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Urogenital disorders in women with adjuvant endocrine therapy after early breast cancer
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GENERAL GYNECOLOGY
Urogenital disorders in women with adjuvant endocrine therapy after early breast cancer Juliane Baumgart, MD; Kerstin Nilsson, MD, PhD; Anneli Stavreus-Evers, PhD; Kristiina Kask, MD, PhD; Kenneth Villman, MD, PhD; Henrik Lindman, MD, PhD; Theodora Kallak, MSc; Inger Sundström-Poromaa, MD, PhD OBJECTIVE: To investigate the prevalence of urogenital symptoms and
vaginal atrophy in postmenopausal breast cancer patients on adjuvant endocrine therapy. STUDY DESIGN: A population-based, cross-sectional study on post-
menopausal breast cancer patients on adjuvant endocrine treatment and age-matched control subjects. Vaginal atrophy was assessed by gynecologic examination and atrophy-related symptoms by validated questionnaires. RESULTS: In all, 57.6% of aromatase inhibitor-treated and 32.4% of
tamoxifen-treated breast cancer patients rated at least 1 vaginal atro-
phy symptom as moderate/severe, which was significantly more common than in control subjects (P ⬍ .01). Aromatase inhibitor-treated patients more often had moderate or severe vaginal atrophy (P ⬍ .05), a more atrophic cytohormonal evaluation, and significantly higher vaginal pH (P ⬍ .05) than all control subjects, irrespective of hormonal use. CONCLUSION: Our findings indicate that the frequency of vaginal atro-
phy symptoms, particularly in aromatase inhibitor-treated women, might have been underestimated in previous clinical trials. Key words: aromatase inhibitors, breast cancer, tamoxifen, urogenital symptoms, vaginal atrophy
Cite this article as: Baumgart J, Nilsson K, Stavreus-Evers A, et al. Urogenital disorders in women with adjuvant endocrine therapy after early breast cancer. Am J Obstet Gynecol 2011;204:26.e1-7.
I
n developed countries approximately 75% of all breast cancers occur in postmenopausal women, and 80% of these cancers are hormone receptor positive.1 Adjuvant endocrine treatments are all primarily directed to induce estrogen deprivation, either at the estrogen receptor level (tamoxifen), or by inhibitFrom the Departments of Obstetrics and Gynecology (Drs Baumgart and Nilsson) and Oncology (Dr Villman), Örebro University Hospital; the School of Health and Medical Sciences, Örebro University (Dr Nilsson), Örebro; the Departments of Women’s and Children’s Health (Drs Stavreus-Evers, Kask, and SundströmPoromaa and Ms Kallak) and Oncology (Dr Lindman), Uppsala University, Uppsala, Sweden. Received March 27, 2010; revised June 7, 2010; accepted Aug. 17, 2010. Reprints not available from the authors. Funding was provided by the Örebro County Council Research Fund, the Uppsala–Örebro Regional Research Council, and the Swedish Cancer Society, Grant no. CAN 2009/773. This study was conducted in the counties of Uppsala and Örebro, Sweden. 0002-9378/$36.00 © 2011 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2010.08.035
26.e1
ing estrogen biosynthesis (aromatase inhibitors). In women with hormone receptor-positive tumors, administration of tamoxifen for 5 years has been shown to reduce breast cancer recurrence by 41% and mortality by 34% compared with placebo.2 Third-generation aromatase inhibitors (AIs), such as anastrozole, letrozole, and exemestane, have been shown to further improve diseasefree survival, although a significant reduction in overall survival for AIs compared with tamoxifen has not yet been proven.3 The use of both tamoxifen and AIs has, however, been associated with gynecologic side effects and worsening of menopausal symptoms. Tamoxifen has been shown to increase the risk for endometrial cancer compared with placebo.3-6 In comparison to tamoxifen, treatment with AIs is associated with lower endometrial thickness, fewer cases of vaginal bleeding, possibly fewer cases of endometrial pathologies,7 and fewer systemic menopausal symptoms such as hot flushes and night sweats.4,5,8,9 Urogenital symptoms are strongly associated with low endogenous estrogen levels and are common in postmenopausal women.10 Vaginal dryness, irrita-
American Journal of Obstetrics & Gynecology JANUARY 2011
tion, discharge, and dyspareunia are frequently reported adverse symptoms in clinical trials with adjuvant endocrine therapy, but urogenital symptoms have otherwise not been extensively studied in patients with breast cancer.11-17 Because no comparative studies have been conducted, it is unknown whether urogenital symptoms in fact are more common in breast cancer patients than in healthy women. With more women receiving adjuvant endocrine therapy after primary therapy for breast cancer, and more women surviving breast cancer, any increase in the frequency of urogenital symptoms represents a clinical challenge, especially because there is now a lack of effective treatment options. Use of systemic hormone replacement therapy in women with a history of breast cancer is generally advised against because of the increased risk of breast cancer recurrence.18,19 Until recently, vaginally administered low-dose estrogen for the treatment of urogenital symptoms has been considered safe, because the systemic absorption of such preparations has been found to be low and within the normal postmenopausal range.20 However, a recent small study of the systemic absorption of vaginally ad-
www.AJOG.org ministered estradiol in patients with adjuvant AI treatment after early breast cancer found a significant increase in systemic levels of estradiol.21 Because the goal of AI treatment is to eliminate the circulating levels of estrogen, professional organizations have concluded that also topical vaginal estrogen treatment should be avoided in women on AI treatment.22 As for nonhormonal interventions, although commonly recommended, the efficacy and tolerability remain to be established. The aim of the current study was to investigate the prevalence and degree of urogenital symptoms and vaginal atrophy in postmenopausal breast cancer patients on adjuvant endocrine therapy with tamoxifen or AIs compared with age-matched women with or without estrogen therapy.
M ATERIALS AND M ETHODS Patients Eligible patients were identified in the Swedish Cancer Registry in the Uppsala/ Örebro Region, Sweden, a populationbased register that covers more than 96% of breast cancer cases. Inclusion criteria were being postmenopausal, residing in the county of Uppsala or Örebro, and being 55 to 70 years old, with estrogen receptor-positive breast cancer diagnosed between 2003 and 2006. Patients still undergoing primary therapy (radiation or chemotherapy) and patients with recurrent cancer were excluded. Patients with other severe diseases that potentially could interfere with sexual functioning or be bothersome for the gynecologic evaluation were excluded. Hence, women with neurologic or rheumatoid disorders associated with impaired mobility (paraplegia, prior stroke with hemiplegia, multiple sclerosis, and severe rheumatoid or musculoskeletal disorders), women hospitalized for depression or psychosis, and women with severe cancer (other than breast cancer) were excluded. Information derived from the Cancer Registry, including TNM classification, was checked with the medical reports of each invited patient. Patients were invited by letter. Age-matched control subjects were selected from the Swedish Population Regis-
General Gynecology try and invited by letter. For each breast cancer patient, 3 control subjects residing in the same county and born during the same year and month as the index patients were randomly selected and invited in turn until 1 agreed to take part. Postmenopausal status, defined as 12 months of amenorrhea after the last bleeding event, was ensured before inclusion, and controls with previous breast cancer or other severe diseases (similar as for breast cancer patients) were excluded. All participants gave written informed consent, and the Independent Ethical Review Board at Uppsala University, Sweden, approved the study.
