Hormone replacement therapy (HRT) in women after genital cancer

Maturitas 41 Suppl. 1 (2002) S105– S111 www.elsevier.com/locate/maturitas

Hormone replacement therapy (HRT) in women after genital cancer Adolf E. Schindler * Department of Obstetrics and Gynaecology, Uni6ersity of Essen, Hufelandstrasse 55, 45122 Essen, Germany

Abstract Women treated for genital cancer are not only suffering from the disease itself, but are in most cases confronted with the side effects of the loss of ovarian function. Therefore, it is of utmost importance for the gynecologist, who cares for these patients, to strongly consider the benefits and drawbacks of hormone replacement therapy (HRT) in these women. Overall, it appears, that in women with vulva, vaginal, cervical, ovarian and tubal cancer individually adjusted HRT can be employed for the benefit and well-being of these patients considering psychosomatic, functional and organic aspects. Patients after endometrial cancer should be differentiated according to the stage of the disease. In all cases the individual minimal effective dose of HRT should be searched for. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hormone replacement therapy; Genital cancer; Ovarian function

1. Introduction Following treatment of genital tract cancer, women are often confronted with an estrogen deficient state. They can suffer from climacteric symptoms, loss of self-esteem and emotional insecurity. In the long term, these women have an increased risk of developing cardiovascular problems, osteoporosis, arthrosis, skin changes, eye changes, mucosal changes of the oral, vulval and vaginal region. For those reasons it appears necessary to review pro and contra of hormone replacement therapy (HRT) in these women. * Tel.: +49-201-7991833; fax: + 49-201-7499533. E-mail address: [email protected] (A.E. Schindler).

To date, there exists no definite therapeutic concepts on how to use HRT in women after treatment for the following genital cancers: 1. Vulva cancer. 2. Vaginal cancer. 3. Cervical cancer. 4. Endometrial cancer. 5. Ovarian cancer. 6. Tubal cancer. Similar as in women without treatment for genital cancer there are a number of indications and benefits of HRT in women after treatment for genital cancer: 1. Elimination of climacteric symptoms. 2. Preservation of tissue integrity: (a) Cardiovascular system; (b) Bone;

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(c) Genito-urinary system; (d) Brain (i.e. Morbus Alzheimer); (e) Gastrointestinal tract; (f) Joints; (g) Skin; (h) Eyes, etc. Two questions will be raised with each cancer: 1. which effect exerts HRT with estrogens and/or progestins at the target organs of the genital tract to promote/induce or decrease cancer risk? 2. which effect exerts HRT with estrogens and/or progestins in women after treatment for genital cancer?

2. Vulva cancer The incidence of vulva cancer is 2.0 per 100 000 women [1]. Estrogens and/or progestins are not known to cause abnormal mitotic activities. Evidenced-based medicine indicates that with estrogens, cancer precursor lesions such as lichen sclerosis and leukoplakia can be effectively treated. Therefore, following cancer surgery there is no contraindication to use estrogen/progestin regimens to alleviate the drawbacks of estrogen deficiency [1,2].

3. Vaginal cancer The incidence of vaginal cancer is low with 0.5 per 100 000 women [1]. The vaginal epithelium contains estrogen as well as progesterone receptors [1,2] and its reaction to estrogens is well known and therefore widely used in atrophy of the vaginal epithelium. As with the vulva there is no hyperplastic growth of the vaginal epithelium following the use of estrogens or progestins. No

information is available about any connection between HRT and vaginal cancer, which is almost exclusively of squamous cell type [1]. Therefore, women who have suffered from vaginal cancer can safely use HRT to relieve their symptoms with no additional cancer risk [2].

4. Cervical cancer A number of studies have shown that HRT can lead to risk reduction of preinvasive and invasive cervical cancer [3–5]. HRT over an average time of 80 months reduced the relative risk of cervical cancer to 0.8% (95% CI; 0.52–1.15) [3]. In another study it was shown that the risk of preinvasive and invasive cervical cancer by HRT is reduced to a relative risk (RR) of 0.5 (95% CI; 0.5– 1.7) for preinvasive lesions and to a RR of 0.9 (95% CI; 0.1–3.4) for invasive cancer [4]. The relative risk decreases with the length of treatment: HRT used for less than 12 months— RR 0.6 HRT used for more than 12 months— RR 0.5 The start of HRT before the age of 50 years was even more favorable. The protective effect was still present for 10 years after discontinuation of HRT [5]. After women have been treated for cervical cancer with surgery or surgery and radiation and recently in neoadjuvant fashion with chemotherapeutic agents [6], HRT with estrogen alone or estrogen/progestins combinations can be used. Available data are limited. The study by Poch [7] is summarized in Table 1. A negative impact on 5 years survival and recurrence rates was not found [7]. An exception represents the adenocarcinoma of the cervix. In a recent epidemiologic study it could be demonstrated that HRT increases the risk of adenocarcinoma of the cervix

Table 1 Hormone therapy after cervical cancer [7]

5 years survival Recurrence

Treatment group estrogen/progestin (n = 80) (%)

Control group (N =40) (%)

Significance

80 20

65 32

n.s. n.s.

