Does a multidisciplinary menopausal symptoms after cancer clinic reduce symptoms?

This study aimed to measure the prevalence of menopausal symptoms in patients attending a multidisciplinary model of care clinic at their initial clinic visit and their subsequent follow-up consultation using a validated patient-reported outcome measure to assess whether menopausal symptoms after cancer had improved. A retrospective review was conducted of patients attending the clinic in a 12-month period in 2017 (n = 189). Recorded variables included patient demographics, details of index cancer, previous treatments, and menopausal symptom management strategies. Severity of menopausal symptoms was evaluated using the Greene Climacteric Scale. The extent to which patients were bothered by symptoms was combined into two categories and dichotomized (present/absent). Differences in symptom prevalence between the initial consultation and first follow-up visit were examined using McNemar’s test. The majority of patients attending the clinic had a history of breast cancer (72%). Fifty-five percent of patients were prescribed a non-hormonal therapy at their initial visit, most commonly gabapentin. Significantly fewer patients reported being bothered by hot flushes, fatigue, sleep difficulties, and loss of interest in sex, anxiety, or troubles concentrating at the first follow-up visit compared to their initial consultation (p < 0.01). In this study, there was an improvement in self-reported menopausal symptoms in a significant proportion of cancer survivors attending a multidisciplinary menopause clinic between their initial and first subsequent follow-up consultations.


Introduction
Menopause is marked by irregular menstrual cycles and hormonal changes and is often accompanied by vasomotor symptoms, sleep and mood disturbances, and changes in sexual desire and function [1]. In Australia, almost a third of women will consult a doctor regarding symptoms of menopause [2]. Although not all women are bothered by symptoms of menopause, those with severe symptoms report significant impacts on their quality of life [3]. The symptoms of menopause in patients with a history of cancer are often more severe, owing to the nature and sudden onset of menopause, the need to abruptly cease menopausal hormone therapy (MHT), or the need for ongoing endocrine therapy if indicated [4]. In a study of more than 500 women with a history of breast cancer, more than 60% of survivors had moderate to severe menopausal symptoms affecting both their and their partner's quality of life [5]. The same study showed that quality of sleep and decreased libido were also problematic in more than 50% of women. Symptom severity can also contribute to poor compliance with prescribed endocrine treatment used to prevent cancer recurrence [6,7].
Breast cancer is the most common cancer in women worldwide with more than 2 million new diagnoses annually [8]. In Australia, it is estimated that 19,807 women were diagnosed with breast cancer in 2020, and that 20-30% were pre-menopausal [9]. Standard treatment (including chemotherapy, radiotherapy, concomitant oophorectomy, and/or anti estrogenic endocrine treatment) often results in either early menopause or the exacerbation of pre-existing or previously controlled menopausal symptoms. MHT should be avoided in patients with a history of breast cancer due to the associated risk of new or recurrent cancer. This recommendation is primarily based upon the results of a large, randomized control trial that was stopped early in 2003, when an interim safety analysis demonstrated an increased risk of breast cancer recurrence in the MHT arm compared to placebo [10]. With advances in diagnosis and treatment resulting in improved 5-year survival, the number of breast cancer survivors is increasing, translating to a significant quality of life issue for many women [11].
The mainstay of management of menopausal symptoms in women with a history of breast cancer, and other estrogen-sensitive malignancies (including endometrioid and low-grade serous ovarian carcinomas, advanced endometrial adenocarcinomas, and leiomyosarcomas), includes lifestyle changes, cognitive behavioral therapy (CBT), and non-hormonal medications such as selective serotonin reuptake inhibitors (SSRI), selective noradrenaline reuptake inhibitors (SNRI), clonidine, and gabapentin [12,13]. A unique multidisciplinary model of care clinic-the Menopausal Symptoms After Cancer (MSAC) Clinicwas developed at a tertiary women's hospital in Western Australia in 2003 and has been replicated throughout Australia and internationally [5]. Women attending the MSAC Clinic receive evidence-based information regarding nonpharmacological and non-hormonal treatments. However, there is limited evidence that such multidisciplinary care improves symptoms, patient satisfaction and quality of life [14]. The aim of the current study was to measure the prevalence of menopausal symptoms at patients' initial clinic visit and their subsequent follow-up consultation using a validated patient-reported outcome measure, the Greene Climacteric Scale [15], to assess whether menopausal symptoms had improved.