Materials and methods All participants attended a health examination at the Department of Women’s and Children’s Health, Uppsala University Hospital, or the Department of Obstetrics and Gynecology, Örebro University Hospital, from November 2008 to March 2009. One experienced gynecologist at each department performed all examinations, which included medical history (with the exception of questions concerning breast cancer or breast cancer treatment), a gynecologic examination, and a transvaginal ultrasound evaluation. Each examiner saw a similar proportion of patients and controls. As many women revealed their breast cancer diagnosis to the examiner, blinding of patient/control status was imperfect. Otherwise, all laboratory analyses were made by staff that was blinded to patient/ control status. Breast cancer history, including previous and current adjuvant endocrine therapy, was taken from the medical records in addition to information obtained directly from the patients (questionnaire). Medical history, including demographic variables and information on reproductive health, previous and ongoing diseases, drug therapy, and previous and current hormonal treatment, was requested. Weight and height were measured in a standardized manner, and body mass index was calculated. The degree of vaginal atrophy was judged by assessing the epithelium according to thickness, color, fluor, and presence of petechial bleeding. A 4-grade
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scale was used for classification purposes (0 ⫽ none, 1 ⫽ mild, 2 ⫽ moderate, 3 ⫽ severe). Vaginal pH was measured using a paper indicator (Machery-Nagel, Düren, Germany) that was placed in the lateral wall of the vagina. Vaginal cytologic smears were obtained from the junction of the upper and middle part of the lateral vaginal wall using a brush (Cytobrush; Medscand, Berlin, Germany). Smears were fixed in 95% alcohol and stained according to Papanicolaou. The Maturation Index, ie, the percentage proportion of parabasal, intermediate, and superficial vaginal epithelial cells was calculated on 300 cells by 1 cytotechnologist at the Department of Clinical Pathology, Örebro University Hospital. Vaginal ultrasound examination was done with a 7-MHz transvaginal probe. The measurements were obtained in real time according to a standardized protocol, with examination of the endometrium performed under the highest possible magnification. Subjective endocrine symptoms were assessed by the Endocrine SubscaleFACT-B, a validated 5-point response scale (not at all/a little bit/somewhat/ quite a bit/very much) developed for breast cancer research.23 Only items reflecting systemic and local estrogen deficiency symptoms were included. Vaginal atrophy symptoms consisted of vaginal itching or irritation, vaginal dryness, and pain or discomfort with intercourse. Urinary incontinence was evaluated with the Incontinence Impact Questionnaire short form (IIQ-7) and the Urogenital Distress Inventory short form (UDI-6), a validated questionnaire using a 4-point response scale (not at all/ slightly/moderately/greatly).24
Statistical methods All values are displayed as mean ⫾ standard deviation (SD). For comparison between breast cancer patients and control subjects independent t tests or MannWhitney U tests were performed, depending on whether the variable was normally distributed. Frequencies were compared between groups by 2 test. For clinical presentation and subjective reports of vaginal atrophy symptoms, 4 distinct groups of women were used: (1)
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TABLE 1
TABLE 2
Demographic and clinical characteristics of the study population
Tumor characteristics of the breast cancer group
Characteristic
Breast cancer patients (n ⴝ 97)
Control subjects (n ⴝ 105)
P value
Characteristic
Age, y
62.7 ⫾ 4.1
62.7 ⫾ 4.2
ns
Tumor size
1.9 ⫾ 1.2
2.1 ⫾ 1.0
ns
..............................................................................................................................................................................................................................................
Parity, children
..............................................................................................................................................................................................................................................
Married or cohabiting, n (%)
72 (74.2)
72 (68.6)
ns
..............................................................................................................................................................................................................................................
n (%)
..................................................................................................
T1 ⱕ2 cm
68 (70.1)
T2 ⬎2–5 cm
26 (27.8)
.................................................................................................. ..................................................................................................
T3 ⬎5 cm
2 (2.1)
T4 Chest wall/skin
1 (1.0)
High school or more, n (%)
31 (32.0)
35 (33.3)
ns
Body mass index, kg/m
27.0 ⫾ 5.3
26.3 ⫾ 4.2
ns
..............................................................................................................................................................................................................................................
...........................................................................................................
Smoker, n (%)
11 (11.3)
7 (6.7)
Nodal status
1 (1.0)
13 (12.4)
.............................................................................................................................................................................................................................................. 2
ns
..............................................................................................................................................................................................................................................
Current systemic estrogen use, n (%)
⬍ .01
..............................................................................................................................................................................................................................................
Current local estrogen use, n (%)
18 (18.6)
36 (34.3)
⬍ .05
..............................................................................................................................................................................................................................................
ns, not significant.
..................................................................................................
..................................................................................................
Node negative
64 (66.0)
Node positive
32 (33.0)
.................................................................................................. ..................................................................................................
Unknown
Baumgart. Urogenital disorders after therapy for breast cancer. Am J Obstet Gynecol 2011.
1 (1.0)
...........................................................................................................
Hormone receptor status
..................................................................................................
control subjects without local or systemic estrogen treatment, (2) control subjects with local or systemic estrogen treatment, (3) tamoxifen-treated breast cancer patients without local or systemic estrogen treatment, and (4) AI-treated breast cancer patients without local or systemic estrogen treatment. Because of the small numbers, breast cancer patients with ongoing local/ systemic estrogen use and breast cancer patients without adjuvant endocrine therapy were excluded from these analyses. Mean values were compared by 1-way analysis of variance (ANOVA) or KruskalWallis test, depending on normal distribution. In cases when the ANOVA or Kruskal-Wallis test was significant, post hoc tests (Tukey HSD) were made for normally distributed variables and MannWhitney U test for skewed data. Subjective symptoms assessed by the ES-FACT-B questionnaire were categorized as light (not at all/a little bit) and moderate/severe (somewhat/quite a bit/ very much), respectively. Symptoms of the IIQ-7 and UDI-6 questionnaire were also categorized as light (not at all/ slightly) and moderate/severe (moderately/greatly), respectively. The SPSS statistical package version 15.0 was used for all analyses (SPSS, Inc, Chicago, IL). A P value less than .05 was considered significant.
R ESULTS Study population In all, 233 breast cancer patients fulfilled the inclusion/exclusion criteria for the 26.e3
study and were invited. Among these, 97 agreed to participate. There were no systematic differences in terms of age, TNM classification, and use of adjuvant endocrine treatment between breast cancer patients who participated and those who declined participation (data not shown). In all, 493 control subjects were invited to the study. Of these, 107 accepted the invitation and 2 were excluded because of previous breast cancer. Hence, the final study sample consisted of 97 breast cancer patients and 105 controls. One control subject did not fill out the questionnaires and has been included in analyses of clinical outcomes only. Demographic data and clinical characteristics of the study population are displayed in Table 1. There were no clinically relevant differences between the 2 groups, except the use of local or systemic estrogen, which was significantly more common among control subjects. One breast cancer patient who had discontinued adjuvant endocrine therapy was currently on systemic estrogen treatment, and 18 (18.6%) breast cancer patients had local estrogen therapy. Tumor characteristics of breast cancer patients are shown in Table 2. Among patients treated with AIs, 24 were on anastrozole, 10 on exemestane, and 1 on letrozole. Between the review of the medical records and the clinical examination, 8 (8.2%) breast cancer patients had discontinued endocrine therapy and 7 (7.2%) had not had any endocrine therapy at all, based on low tumor grade.
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Estrogen receptor positive
97 (100)
Progesterone receptor positive
80 (82.5)
..................................................................................................
...........................................................................................................
HER-2 positive
10 (10.3)
...........................................................................................................
Elston score
6.2 ⫾ 1.6
...........................................................................................................
Histologic type
..................................................................................................
Infiltrating ductal
79 (81.4)
Infiltrating lobular
18 (18.6)
.................................................................................................. ...........................................................................................................
Intended adjuvant endocrine treatment
..................................................................................................
No adjuvant endocrine treatment
7 (7.2)
..................................................................................................
Tamoxifen
43 (44.3)
Switch-treatment
28 (28.9)
Aromatase inhibitors
19 (19.6)
.................................................................................................. .................................................................................................. ...........................................................................................................
Current adjuvant endocrine treatment
..................................................................................................
No adjuvant endocrine treatment
7 (7.2)
..................................................................................................
Tamoxifen
47 (48.5)
Aromatase inhibitors
35 (36.1)
Discontinued endocrine treatment
8 (8.2)
.................................................................................................. ..................................................................................................
...........................................................................................................
Baumgart. Urogenital disorders after therapy for breast cancer. Am J Obstet Gynecol 2011.
