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Hysteroscopic follow-up during Tamoxifen treatment
European Journal of Obstetrics & Gynecology and Reproductive Elsevier
EUROBS
Biology, 35 (1990) 235-238
235
00917
Hysteroscopic follow-up during Tamoxifen treatment Patrick Neven, Xavier De Muylder, Yves Van Belle, Guido Vanderick and Edgard De Muylder Department
Obstetrics and Gynaecology, Clinique G~n~rale Saint-Jean, Bruxelles, Belgium Accepted
for publication
2 August
1989
Summary In order to study the action of Tamoxifen upon the uterus, 16 breast cancer patients were prospectively evaluated by means of an hysteroscopy before Tamoxifen therapy and again after 6 to 36 months of treatment. The results show the occurrence of an endometrial polyp in four cases and of an adenocarcinoma in one case. Moreover, the previously atrophic mucosa became mildly proliferative in seven of the patients who were evaluated. Hysteroscopy;
Tamoxifen
Introduction Presently, Tamoxifen can be regarded as one of the most efficient adjuvant therapies for breast cancer. A recent overview of 61 randomized trials among 28 896 women has established beyond reasonable doubt that Tamoxifen can reduce the five-year mortality [l]. Later, indications for Tamoxifen have been extended to the treatment of cyclical mastalgia and to the prevention of breast neoplasia [2]. However, recent clinical and experimental studies have suggested possible side effects upon lipoprotein synthesis [3], sex hormone binding globulin synthesis [4], and the possible development of hepatocellular carcinoma [2]. Moreover, unfavorable action has also been shown at the level of the uterine cavity [S-6], and Hardell [7] suggested a causal relation between Tamoxifen and the risk of endometrial cancer. In a previous report [8], we described an abnormally high number of uterine lesions (endometrial or endocervical polyp, hyperplasia, adenocarcinoma) among postmenopausal patients treated with Tamoxifen for breast cancer. This prompted Correspondence: Xavier De Muylder, Department Obstetrics Jean, 114, rue du Marais, B 1000 Bruxelles, Belgium.
002%2243/90/$03.50
0 1990 Elsevier Science Publishers
& Gynaecology,
B.V. (Biomedical
Clinique
Division)
G&n&ale
Saint-
52 67 51 63 56 65 47 60 40 56
55 36
56
52 60
78
1 2 3 4 5 6 I 8 9 10
11 12
13
14 15
16
(6 years)
(2 years)
menopausal
(29 years)
lynestrenol(1 year) menopausal (6 years)
menopausal
menopausal triphasic
years)
(3 years) (12 years) (7 years) (13 years) (6 years) (12 years) years) (10 years)
ductal
comedocarcinoma ductal ductal
ductal ductal
lobular ductal ductal ductal ductal ductal ductal papillary ductal ductal
Breast histology
and hysteroscopic
status
menopausal menopausal lynestrenol menopausal menopausal menopausal lynestrenol(5 menopausal triphasic lynestrenol(l0
Menstrual
Clinical
Age
I
data at diagnosis
TABLE
1
1 1
1
3 2
1 1 1 1 1 1 1 1 1 2
4/13
2/17
l/4 2/Il
O/4
O/5 o/11
O/9 10/14
4/6 O/6 9/11 o/15
o/11
lymph nodes
treatment
116.6
11.4 112.9
17.8
34.4 11.4
19.6 1037.0 128.5 1223.5 156.2 16.4 18.0 214.1 5.5 8.6
Estrogen receptors (fmol/l)
Tamoxifen
Positive
under
Grade
finding
5 mg 5 mg
lynestrenol
5 mg
mg
2.5 mg
1 mg
lynestrenol
_
lynestrenol
lynestrenol5
lynestrenol
lynestrenol
Concomitant hormonal therapy
radiother. + chemoth. radiother. + chemoth.
radiother. radiother. + chemoth. radiother. radiother. + chemoth. radiother.
radiother.
chemother. radiother. radiother.