Methods
A retrospective review was conducted of patients attending the MSAC Clinic at King Edward Memorial Hospital, Perth, Western Australia, between 1 January 2017 and 31 December 2017. Inclusion criteria were patients referred with menopausal symptoms and a history of malignancy. Patients that had attended the MSAC Clinic for an initial consultation prior to 1 January 2017 were excluded. Cases were ascertained from clinic appointment lists in the patient administration system WebPAS, and data were extracted from individual patient medical records and entered into a Microsoft Excel database for analysis.

The MSAC Clinic
The MSAC Clinic at this stand-alone tertiary women's hospital, which was started as the first of its kind in 2003 [5], now sees almost 200 new patients per year. There is a diverse range of patients with regard to the index cancer responsible for each patient's referral, with the most common being breast cancer patients which represent just over 70% of the clinic's population.
Patients at their initial consultation are seen by either a gynecologist or specialist Family Practitioner (FP) as well as a clinical nurse specialist. Patients are asked to fill in the Greene Climacteric Scale individually at each clinic visit which provides crucial guidance for areas in need of immediate management. Follow-up visits are based upon what management strategies have been implemented at the visit and the expected time for a change in symptoms to be evident, as well as severity of symptoms as experienced by the patient. Prescribing non-hormonal pharmacologic therapy follows evidence-based recommendations from the Cancer Australia Guideline "Managing Menopausal Symptoms After Breast Cancer" [12]. Venlafaxine (37.5-75 mg/day), clonidine (0.10-0.15 mg/ day), and gabapentin (300-900 mg/day) may be considered for the management of moderate to severe vasomotor symptoms in women with a history of breast cancer [12]. Paroxetine (10-20 mg/day) may also be considered, but because it reduces the serum concentration of tamoxifen and metabolites, it is contraindicated in women on tamoxifen. Escitalopram (10-20 mg/day) and desvenlafaxine (100-150 g/day) are also options to treat moderate to severe vasomotor symptoms, but they may reduce the efficacy of tamoxifen by slowing metabolism to the active form or alter the serum concentration of tamoxifen and metabolites although there is little evidence for clinical concern resulting from their concomitant use [12]. The choice of medication involves shared decision-making between the clinician and patient following discussion of these non-hormonal pharmacologic options and their potential benefits and adverse effects. Any patient who is commenced on a new medication is contacted via phone by the clinical nurse specialist within 2-4 weeks of this initial review. If a patient has discontinued a medication, this is recorded in the patient's medical record by the clinical nurse specialist. Compliance with prescribed treatment is recorded by clinicians at clinical follow-up visits.
In line with the multidisciplinary model of the clinic, there is involvement in patient care by a range of health care professionals including women's health physiotherapists, dieticians, clinical psychologists, and sexual counselors. Care can also be coordinated between the clinic team and their colleagues in genetic counseling and endocrinology. The multidisciplinary team meet on a monthly basis to discuss specific cases and management plans, often for those patients with severe and/or refractory symptoms.

Variables
Variables recorded included patient age, cause of menopause (natural menopause prior to cancer diagnosis, surgical menopause, chemotherapy-induced menopause, or radiationinduced menopause), referral source, details of index cancer, prior use of MHT, time since cancer diagnosis, time since referral to the clinic and initial consultation, current medication including endocrine therapy, management prior to referral, and management instituted at the initial clinic visit. The Greene Climacteric Scale was used to evaluate climacteric symptoms and is composed of 21 items that evaluate vasomotor symptoms (two items), anxiety (six items), depression (five items), somatic symptoms (seven items), and sexuality (one item). For vasomotor symptoms, the two questions were "to what extent are you bothered by hot flushes?" and "to what extent are you bothered by night sweats?" All items have four options that range from not at all (0), a little (1), quite a bit (2), to extremely (3).