Vaginal atrophy Analyses on vaginal atrophy included control subjects without local or systemic estrogen treatment (n ⫽ 55), control subjects with local or systemic estrogen treatment (n ⫽ 49), tamoxifentreated breast cancer patients without local or systemic estrogen treatment (n ⫽
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TABLE 3
Prevalence of moderate or severe endocrine symptoms Control subjects with current estrogen treatment (n ⴝ 49)
Aromatase inhibitor users (n ⴝ 33)
Symptom, n (%)
Control subjects without current estrogen treatment (n ⴝ 55)a
Vaginal bleeding/spotting
0
Vaginal discharge
0
2 (4.1)
6 (17.6)
1 (3.0)
Any vaginal atrophy symptom
1 (1.8)
11 (22.4)
11 (32.4)
19 (57.6)
Vaginal itching/irritation
1 (1.8)
5 (10.2)
3 (8.8)
5 (15.2)
Vaginal dryness
1 (1.8)
5 (10.2)
7 (20.6)
14 (42.4)
Pain or discomfort with intercourse
1 (2.7)
8 (24.2)
8 (34.8)
16 (61.5)
Hot flashes
7 (13.0)
5 (10.2)
17 (50.0)
17 (51.5)
Cold sweats
7 (12.7)
5 (10.6)
11 (33.3)
13 (39.4)
Night sweats
6 (10.9)
9 (18.4)
15 (44.1)
13 (39.4)
Tamoxifen users (n ⴝ 34)
0
2 (5.9)
0
................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ c c c-e ................................................................................................................................................................................................................................................................................................................................................................................ c ................................................................................................................................................................................................................................................................................................................................................................................ c b-d ................................................................................................................................................................................................................................................................................................................................................................................ f c c b-d ................................................................................................................................................................................................................................................................................................................................................................................ f c,d c,d ................................................................................................................................................................................................................................................................................................................................................................................ f c,d c,d ................................................................................................................................................................................................................................................................................................................................................................................ c,d c,d ................................................................................................................................................................................................................................................................................................................................................................................ a
One control subject did not fill out the questionnaires; b Trend toward significant difference in comparison to tamoxifen users, P ⫽ .051–.062; c Significantly different from control subjects without current estrogen treatment, P ⬍ .05–.001; d Significantly different from control subjects with current estrogen treatment, P ⬍ .05–.001; e Significantly different from tamoxifen users, P ⬍ .05; f Percentages reported according to number who responded to the specific question.
Baumgart. Urogenital disorders after therapy for breast cancer. Am J Obstet Gynecol 2011.
34), and AI-treated breast cancer patients without local or systemic estrogen treatment (n ⫽ 33). The proportion of participants with moderate/severe vaginal atrophy symptoms is shown in Table 3. In all, 57.6% of AI-treated breast cancer patients and 32.4% of those on tamoxifen reported at least 1 vaginal atrophy symptom, which differed significantly from both control groups. Vaginal dryness and pain or dis-
comfort with intercourse was more common in AI users than in both control groups and these symptoms also tended to be more common in AI users than in tamoxifen users (Table 3). The only vaginal atrophy symptom that tended to be more common among tamoxifen-treated patients than among AI users was moderateto-severe vaginal discharge (Table 3). On clinical examination, AI users displayed moderate and severe atrophy
more often than both control groups, and severe atrophy was also significantly more common than in patients on tamoxifen (Table 4). AI-treated patients had significantly higher pH values than both control groups and tamoxifen users. According to the Maturation Index, AI users displayed significantly more parabasal cells and fewer superficial cells than controls with estrogen treatment and tamoxifen users, and there was a
TABLE 4
Evaluation of vaginal atrophy
Variable
Control subjects without current estrogen treatment (n ⴝ 56)
Control subjects with current estrogen treatment (n ⴝ 49)
Tamoxifen users (n ⴝ 34)
Aromatase inhibitor users (n ⴝ 33)
Clinical evaluation, n (%)
....................................................................................................................................................................................................................................................................................................................................................................... a b-d
No/light atrophy
40 (72.7)
45 (91.8)
23 (67.6)
10 (30.3)
Moderate atrophy
9 (16.4)
4 (8.2)
9 (26.5)
12 (36.4)
Severe atrophy
6 (10.9)
0
2 (5.95)
11 (33.3)
....................................................................................................................................................................................................................................................................................................................................................................... a,d ....................................................................................................................................................................................................................................................................................................................................................................... a,c,d ................................................................................................................................................................................................................................................................................................................................................................................ b b a,c,d
5.2 ⫾ 0.7
pH
4.5 ⫾ 0.7
4.8 ⫾ 0.7
5.5 ⫾ 0.7
................................................................................................................................................................................................................................................................................................................................................................................
Maturation index
(n ⫽ 28)
(n ⫽ 38)
(n ⫽ 26)
(n ⫽ 11)
....................................................................................................................................................................................................................................................................................................................................................................... b b d,e
4.6 ⫾ 12.9
0.5 ⫾ 0.2
85.9 ⫾ 12.2
82.6 ⫾ 13.1
84.5 ⫾ 11.6
86.8 ⫾ 17.4
Superficial cells, %
9.2 ⫾ 7.7
17.2 ⫾ 13.2
15.5 ⫾ 11.6
6.9 ⫾ 12.9
Endometrial thickness, mm
2.8 ⫾ 2.4
3.2 ⫾ 2.6
7.9 ⫾ 9.8
3.0 ⫾ 1.6
Parabasal cells, %
0
6.3 ⫾ 14.1
.......................................................................................................................................................................................................................................................................................................................................................................
Intermediate cells, %
....................................................................................................................................................................................................................................................................................................................................................................... b a c,d ................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ a
Significantly different from control subjects without current estrogen treatment, P ⬍ .05; Significantly different from control subjects without current estrogen treatment, P ⬍ .01–⬍ .001; Significantly different from tamoxifen users, P ⬍ .01; d Significantly different from control subjects with current estrogen treatment, P ⬍ .01 to ⬍ .001; e Significantly different from tamoxifen users, P ⬍ .05. b
c
Baumgart. Urogenital disorders after therapy for breast cancer. Am J Obstet Gynecol 2011.
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TABLE 5
Frequency of reported moderate or severe incontinence symptoms
Symptom, n (%)
Control subjects without current estrogen treatment (n ⴝ 55)a
Control subjects with current estrogen treatment (n ⴝ 49)
Tamoxifen users (n ⴝ 34)
Aromatase inhibitor users (n ⴝ 33)
Frequent urinationb
30 (54.5)
28 (57.1)
23 (67.6)
21 (63.2)
................................................................................................................................................................................................................................................................................................................................................................................
Urgency incontinence
27 (50.0)
24 (49.0)
19 (55.9)
21 (63.6)
Stress incontinence
29 (53.7)
28 (59.6)
24 (72.7)
23 (69.7)
Small amounts of leakage
20 (37.0)
19 (38.8)
16 (47.1)
15 (45.5)
Difficulties in emptying the bladder
6 (11.1)
12 (24.5)
6 (17.6)
5 (15.6)
Abdominal pain or discomfort
5 (9.3)
9 (18.4)
6 (17.6)
8 (24.2)
................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
No significant differences in reported incontinence symptoms were found between groups. a
One control subject did not fill out the questionnaires; b Percentages reported according to number who responded to the specific question.
Baumgart. Urogenital disorders after therapy for breast cancer. Am J Obstet Gynecol 2011.
trend toward a significant difference in Maturation Index in comparison to controls without estrogen treatment as well. Notably, Maturation Index assessment was only possible in one-third of AI users (Table 4). Tamoxifen-treated patients did not differ in the vaginal atrophy evaluation but had significantly lower pH values and a more mature appearance in the cytologic assessments in comparison to control subjects devoid of estrogen treatment (Table 4). Tamoxifen-treated subjects also displayed an increased endometrial thickness compared with all other groups. One tamoxifen-treated patient was diagnosed with endometrial cancer during the study.
Vasomotor symptoms Both patients on tamoxifen and those on AIs reported moderate or severe vasomotor symptoms, such as hot flashes, cold sweats, and night sweats, more often than both control groups, but there was no difference in vasomotor symptoms between women treated with tamoxifen and AIs (Table 3). Urinary incontinence symptoms There was no difference in frequency or intensity of incontinence symptoms between any of the groups (Table 5).