Adjuvant therapy
36
endometrial
mild proliferat. mild proliferat.
10
adenocarcinoma
no lesion endom. polyp
no lesion
mild proliferat. 10
6
no lesion endom. polyp
no lesion no lesion no lesion no lesion no lesion no lesion endom. polyp no lesion endom. polyp no lesion
hysteroscopy
atrophic atrophic atrophic atrophic atrophic mild proliferat. mild proliferat. atrophic atrophic atrophic
Control
mild proliferat. mild proliferat. 16 7
23 30 22 27 23 6 30 I 7 14
Length of Tamoxifen use (months)
231
us to start a prospective study of Tamoxifen we present the first results.
action
upon uterine
mucosa,
and here
Patients and methods This study includes 16 consecutive patients operated on for breast cancer (modified radical mastectomy or partial mastectomy with axillary nodes dissection), whose clinical data are presented in Table I. Because of positive estrogen receptors, they were treated with 20 mg Tamoxifen daily. According to the clinical staging and evolution, some received adjuvant radiotherapy or chemotherapy but no patient underwent radiotherapeutic castration. The uterine cavity of all these patients was investigated by means of an hysteroscopy before starting Tamoxifen treatment, and a control was suggested after 6 to 36 months treatment. Hysteroscopy was always performed as an outpatient procedure, and carbon dioxide gas was used for distending the uterine cavity. Results At the time the diagnosis of breast cancer was made, the mean age of the patients was 55.8 + 10.2 years and the mean parity was 1.6 k 1.1. There were ten postmenopausal patients and four patients with induced amenorrhoea on continuous lynestrenol therapy. The two other women were premenopausal and were taking combined oral contraceptive tablets (triphasic). All these patients underwent an hysteroscopy before starting Tamoxifen treatment, and all the uterine cavities appeared normal (atrophic endometrium). After surgical therapy, ten patients were given postoperative local radiotherapy and five were treated with chemotherapy. Moreover, six women were prescribed lynestrenol mainly for contraceptive purposes or for chronic pelvic pain. The control hysteroscopy was performed after a mean of 16.7 f 9.8 months of Tamoxifen use. Four patients did present with an endometrial polyp, and one woman had a poorly differentiated adenocarcinoma infiltrating two thirds of the myometrium. Moreover, although the endometrial mucosa remained atrophic in eight patients, it turned out to be mildly proliferative in the other seven. Discussion This preliminary study shows that, among breast cancer patients treated with Tamoxifen, the uterine cavity undergoes some endometrial changes in 9 out of 16 patients (56%): proliferation of the mucosa, endometrial polyp or adenocarcinoma. This finding could be of serious clinical importance and suggests that regular gynaecological examinations are useful in cases of Tamoxifen therapy. Although classically described as an estrogen antagonist, Tamoxifen can activate certain estrogenic effects, and there is no doubt that in some circumstances this drug can act as an estrogen agonist. The estrogen-like effect of Tamoxifen on the vaginal epithelium as reported by Ferrazzi [9] may probably be extended to the uterine mucosa, since we observed seven cases of atrophic endometrium becoming prolifera-
238
tive during this treatment, sometimes even during concomitant progesterone therapy. This agonistic effect would be an explanation for the contrasting actions of Tamoxifen on breast and endometrial tumours described in the athymic mouse [lo]. The occurrence of endometrial cancer in a patient treated with Tamoxifen for breast cancer has already been reported by several authors [5-7,111. However, in all these cases, it is possible Tamoxifen action has been stimulation of an undiagnosed pre-existing endometrial lesion; however, to the best of our knowledge, here is the first report of the development of an adenocarcinoma in a patient whose uterine cavity had been shown to be normal before Tamoxifen treatment. The only