Management of menopausal symptoms in women who have received breast cancer treatment
Systematic review
February 2016
Management of menopausal symptoms in women who have received breast cancer treatment: Systematic review was prepared and produced by:
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Cancer Australia, 2016. Management of menopausal symptoms in women who have received breast cancer treatment: Systematic review, Cancer Australia, Surry Hills, NSW.
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Contents
Acknowledgments
Executive summary
1Introduction
1.1Management of menopausal symptoms in women with a history of breast cancer
1.2Treatment-induced menopause in breast cancer
1.3Symptoms and their prevalence
1.4Severity
1.5Australian clinical practice guidelines
1.6Current systematic review
2Methods
2.1Inclusion criteria
2.2Exclusion criteria
2.3Literature search
2.4Data extraction
2.5Risk of bias
2.6Quality of reporting of secondary outcomes
3Results
3.1Introduction to results
3.2Vasomotor symptoms: hot flushes and night sweats
3.3Sleep disturbance
3.4Vulvovaginal symptoms
3.5Psychological wellbeing
3.6Quality of life
3.7Breast cancer recurrence
3.8Adverse events
3.9Ongoing trials
3.10International guidelines and recommendations
4Discussion
5Appendix A: Literature databases searched
6Appendix B: Search strategy
7Appendix C: Inclusion and exclusion criteria and decision algorithms
8Appendix D: Flowchart for inclusion-exclusion of articles
9Appendix E: Additional RCTs From Updated Search (January 2014 – November 2015)
9.1Methods
9.2Results
10Appendix F: Study characteristics of RCTs not included in the 5 previously published systematic reviews
11Appendix G: Search strategies for international guidelines and conference abstracts
12Appendix H: Summary of key points from international guidelines
13Appendix I: Abbreviations
14Appendix J: Additional tables of interest
14.1Study characteristics of the five previous systematic reviews
14.2RCTs excluded from this systematic review’s Primary Evidence Base
15Appendix K: Properties of some psychological screening instruments
16References
Tables
Table 1: Primary Evidence Base (45 RCTs), comprised of 19 Recent RCTs and sub-studies/updated studies, and 26 RCTs included by the five published systematic reviews
Table 2: Menopausal symptoms and other outcomes reported in individual RCTs, including drug dosages and study risk of bias
Table 3: Characteristics of pharmaceuticals used by women with a history of breast cancer that have been approved by the Therapeutic Goods Administration, including those investigated by RCTs forming the Primary Evidence Base66
Table 4: Studies treating vasomotor symptoms and differences between treatment groups for frequency of hot flushes and night sweats
Table 5: Tools and scales used to measure vasomotor symptoms in 39 studies
Table 6. Sleep disturbance outcomes reported in 19 RCTs
Table 7. Summary of sleep disturbance measures used in the 20 RCTs
Table 8: Vulvovaginal symptom outcomes reported in 12 RCTs
Table 9. Summary of measures used in 12 RCTs reporting vulvovaginal symptoms outcomes
Table 10 Psychological wellbeing reported in 24 RCTs
Table 11 Measures used in RCTs assessing psychological wellbeing
Table 12 Global quality of life outcomes reported in 11 RCTs
Table 13 Summary of quality of life measures used in the Quality of Life and Mental health RCTs
Table 14 Psychological and General Wellbeing scores reported in Frisk et al 2012 (p.720)31
Table 15 Summary of seven RCTs measuring mental health
Table 16: RCTs that assessed for breast cancer recurrence
Table 17. Pharmaceuticals used by women with a history of breast cancer that have been approved by the Therapeutic Goods Administration of Australia: potential safety issues66
Table 18. Ongoing trials as of July 2014
Table 19. Algorithm for including-excluding by abstract
Table 20 Key menopausal symptoms reported in the 4 additional RCTs
Table 21 Summary of 4 RCTs (level II) reporting the effects of high priority interventions in women after breast cancer treatment
Table 22. Study characteristics of Recent RCTs of pharmaceutical therapies for menopausal symptoms in women after breast cancer
Table 23. Study characteristics of Recent RCTs of complementary medicines and therapies for menopausal symptoms in women after breast cancer
Table 24: Search for international guidelines and conference abstracts