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Table 2 Epidemiologic studies of the relative risk for endometrial cancer in women treated with estrogen or estrogen/progestin replacement therapy Author

Relative risk (RR) Estrogen

Meta-analysis Grady et al. [18]: 30 studies Epidemiologic studies Persson et al. [19]: cohort Voigt et al. [20]: case–control Jick et al. [21]: case–control Brinton and Hoover [22]: case–control

Estrogen/progestin

Overall: 2.3; use\10 years: Overall: 0.8; cohort: 0.4; case–control: 1.8 9.5 use\5 years: 5.0 3.1 6.5 3.0

(RR 2.1; 95% CI, 0.95– 4.6) [8]. The same study confirmed the previous findings [3– 5] that the risk to develop an invasive squamous cell carcinoma decreases (RR 0.85; 95% CI, 0.34– 2.1) [8]. In addition, some investigators brought forward data, in which progestins might stimulate the development of adenocarcinoma of the cervix [9].

5. Endometrial cancer Endometrial cancer is the most common cancer of the female genital tract [10]. In US 36 100 new cases of endometrial cancer were diagnosed in the year 2000 and 6500 died of this disease [11]. In Germany about 9000 new cases of endometrial cancer were expected in the year 2000, which represent 5– 6% of all cancers in women in Germany [12]. Before menopause about 7.5% of the cases are diagnosed. The increase in the risk of endometrial cancer is dose and time dependent. Estrogens in higher doses over a long period of time increase the risk of endometrial cancer four to six times [13]. Estrogen monotreatment triples endometrial cancer risk after a few years. The risk elevation remains over years after discontinuation of estrogen intake [14]. Recently, it was pointed out, that estrogen replacement therapy can, already with relative low doses (i.e. 0.3 mg conjugated estrogens), increase the relative risk to 5.4. This risk is

0.09 ProgestinB10 days/month: 2.0; progestin\10 days/month: 0.9 1.9 1.8

particularly high when the intake is longer than 8 years (RR 9.2) [15]. It has been amply shown that progestins counteract estrogen stimulation in the endometrium [14]. The progestin effect is also dose and time dependent. However, Whitehead and coworkers stated, that it might not be the type of the progestin, but rather the length of progestin treatment [16]. In case of cyclic treatment patient should take progestin at least for 12 days per cycle [16]. In our study it appeared that the type of progestin might indeed play a role. Derivatives of 17-alpha hydroxyprogesterone seem to be better than 19-nortestosterone derivatives [17]. Some of the relevant data on the effect of progestins are summarized in Table 2. One should keep in mind that either atypical endometrial hyperplasia or even well-differentiated carcinoma of the endometrium can effectively be treated with progestin alone [23]. Over the past decade a number of studies have demonstrated that in women after endometrial cancer treatment HRT can be used. Lee et al. [24] reported 44 women with endometrial carcinoma stages I and II treated with HRT for 46 months. No recurrence or death occurred while 199 women with endometrial cancer stages I and II without HRT had eight recurrences and eight deaths. In a non-randomized study, 221 stage I endometrial cancer patients were studied [25]. Forty-seven patients received estrogens, 174 pa-

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tients served as controls. The recurrence rate for the untreated patient was 14.9% and for the treated ones 2.1% (P B0.014). Twenty-six patients who were not treated died compared to only one among those who received estrogens (P = 0.014). Patients, who had received estrogen appeared to be protected from the recurrences compared with those who did not receive estrogens. (P = 0.033) [25]. Most recently, a large retrospective study has been presented [26]. Among a cohort of 249 patients treated between 1984 and 1998, 130 women were elected to receive estrogen replacement after primary endometrial cancer therapy. Of these, 75 were chosen for the study. In addition, 75 non-estrogen using patients were identified in the cohort and served as controls. The two groups were matched for age at diagnosis, parity, stage, grade, postoperative radiation therapy and concurrent disease. Although the mean survival was similar in both the groups, the study revealed a statistically significant difference in the disease-free interval (82 months for ERT users vs. 63 months for the non-users; P= 0.02) and disease-free survival (P=0.03) between those patients taking ERT (1.4%) and those who did not take estrogens (14.3%). The mean length of time of follow-up was 83 months for the ERT group and 69 months for the non-estrogen users. Since these data are controversial and are not in accordance with the conventional clinical approach up to now, a trial has been launched in the USA to resolve these discrepancies, but data will only be available in 2 to 3 years [27]. Lauritzen [28] used estrogen/progestin preparations in patients after endometrial cancer FIGO stage I and II and demonstrated, that survival and time of recurrence were not negatively influenced