Statistical analysis
Data were analyzed using SPSS version 26 (IBM Corp., Armonk, NY, USA) with an alpha of 0.01 considered statistically significant. Categorical variables were described using frequency and percentage, with missing data noted. Continuous scale variables were described using mean, median, and standard deviation. The extent to which patients were bothered by symptoms "quite a bit" and "extremely" was combined into one category and dichotomized (present/absent). Differences in symptom prevalence between the initial MSAC consultation and first follow-up visit were examined using McNemar's test.
Menopausal status at the time of cancer diagnosis, cause of menopause, referral source, time since cancer treatment, type of cancer, MHT use, endocrine therapy, and time between MSAC clinic visits were examined for associations with improvements in menopausal symptoms between the initial MSAC consultation and first follow-up visit in a univariate analysis using the chi-square test.
A binary logistic generalized linear model (GLM) was used to examine the odds ratio (OR) for improvement in difficulty sleeping at the first follow-up visit (no improvement set as the reference category) including commonly controlled for confounders. The binary logistic GLM with logit link function included menopausal status at the time of cancer diagnosis, cause of menopause, referral source, time since cancer treatment, type of cancer, MHT use, endocrine therapy, and time between MSAC clinic visits as fixed factors, and age at diagnosis as a fixed covariate.

General
Between 1 January and 31 December 2017, 189 patients were seen for their initial consultation at the MSAC Clinic. The majority of patients (n = 136, 72%) had a history of breast cancer. Other cancers included uterine, cervical, ovarian, haematological, and colorectal, as detailed in Table 1.
Patient characteristics including age, marital and employment status, and geographical location are demonstrated in Table 1. The mean age was 50 years (range, 24-81 years). Most new referrals came from gynecological oncologists (26.5%), oncology nurses (23.8%), and medical oncologists (16.9%) with FPs responsible for 10% of the referrals. Most patients (69.3%) were seen between 2 and 6 months from the time their referral was received, with only 2.6% of patients waiting more than 6 months for their initial consultation.

Menopause and pre-existing symptoms
Two-thirds of patients were post-menopausal. Of these, 30.7% had a natural menopause, 25.9% had a chemotherapyinduced menopause, and 29.6% had a surgically induced menopause. Most patients attended the clinic for the first time within 1 year of the cancer diagnosis (72.5%) with only 2.1% of patients being distant from their diagnosis by more than 10 years. The majority of patients (75.1%) had never used MHT before, with a small proportion of patients (6.9%) reporting ongoing use of MHT. The remainder had ceased MHT prior to review, reporting "past use". Over half (51.2%) of patients were taking an aromatase inhibitor (most commonly letrozole), whilst 8.5% were taking tamoxifen.
The five most troublesome symptoms reported by women who completed the Greene Climacteric Scale were hot flushes, fatigue, difficulty sleeping, night sweats and loss of interest in sex ( Table 2). More than 50% of patients were bothered by these symptoms "quite a bit" or "extremely." These symptoms were all present in more than 50% of patients (range 51.3 to 68.3%). Vaginal dryness was reported as "quite a bit" or "extremely" bothersome in 43.4% of patients, with cognitive and mood symptoms such as anxiety in 34.9%, irritability in 32.3%, and difficulty concentrating in 32.4% of patients.

