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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: Cancer Australia Locked Bag 3 Strawberry Hills NSW 2012 Australia Tel: +61 2 9357 9400 Fax: +61 2 9357 9477 canceraustralia.gov.au © Cancer Australia 2016. ISBN Online: 978-1-74127-316-8 Recommended citation Cancer Australia, 2016. Management of menopausal symptoms in women who have received breast cancer treatment: Systematic review, Cancer Australia, Surry Hills, NSW. Management of menopausal symptoms in women who have received breast cancer treatment: Systematic review can be downloaded or ordered from the Cancer Australia website: canceraustralia.gov.au/resources Copyright statements Internet sites This work is copyright. 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Contents Acknowledgments ............................................................................................................................. vii Executive summary .............................................................................................................................. 8 1 Introduction ............................................................................................................................ 13 1.1 Management of menopausal symptoms in women with a history of breast cancer .............................................................................................................................. 13 2 3 1.2 Treatment-induced menopause in breast cancer ................................................ 13 1.3 Symptoms and their prevalence ............................................................................... 14 1.4 Severity ............................................................................................................................ 14 1.5 Australian clinical practice guidelines ...................................................................... 15 1.6 Current systematic review ........................................................................................... 15 Methods .................................................................................................................................. 16 2.1 Inclusion criteria ............................................................................................................. 16 2.2 Exclusion criteria ............................................................................................................ 17 2.3 Literature search ........................................................................................................... 17 2.4 Data extraction ............................................................................................................. 19 2.5 Risk of bias ...................................................................................................................... 20 2.6 Quality of reporting of secondary outcomes .......................................................... 20 Results ...................................................................................................................................... 21 3.1 Introduction to results ................................................................................................... 21 3.2 Vasomotor symptoms: hot flushes and night sweats ............................................. 34 3.3 Sleep disturbance ......................................................................................................... 64 3.4 Vulvovaginal symptoms ............................................................................................... 82 3.5 Psychological wellbeing .............................................................................................. 98 3.6 Quality of life ................................................................................................................ 123 3.7 Breast cancer recurrence ......................................................................................... 139 3.8 Adverse events ............................................................................................................ 142 3.9 Ongoing trials ............................................................................................................... 149 3.10 International guidelines and recommendations .................................................. 154 4 Discussion ............................................................................................................................. 159 5 Appendix A: Literature databases searched ................................................................... 163 6 Appendix B: Search strategy .............................................................................................. 164 7 Appendix C: Inclusion and exclusion criteria and decision algorithms ....................... 166 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review iii 8 Appendix D: Flowchart for inclusion-exclusion of articles.............................................. 168 9 Appendix E: Additional RCTs From Updated Search (January 2014 – November 2015) ...................................................................................................................................... 169 9.1 Methods ........................................................................................................................ 169 9.2 Results ............................................................................................................................ 173 10 Appendix F: Study characteristics of RCTs not included in the 5 previously published systematic reviews ............................................................................................ 180 11 Appendix G: Search strategies for international guidelines and conference abstracts ............................................................................................................................... 194 12 Appendix H: Summary of key points from international guidelines .............................. 197 13 Appendix I: Abbreviations .................................................................................................. 209 14 Appendix J: Additional tables of interest .......................................................................... 211 14.1 Study characteristics of the five previous systematic reviews ........................... 211 14.2 RCTs excluded from this systematic review’s Primary Evidence Base .............. 214 15 Appendix K: Properties of some psychological screening instruments ........................ 217 16 References ............................................................................................................................ 221 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review iv Tables Table 1: Primary Evidence Base (45 RCTs), comprised of 19 Recent RCTs and substudies/updated studies, and 26 RCTs included by the five published systematic reviews ............................................................................................................... 21 Table 2: Menopausal symptoms and other outcomes reported in individual RCTs, including drug dosages and study risk of bias ............................................................... 25 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 ................................................................................................................... 31 Table 4: Studies treating vasomotor symptoms and differences between treatment groups for frequency of hot flushes and night sweats ................................................. 49 Table 5: Tools and scales used to measure vasomotor symptoms in 39 studies .......................... 58 Table 6. Sleep disturbance outcomes reported in 19 RCTs ............................................................. 65 Table 7. Summary of sleep disturbance measures used in the 20 RCTs ........................................ 73 Table 8: Vulvovaginal symptom outcomes reported in 12 RCTs .................................................... 83 Table 9. Summary of measures used in 12 RCTs reporting vulvovaginal symptoms outcomes .............................................................................................................................. 90 Table 10 Psychological wellbeing reported in 24 RCTs ................................................................... 100 Table 11 Measures used in RCTs assessing psychological wellbeing ........................................... 111 Table 12 Global quality of life outcomes reported in 11 RCTs ....................................................... 124 Table 13 Summary of quality of life measures used in the Quality of Life and Mental health RCTs .......................................................................................................................... 128 Table 14 Psychological and General Wellbeing scores reported in Frisk et al 2012 (p.720)31 ............................................................................................................................... 131 Table 15 Summary of seven RCTs measuring mental health ......................................................... 134 Table 16: RCTs that assessed for breast cancer recurrence .......................................................... 141 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..................................................................................................... 143 Table 18. Ongoing trials as of July 2014 ............................................................................................. 150 Table 19. Algorithm for including-excluding by abstract ............................................................... 166 Table 20 Key menopausal symptoms reported in the 4 additional RCTs .................................... 173 Table 21 Summary of 4 RCTs (level II) reporting the effects of high priority interventions in women after breast cancer treatment..................................................................... 174 Table 22. Study characteristics of Recent RCTs of pharmaceutical therapies for menopausal symptoms in women after breast cancer ............................................ 180 Table 23. Study characteristics of Recent RCTs of complementary medicines and therapies for menopausal symptoms in women after breast cancer .................... 188 Table 24: Search for international guidelines and conference abstracts .................................. 194 Table 25. Characteristics of the five previously published systematic reviews .......................... 211 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review v Table 26: RCTs included by published systematic reviews but excluded from Cancer Australia’s primary evidence base ................................................................................. 214 Table 27. Diagnostic and Statistical Manual of Mental Disorders IV9: Criteria for Mood Disorders .............................................................................................................................. 217 Table 28. Suitable screening tools to measure psychological distress in breast cancer patients (Love, pp. 62-63)97 .............................................................................................. 219 Table 29. Screening tools not considered suitable for researching psychological distress in breast cancer patients (Love, p. 63)97 ......................................................... 219 Table 30. Screening tools considered suitable for specific applications (Love, p. 64) 97 .......... 219 Figures Figure 1. Forest plot of studies that assessed for vasomotor symptoms: Vasomotor outcome - Pharmaceutical interventions ....................................................................... 60 Figure 2. Forest plot of studies that assessed for vasomotor symptoms: Vasomotor outcome - Complementary therapies ............................................................................ 62 Figure 3. Forest plot of studies that assessed for vasomotor symptoms: Vasomotor outcome - Other therapies ................................................................................................ 63 Figure 4. Mean Sexual Activity Questionnaire-Habit scores at baseline, 3 months and 6 months28, 88 ............................................................................................................................. 95 Figure 5 Mean scores reported on Short Form-36 mental health ................................................. 135 Figure 6 Inclusion and exclusion of articles ....................................................................................... 168 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review vi Acknowledgments 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 Hart Fertility Specialist (Chair) Ms Petrina Burnett Consumer Professor Michael Friedlander Medical Oncologist Professor Martha Hickey Obstetrician & Gynaecologist Ms Mary Macheras-Magias Consumer Associate Professor Nicole McCarthy Medical Oncologist Dr Michelle Peate Behavioural Scientist Dr Lesley Ramage General Practitioner Ms Karen Redman Breast Care Nurse Practitioner Dr Kirsty Stuart Radiation Oncologist Professor Owen Ung Surgeon Dr Amanda Vincent Endocrinologist Professor Kate White Cancer 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 Norris Principal Adviser, Guideline Development Dr Nerissa Soh Manager, Evidence Review Dr Vivienne Milch Manager, Breast Cancer Dr Briony Jack Senior Project Officer, Cancer Care Dr Jennifer Taylor Senior Project Officer, Cancer Care Ms Sherin Chikhani Project Officer, Evidence Review Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review vii 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 be placebocontrolled 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). Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 8 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)4-8 that 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 tibolone is 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 were 20 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 17 RCTs 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, purpose-designed 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. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 9 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 health scores 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 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 10 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 Safety Breast cancer recurrence There was no level I evidence from systematic reviews for the recurrence of breast cancer in women who have received breast cancer treatment and were administered menopause hormone treatments. Three RCTs, which investigated menopause hormone therapy, reported on breast cancer recurrence as an outcome. One trial on menopause hormone therapy (HABITS, Holmsberg et al 2004)11 and another on tibolone (LIBERATE) (Kenemans et al 2009)12 reported a statistically significant increase of breast cancer recurrences in patients who had menopause hormone therapy. Due to the increased risk of recurrence, the Swedish HABITS and LIBERATE trials were terminated early. The third RCT (the Stockholm trial, von Schoultz et al 2005)13 did not report a significant increase in breast cancer recurrence but was still terminated early. While menopause hormone therapy is effective in reducing vasomotor symptoms in women who have received breast cancer treatment, there is evidence for an increased risk of breast cancer recurrence. Adverse events Adverse events were poorly and inconsistently reported by the Primary Evidence Base. Consequently, to inform the development of the associated clinical practice guidelines, the systematic review presents safety data from the Therapeutic Goods Administration for the pharmaceuticals assessed by the Primary Evidence Base. Key side effects for antidepressants, which are the largest group of non-hormonal interventions assessed in this systematic review, include nausea, insomnia and gastrointestinal effects. For the anticonvulsants (gabapentin and pregabalin), key side effects are dizziness and drowsiness. In addition, complementary medicines and therapies may also have adverse effects, such as bleeding and bruising with acupuncture and gastrointestinal effects with phytoestrogens. This systematic review sought to identify level I and level II evidence for the safety and effectiveness of different interventions for managing menopausal symptoms in women who have received treatment for breast cancer. There has been a particular focus in the evidence for alternatives to menopause hormone therapies, due to concerns regarding breast cancer recurrence. The primary evidence base identified in the systematic review includes 49 level II studies. The majority of these studies were assessed as having a moderate or high risk of bias. Improvement in vasomotor symptoms was the primary outcome investigated by the majority of studies, with improvement in other symptoms typically assessed as secondary outcomes. Conclusion The systematic review has identified evidence for the treatment of vasomotor symptoms (hot flushes and night sweats) in women previously treated for breast cancer. There is level II evidence for the efficacy of: paroxetine, venlafaxine, clonidine, gabapentin, tibolone, CBT, CBT combined with exercise, purposed design hypnotherapy and yoga. There is also limited evidence for the efficacy of acupuncture and short-term relaxation therapy. For other menopausal symptoms, including sleep disturbances, vulvovaginal symptoms, psychological Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 11 wellbeing and global quality of life, evidence for the effectiveness of individual interventions is limited. In addition, the quality and consistency of the assessment and reporting for these symptoms has been poor. Further studies with larger study samples and greater methodological rigour are needed to assess treatments for sleep disturbances, vulvovaginal symptoms, psychological wellbeing and global quality of life. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 12 1 Introduction Whilst menopause hormone therapy is recognised as efficacious for managing menopausal symptoms in general, its use in women with a history of breast cancer is now either contraindicated or used with caution. Women may experience menopausal symptoms early – that is, before natural menopause – because of the treatments used in breast cancer. Substantial proportions of women diagnosed with breast cancer are diagnosed prior to menopause and consequently receive treatment prior to menopause. Among these women, a substantial proportion will experience menopause and/or menopausal symptoms induced by their treatment and the symptoms are often more severe than in women who have undergone natural menopause. Further, treatments for breast cancer may trigger menopausal symptoms in women who are post-menopausal. This significant burden on the wellbeing of women supports the need to consider the management of menopausal symptoms in women being treated, or who have had treatment, for breast cancer. 1.1 Management of menopausal symptoms in women with a history of breast cancer The management of menopausal symptoms in women with a history of breast cancer is complex, as systemic menopause hormone therapy or hormone replacement therapy (menopause hormone therapy), which is effective, is generally contraindicated in this patient group.14 Potential non-hormonal treatment options to manage hot flushes include antidepressants, antihypertensives, anticonvulsants, complementary and alternative therapies such as vitamins, phytoestrogens and black cohosh and acupuncture.14, 15 Other non-hormonal treatments for managing other symptoms of menopause include vulvovaginal treatments (such as vaginal lubricants and moisturisers) for vaginal dryness and dyspareunia14, 15 and cognitive behavioural therapy (CBT) and physical activity for sleep disturbance and psychological symptoms.14 1.2 Treatment-induced menopause in breast cancer A substantial number of women with breast cancer are diagnosed, and thus will undergo treatment, before menopause. In one Australian cohort, 42% of women with breast cancer were diagnosed when premenopausal.3 Ovarian failure, menopause and/or menopausal symptoms may be induced in women treated for breast cancer by chemotherapy, cessation of oestrogen-containing hormone therapy, endocrine therapy or oophorectomy.3 Premature menopause is medically defined as menopause occurring before 40 years of age.16 The reported incidence of treatment-induced amenorrhoea varies, including by treatment type, with reported rates ranging from 21% of premenopausal women with breast cancer 17 to 78% of pre- and perimenopausal participants with hormone-sensitive breast cancer having chemotherapy-induced amenorrhoea.18 In Australia, Hickey et al 20103 reported that 42% of their cohort of 578 women with breast cancer were diagnosed when premenopausal, 12% perimenopausal and 42% postmenopausal. Twenty-nine per cent of the cohort reported at the time that they had chemotherapy-induced ovarian failure and another 25% had menopausal symptoms induced by other treatments such as endocrine therapy or Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 13 oophorectomy.3 The incidence of breast cancer in Australian women in 2010 was 14,181 and among women aged 20-49 years, there were 3,248 new cases diagnosed in 2010, which was just over a fifth of all new cases diagnosed that year. 2 If 54% of Australian women diagnosed with breast cancer have treatment induced ovarian failure and/or menopausal symptoms 3, it indicates a large number of individuals will be affected. Further, the experience of menopause may be “normal” for women aged in their 50s but for younger women, the changes associated with menopause can be highly distressing and have a negative impact on their quality of life.14 1.3 Symptoms and their prevalence Menopausal symptoms include vasomotor symptoms (hot flushes and night sweats), sleep disturbances, vaginal dryness and psychosocial issues. Duijts 201119 in the Netherlands surveyed 435 women who were premenopausal at the time of diagnosis for breast cancer and then experienced premature menopause induced by treatment, reporting that 58% had medium to high frequency of hot flushes and night sweats. Duijts19 also reported that 21% of their cohort had very high frequencies of hot flushes, night sweats and vaginal dryness, with 53% experiencing moderate to high frequency while 15% had very high frequency. The reported prevalence of depression in breast cancer survivors overall varies greatly, from 1% to 56%, and depends partly on how depression was defined by a study.20 For example, the prevalence in Australian breast cancer survivors has been cited as 3% as measured by the Hospital Anxiety Depression Scale (HADS) and 22% as measured by Depression Anxiety and Stress Scale (DASS).20 Factors associated with depression in breast cancer survivors include fatigue, lower socio-economic status, lower education levels, younger age, being single, having greater numbers of children, pain, sleep disturbance and low sexual desire. 20 Depression is also associated with lower quality of life.20 In Hickey et al 2010 Australian study of 578 women with breast cancer 3, hot flushes, night sweats, loss of interest in sex, sleeping difficulties and fatigue were the most common and severe menopausal symptoms reported. Fifty-one per cent of the women had extreme trouble with between one and five of the menopausal symptoms in the Greene Climacteric Scale.3 The inter-relation between symptoms confounds 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 such as financial pressures or family issues. 1.4 Severity Women with menopausal symptoms induced by breast cancer treatment often face more severe symptoms than do women experiencing natural menopause.14, 21 A Canadian prospective study reported that a significantly greater percentage of women with chemotherapy-induced menopause experienced moderate to severe hot flushes than women who had recently undergone natural menopause.1 Severity of menopausal symptoms is of significant concern as up to 20% of breast cancer patients consider ceasing their endocrine treatment because of such symptoms, even though the treatment reduced breast cancer recurrence.21 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 14 1.5 Australian clinical practice guidelines The National Breast Cancer Centre† (NBCC) Clinical practice guidelines for the management and support of younger women with breast cancer were published in 2004,22 and provide information on the management of younger women with breast cancer, who may be more likely to be affected by treatment-induced menopause. 22 1.6 Current systematic review The present systematic review was undertaken to identify RCTs published since 2001 that investigate the management of menopausal symptoms in women who have received breast cancer treatment. This review will support the development of clinical practice guidelines for the management of menopausal symptoms in this population of women. In February 2008 National Breast Cancer Centre incorporating the Ovarian Cancer Program (NBCC) changed its name to Natonal Breast and Ovarian Cancer Centre (NBOCC). In July 2011, NBOCC amalgamated with Cancer Australia to form a single national agency, Cancer Australia. † Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 15 2 Methods This systematic review addresses the following research question that was developed in consultation with a multidisciplinary working group: What is the effectiveness of interventions for the management of menopausal symptoms in women who have received treatment for breast cancer? 2.1 Inclusion criteria English language. Published from January 2001 to January 2014. Randomised controlled trials, including placebo-controlled trials and head-to-head trials, open label trials. Meta-analyses, reviews and systematic reviews of RCTs, were included. No direct restriction was applied regarding age: results available for age ranges, as reported by studies, are included in the results of the systematic review. No direct restriction was applied regarding type of cancer treatments received by participants: for studies that report the types of cancer treatments their participants have undergone, this was noted in the results of the systematic review. Population Women who are undergoing or who have completed treatment for breast cancer and who are experiencing one or more menopausal symptoms as defined below. Intervention / Comparator Various hormonal interventions Non-hormonal pharmaceutical interventions Non-pharmaceutical interventions (complementary medicines and therapies): o Physical interventions, such as exercise and diet, controlled breathing, yoga o Psychological interventions, such as psychological therapies, hypnotherapy o Relaxation therapies o Acupuncture o Herbal medicines, homeopathy. Outcome measures Improvement/reduction of menopausal symptoms: vasomotor symptoms (hot flushes and/or night sweats), sleep disturbances, vulvovaginal symptoms including vaginal dryness, psychological wellbeing, global quality of life, breast cancer recurrence and adverse events. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 16 Modifications to methodology The original search was focused on identifying younger breast cancer patients specifically with treatment-induced menopause (rather than natural menopause). However, as breast cancer populations often included a broad age range as well as women with menopause from any cause, the exact percentage of women with treatment-induced menopause was often not reported. In consultation with working group members, the population of interest was broadened to include any women with a history of breast cancer experiencing menopausal symptoms. Where available, percentages of women with treatment-induced menopause and age ranges are recorded. The primary search for evidence was restricted to RCTs (level II evidence). For key interventions where no RCTs were identified in the target population, a supplementary search was undertaken in a broader population (women with menopause) and restricted to level I evidence. 2.2 Exclusion criteria Articles were excluded if they met any of the following criteria: Dissertations, which therefore were not published in a peer-reviewed journal. Not published in the English language. Published before 2001. Study populations were not women who had breast cancer. Study populations were women who were at risk of breast cancer but who did not have a personal history of breast cancer. Interventions were not for the purpose of treating menopausal symptoms. Outcomes were not the outcomes described above in the inclusion criteria. Not indexed in PubMed, Medline, Embase, PsycInfo, Cochrane Database or CINAHL. Studies with 10 or fewer participants commencing an intervention in any one arm were excluded. 2.3 Literature search Electronic database search The following electronic databases were searched: PubMed Medline (OVID) Embase (OVID) PsycInfo (OVID) Cochrane Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 17 CINAHL Key terms for conducting the searches were developed with input from the working group members. The databases searches were conducted in January 2014 (Appendix A: Literature databases searched and Appendix B: Search strategy). The searches from PubMed (2,313 citations), Medline (1,826 citations), PsycInfo (306 citations), Embase (1,179 citations), Cochrane (eight citations) and CINAHL (381 citations) were combined into a single Endnote library and duplicate citations were removed. This yielded 4,157 citations. Inclusion-exclusion of articles Two reviewers independently reviewed the 4,157 citations. 1. An initial review by title yielded 2,221 citations for abstract review. 2. Review by abstract resulted in 247 citations for full text review and 212 remaining as background articles 3. Review by full text yielded 46 RCTs, seven systematic reviews published from 2007 to 2013 and seven other comparative studies. An additional two clinical practice guidelines, nine non-systematic review articles and 29 single arm studies were excluded from further analyses. 4. Two systematic reviews were further excluded as they included mixed cancer populations and did not stratify results by cancer type. 5. The remaining 46 RCTs were reconciled with the reference lists of the included five systematic reviews from 2010 to 2013. Trials with 10 or fewer participants in any one arm were excluded. This resulted in 45 studies comprising the Primary Evidence base, of which 26 were included in one or more of the five published systematic reviews and 19 studies (15 RCTs with four sub-studies or updates) that were published more recently. Details of inclusion and exclusion criteria and the reviewers’ decision algorithm are presented in Appendix C: Inclusion and exclusion criteria and decision algorithms and Appendix D: Flowchart for inclusion-exclusion of articles. Databases for ongoing trials The following databases were searched to identify relevant ongoing trials: The World Health Organisation International Clinical Trials Registry Platform Search Portal. This portal includes the various international registries which are updated according to a pre-specified schedule. Australian Clinical Trials Registry ClinicalTrials.gov (US based) Current Controlled Trials (UK based) Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 18 External sources and web-based searches In addition to the electronic literature search the following sources were also reviewed for relevant information: Peer reviewed studies recommended for inclusion by Working Group members, which were not identified by the search strategies in the above databases, including background articles. Conference abstracts searched for from the following associations: o American Society of Clinical Oncology (ASCO) http://www.asco.org/ o San Antonio Breast Cancer Symposium (SABCS) http://www.sabcs.org/ o North American Menopause Society o American Society for Reproductive Medicine o Australasian Menopause Society o International Menopause Society o British Menopause Society International guidelines were searched for using the following sources: o Guidelines International Network o National Institute for Health and Care Excellence (NICE) o National Health and Medical Research Council (NHMRC) guideline portal o National Guidelines Clearinghouse o New Zealand Guidelines Group (NZGG) o Scottish Intercollegiate Guideline Network (SIGN) o Cancer Care Ontario o National Comprehensive Cancer Network (NCCN) o Australasian Menopause Society o Endocrine Society o North American Menopause Society o Google While the conference abstract search identified some relevant abstracts, these had either been superseded by full text publications of the trials or did not provide detailed outcome data. Therefore no further abstracts were included from these searches. The guideline website search identified 11 guidelines and position statements with relevant information with regards to management of menopausal symptoms and/or psychosocial support in breast cancer patients. 2.4 Data extraction Data extraction for each included paper was completed by one reviewer and verified by a second reviewer for accuracy. The data extracted from each paper included study characteristics such as population, interventions, study design and study outcomes, as well as risk of bias assessment. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 19 2.5 Risk of bias The inherent risk of bias in the study design was assessed using criteria based on NHMRC guidance, for systematic reviews and RCTs.23 For systematic reviews the following items were considered: whether an adequate search strategy and appropriate inclusion criteria were used, whether quality assessment was performed whether results were summarised and data pooled appropriately; and whether any heterogeneity was explored. For RCTs the following items were considered: the method of treatment assignment (randomisation method, blinding) and minimisation of selection bias (intention-to-treat analysis, follow-up), whether outcome assessment was standardised, whether baseline characteristics were balanced between groups; and whether the study was adequately powered to detect differences in the outcomes investigated. A reviewer then made a judgement as to whether the risk of bias of a study was high, moderate or low. 2.6 Quality of reporting of secondary outcomes The quality of reporting secondary outcomes was assessed separately from the risk of bias in the study design. For secondary outcomes the following items were considered: whether a validated measure was used whether treatment dose and duration was sufficient to elicit treatment effects whether the size of the study sample was adequate to reveal treatment effects, especially as studies were powered for primary outcomes. The quality of reporting secondary outcomes was subjectively rated into three categories (good, fair, poor) according to the criteria listed above. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 20 3 Results 3.1 Introduction to results Primary Evidence Base: its composition and derivation The Primary Evidence Base is composed of the studies that met the inclusion criteria and encompasses RCTs assessed by five previously published systematic reviews and trials published after those systematic reviews that met the inclusion criteria. Of the five previously published systematic reviews that met the inclusion criteria, the Cochrane Review by Rada et al (2010) and Comité de l’évolution des pratiques en oncologie (CEPO/L’Esperance et al, 2013) are the two key systematic reviews and summarise a range of interventions used to treat hot flushes in women with breast cancer. Rada et al (2010)4 includes RCTs which compare non-hormonal therapies with placebo. The more recently published review by L’Espérance et al (2013)5 includes head-to-head trials but does not include some therapies such as acupuncture and behavioural therapy. The remaining three systematic reviews by Dos Santos et al (2010)8, Chao et al (2009)6 and Lee et al (2009)7 focused on acupuncture and electro-acupuncture in the management of vasomotor symptoms. More than half of the trials identified by these five systematic reviews (26 out of 40) met the inclusion criteria for the Cancer Australia systematic review. The other trials included by the five published systematic reviews but not included by Cancer Australia, were either published before 2001, contained a mixed cancer population (including breast cancer but not stratified by cancer type), or were not focused on menopausal symptoms. See Appendix J: Additional tables of interest for reasons for exclusion (section 14.2 RCTs excluded from this systematic review’s Primary Evidence Base, Table 26). A further 19 studies (15 RCTs and four sub-studies or updates) had not been included in the published systematic reviews, either due to recent publication or because they included interventions or comparisons which were not included in the other reviews. Thus, a total of 45 studies were included in the Primary Evidence Base (Table 1) and were subsequently extracted for data. Table 1: Primary Evidence Base (45 RCTs), comprised of 19 Recent RCTs and substudies/updated studies, and 26 RCTs included by the five published systematic reviews Individual trial reference Intervention investigated Current Cancer Australia systematic review Published systematic reviews CEPO 20135 Rada 20104 Dos Santos 2010*8 Lee 20097 Country Chao 2009*6 15 individual RCTs, 4 sub-studies and updates Bupropion Brazil Bokmand 201325 Acupuncture Denmark Ahimahalle 201226 Gabapentin Iran Lavigne 201227, updated Gabapentin USA Nuñez 201324 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 21 Individual trial reference Intervention investigated Current Cancer Australia systematic review Published systematic reviews CEPO 20135 Rada 20104 Dos Santos 2010*8 Lee 20097 Country Chao 2009*6 analysis of Pandya 2005 Duijts 2012#28 CBT, Exercise, CBT+Exercise The Netherlands Mann 201229 CBT UK Liljegren 201230 Acupuncture Sweden Frisk 201231, updated study of Frisk 2008, substudy of Holmberg 2004, HABITS Electroacupuncture vs Menopause hormone therapy Holmberg 200411 Menopause hormone therapy (HABITS) Fahlén 201132, sub-study of von Schultz 2005, Stockholm trial Von Schoultz 200513 Sweden Menopause hormone therapy Sweden (Stockholm trial) Sismondi, 201133 (LIBERATE), updated study of Kenemans 2009 Tibolone Multinational Kenemans 200912 Lee 201134 Vaginal gel South Korea Walker 2010#35, Acupuncture vs venlafaxine USA Joffe 201036 Zolpidem USA Yoga USA Hypnotherapy USA Menopause hormone therapy UK Carson Elkins 200937 200838 Marsden 200139 26 studies included in published systematic reviews, 25 RCTs and one updated study Loprinzi 200240 Fluoxetine USA Stearns 200541 Paroxetine USA Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 22 Individual trial reference Intervention investigated Current Cancer Australia systematic review Published systematic reviews CEPO 20135 Rada 20104 Dos Santos 2010*8 Lee 20097 Country Chao 2009*6 Kimmick 200642 Sertraline Wu 200943 Sertraline Carpenter 200744 Venlafaxine Boekhout 2011#45 Venlafaxine vs Clonidine The Netherlands Buijs 2009#46 Venlafaxine vs Clonidine The Netherlands Loibl 2007#47 Venlafaxine vs Clonidine Germany Bordeleau 2010#48 Gabapentin vs Venlafaxine Canda Pandya 200549 Gabapentin Gabapentin vs Vitamin E Acupuncture vs Menopause hormone therapy Relaxation therapy Biglia 2009#50 Frisk 2008#51 (Sub-study of Holmberg 2004, HABITs study) Fenlon 200852 Nedstrand 200553 USA USA USA USA Italy Sweden UK Nedstrand 200654, same cohort as Nedstrand 2005 Acupuncture vs Applied relaxation Deng 200755 Acupuncture Acupuncture Carpenter 200257 Magnetic therapy Jacobs 200558 Homeopathy USA Thompson 200559 Homeopathy UK Hernández Muñoz and Pluchino 200360 Black cohosh Venezuela Jacobson 200161 Black cohosh USA Pockaj 200662 Black cohosh USA MacGregor 200563 Isoflavones UK Van Patten 200264 Isoflavones Canada Hervik 200956 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Sweden USA Norway USA 23 Individual trial reference Nikander 200365 Intervention investigated Phytoestrogens Current Cancer Australia systematic review Published systematic reviews CEPO 20135 Rada 20104 Dos Santos 2010*8 Lee 20097 Country Chao 2009*6 Finland In regard to sub-studies and updates*, four studies were identified as having parent RCTs. One RCT on gabapentin by Pandya et al (2005)49 was previously reported in the systematic reviews and now has a recently published analysis focusing on anxiety by Lavigne et al (2012)27 from the same cohort. Also, two trials