Table 25. Characteristics of the five previously published systematic reviews
Table 26: RCTs included by published systematic reviews but excluded from Cancer Australia’s primary evidence base
Table 27. Diagnostic and Statistical Manual of Mental Disorders IV9: Criteria for Mood Disorders
Table 28. Suitable screening tools to measure psychological distress in breast cancer patients (Love, pp. 62-63)97
Table 29. Screening tools not considered suitable for researching psychological distress in breast cancer patients (Love, p. 63)97
Table 30. Screening tools considered suitable for specific applications (Love, p. 64)97
Figures
Figure 1. Forest plot of studies that assessed for vasomotor symptoms: Vasomotor outcome - Pharmaceutical interventions
Figure 2. Forest plot of studies that assessed for vasomotor symptoms: Vasomotor outcome - Complementary therapies
Figure 3. Forest plot of studies that assessed for vasomotor symptoms: Vasomotor outcome - Other therapies
Figure 4. Mean Sexual Activity Questionnaire-Habit scores at baseline, 3 months and 6 months28, 88
Figure 5 Mean scores reported on Short Form-36 mental health
Figure 6 Inclusion and exclusion of articles
Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review / 1Acknowledgments
Contributors
Cancer Australia gratefully acknowledges the support of the many individuals and groups who contributed to the development of this report.
Management of menopausal symptoms in women who have received breast cancer treatment: Systematic review was developed with input from an expert multidisciplinary Working Group with the following members:
- Professor Roger HartFertility Specialist (Chair)
- Ms Petrina Burnett Consumer
- Professor Michael Friedlander Medical Oncologist
- Professor Martha HickeyObstetrician & Gynaecologist
- Ms Mary Macheras-MagiasConsumer
- Associate Professor Nicole McCarthyMedical Oncologist
- Dr Michelle Peate Behavioural Scientist
- Dr Lesley RamageGeneral Practitioner
- Ms Karen RedmanBreast Care Nurse Practitioner
- Dr Kirsty StuartRadiation Oncologist
- Professor Owen UngSurgeon
- Dr Amanda Vincent Endocrinologist
- Professor Kate WhiteCancer Nurse (Research)
Cancer Australia staff
The following Cancer Australia staff were involved in developing Management of menopausal symptoms in women who have received breast cancer treatment: Systematic review
- Dr Anne Nelson Director, Evidence Translation
- Dr Sarah NorrisPrincipal Adviser, Guideline Development
- Dr Nerissa Soh Manager, Evidence Review
- Dr Vivienne MilchManager, Breast Cancer
- Dr Briony JackSenior Project Officer, Cancer Care
- Dr Jennifer TaylorSenior Project Officer, Cancer Care
- Ms Sherin ChikhaniProject Officer, Evidence Review
Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review / 1
Executive summary
Cancer Australia has undertaken a systematic review to support the development of clinical practice guidelines for the treatment and management of menopausal symptoms in women who have received treatment for breast cancer. Conventional hormonal therapies for the management of menopausal symptoms, while effective, are often contraindicated in this population. Further, menopausal symptoms in women whose symptoms are induced by treatment are also more severe than in women experiencing “natural” menopause.1
A substantial proportion of Australian women diagnosed with breast cancer are diagnosed prior to menopause: in 2010, 3,248 (23%) new cases of breast cancer were diagnosed in Australian women aged 20-49 years;2 and as many as 29% of Australian women diagnosed with breast cancer reported chemotherapy-induced ovarian failure, with another 25% having menopausal symptoms induced by other treatments such as endocrine therapy or oophorectomy.3 The significant burden on the wellbeing of women supports the need to consider the management of menopausal symptoms in women who have completed or who are receiving treatment for breast cancer.
This systematic review was undertaken to identify evidence of the safety and effectiveness of different interventions for managing menopausal symptoms in women who have received treatment for breast cancer. The types of menopausal symptoms considered were vasomotor symptoms (hot flushes and night sweats), sleep disturbances, vulvovaginal symptoms (including vaginal dryness), psychosocial issues such as anxiety and depression and global quality of life. Breast cancer recurrence was also included as an symptom or outcome.