C OMMENT Vaginal atrophy symptoms and signs of vaginal atrophy were found to be common in breast cancer patients on adjuvant endocrine therapy in this popula26.e5
tion-based, cross-sectional study. In particular, those breast cancer patients who were on AI treatment were found to be most affected. These women reported vaginal dryness and dyspareunia far more often than both control groups, and there was also a tendency that these symptoms were more common than in tamoxifen users. Furthermore, AItreated patients had higher vaginal pH than all other examined groups, and their Maturation Index indicated a higher grade of atrophy than tamoxifen users and control subjects on estrogen. To our knowledge, this is the first study to evaluate urogenital symptoms and vaginal atrophy in breast cancer patients on adjuvant endocrine treatment in comparison to control subjects. The prevalence of any vaginal atrophy symptom in breast cancer patients was about 58%, which was substantially higher than 2-26% in previous studies.12,13,25 Furthermore, dyspareunia has been reported to occur in 15-25% of AI-treated women,8,13,14,23 whereas the corresponding number in our study was 65%. There are several possible explanations why our prevalence rates of vaginal atrophy symptoms are higher than in previous clinical trials. First, women may be more inclined to disclose these symptoms to a gynecologist than to the oncologist. Second, the results of an RCT may not always translate into clinical practice. Finally, as the invitation for our study was directed at urogenital symptoms, it is possible that we have a selec-
American Journal of Obstetrics & Gynecology JANUARY 2011
tion of women with such symptoms compared with previous clinical trials. However, our results are in concordance with the results from Chin et al,26 who conducted an uncontrolled study on urogenital symptoms in breast cancer patients in clinical routine practice and by a later substudy of the TEAM trial, where vaginal dryness was reported in 50% of women treated with exemestane.11 Clearly, our findings indicate that the frequency of vaginal atrophy symptoms, particularly in women treated with AIs, might previously have been underestimated. On clinical examination, women treated with tamoxifen displayed fewer signs of vaginal atrophy and resembled the estrogen users in many aspects, including measurements of pH and Maturation Index. Tamoxifen-treated women also had a tendency toward increased reporting of vaginal discharge, at least in comparison with women on AIs. These findings are in line with previous studies of tamoxifen in breast cancer patients, suggesting estrogen agonism on the vaginal mucosa and endometrium in postmenopausal women.13-16,27-31 Surprisingly, control subjects with current estrogen treatment reported significantly more vaginal atrophy symptoms than controls without current estrogen treatment. This result may seem counterintuitive but is presumably due to the cross-sectional design of the study. In these age groups, women with atrophy symptoms are more likely to use es-
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www.AJOG.org trogen treatment, whereas women with no vaginal problems presumably are less inclined to see a gynecologist and receive treatment. Prior studies have indicated that the use of AIs is less often associated with vasomotor symptoms than the use of tamoxifen,3,32 a finding that was not confirmed by our results. Because of the cross-sectional design of our study, we have not been able to control for the degree of vasomotor symptoms before the start of adjuvant endocrine therapy, and, furthermore, it can be assumed that women had switched from tamoxifen to AIs because of troublesome vasomotor symptoms. Urinary incontinence symptoms did not differ between AI- or tamoxifentreated breast cancer patients and control subjects in our study. The influence of adjuvant endocrine therapy on urinary incontinence has not been extensively studied before, and there is little and inconclusive information from the literature. In a short-term follow-up study of treatment with raloxifen, another selective estrogen receptor modulator, no influence was found on urinary incontinence symptoms.33 In a comparative study, urinary problems were seen in 15% of women on AIs and 9% of those on tamoxifen,14 which was considerably lower than in our study. However, the prevalence of urinary incontinence in healthy postmenopausal women has been found to differ considerably between studies, which should be kept in mind when considering the current findings. Clearly, further controlled studies on urinary incontinence symptoms in different adjuvant endocrine treatment settings are warranted. Strengths of our study include its population-based design and close relation to clinical practice. Admittedly, the study has some limitations. One is selection bias, as discussed previously. It could be argued that women with symptoms were more prone to take part in the study, thus potentially skewing the results. However, the prevalence of symptoms in subjects using AIs would still be substantial. The difference in prevalence of symptoms between cases and controls would also remain valid, because any
bias arising from the willingness to participate because of the presence of symptoms would most likely affect both groups alike. Another limitation was the limited sample size, and consequently the lack of power for some of the analyses. The low power presumably affected the urinary incontinence findings and some of the comparisons between AI users and tamoxifen users. However, the study size was calculated based on previous findings on the prevalence of dyspareunia. Because the prevalence rate of dyspareunia was higher in our study, power was more than adequate for this item. Furthermore, the imperfect blinding of the examining gynecologist regarding the vaginal atrophy grading was also a limitation. However, the high proportion of AI users with moderate and severe vaginal atrophy is consistent with the objective assessment of the biochemical effects on the vaginal mucosa. Finally, the cytohormonal analysis was based on a small sample, as the presence (and number) of degenerated and inflammatory cells made it impossible to calculate the Maturation Index in a substantial proportion of samples. This particularly affected subjects on AI treatment, but because inflammatory cells and degeneration are part of the overall picture of atrophy, the low number of adequate samples actually strengthens our finding of a high prevalence of atrophy in these patients. Because the majority of women who had breast cancer diagnosed expect to be cured or to live for a long period with their disease, the impact of any given treatment on symptoms that may affect quality of life is extremely important. Adjuvant endocrine therapy, especially AIs, was found to increase urogenital symptoms and vaginal atrophy compared with control subjects. The underlying pathophysiology and the impact of these symptoms on quality of life need to be studied more intensively to optimize breast cancer therapy. f REFERENCES 1. Anderson WF, Chatterjee N, Ershler WB, Brawley OW. Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology,
Research
and End Results database. Breast Cancer Res Treat 2002;76:27-36. 2. Early Breast Cancer Trialists’ Collaboraive group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;365: 1687-717. 3. Lin N, Winer EP. Advances in adjuvant endocrine therapy for postmenopausal women. J Clin Oncol 2008;36:798-805. 4. Howell A, Cuzick J, Baum M, et al; ATAC Trialists’ Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005;365:60-2. 5. Mouridsen H, Giobbie-Hurder A, Goldhirsch A, et al. Letrozole therapy alone or in sequence tamoxifen in women with breast cancer. N Engl J Med 2009;361:766-76. 6. Braithwaite RS, Chlebowski RT, Lau J, George S, Hess R, Col NF. Meta-analysis of vascular and neoplastic events associated with tamoxifen. J Gen Intern Med 2003;18:937-47. 7. Cohen I. Aromatase inhibitors and the endometrium. Maturitas 2008;59:285-92. 8. Fallowfield L, Cella D, Cuzick J, Francis S, Locker G, Howell A. Quality of life of postmenopausal women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Adjuvant Breast Cancer Trial. J Clin Oncol 2004;22: 4261-71. 9. Koeberle D, Thuerlimann B. Letrozole as upfront endocrine therapy for postmenopausal women with hormone-sensitive breast cancer: BIG 1-98. Breast Cancer Res Treat 2007; 105(Suppl 1):55-66. 10. Suckling J, Lethaby A, Kennedy R. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Syst Rev 2006:CD001500. 11. Jones SE, Cantrell J, Vukelja S, et al. Comparison of menopausal symptoms during the first year of adjuvant therapy with either exemestane or tamoxifen in early breast cancer: report of a Tamoxifen Exemestane Adjuvant Multicenter trial substudy. J Clin Oncol 2007; 25:4765-71. 12. Whelan TJ, Goss PE, Ingle JN, et al. Assessment of quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 2005;23:6931-40. 13. Cella D, Fallowfield L, Barker P, Cuzick J, Locker G, Howell A. Quality of life of postmenopausal women in the ATAC (”Arimidex”, tamoxifen, alone or in combination) trial after completion of 5 years’ adjuvant treatment for early breast cancer. Breast Cancer Res Treat 2006; 100:273-84. 14. Morales L, Neven P, Timmerman D, et al. Acute effects of tamoxifen and third-generation aromatase inhibitors on menopausal symptoms of breast cancer patients. Anticancer Drugs 2004;15:753-60. 15. Mortimer JE, Boucher L, Baty J, Knapp DL, Ryan E, Rowland JH. Effect of tamoxifen on