investigating menopause hormone therapies (HABITS by Holmberg et al 200411 and Stockholm trials by Von Schoultz et al 2005)13 had smaller sub-studies associated with them (Frisk et al 200851 and 201231 for the HABITS study and Fahlen et al 201132 for the Stockholm trial)*. Outcomes reported in the Primary Evidence Base Table 2 indicates which outcomes were reported in each individual study, including each study’s risk of bias. Active-controlled/head-to-head trials are listed in all relevant sections and therefore there is some duplication. The relevant intervention for each section is in bold. Dots indicate that the outcome was reported in the individual paper, however they do not indicate whether it was statistically significant or the direction of any effect (if present). All outcomes were extracted in the present systematic review by Cancer Australia. As described in the Introduction, menopausal symptom outcomes are complex and interrelated. For this systematic review, the outcomes are reported in the following groupings: Vasomotor symptoms: includes hot flushes and night sweats. Sleep disturbance: includes restless sleep, sleepiness, trouble sleeping, difficulty sleeping, interrupted sleep, unrefreshing sleep, and insomnia. Vulvovaginal symptoms: includes sexual desire (libido), sexual activity (frequency or habit), sexual pleasure, pain or discomfort during intercourse (vaginal symptoms or dyspareunia) and orgasm. Psychological wellbeing: includes clinical depression and anxiety, mood, emotional wellbeing, and mental health. Global quality of life: includes studies that report the overall or global quality of life scores. Breast cancer recurrence: as a primary outcome measure (not a measure of individual adverse events). Of the 45 studies, 12 had high risk of bias, 22 had moderate risk of bias and 11 had low risk of bias (see Table 2). A sub-study denotes that a sub-set of participants from the original cohort of a parent study were analysed. An updated analysis or updated study denotes a more recently published study presenting additional data or analyses from the same cohort in the parent study. * Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 24 Table 2: Menopausal symptoms and other outcomes reported in individual RCTs, including drug dosages and study risk of bias Individual trial reference Intervention Vasomotor symptoms Sleep Vulvovaginal Psychological Global disturbance symptoms Wellbeing QOL ● ● ● Breast cancer recurrence Risk of Bias Pharmaceutical Interventions Antidepressants and sedatives Nunez 201324 Bupropion (150mg/d for 3d, then 150mg x 2/d for 4wk) ● Loprinzi 200240 Fluoxetine (20mg/d) ● ● ● ● ● Stearns 200541 Paroxetine (10mg/d and 20mg/d) ● ● ● ● ● Kimmick 200642 Sertraline (50mg/d) ● ● ● Sertraline (25-100mg/d) ● ● Wu 200943 Carpenter 200744 Venlafaxine (37.5mg/d or 37.5mg/d for 1wk, 75mg/d for 4wk, then 37.5mg/d for 1wk) ● ● Boekhout 2011# 45 Venlafaxine (75mg/d) vs Clonidine (0.1mg/d) ● ● ● ● Buijs 2009# 46 Venlafaxine(75mg/d) vs Clonidine (0.05mg/d) ● ● ● ● Loibl 2007# 47 Venlafaxine(37.5mg/d) vs Clonidine (0.075mg/d) ● ● Bordeleau 2010# 48 Gabapentin (300mg/d for 3d, 600mg/d for 3d, 900mg/d for 22d, then 100mg/d for 3d) vs Venlafaxine (37.5mg/d for 7d, 75mg/d for 21d, then 37.5mg/d for 3d) Moderate Low Low Moderate Moderate Moderate ● ● Low Moderate Moderate Moderate ● Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review ● ● ● 25 Individual trial reference Walker 2010# 35 Intervention Vasomotor symptoms Sleep Vulvovaginal Psychological Global disturbance symptoms Wellbeing QOL Acupuncture (2 times/wk for 4wk, then 1/wk for 8wk) vs Venlafaxine (37.5mg/d for 1wk, then 75mg/d for 11wk) ● ● ● Zolpidem(10mg/d), in addition to SSRI ● ● ● Boekhout 2011# 45 Venlafaxine (75mg/d) vs Clonidine (0.1mg/d) ● ● ● ● Buijs 2009# 46 Venlafaxine(75mg/d) vs Clonidine (0.05mg/d) ● ● ● ● Loibl 2007# 47 Venlafaxine (37.5mg/d) vs Clonidine (0.075mg/d) ● ● Gabapentin (300mg/d) vs megestrol acetate (40mg/d) ● Joffe 201036 Breast cancer recurrence Risk of Bias Moderate ● Moderate Antihypertensives ● Low Moderate Moderate Anticonvulsants Ahimahalle 201226 Lavigne 201227 Pandya 200549 Bordeleau 2010# 48 Biglia 2009# 50 Gabapentin (300mg/d and 900mg/d) High ● ● ● Gabapentin (300mg/d for 3d, 600mg/d for 3d, 900mg/d for 22d, then 100mg/d for 3d) vs Venlafaxine (37.5mg/d for 7d, 75mg/d for 21d, then 37.5mg/d for 3d) ● ● Gabapentin (300mg/d for 3d, 600mg/d for 3d, then 900mg/d for rest of 12wk ● ● Moderate Moderate Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review ● ● ● 26 Moderate Individual trial reference Intervention Vasomotor symptoms Sleep Vulvovaginal Psychological Global disturbance symptoms Wellbeing QOL ● ● ● ● Breast cancer recurrence Risk of Bias study) vs vitamin E (800IU/d) Menopause hormone therapy Fahlen 201132 (Stockholm trial), sub-study of Von Schoultz 2005 Von Schoultz 200513 Menopause hormone therapy (2mg/d cyclic oestradiol for 21d with 10mg medroxyprogesterone High acetate for the last 10d, or 2mg/d oestradiol for 84d ● with 20mg/d medroxyprogesterone acetate for the last 14d) Frisk 2008# 51, HABITS substudy, Holmsberg 2004 Frisk 2012# 31, update of Frisk 2008, HABITS substudy Holmberg 200411, HABITS study Electro-acupuncture (30min 2 times/wk for 2 wks, then 1 time/wk for 10 wks) vs menopause hormone ● High ● ● ● therapy (sequential or High continuous combined oestrogen/progestagen, dosage not stated) ● (Dosage not stated in Holmberg 2004)) Marsden 200139 Kenemans 200912, High Menopause hormone therapy (2mg/d oestradiol valerate, with 75μg levonorgestrel in women with an intact uterus) Tibolone (2.5mg/d) ● Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review ● ● ● ● ● 27 Low Individual trial reference Intervention Vasomotor symptoms Sleep Vulvovaginal Psychological Global disturbance symptoms Wellbeing QOL ● ● ● Breast cancer recurrence Risk of Bias LIBERATE trial Sismondi 201133, update of Kenemans 2009, LIBERATE trial ● Other Lee 201134 Low ● Vaginal gel (3 times/wk) Complementary Medicine and Therapy Psychological and physical interventions Duijts 2012# 28 CBT (90min/wk), Exercise (2.5-3h/wk), CBT+Exercise ● Mann 201229 CBT (90min/wk for 6wks) ● ● Elkins 200838 Hypnotherapy (1 time/wk) ● ● Nedstrand 2005# 53 Electro-acupuncture (30min 2 times/wk for 2wks, then 1 time/wk for 10wks) vs relaxation ● 2006# 54, Nedstrand updated study of Nestrand 2005 ● ● ● ● Moderate ● Moderate ● Moderate ● High Acupuncture and electro-acupuncture Bokmand 201325 Acupuncture (1 time/wk for 5wks) ● Deng 200755 Acupuncture (2 times/wk for 4wks) ● Hervik 200956 Acupuncture (30min 2 times/wk for 1wk, then 1 time/wk for 5wks) ● Acupuncture (20min 2 times/wk) ● Liljegren 201230 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Low ● Moderate Low Moderate 28 Individual trial reference Nedstrand 2005# 53 Nedstrand 2006# 54, updated study of Nedstrand 2005 Frisk 2008# 51, sub-study of HABITS study, Holmberg 2004 Frisk 2012# 31, updated study of Frisk 2008, HABITS sub-study) Walker 2010# 35 Intervention Electro-acupuncture (30min 2 times/wk for 2wks, then 1 time/wk for 10wks) vs relaxation Electro-acupuncture (30min 2 time/wk for 2 wks, then 1 time/wk for 10 wks) vs Menopause hormone therapy (sequential or continuous combined oestrogen/progestagen, dosage not stated) Vasomotor symptoms Sleep Vulvovaginal Psychological Global disturbance symptoms Wellbeing QOL Breast cancer recurrence Risk of Bias ● ● High ● ● Moderate ● Acupuncture (2 times/wk for 4wk, 1/wk for 8wk) vs Venlafaxine (37.5mg/d for 1wk, 75mg/d for 11wk) ● Relaxation therapy ● Electro-acupuncture (30min 2 times/wk for 2wks, then 1 time/wk for 10wks) vs relaxation ● Yoga ● ● ● Moderate ● ● Relaxation Fenlon 200852 Nedstrand 2005# 53 Nedstrand 2006# 54, updated study of Nedstrand 2005 ● ● ● ● Low High Yoga Carson 200937 ● ● Moderate Other therapies Jacobs 200558 Homeopathy (amyl nitrate 3x 1:1000 dilution, Sanguinaria canadensis 3x 1:1000 dilution and Lachesis 12x 1:1012 dilution) High ● Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 29 Individual trial reference Intervention Vasomotor symptoms Sleep Vulvovaginal Psychological Global disturbance symptoms Wellbeing QOL ● ● Breast cancer recurrence Risk of Bias in 3 tablets/d Thompson 200559 Homeopathy (fluctuating dosages) ● Hernandez Munoz 200360 Black cohosh (20mg/d) with tamoxifen (20mg/d) ● Black cohosh (2 tablets/d, dosage not reported) ● Black cohosh (20mg/d) ● MacGregor 200563 Isoflavones (70mg/d isoflavines) ● Van Patten 200264 Isoflavones (soybean beverage, 90mg isoflavones/d) ● Nikander 200365 Phytoestrogens (114mg/d, 58% glycitein, 36% daidzein, 6% genistein) ● Biglia 2009# 50 Gabapentin (300mg/d for 3d, 600mg/d for 3d, then 900mg/d for rest of 12wk study) vs Vitamin E (800IU/d) ● Magnetic therapy ● Jacobson 200161 Pockaj 200662 Carpenter 200257 #also Low High Low Moderate ● Low High Moderate ● Moderate ● ● ● listed in other sections, active-controlled trial; relevant intervention for each section in bold. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 30 Moderate Categories of interventions investigated by the Primary Evidence Base For the purposes of this systematic review, interventions are defined as Pharmaceutical: a prescribed drug intervention o Antidepressants Atypical antidepressants Selective serotonin re-uptake inhibitors (SSRIs) Serotonin noradrenaline re-uptake inhibitors (SNRIs) o Antihypertensives o Anticonvulsants o Menopause hormone therapies (or hormone replacement therapies) o Sedatives o Topical gels with a pharmacological effect (e.g., alters pH or has a hormonal effect) Complementary medicines and therapies o Psychological treatments Cognitive behavioural therapy Hypnotherapy o Physical exercise o Acupuncture o Yoga o Relaxation o Other complementary treatments Herbal remedies Homeopathy Magnetic therapy. Each intervention that was assessed for a particular menopausal symptom or outcome is reported on in the individual outcome results sections below. If the intervention is not stated under a particular outcome, it indicates that no RCT meeting the inclusion criteria investigated this intervention as a treatment for that particular symptom. Table 3 shows the characteristics of the drug interventions commonly used by women with a history of breast cancer, including those assessed by the Primary Evidence Base. The information was sourced from the Therapeutic Goods Administration’s drug product information. 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 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 31 Generic name Indications, as approved by the TGA Daily dose Duration of onset* Bupropion nicotine dependence 150 - 300mg not specified Citalopram major depression 20 - 40mg 2-3 weeks major depression 20 - 80mg 4 weeks obsessive compulsive disorder 20 - 80mg 5 weeks premenstrual dysphoric disorder 20mg 14 days major depression 20 - 50mg 2-3 weeks obsessive compulsive disorder 20 - 60mg not specified panic disorder 10 - 60mg not specified social anxiety disorder 20 - 50mg not specified major depression 50 - 200mg 2-4 weeks social anxiety disorder 25 - 50mg 2-4 weeks premenstrual dysphoric disorder 50 - 150mg 14 days 25 - 200mg 2 weeks major depression 75 - 225mg 2 weeks general anxiety disorder 75 - 225mg 1 week social anxiety disorder 75 - 225mg 1 week panic disorder 75 - 225mg 1 week hypertension 150 - 600mg not specified migraine prophylaxis 50 – 150mg 2 weeks menopausal flushing 50 – 150mg 2 weeks epilepsy 900 - 1800mg 2-3 days neuropathic pain 900 - 3600mg not specified neuropathic pain 150 - 600mg 3-7 days epilepsy 150 - 600mg 1 week insomnia 5-10mg immediate menopause symptoms 2.5mg not specified bone mineral density loss 2.5mg a few weeks breast cancer 20 - 40mg not specified Fluoxetine Paroxetine Sertraline obsessive compulsive disorder in children Venlafaxine Clonidine Gabapentin Pregabalin Zolpidem Tibolone Tamoxifen Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 32 Generic name Indications, as approved by the TGA Daily dose Duration of onset* male hypogonadism 100 - 200mg 15 days male testosterone deficiency 2.5 - 7.5mg not specified major depression 50 – 200mg not specified major depression 10 – 20mg 2-4 weeks social anxiety disorder 10 – 20mg not specified general anxiety disorder 10 – 20mg not specified obsessive compulsive disorder 10 – 20mg not specified Megestrol acetate Palliative treatment of breast cancer 160 mg not specified Vaginal oestrogen climacteric symptoms 0.3 – 1.25mg not specified Testosterone Desvenlafaxine Escitalopram * The minimum times from commencement of treatment to the onset of therapeutic effectiveness. Interventions for which no relevant studies were identified The following interventions were searched for but did not yield any individual RCTs, or RCTs as reviewed by published systematic reviews, that matched the inclusion criteria: The interventions for which no relevant studies were identified were: Pharmaceutical o Antidepressants Tetra-cyclic Mirtazapine Trazodone Selective serotonin re-uptake inhibitors (SSRIs) o Antipsychotic o Pregabalin Menopause hormone therapies o Veralipride Anticonvulsants o Citalopram Bioidentical hormone therapy Vaginal oestrogen Complementary medicines and therapies o Stellate ganglion block o Other complementary treatments Aromatherapy Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 33 Paced respiration Herbal remedies Ayurveda Belladonna Red clover St John’s wort Biofeedback Meditation Other interventions for menopausal symptoms known to be used include magnesium 67, olive oil68, vaginal exercises68, lactobacillus69, topical testosterone70, topical lidocaine71 and oxybutynin72, but were outside the scope of the present systematic review. 