other important drug administered over the same period was systemic chemotherapy; however, it is unlikely that six cycles of cyclophosphamide, methotrexate and fluorouracil could have induced this carcinoma. Although no definite conclusion can be drawn from our results, it seems safer to offer all patients under Tamoxifen treatment regular assessment of their uterine cavity. According to our experience, hysteroscopy with CO, is one of the easiest means to perform this control. References 1 Early Breast Cancer Trialists’ Collaborative Group. Effects of adjuvant Tamoxifen and of cytoxic therapy on mortality in early breast cancer: an overview of 61 randomized trials among 28896 women. N Engl J Med 1988; 319:1681-1692. 2 Fentiman I, Powles T. Tamoxifen and benign breast problems. Lancet 1987; ii:1070-1071. 3 Rossner S, Wallgren A. Serum lipoproteins and proteins after breast cancer surgery and effects of Tamoxifen. Atherosclerosis 1984;52:339-346. 4 Sakai F, Cheix F, Clavel N. Increases in steroid binding globulins induced by Tamoxifen in patients with carcinoma of the breast. J Endocrinol 1978;76:219-226. 5 Killackey M, Hakes T, Pierce V. Endometrial adenocarcinoma in breast cancer patients receiving antiestrogens. Cancer Treat Rep 1985;69:237-238. 6 Pons J, Saha V, De Baecque C, De Brux J. Effets agonistes-antagonistes estrogeniques partiels du Tamoxifene sur le tractus genital des femmes traittes pour un cancer du sein. Gynecologie 1986;37:324-330. 7 Hardell L. Tamoxifen as risk factor for carcinoma of corpus uteri. Lancet 1988;ii:563. 8 Neven P, De Muylder X, Van Belle Y, Vanderick G, De Muylder E. Tamoxifen and the uterus and endometrium. Lancet 1989;i:375. 9 Ferrazzi E, Cartei G, Mattarazzo R, Fiorentino M. Estrogen-like effect of Tamoxifen on vaginal epithelium. Br Med J 1977;i:1351-1352. 10 Gottardis M, Robinson S, Satyaswaroop P, Jordan V. Contrasting actions of Tamoxifen on endometrial breast tumor growth in the athymic mouse. Cancer Res 1988;48:812-815. 11 Fomander T, Rutquist L, Cedermark B et al: Adjuvant Tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989;i:117-119.
EUROBS
Biology, 35 (1990) 235-238
235
00917
Hysteroscopic follow-up during Tamoxifen treatment Patrick Neven, Xavier De Muylder, Yves Van Belle, Guido Vanderick and Edgard De Muylder Department
Obstetrics and Gynaecology, Clinique G~n~rale Saint-Jean, Bruxelles, Belgium Accepted
for publication
2 August
1989
Summary In order to study the action of Tamoxifen upon the uterus, 16 breast cancer patients were prospectively evaluated by means of an hysteroscopy before Tamoxifen therapy and again after 6 to 36 months of treatment. The results show the occurrence of an endometrial polyp in four cases and of an adenocarcinoma in one case. Moreover, the previously atrophic mucosa became mildly proliferative in seven of the patients who were evaluated. Hysteroscopy;
Tamoxifen
Introduction Presently, Tamoxifen can be regarded as one of the most efficient adjuvant therapies for breast cancer. A recent overview of 61 randomized trials among 28 896 women has established beyond reasonable doubt that Tamoxifen can reduce the five-year mortality [l]. Later, indications for Tamoxifen have been extended to the treatment of cyclical mastalgia and to the prevention of breast neoplasia [2]. However, recent clinical and experimental studies have suggested possible side effects upon lipoprotein synthesis [3], sex hormone binding globulin synthesis [4], and the possible development of hepatocellular carcinoma [2]. Moreover, unfavorable action has also been shown at the level of the uterine cavity [S-6], and Hardell [7] suggested a causal relation between Tamoxifen and the risk of endometrial cancer. In a previous report [8], we described an abnormally high number of uterine lesions (endometrial or endocervical polyp, hyperplasia, adenocarcinoma) among postmenopausal patients treated with Tamoxifen for breast cancer. This prompted Correspondence: Xavier De Muylder, Department Obstetrics Jean, 114, rue du Marais, B 1000 Bruxelles, Belgium.