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General Gynecology
sexual functioning in patients with breast cancer. J Clin Oncol 1999;17:1488-92. 16. Mourits MJ, Bockermann I, de Vries EG, et al. Tamoxifen effects on subjective and psychosexual well-being, in a randomised breast cancer study comparing high-dose and standarddose chemotherapy. Br J Cancer 2002;86: 1546-50. 17. Day R. Quality of life and tamoxifen in a breast cancer prevention trial: a summary of findings from the NSABP P-1 study. National Surgical Adjuvant Breast and Bowel Project. Ann N Y Acad Sci 2001;949:143-50. 18. Holmberg L, Anderson H. HABITS (hormonal replacement therapy after breast cancer—is it safe?), a randomised comparison: trial stopped. Lancet 2004;363:453-5. 19. Holmberg L, Iversen OE, Rudenstam CM, et al. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst 2008;100:475-82. 20. Weisberg E, Ayton R, Darling G, et al. Endometrial and vaginal effects of low-dose estradiol delivered by vaginal ring or vaginal tablet. Climacteric 2005;8:83-92. 21. Kendall A, Dowsett M, Folkerd E, Smith I. Caution: vaginal estradiol appears to be contraindicated in postmenopausal women on adju-
26.e7
vant aromatase inhibitors. Ann Oncol 2006; 17:584-7. 22. Swedish Breast Cancer Group. Available at: www.swebcg.se. Accessed June 2, 2010. 23. Fallowfield L, Leaity S, Howell A, Benson S, Cella D. Assessment of quality of life in women undergoing hormonal therapy for breast cancer: validation of an endocrine symptom subscale for the FACT-B. Breast Cancer Res Treat 1999;55:189-99. 24. Harvey M, Kristjansson B, Griffith D, Versi E. The Incontinence Impact Questionnaire and the Urogenital Distress Inventory: a revisit of their validity in women without a urodynamic diagnosis. Am J Obstet Gynecol 2001;185,25-31. 25. Fallowfield LJ, Bliss JM, Porter LS. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol 2006;24:910-7. 26. Chin S, Trinkaus M, Simmons C, et al. Prevalence and severity of urogenital symptoms in postmenopausal women receiving endocrine therapy for breast cancer. Clin Breast Cancer 2009;9:108-17. 27. Dibi RP, Zettler CG, Pessini SA, Ayub AV, de Almeida SB, da Silveira GP. Tamoxifen use and endometrial lesions: hysteroscopic, histo-
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www.AJOG.org logical, and immunohistochemical findings in postmenopausal women with breast cancer. Menopause 2009;16:293-300. 28. Ferrazzi E, Cartei G, Mattarazzo R, Fiorentino M. Oestrogen-like effect of tamoxifen on vaginal epithelium. Br Med J 1977;1:1351-2. 29. Boccardo F, Bruzzi A, Rubagotti A, Nicolò GU, Rosso R. Estrogen-like action of tamoxifen on vaginal epithelium in breast cancer patients. Oncology 1981;38:281-5. 30. Love RR, Kurtycz DF, Dumesic DA, Laube DW, Yang Y. The effects of tamoxifen on the vaginal epithelium in postmenopausal women. J Womens Health Gend Based Med 2000; 9:559-63. 31. Friedrich M, Mink D, Villena-Heinsen C, Woll-Hermann A, Wagner S, Schmidt W. The influence of tamoxifen on the maturation index of vaginal epithelium. Clin Exp Obstet Gynecol 1998;25:121-4. 32. Perez EA. Safety of aromatase inhibitors in the adjuvant setting. Breast Cancer Res Treat 2007;105(Suppl 1):75-89. 33. Waetjen LE, Brown JS, Modelska K, Blackwell T, Vittinghoff E, Cummings SR. Effect of raloxifene on urinary incontinence: a randomized controlled trial. Obstet Gynecol 2004; 103:261-6.
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GENERAL GYNECOLOGY
Urogenital disorders in women with adjuvant endocrine therapy after early breast cancer Juliane Baumgart, MD; Kerstin Nilsson, MD, PhD; Anneli Stavreus-Evers, PhD; Kristiina Kask, MD, PhD; Kenneth Villman, MD, PhD; Henrik Lindman, MD, PhD; Theodora Kallak, MSc; Inger Sundström-Poromaa, MD, PhD OBJECTIVE: To investigate the prevalence of urogenital symptoms and
vaginal atrophy in postmenopausal breast cancer patients on adjuvant endocrine therapy. STUDY DESIGN: A population-based, cross-sectional study on post-
menopausal breast cancer patients on adjuvant endocrine treatment and age-matched control subjects. Vaginal atrophy was assessed by gynecologic examination and atrophy-related symptoms by validated questionnaires. RESULTS: In all, 57.6% of aromatase inhibitor-treated and 32.4% of
tamoxifen-treated breast cancer patients rated at least 1 vaginal atro-
phy symptom as moderate/severe, which was significantly more common than in control subjects (P ⬍ .01). Aromatase inhibitor-treated patients more often had moderate or severe vaginal atrophy (P ⬍ .05), a more atrophic cytohormonal evaluation, and significantly higher vaginal pH (P ⬍ .05) than all control subjects, irrespective of hormonal use. CONCLUSION: Our findings indicate that the frequency of vaginal atro-
phy symptoms, particularly in aromatase inhibitor-treated women, might have been underestimated in previous clinical trials. Key words: aromatase inhibitors, breast cancer, tamoxifen, urogenital symptoms, vaginal atrophy
Cite this article as: Baumgart J, Nilsson K, Stavreus-Evers A, et al. Urogenital disorders in women with adjuvant endocrine therapy after early breast cancer. Am J Obstet Gynecol 2011;204:26.e1-7.
I
n developed countries approximately 75% of all breast cancers occur in postmenopausal women, and 80% of these cancers are hormone receptor positive.1 Adjuvant endocrine treatments are all primarily directed to induce estrogen deprivation, either at the estrogen receptor level (tamoxifen), or by inhibitFrom the Departments of Obstetrics and Gynecology (Drs Baumgart and Nilsson) and Oncology (Dr Villman), Örebro University Hospital; the School of Health and Medical Sciences, Örebro University (Dr Nilsson), Örebro; the Departments of Women’s and Children’s Health (Drs Stavreus-Evers, Kask, and SundströmPoromaa and Ms Kallak) and Oncology (Dr Lindman), Uppsala University, Uppsala, Sweden. Received March 27, 2010; revised June 7, 2010; accepted Aug. 17, 2010. Reprints not available from the authors. Funding was provided by the Örebro County Council Research Fund, the Uppsala–Örebro Regional Research Council, and the Swedish Cancer Society, Grant no. CAN 2009/773. This study was conducted in the counties of Uppsala and Örebro, Sweden. 0002-9378/$36.00 © 2011 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2010.08.035
26.e1
ing estrogen biosynthesis (aromatase inhibitors). In women with hormone receptor-positive tumors, administration of tamoxifen for 5 years has been shown to reduce breast cancer recurrence by 41% and mortality by 34% compared with placebo.2 Third-generation aromatase inhibitors (AIs), such as anastrozole, letrozole, and exemestane, have been shown to further improve diseasefree survival, although a significant reduction in overall survival for AIs compared with tamoxifen has not yet been proven.3 The use of both tamoxifen and AIs has, however, been associated with gynecologic side effects and worsening of menopausal symptoms. Tamoxifen has been shown to increase the risk for endometrial cancer compared with placebo.3-6 In comparison to tamoxifen, treatment with AIs is associated with lower endometrial thickness, fewer cases of vaginal bleeding, possibly fewer cases of endometrial pathologies,7 and fewer systemic menopausal symptoms such as hot flushes and night sweats.4,5,8,9 Urogenital symptoms are strongly associated with low endogenous estrogen levels and are common in postmenopausal women.10 Vaginal dryness, irrita-
American Journal of Obstetrics & Gynecology JANUARY 2011
tion, discharge, and dyspareunia are frequently reported adverse symptoms in clinical trials with adjuvant endocrine therapy, but urogenital symptoms have otherwise not been extensively studied in patients with breast cancer.11-17 Because no comparative studies have been conducted, it is unknown whether urogenital symptoms in fact are more common in breast cancer patients than in healthy women. With more women receiving adjuvant endocrine therapy after primary therapy for breast cancer, and more women surviving breast cancer, any increase in the frequency of urogenital symptoms represents a clinical challenge, especially because there is now a lack of effective treatment options. Use of systemic hormone replacement therapy in women with a history of breast cancer is generally advised against because of the increased risk of breast cancer recurrence.18,19 Until recently, vaginally administered low-dose estrogen for the treatment of urogenital symptoms has been considered safe, because the systemic absorption of such preparations has been found to be low and within the normal postmenopausal range.20 However, a recent small study of the systemic absorption of vaginally ad-
www.AJOG.org ministered estradiol in patients with adjuvant AI treatment after early breast cancer found a significant increase in systemic levels of estradiol.21 Because the goal of AI treatment is to eliminate the circulating levels of estrogen, professional organizations have concluded that also topical vaginal estrogen treatment should be avoided in women on AI treatment.22 As for nonhormonal interventions, although commonly recommended, the efficacy and tolerability remain to be established. The aim of the current study was to investigate the prevalence and degree of urogenital symptoms and vaginal atrophy in postmenopausal breast cancer patients on adjuvant endocrine therapy with tamoxifen or AIs compared with age-matched women with or without estrogen therapy.