3.2 Vasomotor symptoms: hot flushes and night sweats Definition of vasomotor symptoms Vasomotor symptoms are defined in the present systematic review as hot flushes and night sweats. Table 4 provides a summary of the RCTs that investigated vasomotor symptoms and any significant differences reported between treatment groups. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 34 Previous systematic reviews In regard to level I evidence, five systematic reviews published between 2001 and 2013 4-8 examined the effects of treatment on vasomotor symptoms in women treated for breast cancer. The two key systematic reviews4, 5 investigated a range of therapies. Both key reviews reported that pharmacologic agents such as SNRIs/SSRIs, antihypertensive and anticonvulsant agents were effective in treating hot flushes in women with breast cancer. Non-pharmacologic agents were shown to have either no or limited effectiveness for alleviating hot flushes. The remaining three systematic reviews6-8 focused on acupuncture and electro-acupuncture. Primary Evidence Base Thirty-nine studies (36 RCTs with three updated analyses or sub-studies) out of the 45 studies in the full Primary Evidence Base reported on management of vasomotor symptoms. Of these studies, all assessed the frequency, severity and/or problems/bother of hot flushes, with four trials28, 30 37 61 also reporting on sweating and/or night sweats. Many of the studies measured frequency and intensity of vasomotor symptoms subjectively through the patients’ reports and therefore a level of bias may exist, but this is not considered a limitation. Table 5 presents the assessment tools used to measure vasomotor symptoms. Sixteen of the 39 studies used more than one method and 19 used a formal and standardised scale; only eight studies used a diary or logbook alone. The Kupperman’s Index (KI) was used by five of the studies and is a numerical index that scores 11 menopausal symptoms: hot flushes, paraesthesia, insomnia, nervousness, melancholia, vertigo, weakness, arthralgia/myalgia, headache, palpitations and formication. The maximum score on the Kupperman’s Index is 51 with higher scores indicating more severe menopausal symptoms. 73 A Hot Flash or Hot Flush Score was another commonly used measure. Nine RCTs used this Score, which encompasses both frequency and severity of hot flushes by multiplying frequency with the severity of a hot flush as recorded by a diary or logbook. The results of these studies are presented below and summarised in Table 4. Figure 1 to Figure 3 show Forest plots representing the magnitude and direction of impact of interventions on vasomotor symptoms. Pharmaceutical interventions Twenty-two studies (19 studies12, 24, 26, 32, 35, 36, 39-51 with three updated analyses)†27, 31, 33 investigated pharmaceutical interventions. Antidepressants Twelve studies investigated antidepressants. Of the antidepressants investigated, the SNRI venlafaxine is the better studied, with seven RCTs included in the Primary Evidence Base. Another four RCTs investigated SSRI antidepressants (one each for fluoxetine and paroxetine and two for sertraline) and one investigated the atypical antidepressant bupropion. Both Frisk et al (2008) and its updated study Frisk et al (2012) were sub-studies of the HABITS study by Holmberg et al (2004), but Holmberg et al (2004) did not assess vasomotor symptoms. † Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 35 Atypical antidepressant: bupropion The RCT by Nunez et al (2013)24 compared the atypical antidepressant bupropion (300mg/d) with placebo over 10 weeks. While there was a significant improvement in number and severity of hot flushes with both bupropion and placebo after 10 weeks, differences between the groups were not statistically significant, indicating a strong placebo effect. Selective serotonin re-uptake inhibitors: sertraline, fluoxetine and paroxetine Two RCTs compared sertraline to placebo. In Wu et al (2009)43 four week trial, women were given sertraline in dosages ranging from 25mg to 100mg/d: frequency of hot flushes and Hot Flash Scores (which incorporate both frequency and severity) did not differ from placebo at baseline or at the end of the trial. The frequency of hot flushes and Hot Flash Scores decreased from baseline in the sertraline group by week 6 but despite being twice the decrease of that in the placebo group, the difference between the groups was not statistically significant. Kimmick et al (2006)42 compared 50mg/d sertraline with placebo in a cross-over trial with two six-week study periods and reported that there was no difference in frequency at six weeks but at 12 weeks, cross-over analyses showed the group taking sertraline had reduced their frequency of hot flushes from week 6 by 0.9 flushes/day. This was a significantly greater improvement than in the group taking the placebo over weeks 6-12, who had increased frequency of hot flushes, by 1.5 flushes/day. Loprinzi et al (2002)40 compared fluoxetine (20mg/d) with placebo over nine weeks (two fourweek study periods in a cross-over trial). At four weeks, the frequency of hot flushes and Hot Flash Scores (encompassing both severity and frequency) decreased in both the placebo and fluoxetine groups but the difference between the groups was not significant. At the end of the trial (nine weeks), cross-over analyses showed women taking fluoxetine had significantly fewer hot flushes (median reduction by 1.5 flushes/d; p=0.01) and significantly lower Hot Flash Scores (median reduction by 3.1 units/d; p=0.02) compared with placebo. Severity of hot flushes did not differ significantly between treatment and placebo.40 Stearns et al (2005)41 conducted an RCT with four treatment arms, comparing paroxetine (10mg/d and 20mg/d) to placebo in a cross-over design (two four-week study periods). Analyses of participants who completed the full study showed both dosages of paroxetine significantly reduced the frequency of hot flushes from baseline when compared to the reduction in the placebo group, by 40.6% in the 10mg/d group (13.7% in corresponding placebo group) and 51.7% in the 20mg group (26.6% in the corresponding placebo group). Hot Flash Scores (encompassing severity and frequency) were also significantly reduced from baseline in both paroxetine groups when compared to placebo: 45.6% for the 10mg group (13.7% in the corresponding placebo group) and 56.1% in the 20mg group (28.5% in the corresponding placebo group). Twenty-nine per cent of participants only completed the first study period and when only the first study period was analysed and included these participants, the results were consistent with the full study’s data: compared to the placebo group, those on 10mg/d paroxetine significantly reduced the number of hot flushes by 51.0% and Hot Flash Scores by 53.9% from baseline while those on 20mg/d paroxetine had significantly reduced the number of hot flushes by 50.0% and Hot Flash Scores by 54.3% from baseline. In contrast, the placebo groups for both arms reduced their number of hot flushes by an average of 16.0% and their Hot Flash Scores by an average of 19.1% from baseline. However, the CEPO/L’Esperance systematic review5 notes that paroxetine is considered effective for breast cancer patients not being treated with tamoxifen but that paroxetine should be avoided for those on tamoxifen given it may reduce the efficacy of tamoxifen. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 36 Serotonin noradrenaline re-uptake inhibitors: venlafaxine Of the seven venlafaxine studies, five were head-to-head trials, one was placebo-controlled and one investigated the augmentation of venlafaxine and other SSRIs with the sedative zolpidem. Of the five head-to-head trials, three compared venlafaxine with the antihypertensive clonidine45-47, one with the anticonvulsant gabapentin 48 and one with acupuncture.35 The details of the RCT with zolpidem, by Joffe et al (2010),36 are presented below in the section Sedative: zolpidem (p38). The placebo-controlled RCT by Carpenter et al (2007) showed that over 14 weeks, venlafaxine (37.5mg/d )significantly improved the frequency of hot flushes from baseline as measured by electronic monitor compared with placebo (difference in percentage change from baseline between the groups was 22.6%). The decrease from baseline in the 37.5mg/d venlafaxine group was 22%. Severity of hot flushes over the 14 weeks, as recorded by diary, decreased by 4% in the venlafaxine group, but increased by 6% in the placebo group, the difference between the groups being significant. Carpenter et al (2007) also investigated 75mg/d venlafaxine as an intervention, but as there were only nine participants each in the intervention and placebo arms, the results will not be reported on further here.44 Boekhout et al (2011)45 compared three groups over 12 weeks: 75mg venlafaxine/d, 0.1mg/d of clonidine and placebo. At 12 weeks, there was no significant difference between venlafaxine and clonidine or between venlafaxine and placebo in Hot Flash Scores, which encompass both frequency and severity of hot flushes (see the section Antihypertensives: clonidine, p38, for Boekhout et al comparison between clonidine and placebo). However, the reduction in Hot Flash Scores from baseline in the venlafaxine group was significantly greater at 12 weeks that the reduction in the placebo group (41%). 45 Further, the effects of venlafaxine occurred more rapidly than with clonidine: over weeks 1-4, the decrease from baseline in Hot Flash Scores was 42% greater than that of the placebo group while the decrease in the clonidine group was only 22% greater than that of the placebo group. A second trial by Loibl et al (2007)47 compared twice-daily 37.5mg venlafaxine to twice-daily 0.075mg clonidine over four weeks. Hot flushes decreased from baseline by a median 7.6 per day in those receiving venlafaxine compared to only 4.85 per day in those receiving clonidine and the changes from baseline were significantly different between the groups. 47 Loibl et al (2007) did not assess for changes in severity of hot flushes. The third trial, by Buijs et al (2009),46 showed no significant difference in frequency or severity of hot flushes (Hot Flash Scores) between groups administered with venlafaxine (75mg/d) and clonidine (0.05mg/d) after eight weeks. Buijs et al (2009) reported both venlafaxine and clonidine reduced the median Hot Flash Scores (that is, severity and frequency) from baseline, with 50% of the women taking venlafaxine and 55% of those taking clonidine reported a 50% or greater reduction in Scores. However, the decreases from baseline were not significantly different between treatment groups. Regarding sweats, there was no difference in frequency between groups at weeks 2 and 8 and no significant decreases from baseline in either group: the decreases from baseline were not compared between groups. Bordeleau et al (2010)48 conducted a head-to-head cross-over trial comparing gabapentin (300mg/d increased to 300mg three times per day) with venlafaxine (75mg/d) over two fourweek study periods, where both gabapentin and venlafaxine significantly reduced frequency and severity of hot flushes according to Hot Flash Scores by an average of 66% and there was no significant differences between the groups. However significantly more patients (68%) preferred venlafaxine on the basis that it reduced hot flush severity and frequency by a greater degree and had fewer adverse effects. The 12 week trial by Walker et al (2010)35 comparing venlafaxine (75mg/d) with acupuncture (two sessions per week for four weeks and then once per week for eight weeks) reported that both acupuncture and venlafaxine significantly reduced hot flush frequency and severity (Hot Flash Diary) post-treatment by 50% from baseline, with a return towards baseline values at follow-up time points (up to 12 months). The changes from baseline were similar between Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 37 the groups. The effects of acupuncture were reported as lasting longer than venlafaxine after treatment, but this was not statistically tested for.35 Sedative: zolpidem The RCT by Joffe et al (2010)36 reported on the use of the sedative zolpidem (10mg/d) compared to placebo, in women who were taking venlafaxine or other SSRIs/SNRIs. No significant difference between zolpidem and placebo was observed for perceived daytime hot flushes or objectively measured night-time hot flushes. Antihypertensives: clonidine Three RCTs45-47 investigated clonidine and all were head-to-head studies with venlafaxine. Boekhout et al (2011)45 compared three groups over 12 weeks: 75mg venlafaxine/d, 0.1mg/d of clonidine and placebo. Frequency and severity of hot flushes, according to Hot Flash Scores, in the clonidine group were significantly lower than in the placebo group at 12 weeks (47.6% decrease from baseline versus 24.3% respectively). Also the reduction in Hot Flash Scores from baseline in the clonidine group (26%) was significantly greater than the reduction in the placebo group. Loibl et al (2007)47 compared 37.5mg twice per day venlafaxine to 0.075mg twice per day clonidine over four weeks, with venlafaxine being more effective than clonidine in reducing the frequency of hot flushes. Buijs et al (2009) 46 reported no significant difference in frequency or severity of hot flushes (Hot Flash Scores) or frequency of sweating between groups administered with venlafaxine (75mg/d) and clonidine (0.05mg/d) after eight weeks and that both drugs reduced the median Hot Flash Scores from