002%2243/90/$03.50
0 1990 Elsevier Science Publishers
& Gynaecology,
B.V. (Biomedical
Clinique
Division)
G&n&ale
Saint-
52 67 51 63 56 65 47 60 40 56
55 36
56
52 60
78
1 2 3 4 5 6 I 8 9 10
11 12
13
14 15
16
(6 years)
(2 years)
menopausal
(29 years)
lynestrenol(1 year) menopausal (6 years)
menopausal
menopausal triphasic
years)
(3 years) (12 years) (7 years) (13 years) (6 years) (12 years) years) (10 years)
ductal
comedocarcinoma ductal ductal
ductal ductal
lobular ductal ductal ductal ductal ductal ductal papillary ductal ductal
Breast histology
and hysteroscopic
status
menopausal menopausal lynestrenol menopausal menopausal menopausal lynestrenol(5 menopausal triphasic lynestrenol(l0
Menstrual
Clinical
Age
I
data at diagnosis
TABLE
1
1 1
1
3 2
1 1 1 1 1 1 1 1 1 2
4/13
2/17
l/4 2/Il
O/4
O/5 o/11
O/9 10/14
4/6 O/6 9/11 o/15
o/11
lymph nodes
treatment
116.6
11.4 112.9
17.8
34.4 11.4
19.6 1037.0 128.5 1223.5 156.2 16.4 18.0 214.1 5.5 8.6
Estrogen receptors (fmol/l)
Tamoxifen
Positive
under
Grade
finding
5 mg 5 mg
lynestrenol
5 mg
mg
2.5 mg
1 mg
lynestrenol
_
lynestrenol
lynestrenol5
lynestrenol
lynestrenol
Concomitant hormonal therapy
radiother. + chemoth. radiother. + chemoth.
radiother. radiother. + chemoth. radiother. radiother. + chemoth. radiother.
radiother.
chemother. radiother. radiother.
Adjuvant therapy
36
endometrial
mild proliferat. mild proliferat.
10
adenocarcinoma
no lesion endom. polyp
no lesion
mild proliferat. 10
6
no lesion endom. polyp
no lesion no lesion no lesion no lesion no lesion no lesion endom. polyp no lesion endom. polyp no lesion
hysteroscopy
atrophic atrophic atrophic atrophic atrophic mild proliferat. mild proliferat. atrophic atrophic atrophic
Control
mild proliferat. mild proliferat. 16 7
23 30 22 27 23 6 30 I 7 14
Length of Tamoxifen use (months)
231
us to start a prospective study of Tamoxifen we present the first results.
action
upon uterine
mucosa,
and here
Patients and methods This study includes 16 consecutive patients operated on for breast cancer (modified radical mastectomy or partial mastectomy with axillary nodes dissection), whose clinical data are presented in Table I. Because of positive estrogen receptors, they were treated with 20 mg Tamoxifen daily. According to the clinical staging and evolution, some received adjuvant radiotherapy or chemotherapy but no patient underwent radiotherapeutic castration. The uterine cavity of all these patients was investigated by means of an hysteroscopy before starting Tamoxifen treatment, and a control was suggested after 6 to 36 months treatment. Hysteroscopy was always performed as an outpatient procedure, and carbon dioxide gas was used for distending the uterine cavity. Results At the time the diagnosis of breast cancer was made, the mean age of the patients was 55.8 + 10.2 years and the mean parity was 1.6 k 1.1. There were ten postmenopausal patients and four patients with induced amenorrhoea on continuous lynestrenol therapy. The two other women were premenopausal and were taking combined oral contraceptive tablets (triphasic). All these patients underwent an hysteroscopy before starting Tamoxifen treatment, and all the uterine cavities appeared normal (atrophic endometrium). After surgical therapy, ten patients were given postoperative local radiotherapy and five were treated with chemotherapy. Moreover, six women were prescribed lynestrenol mainly for contraceptive purposes or for chronic pelvic pain. The control hysteroscopy was performed after a mean of 16.7 f 9.8 months of Tamoxifen use. Four patients did present with an endometrial polyp, and one woman had a poorly differentiated adenocarcinoma infiltrating two thirds of the myometrium. Moreover, although the endometrial mucosa remained