M ATERIALS AND M ETHODS Patients Eligible patients were identified in the Swedish Cancer Registry in the Uppsala/ Örebro Region, Sweden, a populationbased register that covers more than 96% of breast cancer cases. Inclusion criteria were being postmenopausal, residing in the county of Uppsala or Örebro, and being 55 to 70 years old, with estrogen receptor-positive breast cancer diagnosed between 2003 and 2006. Patients still undergoing primary therapy (radiation or chemotherapy) and patients with recurrent cancer were excluded. Patients with other severe diseases that potentially could interfere with sexual functioning or be bothersome for the gynecologic evaluation were excluded. Hence, women with neurologic or rheumatoid disorders associated with impaired mobility (paraplegia, prior stroke with hemiplegia, multiple sclerosis, and severe rheumatoid or musculoskeletal disorders), women hospitalized for depression or psychosis, and women with severe cancer (other than breast cancer) were excluded. Information derived from the Cancer Registry, including TNM classification, was checked with the medical reports of each invited patient. Patients were invited by letter. Age-matched control subjects were selected from the Swedish Population Regis-
General Gynecology try and invited by letter. For each breast cancer patient, 3 control subjects residing in the same county and born during the same year and month as the index patients were randomly selected and invited in turn until 1 agreed to take part. Postmenopausal status, defined as 12 months of amenorrhea after the last bleeding event, was ensured before inclusion, and controls with previous breast cancer or other severe diseases (similar as for breast cancer patients) were excluded. All participants gave written informed consent, and the Independent Ethical Review Board at Uppsala University, Sweden, approved the study.
Materials and methods All participants attended a health examination at the Department of Women’s and Children’s Health, Uppsala University Hospital, or the Department of Obstetrics and Gynecology, Örebro University Hospital, from November 2008 to March 2009. One experienced gynecologist at each department performed all examinations, which included medical history (with the exception of questions concerning breast cancer or breast cancer treatment), a gynecologic examination, and a transvaginal ultrasound evaluation. Each examiner saw a similar proportion of patients and controls. As many women revealed their breast cancer diagnosis to the examiner, blinding of patient/control status was imperfect. Otherwise, all laboratory analyses were made by staff that was blinded to patient/ control status. Breast cancer history, including previous and current adjuvant endocrine therapy, was taken from the medical records in addition to information obtained directly from the patients (questionnaire). Medical history, including demographic variables and information on reproductive health, previous and ongoing diseases, drug therapy, and previous and current hormonal treatment, was requested. Weight and height were measured in a standardized manner, and body mass index was calculated. The degree of vaginal atrophy was judged by assessing the epithelium according to thickness, color, fluor, and presence of petechial bleeding. A 4-grade
Research
scale was used for classification purposes (0 ⫽ none, 1 ⫽ mild, 2 ⫽ moderate, 3 ⫽ severe). Vaginal pH was measured using a paper indicator (Machery-Nagel, Düren, Germany) that was placed in the lateral wall of the vagina. Vaginal cytologic smears were obtained from the junction of the upper and middle part of the lateral vaginal wall using a brush (Cytobrush; Medscand, Berlin, Germany). Smears were fixed in 95% alcohol and stained according to Papanicolaou. The Maturation Index, ie, the percentage proportion of parabasal, intermediate, and superficial vaginal epithelial cells was calculated on 300 cells by 1 cytotechnologist at the Department of Clinical Pathology, Örebro University Hospital. Vaginal ultrasound examination was done with a 7-MHz transvaginal probe. The measurements were obtained in real time according to a standardized protocol, with examination of the endometrium performed under the highest possible magnification. Subjective endocrine symptoms were assessed by the Endocrine SubscaleFACT-B, a validated 5-point response scale (not at all/a little bit/somewhat/ quite a bit/very much) developed for breast cancer research.23 Only items reflecting systemic and local estrogen deficiency symptoms were included. Vaginal atrophy symptoms consisted of vaginal itching or irritation, vaginal dryness, and pain or discomfort with intercourse. Urinary incontinence was evaluated with the Incontinence Impact Questionnaire short form (IIQ-7) and the Urogenital Distress Inventory short form (UDI-6), a validated questionnaire using a 4-point response scale (not at all/ slightly/moderately/greatly).24
Statistical methods All values are displayed as mean ⫾ standard deviation (SD). For comparison between breast cancer patients and control subjects independent t tests or MannWhitney U tests were performed, depending on whether the variable was normally distributed. Frequencies were compared between groups by 2 test. For clinical presentation and subjective reports of vaginal atrophy symptoms, 4 distinct groups of women were used: (1)
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TABLE 1
TABLE 2
Demographic and clinical characteristics of the study population
Tumor characteristics of the breast cancer group
Characteristic
Breast cancer patients (n ⴝ 97)
Control subjects (n ⴝ 105)
P value
Characteristic
Age, y
62.7 ⫾ 4.1
62.7 ⫾ 4.2
ns
Tumor size
1.9 ⫾ 1.2
2.1 ⫾ 1.0
ns
..............................................................................................................................................................................................................................................
Parity, children
..............................................................................................................................................................................................................................................
Married or cohabiting, n (%)
72 (74.2)
72 (68.6)
ns
..............................................................................................................................................................................................................................................
n (%)
..................................................................................................
T1 ⱕ2 cm
68 (70.1)
T2 ⬎2–5 cm
26 (27.8)
.................................................................................................. ..................................................................................................
T3 ⬎5 cm
2 (2.1)
T4 Chest wall/skin
1 (1.0)
High school or more, n (%)
31 (32.0)
35 (33.3)
ns
Body mass index, kg/m
27.0 ⫾ 5.3
26.3 ⫾ 4.2
ns
..............................................................................................................................................................................................................................................
...........................................................................................................
Smoker, n (%)
11 (11.3)
7 (6.7)
Nodal status
1 (1.0)
13 (12.4)
.............................................................................................................................................................................................................................................. 2
ns
..............................................................................................................................................................................................................................................
Current systemic estrogen use, n (%)
⬍ .01
..............................................................................................................................................................................................................................................
Current local estrogen use, n (%)
18 (18.6)
36 (34.3)
⬍ .05
..............................................................................................................................................................................................................................................
ns, not significant.
..................................................................................................
..................................................................................................
Node negative
64 (66.0)
Node positive
32 (33.0)
.................................................................................................. ..................................................................................................
Unknown
Baumgart. Urogenital disorders after therapy for breast cancer. Am J Obstet Gynecol 2011.
1 (1.0)
...........................................................................................................
Hormone receptor status
..................................................................................................
control subjects without local or systemic estrogen treatment, (2) control subjects with local or systemic estrogen treatment, (3) tamoxifen-treated breast cancer patients without local or systemic estrogen treatment, and (4) AI-treated breast cancer patients without local or systemic estrogen treatment. Because of the small numbers, breast cancer patients with ongoing local/ systemic estrogen use and breast cancer patients without adjuvant endocrine therapy were excluded from these analyses. Mean values were compared by 1-way analysis of variance (ANOVA) or KruskalWallis test, depending on normal distribution. In cases when the ANOVA or Kruskal-Wallis test was significant, post hoc tests (Tukey HSD) were made for normally distributed variables and MannWhitney U test for skewed data. Subjective symptoms assessed by the ES-FACT-B questionnaire were categorized as light (not at all/a little bit) and moderate/severe (somewhat/quite a bit/ very much), respectively. Symptoms of the IIQ-7 and UDI-6 questionnaire were also categorized as light (not at all/ slightly) and moderate/severe (moderately/greatly), respectively. The SPSS statistical package version 15.0 was used for all analyses (SPSS, Inc, Chicago, IL). A P value less than .05 was considered significant.