baseline. More details of the effects of venlafaxine in the trials by Boekhout et al (2011), Loibl et al (2007) and Buijs et al (2009) are reported earlier (see Serotonin noradrenaline re-uptake inhibitors: venlafaxine, p37). Anticonvulsants: gabapentin Four studies investigated gabapentin. Of these, three were head-to-head trials and one was placebo-controlled. In an eight-week placebo-controlled trial by Pandya et al (2005)49 for two different doses of gabapentin (300mg/d and 900mg/d), only the 900mg/d dose showed a distinct benefit over placebo. The decrease in frequency of hot flushes from baseline for the 300g/day gabapentin group was 2.86 flushes/day at 8 weeks, which is slightly greater than the 2.25 flushes/day decrease in the placebo group. Changes in severity of hot flushes from baseline were not significant in the 300mg/d group (decrease of 7.75 units) when compared with placebo (decrease of 6.61 units). For the 900mg/d gabapentin group, the decrease in frequency of hot flushes from baseline at 8 weeks was 4.21 flushes/day, significantly greater than the 2.25 flushes/day decrease in placebo group, and the decrease in severity from baseline was also significant, at 9.94 units compared with 6.61 units in the placebo group.49 For the three head-to-head trials, one compared gabapentin to venlafaxine, one to vitamin E and one to megestrol acetate. Bordeleau et al (2010)48 conducted a head-to-head RCT comparing gabapentin with venlafaxine: this was reported on earlier (see Serotonin noradrenaline re-uptake inhibitors: venlafaxine, p37) where both gabapentin and venlafaxine improved hot flushes but there was no significant difference between the groups. Biglia et al (2009)50 compared gabapentin (900mg/d) to vitamin E (800IU/d) over 12 weeks. Gabapentin (900mg/d) significantly reduced the frequency of hot flushes by 32.37% and Hot Flush Score (encompassing severity and frequency) by 39.84% from baseline over 12 weeks. Vitamin E reduced the frequency of hot flushes (10.02%) and Hot Flush Score (7.28%) from Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 38 baseline but the reductions were not significant. However, Biglia et al (2009) did not directly compare between gabapentin and vitamin E arms. Ahimahalle et al (2012)26 compared gabapentin (300mg/d) with megestrol acetate (40mg/d), a palliative treatment for recurrent inoperable or metastatic breast cancer (see Table 3). After eight weeks of treatment, both groups showed significant improvements in hot flush frequency and severity compared with before treatment: the gabapentin group had 44.8% decreased frequency of hot flushes from baseline and a 24.6% decrease in severity, while the megestrol acetate group had a 64.3% decrease in frequency and 37.1% decrease in severity from baseline. However, the reductions in severity and frequency in the megestrol acetate arm were significantly greater than the reductions in the gabapentin arm. 26 Menopause hormone therapies Two RCTs and their respective updates investigated menopause hormone therapies. The LIBERATE trial, reported on by Sismondi et al (2011)33 and Kenemans et al (2009)12 had a median treatment duration of 2.75 years and found that tibolone (2.5mg/d) reduced the frequency of hot flushes from baseline at week 12 (43.1%) and this was significantly greater than the decrease in the placebo group (27.5%). Similarly, at week 104, the tibolone group had 65.6% decrease in frequency of hot flushes from baseline, which was significantly greater compared to the 52.5% decrease in the placebo group. Severity also decreased by 10.6% from baseline in the tibolone group at 12 weeks, which was a significantly greater reduction than that in the placebo group (7.7%); severity was not reported on at 104 weeks. Subgroup analyses were performed by adjuvant therapy, chemotherapy and age. Women on tamoxifen and tibolone reported less improvement in the number of hot flushes compared with those on tibolone without adjuvant therapy. The use of chemotherapy did not affect the number or severity of hot flushes. No differences in hot flushes were seen between age subgroups of <50, 50-59 and >60 years. The RCT by Frisk et al (2012)31 is an update of the study by Frisk et al (2008),51 comparing menopause hormone therapy (oestrogen/progestagen for 24 months) and electroacupuncture (30min twice a week for two weeks and then once per week for 10 weeks) on the frequency of hot flushes. Both interventions yielded significant decreases in frequency of hot flushes from baseline at each time point over 24 months. The electro-acupuncture group had a significant mean reduction of 6.4 flushes/day compared with baseline and a significant 18.1 unit decrease in Kupperman’s Index scores from baseline. The oestrogen/progestagen group also had a significant decrease in at 24 months in their Kupperman’s Index score, at 15.9 units from baseline (number of flushes/day not reported). Comparisons between groups were not reported on. Complementary medicines and therapies Psychological and physical interventions Cognitive behavioural therapy and exercise Two trials investigated CBT compared with wait-list controls (Duijts et al 2012)28 or usual care (Mann et al 2012).29 Mann et al (2012)29 investigated 90min CBT/week for six weeks compared with usual care. There were no significant improvements between treatment and control groups in their frequencies of hot flushes and nights sweats at nine or 26 weeks follow-up, nor were there significant changes within each group from baseline. For hot flushes/nights sweats problem ratings, the CBT group had significantly lower ratings than the usual care group at both nine Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 39 weeks (1.67 units) and 26 weeks (1.76 units). The decreases in problem ratings from baseline were also significantly greater in the CBT group than in the usual care group: 46% in the CBT group compared to 19% in the usual care group at nine weeks and 52% decrease from baseline in the CBT group compared to 25% in the usual care group at 26 weeks. Duijts et al trial28 included four arms: CBT (90min group session/week for six weeks), physical exercise (2.5-3h/week for 12 weeks), a combined CBT/exercise arm and a wait-list control. Significant improvements from baseline were observed in the combined CBT/exercise arm in the hot flushes/night sweats problem rating at both 12 weeks (decrease of 1.2 units) and six months (decrease of 0.84 units), similar to the CBT alone arm (decrease of 1.05 units at 12 weeks and 0.85 units at six months). In intention-to-treat analyses of the CBT/exercise group and the CBT alone groups, the decreases in hot flushes/night sweats problem ratings from baseline were significant when compared to the wait-list control group. Exercise alone did not improve either the hot flushes/night sweats problem rating at any time point compared with wait-list controls (Table 4). However, intention to treat analyses showed no significant differences between groups for improvements in hot flushes/night sweats frequency rating (data not reported). There was a high level of participant under compliance with the protocol (58% CBT, 64% exercise and 70% CBT/exercise) and when per-protocol analyses were conducted, the hot flushes/night sweats frequency rating also significantly improved in the CBT/exercise group compared with wait list controls at 12 weeks (decreased by 4.45 units) but this effect was no longer significant at six months follow-up. Hot flushes/night sweats problem ratings were still significantly reduced from baseline in this arm in per protocol analyses at 12 weeks (1.77 units) and six months (1.16 units). CBT alone did not significantly decrease the frequency of hot flushes and night sweats at either 12 weeks or six months in the per protocol analyses, although problem ratings were still significantly reduced from baseline at both 12 weeks (1.55 units) and six months (1.31 units). Exercise alone did not significantly reduce hot flush/night sweat problem ratings or frequency ratings at either time points in the per protocol analyses. Hypnotherapy One trial (Elkins 2008) investigated hypnotherapy (50min/week) compared to no treatment over five weeks.38 In the trial,38 hypnotherapy significantly reduced both hot flush frequency (4.39 units), Hot Flash Score (encompassing frequency and severity, 10.18 units) and Hot Flash Related Daily Interference Scale scores (29.1 units) from baseline and these differences were significantly greater than those in the control group (0.09 units decrease from baseline for hot flush frequency, 1.57 units decrease for Hot Flash Scores and 7.24 unit decrease in Hot Flash Related Daily Interference Scale scores). Acupuncture and electro-acupuncture Nine studies investigated acupuncture: Walker et al (2010)35, Frisk et al- (2008)51, Frisk et al (2012)31, Nedstrand et al (2005)53; Nedstrand et al (2006)54, Bokmand et al (2013)25, Deng et al (2007)55, Hervik et al (2009)56 and Liljgren et al (2012)30. Of these, Frisk et al (2012)31 is an updated follow-up RCT of the by Frisk et al (2008)51, representing the same cohort; Nedstrand et al (2005)53 and Nedstrand et al (2006)54 are also derived from the same cohort. Head to head trials of acupuncture The studies by Frisk et al (2012)31 and Frisk et al (2008)51 which investigated electroacupuncture and menopause hormone therapy, and the study by Walker (2010)35 which investigated acupuncture and venlafaxine have been described earlier (see section Serotonin noradrenaline re-uptake inhibitors: venlafaxine, p37 and section Menopause hormone therapies above). Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 40 Walker et al (2010)35 compared venlafaxine (37.5mg/d) with acupuncture (two sessions per week for four weeks and then once per week for eight weeks) reported that both acupuncture and venlafaxine reduced hot flush frequency and severity (Hot Flash Diary) post-treatment by 50% from baseline, with a return towards baseline values at follow-up time points (up to 12 months). The effects of acupuncture were reported as lasting longer than venlafaxine after treatment, but this was not statistically tested for.35 Frisk et al (2012)31 and Frisk et al (2008)51 evaluated menopause hormone therapy (oestrogen/progestagen for 24 months) and electro-acupuncture (30min twice a week for two weeks and then once per week for 10 weeks) on the frequency of hot flushes in the same cohort but did not compare between groups. Both interventions yielded significant decreases in frequency of hot flushes from baseline at each time point over 24 months: the electro-acupuncture group had a significant 6.4 flushes/d reduction compared with baseline and a significant 18.1 unit decrease in Kupperman’s Index scores from baseline. Acupuncture and sham acupuncture Four trials comparing true acupuncture with sham acupuncture 25, 30, 55, 56 reported inconsistent results. Bokmand et al (2013)25 compared true acupuncture, sham acupuncture and no treatment over five weeks. True acupuncture treatment comprised 15-20min sessions once a week for the five weeks and sham acupuncture comprised superficially inserting needles at the “nonacupuncture” points. Bokmand et al reported significant decreases from baseline in the nuisance of hot flushes in the true acupuncture arm compared with sham acupuncture at six weeks (2 units versus 0.9 units on the Visual Analogue Scale (VAS)) and 12 weeks (1.9 units versus 0.9 units). The Bokmand trial25 also reported that true acupuncture significantly decreased the nuisance of hot flushes compared with no treatment at both six and 12 weeks (0.1 units and 0 units respective), while no differences were observed between the sham acupuncture and no treatment arm. However, Bokmand et al did not compare the changes in symptoms from baseline across their three groups. Hervik et al (2009)56 compared true acupuncture to sham acupuncture, with sham acupuncture also conducted by superficially inserting needles in “non-acupuncture” points. Treatment consisted of 30min sessions twice per week for five weeks and then once per week for another five weeks. This trial reported true acupuncture significantly reduced the frequency of hot flushes by 4.8 flushes/d (50%) at 10 weeks from baseline and a further reduction by an additional 1.5 flushes/d was seen at 22 weeks. There were no significant reductions in the sham group at 10 or 22 weeks and thus the changes from baseline were significantly in favour of true acupuncture. For hot flushes at night, the true acupuncture group had significantly decreased frequency of hot flushes from baseline at 10 weeks (by 3.4 flushes/night) and a further reduction at 22 weeks (an additional 0.9 flushes/night). In the sham group, there was a significant reduction from baseline to 10 weeks (by 1.8 flushes/night) but this was reversed by 22 weeks, with hot flushes increasing to only 1.1 flushes/night below baseline. The decreases in hot flushes at night were significantly different between true and sham acupuncture groups at both time points, in favour of the true acupuncture group. Kupperman’s Index scores were significantly reduced from baseline in the true acupuncture group by 7.4 units at 10 weeks, although this increased by 1.8 units between 10 and 22 weeks. In the sham acupuncture group, changes in the Kupperman’s Index scores were not significant at either time point. The changes in Kupperman’s Index scores from baseline were significantly different between true and sham acupuncture groups at both 10 and 22 weeks and in favour of the true acupuncture group. Liljegren et al (2012)30 compared true acupuncture with sham