Interventions included pharmaceutical treatments (antidepressants, anticonvulsants, antihypertensives, menopause hormone therapies) and complementary medicines and therapies (psychotherapies, physical exercise, relaxation, yoga, acupuncture, vitamin E, herbal remedies, homeopathy and magnetic therapy). In assessing the evidence, the current systematic review acknowledges the inter-relation between symptoms (which can confound the assessment of the efficacy of interventions): for example, sleep disturbances occurring in a woman with vasomotor symptoms and a history of breast cancer may be due to the vasomotor symptoms themselves, the psychological distress of having breast cancer, or other stressors related to being treated for breast cancer.
The search for the systematic review was undertaken for trials in humans published between 2001 and January 2014. To meet the inclusion criteria, studies needed to beplacebo-controlled or head-to-head randomised controlled trials (RCTs) with at least 10 participants per trial arm, conducted in women who had previously been treated for breast cancer and in whom the interventions were for the purpose of treating menopausal symptoms.
The initial search identified 45 studies that met the inclusion criteria: 26 RCTs that were included across five previously published systematic reviews and an additional 19 studies (15 RCT cohorts with four update studies or sub-studies) which had not been included by the previously published reviews. These studies comprised the Primary Evidence Base and were conducted in a wide range of countries, although none were carried out in Australia.
An updated search was carried out in November 2015 to identify additional studies published after the initial search date of January 2014 that met the original inclusion criteria. Four additional RCTs were identified and included into the Primary Evidence Base. The search criteria, study characteristics and results for these four RCTs are described in Appendix E: Additional RCTs From Updated Search (January 2014 – November 2015).
Summary of results
Effectiveness
Vasomotor symptoms
For the purposes of this systematic review, vasomotor symptoms include hot flushes and night sweats.
The level I evidence comprised five systematic reviews published between 2001 and 2013 (Rada et al 2010, L’Esperance et al 2013, Chao et al 2009, Lee et al 2009 and Dos Santos et al 2010)4-8that examined the effects of treatment on vasomotor symptoms in women treated for breast cancer.
Of the 49 studies in the Primary Evidence Base, 41 reported on vasomotor symptoms as the primary menopausal symptom of interest; these comprised 38 RCTs, with three follow-up studies (10 with high risk of bias, 20 with moderate risk of bias and 11 with low risk of bias) with a total of 6,625 study participants. As vasomotor symptoms were the primary outcome of interest for these studies, the quality of reporting was fair to good, with a range of tools used: 16 of the 41 studies used more than one method and 20 used a formal and standardised scale; only nine studies used a diary or logbook alone. Studies were conducted in a wide range of countries, but none were conducted in Australia.
Overall, in treating vasomotor symptoms in women who have received breast cancer treatment, there is level II evidence for the efficacy of paroxetine, venlafaxine, clonidine,gabapentin, tibolone, cognitive behavioural therapy (CBT), CBT combined with exercise, purpose-designed hypnotherapy and yoga. There is limited evidence (level II) for acupuncture and short-term relaxation therapy. Moreover there is evidence of no effect or no consistent effect (level II), of bupropion, fluoxetine, sertraline, zolpidem augmentation of selective serotonin re-uptake inhibitors (SSRIs) or serotonin noradrenaline re-uptake inhibitors (SNRIs), black cohosh, homeopathy, phytoestrogens or magnetic therapy. It should be noted that tiboloneis associated with an increased risk of breast cancer recurrence.
Sleep disturbance
There was no level I evidence from systematic reviews that examined the effects of treatment on sleep disturbance associated with menopausal symptoms in women after breast cancer. There were20 RCTs (nine of fair quality and 11 of poor quality)that reported sleep disturbance as an outcome measure and included a total of 4,447 women. The patients in the RCTs were women with a history of breast cancer, high risk of breast cancer or primary metastatic breast cancer.
Of the 20 RCTs, sleep disturbance was a primary outcome in only three of the trials. Only 17RCTs reported sufficient data to allow interpretation of the findings. The RCTs included sites from the UK, Denmark, USA, Netherlands, Germany, Canada, Sweden, Austria and Italy. None of the included RCTs were conducted in Australia.