Symptom management and multidisciplinary care
Twenty-eight percent of patients either were already taking or had previously tried a systemic non-hormonal therapy (NHT) such as gabapentin, venlafaxine, or clonidine and 55% of patients were commenced on a NHT at the initial visit, most commonly gabapentin (24.3%) followed by venlafaxine (13.2%). Non-hormonal vaginal moisturizer was recommended three times more often than topical vaginal estrogen, which was prescribed in 5.8% of patients (see Table 3).   Information regarding lifestyle modifications that may contribute to improved quality of life was provided to almost one-third of patients (n = 56, 30.6%). This included advice regarding dietary changes, referral to an exercise program, or information on the utility of CBT, mindfulness, or acupuncture. Thirty-two percent of patients were referred to an allied health professional, mostly commonly a clinical psychologist (14.8%) or women's health physiotherapist (13.2%).
Complete data were available for 124 patients detailing severity of symptoms, as per the Greene Climacteric Scale, who attended both an initial consultation and a first followup visit. Fewer patients reported being bothered by hot flushes, fatigue, sleep difficulties, and loss of interest in sex, anxiety, or troubles concentrating at the first follow-up visit compared to their initial consultation (p < 0.01) ( Table 4). Incomplete data were most often attributed to a failure of the patient to attend a face-to-face follow-up visit (n = 60/65, 92.3%). Thirty-one of these followed up via telephone consult with the remaining 29 were not reviewed after their initial consultation. Three patients had not completed the questionnaire at the initial consult and so no data were available for comparison, and only 2 patients who attended a face-toface appointment and who had filled in the questionnaire at their first visit did not complete it at the first follow-up visit.
Menopausal status at the time of cancer diagnosis, cause of menopause, referral source, time since cancer treatment, type of cancer, MHT use, endocrine therapy, and time between MSAC clinic visits were examined for associations with improvements in the four most prevalent symptoms (hot flushes, fatigue, difficulty sleeping, and night sweats) between the initial MSAC consultation and first followup visit. On univariate analysis, less difficulty sleeping was associated with menopausal status at cancer diagnosis. Thirty percent of patients who were pre-menopausal and 38.9% who were peri-menopausal at cancer diagnosis reported improvement in sleep at their first follow-up visit compared to 18.6% of women who were post-menopausal at cancer diagnosis (p = 0.002). No other significant associations were observed on univariate analysis (Table 5). In a multivariate model that included cause of menopause, referral source, time since cancer treatment, type of cancer, MHT use, endocrine therapy, time between MSAC clinic visits, and age at diagnosis, the association between menopausal status at the time of cancer diagnosis and difficulty sleeping was not significant (odds ratios for pre-menopausal and perimenopausal patients reporting improvement in sleep compared to post-menopausal patients 0.36, 95% CI 0.05-2.64, and 0.17, 95% CI 0.026-1.11, respectively).

Discussion
Menopausal symptoms after cancer can have a significant impact on quality of life and may be more severe than after natural menopause. With the increasing incidence of cancer and improved survival rates, women in this situation represent an important population where the approach to symptoms needs to be coordinated, holistic, and provided by an informed practitioner due to the need for avoidance of MHT in patients with estrogen-sensitive cancers, and because of the multifaceted causes of such symptoms. Our findings are consistent with those of a cross-sectional study of 524 community-dwelling Australian breast cancer survivors, most of whom (66%) had received chemotherapy and were taking endocrine therapy (64%), which reported that the most common symptoms were hot flushes/night sweats and sleep disturbance (both 89%) [16]. Symptoms were moderate (21-38%) in around one-third and severe in up to one-quarter (8-26%). A previous study of 934 cancer survivors attending our MSAC Clinic between 2003 and 2010 found that 75.1% and 67.7% had current severe trouble with hot flushes and night sweats respectively and that 61.3% had reported poor sleep in the previous week [5]. In a population-based Chinese cohort study of 5023 Chinese breast cancer survivors, 67.2% of pre-menopausal women had at least one menopausal symptom [17].

Symptom management
Non-hormonal pharmacological and non-pharmacological therapies, in combination with lifestyle changes, are the mainstay of management in women with troublesome menopausal symptoms where MHT is contraindicated. Several studies have demonstrated that SSRIs and venlafaxine are effective in reducing the severity of hot flushes in this population [18,19]. Purpose-designed CBT, hypnotherapy, and acupuncture all show promising improvement in a range of symptoms including the severity and impact of hot flushes, quality of sleep, and even sexual function [20].
Current clinical guidelines suggest the following for the management of vasomotor symptoms and sleep disturbance: SSRIs, SNRIs, gabapentin in combination with CBT, acupuncture, and hypnotherapy [12]. The basis of these recommendations is the suggestion of benefit, without increasing the risk of new or recurrent malignancy.
Gabapentin was the most commonly prescribed nonhormonal pharmacological therapy (prescribed to 24% of patients), followed by venlafaxine which was prescribed in 13% of patients. Gabapentin has been found in meta-analyses of randomized controlled trials to be associated with a significant reduction in the frequency and composite score of hot flushes compared to placebo [21,22]. Guidelines advise against the use of both vitamin E and isoflavones for sleep disturbance due to the lack of evidence of any benefit [12]. In keeping with this, the recommendation of vitamin E supplementation was uncommon in our study, occurring in only 1.6% of patients.