acupuncture, in 20min sessions twice per week for five weeks. The sham method differed from Hervik et al and Bokmand et al, in that special “sham” needles were used which did not penetrate the skin. Liljegren et al defined clinical improvement in vasomotor symptoms as an improvement by at least one unit on the severity scales used. Following this definition, 42% of the true acupuncture group Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 41 and 47% of the sham group reported improvements in severity after six weeks, but these improvements were not significant between the groups. For sweating, 55% of the true acupuncture group and 47% of the sham group reported fewer problems at six weeks, with the improvements being significantly greater in the true acupuncture group. Regarding frequency of hot flushes, both true acupuncture and sham acupuncture groups had significant reductions from baseline at six weeks (2.7 flushes/24h and 2.6 flushes/24h respectively), but there were no significant differences between the groups. Regarding the frequency of night sweats, there were also significant reductions in both true and sham acupuncture groups at six weeks (2.8 sweats/24h and 2.0 sweats/24h respectively) but there were no significant differences between the groups for improvement.30 Deng et al (2007)55 compared true acupuncture with sham acupuncture, where special “sham” needles that did not penetrate the skin were also used. Acupuncture sessions were 20min long twice per week for four weeks. At week 6, the true acupuncture group had 0.8 fewer hot flushes per day than the sham group, although this was not significantly different. Further, the difference between groups was not significant at weeks 1, 2, 3, 4 or 5. There was also no difference between true and sham acupuncture groups in frequency of hot flushes at seven days or at six months. Deng et al did not report whether improvements from baseline in either group were significant. All four RCTs had similar sample sizes and study durations, although Hervik et al treatment period was nearly double that of the other RCTs. A possible reason for the inconsistent results may be the different sham methods used. Hervik et al and Bokmand et al used techniques that still superficially penetrated the skin and their studies reported significant differences between true and sham treatments, although Bokmand et al only compared groups at specific time points and not their changes from baseline and thus there were limitations in the reporting of results. In contrast, Liljegren et al and Deng et al employed special sham needles that did not penetrate the skin and did not find a difference between treatment groups. Electro-acupuncture Nedstrand et al (200553 and 2006)‡54 compared electro-acupuncture (30min twice per week for two weeks and then once per week for 10 weeks) with applied relaxation over 12 weeks. Both groups demonstrated a significant decrease in frequency of hot flushes from baseline at each time point, up to six months follow-up where the number of hot flushes decreased by 4.9/day and Kupperman’s Index scores decreased by 10 units in the electro-acupuncture group and number of hot flushes decreased by 5.3/day and Kupperman’s Index scores decreased by 0.6 units in the applied relaxation group. However, between groups comparisons were not reported on. Relaxation Two RCTs investigated relaxation therapy (Fenlon et al (2008) and Nedstrand et al (2005)). 52, 53 Fenlon et al (2008)52 provided a single 1h training session for relaxation together with an audio tape to conduct sessions at home (20min/d for at least one month) Fenlon et al reported relaxation therapy was beneficial compared to a control group, with reductions in hot flushes by a median of seven per week at one month, while the control group had a reduction of one hot flush per week. Severity also improved significantly when compared with the control group, decreasing by a median of 0.47 units per flush, while there was no change from baseline in the control group. However, differences between groups for improvements in severity and frequency were no longer significant at three months. The same cohort. Nedstrand et al (2006), in its update, reports on psychological wellbeing, which is described in the present systematic review in Psychological wellbeing, pp86-105 ‡ Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 42 A second RCT by Nedstrand et al (2005) compared acupuncture with applied relaxation and reported both interventions significantly reduced the frequency and severity of hot flushes from baseline (see section Acupuncture and electro-acupuncture, p40). Yoga One RCT assessed the effectiveness of yoga. Carson et al (2009)37 compared an eight-week yoga program with wait-list controls for management of hot flushes and the occurrence of night sweats. Yoga significantly reduced the frequency of hot flushes from baseline after eight weeks (0.71 units) compared with controls, who had an increase in frequency of 0.11 units. After eight weeks, the yoga group also had significantly decreased hot flush severity from baseline (0.95 units) compared with the control group (decrease of 0.26 units). The yoga group maintained their reduced frequency (1.27 units) and severity (0.97 units) of hot flushes from baseline at three months follow-up and this was still significantly different compared to controls (frequency increased by 0.08 units and severity decreased by 0.31 units). However, there were no differences observed between groups either post-treatment or at three months follow-up for night sweats. Other therapies Black cohosh Three RCTs investigated black cohosh against placebo60-62 The trials by Pockaj et al (2006) (20mg/d black cohosh for nine weeks) and Jacobson et al (2001) (2 tablets/d black cohosh for two months and also included women taking tamoxifen) found no significant difference in frequency or severity of hot flushes between intervention and controls groups and no significant differences from baseline. The 12 month trial by Herñandez Muñoz and Pluchino (2003)60 investigated black cohosh (20mg/d) in women who were all taking 20mg/d tamoxifen and all were experiencing hot flushes. Herñandez Muñoz and Pluchino reported significant decreases in the frequency of hot flushes from baseline in the group taking black cohosh, while decreases in the control group were not significant, but comparisons between groups were not statistically assessed. At the end of the trial, 46.7% of the intervention group no longer had hot flushes, 28.6% still had moderate hot flushes while 24.4% had severe hot flushes. In contrast, in the usual care group, all still experienced hot flushes, with 26.1% experiencing moderate and 73.9% experiencing severe hot flushes. A potential confounding factor should be mentioned: Jacobson et al (2001) 61 stated the trial administered two tablets of black cohosh per day but the amount of black cohosh contained in the tablets was not reported. Homeopathy Two RCTs investigated homeopathy against placebo58, 59 Thompson et al (2005) compared a homeopathic preparation against placebo for 16 weeks and reported no differences between treatment and control groups for hot flush frequency or severity; comparisons between groups’ changes from baseline were not reported. Jacobs et al (2005) compared two different homeopathic preparations (single or combined remedies in 3 tablets/d) and placebo for one year and reported no significant differences in severity or frequency according to Hot Flash Scores across the three groups and no differences in Kupperman’s (Menopausal) Index scores, adjusted for baseline values and tamoxifen use. Jacobs et al (2005) also conducted subgroup analyses according to tamoxifen use. For women not receiving tamoxifen, severity and frequency of hot flushes increased significantly from baseline in those receiving combination remedies compared to placebo (difference of 26.7 units after adjusting for baseline scores) and when compared with single remedy Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 43 homeopathy (difference of 33.5 units). In women receiving tamoxifen, there were no differences in frequency or severity of hot flushes.58 There is a potential confounding factor in that the RCTs on homeopathy by Thomson et al (2005)59 and Jacobs et al (2005)58 did not quantify the active ingredients administered. Further, Thompson et al (2005) allowed for continually changing dosages throughout the treatment phase and in Jacobs et al (2005) study, only the dilution factors were reported and that the preparations were administered in three tablets per day. Phytoestrogens Three RCTs investigated phytoestrogens.63-65 Nikander et al (2003)65 compared 114mg isoflavonoids to placebo in a cross-over design (3 month study period and then 2 month study period). Phytoestrogens significantly reduced Kupperman Index scores from baseline by 4.2 units but this reduction was not significantly different to that of the control group, with a decrease of 4.0 units, and at the end of the trial, Kupperman Index scores did not differ between the groups. Van Patten et al (2002)64 compared isoflavones administered as a soy beverage (500ml/d, 90mg isoflavones/d) to a rice beverage control for 12 weeks. Both groups experienced a significant decrease in the frequency of hot flushes (5.2 flushes/24h in the isoflavone group and 2.5 flushes/24h in the control group) and Hot Flash Scores (encompassing frequency and severity, 5.4 units in the isoflavone group and 7.5 units in the control group, over 24h) at final four weeks of the study from baseline. However, there were no differences in the magnitude of reductions between treatment and control groups. MacGregor et al (2005)63 compared 70mg/d isoflavines with placebo for 12 weeks and reported no significant differences between the groups for severity of hot flushes or sweats at the end of the trial, including controlling for baseline severity, tamoxifen use at baseline and whether or not participants had ovarian suppression. Overall, there is no evidence phytoestrogens improved vasomotor symptoms when compared with placebo. Magnetic therapy One RCT by Carpenter et al (2002)57 investigated magnetic therapy against placebo in a cross-over study design with two three-day study periods.57 The intervention consisted of six magnetic devices or placebo devices placed over acupuncture sites for three days. There was no difference between treatment and placebo for reducing the severity of hot flushes, but the placebo resulted in significantly reduced frequency (3.81 units) and daily “bother” of hot flushes (1.19 units) from baseline compared to the magnetic therapy group (0.19 units and 0.11 units respectively). There were no significant differences reported in interference by hot flushes between the treatments. Vasomotor symptoms: quality of reporting As vasomotor symptoms were the primary outcome of the RCTs described in this section, it is accepted that the quality of reporting for this outcome was high overall. A range of tools and methods were used to measure severity and frequency of vasomotor symptoms, including formal standardised questionnaires or scales, diaries or logbooks, subjective scales or questionnaires, electronic hot-flash monitors and clinical assessment (Table 5). Sixteen of the 39 studies used more than one method. A formal and standardised Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 44 scale was used by 19 of the studies, two of which also used an “electronic hot-flash monitor”, which measures sternal skin conductance. Eight studies used a diary or logbook alone, although some studies reported their diary method was “validated”. Only one study (Ahimahalle et al, 2012)26 used clinical assessment to measure vasomotor symptoms. Evidence summary: Vasomotor symptoms In regard to level I evidence, 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)4-8 examined the effects of treatment on vasomotor symptoms in women treated for breast cancer. Out of the 45 studies in the Primary Evidence Base, 39 reported on vasomotor symptoms as the primary menopausal symptom of interest; these comprised 36 RCTs, with three follow-up studies (10 with high risk of bias, 18 with moderate risk of bias and 11 with low risk of bias) with a total of 6,465 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 39 studies used more than one method and 19 used a formal and standardised scale; only eight studies used a diary or logbook alone. Among the RCTs, the following treatments were investigated: seven venlafaxine (three headto-head with clonidine, one head-to-head with gabapentin, one head-to-head with acupuncture and one with augmentation with zolpidem), sertraline (two RCTs), fluoxetine (one RCT), paroxetine (one RCT), bupropion (one RCT), gabapentin (four RCTs including three head-to-head trials: one with venlafaxine, one with vitamin E and one with megestrol acetate), menopause hormone therapies (two RCTs including one head-to-head with electro-acupuncture, and two updates), CBT (two RCTs with one including exercise), hypnotherapy (one RCT), acupuncture and electro-acupuncture (seven RCTs and two updates: one head-to-head with venlafaxine, one electro-acupuncture RCT and its update head-to-head with applied relaxation, one RCT and its update head-to-head with menopause hormone therapy), relaxation (two RCTs) and one update (one RCT and its update head-to-head with electro-acupuncture), yoga (one RCT), black cohosh (two RCTs), phytoestrogens and isoflavones (three RCTs), homeopathy (two RCTs) and magnetic therapy (one RCT). Studies were conducted in a wide range of countries (see Table 1), but none were conducted in Australia. The evidence for the effectiveness of the various interventions for vasomotor symptoms is summarised in the Evidence Summaries below that are numbered for reference with the clinical practice guidelines developed from this systematic review. One RCT (with a moderate risk of bias) in women after breast cancer found that 4 weeks of bupropion (300 mg/day) had no statistically significant effect on the severity of hot flushes compared to placebo (Nunez 2013).24 [Evidence Summaries #1] One RCT (with a low risk of bias) in women after breast cancer found that paroxetine (10 or 20 mg/d for 4 weeks) significantly reduced hot flush frequency and severity compared to placebo (Stearns 2005).41 Three RCTs (with low to moderate risk of bias) in women after breast cancer found that neither fluoxetine (20 mg/d for 4 weeks) (Loprinzi 2002) 40 nor sertraline (25 to 100 mg/d for 4-6 weeks) (Kimmick 2006; Wu 2009)42, 43 had a consistent effect on hot flushes compared to placebo. [Evidence Summaries #2] One RCT (with low risk of bias) in women after breast cancer found that 12 weeks of venlafaxine at 75 mg/d (slow release) significantly reduced hot flush frequency and severity compared with placebo (Boekhout 2011).45 One RCT (with moderate risk of bias) in women after breast cancer found that 14 weeks of venlafaxine at 37.5mg/d significantly reduced Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 45 hot flush frequency and severity compared with placebo (Carpenter 2007).44 One RCT (with a low risk of bias) in women after breast cancer found that venlafaxine (75mg/d for 12 weeks) was equally effective as clonidine (0.1mg/d for 12 weeks) at reducing hot flush frequency and severity (Boekhout 2011). 