Overall there is limited level II evidence regarding the effects of the interventions studied on sleep disturbance associated with menopausal symptoms in women who have received breast cancer treatment. There was level II evidence for improved sleep for the interventions: paroxetine, zolpidem (in women taking an SSRI or SNRI), tibolone, CBT, purposedesigned hypnotherapy, yoga and acupuncture, compared to placebo. However, these studies were of fair or poor quality in terms of reporting sleep disturbance as an outcome measure and had small numbers of subjects. More studies of higher methodological quality are needed to determine the efficacy of treatments on sleep disturbance for menopausal women after breast cancer, with greater sample sizes and higher quality of reporting.
Vulvovaginal symptoms
For the purposes of this systematic review, vulvovaginal symptoms include aspects of sexual desire (libido), sexual activity (frequency or habit), sexual pleasure, pain or discomfort during intercourse (vulvovaginal symptoms or dyspareunia) and orgasm. It does not include sexual dysfunction (as defined in the American Psychiatric Association, 2013)9, satisfaction with sexual relationships (including communication or intimacy with sexual partner) or aspects of sexual self-concept (such as body image, sexual esteem or sexual self-schema).
There was no level I evidence from systematic reviews that examined the effects of treatment on vulvovaginal symptoms after treatment of breast cancer. However, there is level II evidence from 13 RCTS.
Overall, in treating vulvovaginal symptoms in women who have received breast cancer treatment, there is insufficient evidence for the use of antidepressants. Furthermore there is limited evidence in the treatment of vulvovaginal symptoms associated with menopausal symptoms in women who have received breast cancer treatment for the interventions: vaginal pH-balanced gel, topical lidocaine solutions, CBT and CBT combined with exercise. In contrast, tibolone has been shown to improve vulvovaginal symptoms, but increases the risk of breast recurrence.
Psychological wellbeing
For the purposes of this systematic review, “psychological wellbeing” is defined to include clinical anxiety and depression, mood, emotional wellbeing (distress that might be considered “appropriate sadness,”10) and mental health (as an aspect of quality of life, measured on the SF-36). The distress caused by a hot flush, as reported in non-validated symptom diaries, was not included. This definition of psychological wellbeing was driven by the included studies and the measures that they used.
There was no level I evidence from systematic reviews that examined the effects of treatment on psychological wellbeing, depression, anxiety, mood, emotional wellbeing or mental health associated with menopausal symptoms in women who have received breast cancer treatment. There were 26 RCTs that reported on secondary outcome measures of depression, anxiety, negative mood and emotional wellbeing.
Overall, the quality of the 26 studies that measured treatment effects on psychological outcomes was poor. There is limited level II evidence for improvement of some measures of psychological wellbeing associated with menopausal symptoms in women after breast cancer, for venlafaxine, sertraline, gabapentin, tibolone, CBT, hypnotherapy and yoga. The studies indicate that although the effects on psychological wellbeing are uncertain, the interventions studied do not induce psychopathology (i.e. they do not appear to increase depression, anxiety, negative mood, or to reduce emotional wellbeing).
Seven RCTs reported on specific mental health scores as a secondary outcome, including 893 women across all seven studies. Overall, there is limited evidence on the effects of the interventions studied to improve mental healthscores associated with menopausal symptoms in women after breast cancer treatment. While there is a need for further studies of high methodological rigour to establish the benefits of treatment on mental health scores associated with menopausal symptoms in women after breast cancer treatment, there is no evidence that treatment has an adverse effect on mental health scores.
Global quality of life
There was no level I evidence from systematic reviews that examined the effects of treatment on global quality of life associated with menopausal symptoms in women after breast cancer. There is level II evidence from 13 RCTs with quality of life as a secondary outcome measure, in a total of 912 women across all studies.
Overall, the reporting of global quality of life outcomes was poor, and there is limited evidence on the effects of the interventions studied to improve global quality of life associated with menopausal symptoms in women after breast cancer treatment. However, there is also no evidence that the interventions studies significantly reduce global quality of life. There is a need for more studies of higher methodological quality, on global quality of life associated with women experiencing menopausal symptoms after breast cancer treatment