder is still unclear. R R Barakat and colleagues3 saw in 111 tamoxifen-treated patients who underwent 6-monthly endometrial biopsy for 2 years, four (3·6%) polyps and, one complex, and one simple hyperplasia, which is even lower than our values. For diagnostic procedures, spotting or bloodstained discharge could be the first sign of endometrial cancer,4 but the usefulness of transvaginal ultrasonography will be limited by decidualisation and the device itself. Furthermore, in most patients with a levonorgestrel-releasing intrauterine system, the serum levonorgestrel concentration exceeds 200 pg/mL, and its impact on the effectiveness
of tamoxifen in reduction of recurrences is unsolved. Before fitting of the levonorgestrel intrauterine devices in postmenopausal tamoxifen-treated patients, more patients need to be assessed over a longer period of time. *Bernd Gerber, Toralf Reimer, Annette Krause, Klaus Friese, Heiner Müller Department of Obstetrics and Gynaecology, University of Rostock, 18055 Rostock, Germany (e-mail: [email protected]) 1
2
3
4
5
Gardner FJE, Konje JC, Abrams KR, et al. Endometrial protection from tamoxifenstimulated changes by a levonorgestrelreleasing intrauterine system: a randomised controlled trial. Lancet 2000; 356: 1711–17. Gerber B, Krause A, Müller H, et al. Effects of adjuvant tamoxifen on the endometrium in postmeonpausal women with breast cancer: a prospective long-term study using transvaginal ultrasound. J Clin Oncol 2000; 18: 3464–70. Barakat RR, Gilewski TA, Almadrones L, et al. Effects of adjuvant tamoxifen on the endometrium in women with breast cancer: a prospective study using office endometrial biopsy. J Clin Oncol 2000; 18: 3459–63. Gerber B, Krause A, Müller H, et al. Ultrasonographic detection of asymptomatic endometrial cancer in postmenopausal patients offers no prognostic advantages over symptomatic disease discovered by uterine bleeding. Eur J Cancer 2001; 37: 64–71. Jarvela I, Tekay A, Jouppila P. The effect of a levonorgestrel-releasing intrauterune system on uterine artery blood flow, hormone concentrations and ovarian cyst formation in fertile women. Hum Reprod 1998; 13: 3379–83.
Liposomal amphotericin B Sir—In his Sept 23 news item, A Pirisi,1 erroneously referred to us as having infused 7·5 mg/kg dose of amphotericin in a single injection. This in untrue, since we used liposomal amphotericin B (AmBisome, Nexstar Pharmaceuticals, San Dimas, California, USA), which is a lipid-associated amphotericin B. The daily dose of conventional amphotericin B is 0·5–1·0 mg daily or on alternate days.2 Higher doses are toxic and can result in severe toxic effects, nephrotoxic effects being the most important. Lipidassociated amphotericin B is devoid of such toxic effects, and permits higher daily doses with little or no adverse events. On the issue of failure rate and cost of therapy raised A Bryceson (Dec 2, p 1933),3 he bases his conclusions on a news report of a short presentation. It will be better if we wait for the full publication before making pre-emptive judgments. The relapse rate was 6% and not 10% as he comments. It is up to the manufacturers of the drug to make it available at an affordable price, which is under active consideration of the company. Single-shot therapy has a
801
For personal use only. Reproduce with permission from The Lancet Publishing Group.