R ESULTS Study population In all, 233 breast cancer patients fulfilled the inclusion/exclusion criteria for the 26.e3
study and were invited. Among these, 97 agreed to participate. There were no systematic differences in terms of age, TNM classification, and use of adjuvant endocrine treatment between breast cancer patients who participated and those who declined participation (data not shown). In all, 493 control subjects were invited to the study. Of these, 107 accepted the invitation and 2 were excluded because of previous breast cancer. Hence, the final study sample consisted of 97 breast cancer patients and 105 controls. One control subject did not fill out the questionnaires and has been included in analyses of clinical outcomes only. Demographic data and clinical characteristics of the study population are displayed in Table 1. There were no clinically relevant differences between the 2 groups, except the use of local or systemic estrogen, which was significantly more common among control subjects. One breast cancer patient who had discontinued adjuvant endocrine therapy was currently on systemic estrogen treatment, and 18 (18.6%) breast cancer patients had local estrogen therapy. Tumor characteristics of breast cancer patients are shown in Table 2. Among patients treated with AIs, 24 were on anastrozole, 10 on exemestane, and 1 on letrozole. Between the review of the medical records and the clinical examination, 8 (8.2%) breast cancer patients had discontinued endocrine therapy and 7 (7.2%) had not had any endocrine therapy at all, based on low tumor grade.
American Journal of Obstetrics & Gynecology JANUARY 2011
Estrogen receptor positive
97 (100)
Progesterone receptor positive
80 (82.5)
..................................................................................................
...........................................................................................................
HER-2 positive
10 (10.3)
...........................................................................................................
Elston score
6.2 ⫾ 1.6
...........................................................................................................
Histologic type
..................................................................................................
Infiltrating ductal
79 (81.4)
Infiltrating lobular
18 (18.6)
.................................................................................................. ...........................................................................................................
Intended adjuvant endocrine treatment
..................................................................................................
No adjuvant endocrine treatment
7 (7.2)
..................................................................................................
Tamoxifen
43 (44.3)
Switch-treatment
28 (28.9)
Aromatase inhibitors
19 (19.6)
.................................................................................................. .................................................................................................. ...........................................................................................................
Current adjuvant endocrine treatment
..................................................................................................
No adjuvant endocrine treatment
7 (7.2)
..................................................................................................
Tamoxifen
47 (48.5)
Aromatase inhibitors
35 (36.1)
Discontinued endocrine treatment
8 (8.2)
.................................................................................................. ..................................................................................................
...........................................................................................................
Baumgart. Urogenital disorders after therapy for breast cancer. Am J Obstet Gynecol 2011.
Vaginal atrophy Analyses on vaginal atrophy included control subjects without local or systemic estrogen treatment (n ⫽ 55), control subjects with local or systemic estrogen treatment (n ⫽ 49), tamoxifentreated breast cancer patients without local or systemic estrogen treatment (n ⫽
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TABLE 3
Prevalence of moderate or severe endocrine symptoms Control subjects with current estrogen treatment (n ⴝ 49)
Aromatase inhibitor users (n ⴝ 33)
Symptom, n (%)
Control subjects without current estrogen treatment (n ⴝ 55)a
Vaginal bleeding/spotting
0
Vaginal discharge
0
2 (4.1)
6 (17.6)
1 (3.0)
Any vaginal atrophy symptom
1 (1.8)
11 (22.4)
11 (32.4)
19 (57.6)
Vaginal itching/irritation
1 (1.8)
5 (10.2)
3 (8.8)
5 (15.2)
Vaginal dryness
1 (1.8)
5 (10.2)
7 (20.6)
14 (42.4)
Pain or discomfort with intercourse
1 (2.7)
8 (24.2)
8 (34.8)
16 (61.5)
Hot flashes
7 (13.0)
5 (10.2)
17 (50.0)
17 (51.5)
Cold sweats
7 (12.7)
5 (10.6)
11 (33.3)
13 (39.4)
Night sweats
6 (10.9)
9 (18.4)
15 (44.1)
13 (39.4)
Tamoxifen users (n ⴝ 34)
0
2 (5.9)
0
................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ c c c-e ................................................................................................................................................................................................................................................................................................................................................................................ c ................................................................................................................................................................................................................................................................................................................................................................................ c b-d ................................................................................................................................................................................................................................................................................................................................................................................ f c c b-d ................................................................................................................................................................................................................................................................................................................................................................................ f c,d c,d ................................................................................................................................................................................................................................................................................................................................................................................ f c,d c,d ................................................................................................................................................................................................................................................................................................................................................................................ c,d c,d ................................................................................................................................................................................................................................................................................................................................................................................ a
One control subject did not fill out the questionnaires; b Trend toward significant difference in comparison to tamoxifen users, P ⫽ .051–.062; c Significantly different from control subjects without current estrogen treatment, P ⬍ .05–.001; d Significantly different from control subjects with current estrogen treatment, P ⬍ .05–.001; e Significantly different from tamoxifen users, P ⬍ .05; f Percentages reported according to number who responded to the specific question.
Baumgart. Urogenital disorders after therapy for breast cancer. Am J Obstet Gynecol 2011.
34), and AI-treated breast cancer patients without local or systemic estrogen treatment (n ⫽ 33). The proportion of participants with moderate/severe vaginal atrophy symptoms is shown in Table 3. In all, 57.6% of AI-treated breast cancer patients and 32.4% of those on tamoxifen reported at least 1 vaginal atrophy symptom, which differed significantly from both control groups. Vaginal dryness and pain or dis-
comfort with intercourse was more common in AI users than in both control groups and these symptoms also tended to be more common in AI users than in tamoxifen users (Table 3). The only vaginal atrophy symptom that tended to be more common among tamoxifen-treated patients than among AI users was moderateto-severe vaginal discharge (Table 3). On clinical examination, AI users displayed moderate and severe atrophy
more often than both control groups, and severe atrophy was also significantly more common than in patients on tamoxifen (Table 4). AI-treated patients had significantly higher pH values than both control groups and tamoxifen users. According to the Maturation Index, AI users displayed significantly more parabasal cells and fewer superficial cells than controls with estrogen treatment and tamoxifen users, and there was a
TABLE 4
Evaluation of vaginal atrophy
Variable
Control subjects without current estrogen treatment (n ⴝ 56)
Control subjects with current estrogen treatment (n ⴝ 49)
Tamoxifen users (n ⴝ 34)
Aromatase inhibitor users (n ⴝ 33)
Clinical evaluation, n (%)
....................................................................................................................................................................................................................................................................................................................................................................... a b-d
No/light atrophy
40 (72.7)
45 (91.8)
23 (67.6)
10 (30.3)
Moderate atrophy
9 (16.4)
4 (8.2)
9 (26.5)
12 (36.4)
Severe atrophy
6 (10.9)
0
2 (5.95)
11 (33.3)
....................................................................................................................................................................................................................................................................................................................................................................... a,d ....................................................................................................................................................................................................................................................................................................................................................................... a,c,d ................................................................................................................................................................................................................................................................................................................................................................................ b b a,c,d
5.2 ⫾ 0.7
pH
4.5 ⫾ 0.7
4.8 ⫾ 0.7
5.5 ⫾ 0.7
................................................................................................................................................................................................................................................................................................................................................................................
Maturation index
(n ⫽ 28)
(n ⫽ 38)
(n ⫽ 26)
(n ⫽ 11)
....................................................................................................................................................................................................................................................................................................................................................................... b b d,e
4.6 ⫾ 12.9
0.5 ⫾ 0.2
85.9 ⫾ 12.2
82.6 ⫾ 13.1
84.5 ⫾ 11.6
86.8 ⫾ 17.4
Superficial cells, %
9.2 ⫾ 7.7
17.2 ⫾ 13.2
15.5 ⫾ 11.6
6.9 ⫾ 12.9
Endometrial thickness, mm
2.8 ⫾ 2.4
3.2 ⫾ 2.6
7.9 ⫾ 9.8
3.0 ⫾ 1.6
Parabasal cells, %
0
6.3 ⫾ 14.1
.......................................................................................................................................................................................................................................................................................................................................................................
Intermediate cells, %
....................................................................................................................................................................................................................................................................................................................................................................... b a c,d ................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ a
Significantly different from control subjects without current estrogen treatment, P ⬍ .05; Significantly different from control subjects without current estrogen treatment, P ⬍ .01–⬍ .001; Significantly different from tamoxifen users, P ⬍ .01; d Significantly different from control subjects with current estrogen treatment, P ⬍ .01 to ⬍ .001; e Significantly different from tamoxifen users, P ⬍ .05. b
c
Baumgart. Urogenital disorders after therapy for breast cancer. Am J Obstet Gynecol 2011.