Symptom improvement
Not all patients who attended the initial consultation attended for a follow-up visit; however, complete data were available for 124 patients who attended and completed the Greene Climacteric Scale on both occasions. Unsurprisingly, the most commonly troublesome complaints were vasomotor symptoms including hot flushes and night sweats. This subset of patients demonstrated a clear and statistically significant improvement in the top 4 most bothersome symptoms when their self-assessment was compared (p < 0.01). Approximately 17% of patients reported improvement of hot flushes, sleeping difficulties, and fatigue from "quite a bit" and "extremely" to "not at all" or "a little" (Table 4). Both anxiety and difficulty concentrating were also significantly improved at first follow-up visit. Although not reaching statistical significance, improvement was also demonstrated in many other menopausal symptoms including irritability, muscle and joint pains and sexual function (loss of interest in sex and vaginal dryness).
It is not possible to compare the findings of the current study with studies of specific therapeutic agents because gabapentin and venlafaxine were only prescribed to 24.3% and 13.2% of patients respectively. We measured symptom improvement following first attendance at a multidisciplinary clinic where the treatment initiated at the initial visit varied. However, the efficacy of our multidisciplinary model of care may be comparable to a randomized clinical trial of gabapentin that found a 21% in hot flush severity at a 900 mg/day dose and concluded that the drug should be considered for treatment of hot flushes in women with breast cancer [23]. We observed a 17% reduction at the first follow-up clinic visit in patients reporting "quite a bit" and "extreme" bother due to hot flushes. The implications for clinical practice are that a multidisciplinary MSAC clinic should be considered for all women with menopausal symptoms after cancer, where such clinics are available, but further prospective studies are required.

Strengths and limitations
A strength of the study was the use of the Greene Climacteric Scale which allows direct assessment of health-related quality of life and has been validated for use in different populations [24]. Confirmatory factor analysis has shown construct validity and test-retest reliability coefficients for all subscales have been evaluated as good, with the vasomotor scale reported as having a coefficient of 0.83, and the questionnaire can be used to determine clinically important changes resulting from an intervention [24].
The study has important limitations that should be acknowledged including its retrospective design which has inherent selection bias. Data collection is limited by the quality and accuracy of record keeping. The study design prohibited the ability to control for confounding factors that may have been associated with menopausal symptoms. Several patients were lost to follow-up, and missing data for these patients could not be included in the analysis, which may have biased the study's findings. Data collectors were not blinded to the aims of this study presenting another opportunity for bias. Further, our study may have been underpowered to detect associations between clinical variables and symptom improvement due to the small sample size, and the heterogeneous patient population limits generalizability to larger patient populations in alternate settings.

Conclusion
In this study, there was an improvement in self-reported menopausal symptoms in a significant proportion of cancer survivors attending a multidisciplinary menopause clinic between their initial and first subsequent follow-up consultations. Further research to investigate symptom prevalence beyond the first follow-up visit and assessment of specific non-hormonal pharmacological and non-pharmacological therapies, and their combinations, is warranted.
Author contribution Jade Hollingworth: substantial contribution to the conception and design, acquisition of data, drafted the work, and approved the version to be published.
Lucy Walsh, Stephanie Tran: substantial contribution to the acquisition of data, revised the work critically, and approved the version to be published.
Lesley Ramage, Manju Ambekar, Jane Weeks, Lucy Williams: substantial contribution to the conception of the work, revised the work critically, and approved the version to be published.
Shavita Patel-Brown: substantial contribution to the acquisition of data, revised the work critically, and approved the version to be published.
Paul Cohen: substantial contribution to the conception and design, interpretation of data, revised the work critically, and approved the version to be published.

Availability of data and material Available on request.
Code availability NA.

Declarations
Ethics approval Ethical approval for the study was granted by the Womens and Newborns Health Service Ethics Committee (Reference 27240, approved 6 June 2019).