atrophic in eight patients, it turned out to be mildly proliferative in the other seven. Discussion This preliminary study shows that, among breast cancer patients treated with Tamoxifen, the uterine cavity undergoes some endometrial changes in 9 out of 16 patients (56%): proliferation of the mucosa, endometrial polyp or adenocarcinoma. This finding could be of serious clinical importance and suggests that regular gynaecological examinations are useful in cases of Tamoxifen therapy. Although classically described as an estrogen antagonist, Tamoxifen can activate certain estrogenic effects, and there is no doubt that in some circumstances this drug can act as an estrogen agonist. The estrogen-like effect of Tamoxifen on the vaginal epithelium as reported by Ferrazzi [9] may probably be extended to the uterine mucosa, since we observed seven cases of atrophic endometrium becoming prolifera-
238
tive during this treatment, sometimes even during concomitant progesterone therapy. This agonistic effect would be an explanation for the contrasting actions of Tamoxifen on breast and endometrial tumours described in the athymic mouse [lo]. The occurrence of endometrial cancer in a patient treated with Tamoxifen for breast cancer has already been reported by several authors [5-7,111. However, in all these cases, it is possible Tamoxifen action has been stimulation of an undiagnosed pre-existing endometrial lesion; however, to the best of our knowledge, here is the first report of the development of an adenocarcinoma in a patient whose uterine cavity had been shown to be normal before Tamoxifen treatment. The only other important drug administered over the same period was systemic chemotherapy; however, it is unlikely that six cycles of cyclophosphamide, methotrexate and fluorouracil could have induced this carcinoma. Although no definite conclusion can be drawn from our results, it seems safer to offer all patients under Tamoxifen treatment regular assessment of their uterine cavity. According to our experience, hysteroscopy with CO, is one of the easiest means to perform this control. References 1 Early Breast Cancer Trialists’ Collaborative Group. Effects of adjuvant Tamoxifen and of cytoxic therapy on mortality in early breast cancer: an overview of 61 randomized trials among 28896 women. N Engl J Med 1988; 319:1681-1692. 2 Fentiman I, Powles T. Tamoxifen and benign breast problems. Lancet 1987; ii:1070-1071. 3 Rossner S, Wallgren A. Serum lipoproteins and proteins after breast cancer surgery and effects of Tamoxifen. Atherosclerosis 1984;52:339-346. 4 Sakai F, Cheix F, Clavel N. Increases in steroid binding globulins induced by Tamoxifen in patients with carcinoma of the breast. J Endocrinol 1978;76:219-226. 5 Killackey M, Hakes T, Pierce V. Endometrial adenocarcinoma in breast cancer patients receiving antiestrogens. Cancer Treat Rep 1985;69:237-238. 6 Pons J, Saha V, De Baecque C, De Brux J. Effets agonistes-antagonistes estrogeniques partiels du Tamoxifene sur le tractus genital des femmes traittes pour un cancer du sein. Gynecologie 1986;37:324-330. 7 Hardell L. Tamoxifen as risk factor for carcinoma of corpus uteri. Lancet 1988;ii:563. 8 Neven P, De Muylder X, Van Belle Y, Vanderick G, De Muylder E. Tamoxifen and the uterus and endometrium. Lancet 1989;i:375. 9 Ferrazzi E, Cartei G, Mattarazzo R, Fiorentino M. Estrogen-like effect of Tamoxifen on vaginal epithelium. Br Med J 1977;i:1351-1352. 10 Gottardis M, Robinson S, Satyaswaroop P, Jordan V. Contrasting actions of Tamoxifen on endometrial breast tumor growth in the athymic mouse. Cancer Res 1988;48:812-815. 11 Fomander T, Rutquist L, Cedermark B et al: Adjuvant Tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989;i:117-119.