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TABLE 5
Frequency of reported moderate or severe incontinence symptoms
Symptom, n (%)
Control subjects without current estrogen treatment (n ⴝ 55)a
Control subjects with current estrogen treatment (n ⴝ 49)
Tamoxifen users (n ⴝ 34)
Aromatase inhibitor users (n ⴝ 33)
Frequent urinationb
30 (54.5)
28 (57.1)
23 (67.6)
21 (63.2)
................................................................................................................................................................................................................................................................................................................................................................................
Urgency incontinence
27 (50.0)
24 (49.0)
19 (55.9)
21 (63.6)
Stress incontinence
29 (53.7)
28 (59.6)
24 (72.7)
23 (69.7)
Small amounts of leakage
20 (37.0)
19 (38.8)
16 (47.1)
15 (45.5)
Difficulties in emptying the bladder
6 (11.1)
12 (24.5)
6 (17.6)
5 (15.6)
Abdominal pain or discomfort
5 (9.3)
9 (18.4)
6 (17.6)
8 (24.2)
................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ b ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
No significant differences in reported incontinence symptoms were found between groups. a
One control subject did not fill out the questionnaires; b Percentages reported according to number who responded to the specific question.
Baumgart. Urogenital disorders after therapy for breast cancer. Am J Obstet Gynecol 2011.
trend toward a significant difference in Maturation Index in comparison to controls without estrogen treatment as well. Notably, Maturation Index assessment was only possible in one-third of AI users (Table 4). Tamoxifen-treated patients did not differ in the vaginal atrophy evaluation but had significantly lower pH values and a more mature appearance in the cytologic assessments in comparison to control subjects devoid of estrogen treatment (Table 4). Tamoxifen-treated subjects also displayed an increased endometrial thickness compared with all other groups. One tamoxifen-treated patient was diagnosed with endometrial cancer during the study.
Vasomotor symptoms Both patients on tamoxifen and those on AIs reported moderate or severe vasomotor symptoms, such as hot flashes, cold sweats, and night sweats, more often than both control groups, but there was no difference in vasomotor symptoms between women treated with tamoxifen and AIs (Table 3). Urinary incontinence symptoms There was no difference in frequency or intensity of incontinence symptoms between any of the groups (Table 5).
C OMMENT Vaginal atrophy symptoms and signs of vaginal atrophy were found to be common in breast cancer patients on adjuvant endocrine therapy in this popula26.e5
tion-based, cross-sectional study. In particular, those breast cancer patients who were on AI treatment were found to be most affected. These women reported vaginal dryness and dyspareunia far more often than both control groups, and there was also a tendency that these symptoms were more common than in tamoxifen users. Furthermore, AItreated patients had higher vaginal pH than all other examined groups, and their Maturation Index indicated a higher grade of atrophy than tamoxifen users and control subjects on estrogen. To our knowledge, this is the first study to evaluate urogenital symptoms and vaginal atrophy in breast cancer patients on adjuvant endocrine treatment in comparison to control subjects. The prevalence of any vaginal atrophy symptom in breast cancer patients was about 58%, which was substantially higher than 2-26% in previous studies.12,13,25 Furthermore, dyspareunia has been reported to occur in 15-25% of AI-treated women,8,13,14,23 whereas the corresponding number in our study was 65%. There are several possible explanations why our prevalence rates of vaginal atrophy symptoms are higher than in previous clinical trials. First, women may be more inclined to disclose these symptoms to a gynecologist than to the oncologist. Second, the results of an RCT may not always translate into clinical practice. Finally, as the invitation for our study was directed at urogenital symptoms, it is possible that we have a selec-
American Journal of Obstetrics & Gynecology JANUARY 2011
tion of women with such symptoms compared with previous clinical trials. However, our results are in concordance with the results from Chin et al,26 who conducted an uncontrolled study on urogenital symptoms in breast cancer patients in clinical routine practice and by a later substudy of the TEAM trial, where vaginal dryness was reported in 50% of women treated with exemestane.11 Clearly, our findings indicate that the frequency of vaginal atrophy symptoms, particularly in women treated with AIs, might previously have been underestimated. On clinical examination, women treated with tamoxifen displayed fewer signs of vaginal atrophy and resembled the estrogen users in many aspects, including measurements of pH and Maturation Index. Tamoxifen-treated women also had a tendency toward increased reporting of vaginal discharge, at least in comparison with women on AIs. These findings are in line with previous studies of tamoxifen in breast cancer patients, suggesting estrogen agonism on the vaginal mucosa and endometrium in postmenopausal women.13-16,27-31 Surprisingly, control subjects with current estrogen treatment reported significantly more vaginal atrophy symptoms than controls without current estrogen treatment. This result may seem counterintuitive but is presumably due to the cross-sectional design of the study. In these age groups, women with atrophy symptoms are more likely to use es-
General Gynecology
www.AJOG.org trogen treatment, whereas women with no vaginal problems presumably are less inclined to see a gynecologist and receive treatment. Prior studies have indicated that the use of AIs is less often associated with vasomotor symptoms than the use of tamoxifen,3,32 a finding that was not confirmed by our results. Because of the cross-sectional design of our study, we have not been able to control for the degree of vasomotor symptoms before the start of adjuvant endocrine therapy, and, furthermore, it can be assumed that women had switched from tamoxifen to AIs because of troublesome vasomotor symptoms. Urinary incontinence symptoms did not differ between AI- or tamoxifentreated breast cancer patients and control subjects in our study. The influence of adjuvant endocrine therapy on urinary incontinence has not been extensively studied before, and there is little and inconclusive information from the literature. In a short-term follow-up study of treatment with raloxifen, another selective estrogen receptor modulator, no influence was found on urinary incontinence symptoms.33 In a comparative study, urinary problems were seen in 15% of women on AIs and 9% of those on tamoxifen,14 which was considerably lower than in our study. However, the prevalence of urinary incontinence in healthy postmenopausal women has been found to differ considerably between studies, which should be kept in mind when considering the current findings. Clearly, further controlled studies on urinary incontinence symptoms in different adjuvant endocrine treatment settings are warranted. Strengths of our study include its population-based design and close relation to clinical practice. Admittedly, the study has some limitations. One is selection bias, as discussed previously. It could be argued that women with symptoms were more prone to take part in the study, thus potentially skewing the results. However, the prevalence of symptoms in subjects using AIs would still be substantial. The difference in prevalence of symptoms between cases and controls would also remain valid, because any
bias arising from the willingness to participate because of the presence of symptoms would most likely affect both groups alike. Another limitation was the limited sample size, and consequently the lack of power for some of the analyses. The low power presumably affected the urinary incontinence findings and some of the comparisons between AI users and tamoxifen users. However, the study size was calculated based on previous findings on the prevalence of dyspareunia. Because the prevalence rate of dyspareunia was higher in our study, power was more than adequate for this item. Furthermore, the imperfect blinding of the examining gynecologist regarding the vaginal atrophy grading was also a limitation. However, the high proportion of AI users with moderate and severe vaginal atrophy is consistent with the objective assessment of the biochemical effects on the vaginal mucosa. Finally, the cytohormonal analysis was based on a small sample, as the presence (and number) of degenerated and inflammatory cells made it impossible to calculate the Maturation Index in a substantial proportion of samples. This particularly affected subjects on AI treatment, but because inflammatory cells and degeneration are part of the overall picture of atrophy, the low number of adequate samples actually strengthens our finding of a high prevalence of atrophy in these patients. Because the majority of women who had breast cancer diagnosed expect to be cured or to live for a long period with their disease, the impact of any given treatment on symptoms that may affect quality of life is extremely important. Adjuvant endocrine therapy, especially AIs, was found to increase urogenital symptoms and vaginal atrophy compared with control subjects. The underlying pathophysiology and the impact of these symptoms on quality of life need to be studied more intensively to optimize breast cancer therapy. f REFERENCES 1. Anderson WF, Chatterjee N, Ershler WB, Brawley OW. Estrogen receptor breast cancer phenotypes in the Surveillance, Epidemiology,
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