(Tables 3 and 4). Chapman et al. [29] reported a retrospective analysis of 123 patients with endometrial cancer stage I and II (62 with HRT; 61 without HRT) demonstrating no difference regarding recurrence or death rate. Patients younger than 70 years with HRT had a longer recurrence free interval. Using progestins alone as adjuvant, treatment after endometrial cancer, randomized over a period of 5 years a significant (PB 0.001) increase in survival time was obtained [30]. Therefore, patients with more progressive endometrial cancer should be primarily treated with higher doses of progestins (100– 500 mg MPA daily) [31]. If climacteric symptoms persist a small dose of estrogens might be added. There are no data that such combined treatment will have an adverse effect [2].

6. Ovarian cancer For ovarian cancer a risk reduction was found for estrogen/progestin treatment including oral contraceptives. The risk reduction can be up to 60% [28]. Hempling et al. [32] could not demonstrate a significant association between the use of HRT and risk of developing epithelial ovarian cancer even with prolonged exposure. This is in accordance with the hypothesis of ovarian cancer epidemiology (ovulation- and gonadotropin hypothesis) [33,34]. However, there are data which indicate that ERT leads to a significant risk increase in endometroid and clear cell ovarian cancer [35]. A meta-analysis from 1966 through 1997 found for HRT a relative risk increase of 15%. Use of HRT for more than 10 years resulted in a relative risk increase of 27% [36]. In another study

Table 3 Effects of estrogen/progestin treatment in patients with endometrial cancer stage I [28] Hormone treatment

n

10 years survival (%)

Years of survival

Years until recurrence

Controls Estrogens/progestin after operation Estrogen/progestin before and after operation Significance

83 37 41 –

83 88 95 P= 0.05

6.3 7.8 9.7 P = 0.04

3.4 3.8 4.1 PB0.08

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Table 4 Effects of estrogen/progestin treatment in patients with endometrial cancer stage II [28] Hormone treatment

n

10 years survival (%)

Years of survival

Years until recurrence

Controls Estrogens/progestin after operation Estrogen/progestin before and after operation Significance

71 42 21 –

70 76 81 PB0.04

6.4 7.6 8.8 PB0.07

2.4 3.9 4.8 P=0.05

[37] ever use of estrogens replacement therapy resulted in a relative risk for fatal ovarian cancer of 1.15. The mortality rate increased, with the duration of use prior to entry to the study, to 1.4 with 6–10 years of use and 1.71 with ] 11 years of use. Most recently, a follow-up and extended study has been presented [38] including 944 ovarian cancer deaths in 14 years of follow-up. Women who were using ERT at baseline had higher death rates from ovarian cancer than never users (RR 1.51); 95% CI, 1.16– 1.96. The risk was slightly but not significantly increased among former estrogen users (RR, 1.16; 95% CI, 0.99– 1.37). The duration of use was associated with increased risk in both baseline and former users. Baseline users with ten or more years of use had an RR of 2.20 (95% CI, 1.53– 3.17), while former users with ten or more years of use had an RR of 1.59 (95% CI, 1.13–2.25). Annual age-adjusted ovarian cancer death rates per 100 000 women were 64.4 for baseline users with ten or more years of use, 38.3 for former users with ten or more years of use, 26.4 for never users. Among former users with ten or more years of use, risk decreased with time since last use reported at study entry (RR for last use B 15 years ago, 2.05; 95% CI, 1.29– 3.25; RR for last use ] 15 years ago, 1.31; 95% CI, 0.79– 2.17). In this population, postmenopausal estrogen use for ten or more years was associated with increased risk of ovarian cancer mortality that persisted up to 29 years after cessation of use. On the other hand, HRT in women after ovarian cancer was found to lead to a risk reduction (RR 0.9). The morbidity of the hormone treated group was 29% lower than that of the comparative group [39]. Also, favorable effects have been reported by others [40]. The relative risk for dying in those who received HRT was

0.73 (95% CI; 0.44–1.22). In a recent study [41], occurrence of relapse according to stage, differentiation of the tumor and debulking surgery was not significantly influenced by estrogen replacement therapy. It should be taken into account that progestins inhibit cell proliferation of ovarian cancer and lead to apoptosis. In addition, progestins induce the p53 expression. This indicates that p53 plays a role in the progestin-induced apoptosis [42]. For patients with endometroid or clear cell tumor the addition of progestins should be considered [2].

7. Tubal cancer It is should be noted that there appears to be no contraindication for HRT in patients with tubal cancer [2,43].

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