6 One cross-over RCT (with a moderate risk of bias) in women after breast cancer found that venlafaxine (75mg/d for 8 weeks) was equally effective as clonidine (0.1mg/d for 8 weeks) at reducing hot flush frequency and severity (Buijs 2009). 8 One RCT (with a moderate risk of bias) in women after breast cancer found that venlafaxine (75mg/d for 4 weeks) was more effective than clonidine (0.15mg/d for 4 weeks) at reducing the frequency of hot flushes (Loibl 2007).46, 47 One RCT (with a moderate risk of bias) in women after breast cancer found that 4 weeks of venlafaxine (37.5mg/d for 7 days and 75mg/d for 21 days) or gabapentin (300mg/d for 3 days, 900mg/d for 3 days, and 1200mg/d for 22 days) were associated with equivalent reductions in hot flash scores (Bordeleau 2010).48 One RCT (with a moderate risk of bias) in women after breast cancer found 12 weeks of venlafaxine (37.5mg/d for 1 week and 75mg/d for 11 weeks) or a course of acupuncture (twice per week for 4 weeks, and once per week for 8 weeks) were associated with similar reductions in hot flash frequency and severity (Walker 2010). 35 [Evidence Summaries #3] One RCT (with a moderate risk of bias) in women after breast cancer found that augmentation of an SSRI or SNRI with 5 weeks of zolpidem (10mg/d) has no statistical significant additional effect on vasomotor symptoms compared to placebo (Joffe 2010). 36 [Evidence Summaries #4] One RCT (with a low risk of bias) in women after breast cancer found that clonidine (0.1 mg/d) significantly reduced the frequency and severity of hot flushes relative to placebo (Boekhout 2011).45 [Evidence Summaries#5] One RCT (with a moderate risk of bias) in women after breast cancer found that 4-8 weeks of gabapentin (900 mg/d) was associated with a reduction in hot flush frequency and severity compared to placebo (Pandya 2005).49 Three RCTs (two with a moderate risk of bias and one with a high risk of bias) in women after breast cancer found that 4-12 weeks of gabapentin (900mg/d or 300mg/d) was associated with a significant reduction in hot flush frequency and severity compared to baseline (Bordeleau 2010, Ahimahalle 2012, Biglia 2009) and one of the RCTs found a significant reduction in hot flush frequency between groups (Ahimahalle 2012)26, 48, 50 In one of these RCTs the effect size was equivalent to that observed with venlafaxine (37.5mg/d for 7 days and 75mg/d for 21 days, Bordeleau 2010).48 In one of these RCTs the effect size was less than that observed with megestrol acetate (40mg/d, Ahimahalle 2012).26 [Evidence Summaries #6] One RCT (with a low risk of bias) in women after breast cancer found that tibolone (2.5 mg/d) for up to 2.75 years significantly reduced the frequency and severity of hot flushes compared to placebo (Kenemans 2009/ Sismondi 2011 LIBERATE study).12, 33 One RCT (with high risk of bias) in women after breast cancer found that menopause hormone therapy (sequential or combined oestrogen/progestagen for 24 months) and electro-acupuncture (for 12 weeks) statistically significant reduced the number of night-time hot flushes over 2 years (Frisk 2012). 19 Menopause hormone therapy appeared to be more effective than electro-acupuncture although between groups statistically significance was not reported (Frisk 2008/Frisk 2012 HABITS study).31, 51[Evidence Summaries #7] One RCT (with moderate risk of bias) in women after breast cancer found that purposedesigned group CBT (90min per week for 6 weeks) alone versus usual care had no effect on the frequency of hot flushes, but reduced problem rating of hot flushes and night sweats (Mann 2012).29 One RCT (with moderate risk of bias) in women after breast cancer found that purpose-designed group CBT (90min per week for 6 weeks) in combination with physical exercise (2.5 to 3 hours per week) versus no intervention reduced the problem rating of hot flushes and night sweats (Duijts 2012).28 [Evidence Summaries #8] Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 46 One RCT (with moderate risk of bias) in women after breast cancer reported that a purposedesigned hypnotherapy protocol delivered once/week for 5 weeks reduced hot flush frequency and severity compared to no treatment (Elkins 2008).38 [Evidence Summaries #9] One RCT (with low risk of bias) in women after breast cancer comparing acupuncture (needle inserted 0.5-3cm deep for 30min) to sham acupuncture (needle inserted 2-3mm deep for 30min), reported a reduction in frequency and severity of hot flushes (Hervik 2009).56 Two RCTs (with moderate risk of bias) in women after breast cancer found no difference between acupuncture (needle inserted 5–20 mm deep for 20min or 0.25 to 0.5 inches deep) and sham acupuncture, in terms of frequency and severity of hot flushes (Liljegren 2012; Deng 2007).30, 55 One RCT (with low risk of bias) in women after breast cancer reported acupuncture (for 15-20min once a week) reduced the nuisance of hot flushes, but did not report between-group differences compared to sham or no treatment (Bokmand 2013).25 One RCT (with a high risk of bias) in women after breast cancer found that electroacupuncture (for 12 weeks) and menopause hormone therapy (for 24 months) were effective at reducing night-time hot flushes (Frisk 2008/Frisk 2012).31, 51 One RCT (with a high risk of bias) in women after breast cancer found electro-acupuncture (for 12 weeks) and applied relaxation (for 12 weeks) were equally effective at decreasing the frequency of hot flushes and improving the Kuppermann Index (Nedstrand 2005/Nedstrand 2006).53, 54 One RCT (with a high risk of bias) in women after breast cancer found that acupuncture (for 12 weeks) and venlafaxine (75mg/d for 12 weeks) were equally effective at reducing frequency and severity of hot flushes (Walker 2010).35 [Evidence Summaries #10] One RCT (with a low risk of bias) in women after breast cancer reported reduced hot flush frequency and severity during relaxation therapy treatment at one month (one hour session and a 20min tape to use once a day) versus no treatment (Fenlon 2008).52 [Evidence Summaries#11] One RCT (with a moderate risk of bias) in women after breast cancer found that an 8 week Yoga program reduced the frequency and severity of hot flushes compared to no intervention (Carson 2009).37 [Evidence Summaries #12] Two RCTs (with a low to moderate risk of bias) in women after breast cancer reported no difference in severity and frequency of hot flushes, between black cohosh (1 capsule, Cimicifuga racemosa 20 mg BID) and placebo (Pockaj 2006; Jacobson 2001).62 61 One RCT (with a high risk of bias) in women after breast cancer compared tamoxifen (20mg/d) with black cohosh (1 capsule, Cimicifuga racemosa, CR BNO 1055) for 12 months, but did not adequately report data on the frequency or severity of hot flushes (Hernandez Munoz 2003).60 [Evidence Summaries #13] Two RCTs (with a low and high risk of bias) in women after breast cancer found no effect of homeopathy (in tablet, granule, or liquid form) versus placebo on hot flush frequency or severity (Thompson 2005; Jacobs 2005).58, 59 [Evidence Summaries #14] Three RCTs (with a low to high risk of bias) in women after breast cancer found no effect of phytoestrogens (tablets, 114 mg of isoflavonids or soybean beverage or 235 mg of soy extract with 17.5 mg of Isoflavines 70mg/d) versus placebo on the Kupperman’s Index, as well as no effect on the frequency or severity of hot flushes (Nikander 2003; Van Patten 2002; MacGregor 2005).63-65 [Evidence Summaries #15] One RCT (with a moderate risk of bias) in women after breast cancer found that 3 days of magnetic therapy (6 magnets on acupuncture pressure sites per participant) had no effect on the severity of hot flushes compared to placebo; the placebo was reported to have had a greater effect than the magnetic therapy on frequency of hot flushes (Carpenter 2002). 57 [Evidence Summaries #16] 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, CBT, CBT combined with exercise, purposed design hypnotherapy and Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 47 yoga; limited evidence for acupuncture and short-term relaxation therapy; and evidence for no effect, or no consistent effect, of bupropion, fluoxetine, sertraline, zolpidem augmentation of SSRIs or SNRIs, black cohosh, homeopathy, phytoestrogens, or magnetic therapy. It should be noted that tibolone is associated with increased risk of breast cancer recurrence. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 48 Table 4: Studies treating vasomotor symptoms and differences between treatment groups for frequency of hot flushes and night sweats For this table, calculations of between-group mean changes from baseline and between-group percentage change from baseline were undertaken by Cancer Australia staff using data from hot flush and night sweats frequency reported by the RCTs. RCTs which provided combined frequency and severity scores instead of frequency alone are noted under their respective entries. Some studies provided median values instead of means and these are also noted under their respective entries Author Population N, Age, Study duration Measure (s) Pharmaceutical Interventions Atypical antidepressant 55 Age 49y (median) 10 weeks Nunez 201324 Questionnaire related to hot flush interference SSRI antidepressants 46 Age 55y (average) Wu 200943 6 weeks Kimmick 200642 Loprinzi 200240 Diary 62 Age 53.9y (median) 12 weeks Diary Hot flash score 72 Age <49 ; >50y 9 weeks 151 Age 50, 55y (medians) Stat. Sig. between groups as per author (Y/N) Comparator (n†), dose Vasomotor outcome (per day unless otherwise stated) Bupropion, n=25 150mg/d for 3 days, then 300mg/d for remainder of 4 week period Placebo, n=24 1 tablet for 3 days, then 2 tablets for remainder of 4 week period Hot flushes (scores) 0.85 7.71% N Sertraline, n=24 25mg/day to 100mg/day Placebo, n=22 Hot flushes (medians) -11.15 -18.21% N Sertraline, n=29 50mg/day Placebo, n=25 Hot flushes, week 06 -0.1 0.33% Sertraline, n=25 Placebo, n=22 Hot flushes, week 612 0.4 9.42% NR ŧ Fluoxetine, n=32 20mg/day Placebo, n=34 Identical appearing to intervention Hot flushes, week 9 (median) -1.5 -19% Y Paroxetine, n=32 10mg daily Placebo, n=28 Hot flushes, week 5 -2.56 -34.56% Y Hot flushes, week 9 0.45 7.20% Y Intervention (n†), dose Diary Questionnaire Stearns 200541 Difference between groups in percentage change in vasomotor symptoms from baseline (negative favours intervention / positive favours comparator) Difference between groups in their changes from baseline (Intervention – Comparator)a Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 49 NR ŧ 9 weeks Diary Hot flash score Hot flushes, week 5 -2.27 -35.39% Y Hot flushes, week 9 1.23 11.32% Y Placebo, n=22 Hot flushes, low dose (electronic monitoring) -1.69 -22.65% Y Venlafaxine, n=39 75mg/day Clonidine, n=39 0.1mg/day Hot flushes (scores) 1.1 4.70%* NR Venlafaxine, n=39 Placebo, n=19 Hot flushes (scores) -2.2 -18.55% Y Clonidine, n=39 Placebo, n=19 Hot flushes (scores) -3.3 -23.25% Y Venlafaxine, n=31 37.5mg twice daily Clonidine, n=33 0.075mg twice daily Hot flushes, 4 weeks (medians) -2.75 -20.00% Y Hot flushes (medians) NR 4.00% N Sweating Frequency not reported – Only % women who experienced sweats -3 -3.09% NR Paroxetine, n=24 20mg daily Placebo, n=23 Venlafaxine, n=23 37.5mg/day SNRI antidepressants 52 Age 50.5y (average) 14 weeks Carpenter 200744 Diary Electronic Hot-flash Monitor HFRDIS Boekhout 201145 94 Age 48y (average) 12 weeks Diary Loibl 200747 Buijs 200946 64 Age > 18y 4 weeks Questionnaire 60 Age 49, 51y (medians) 8 weeks Venlafaxine, n=22 75mg/day Clonidine, n=20 0.05mg/day Diary/Questionnaire HFRDIS Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 50 Bordeleau 201048 63 Age 54.9, 57.6y (average) 4 weeks Venlafaxine, n=34 37.5mg/day for 1 week, 75mg/day for 3 weeks Walker 201035 Diary Venlafaxine, n=22 37.5 mg at night for 1 week, then 75 mg at night for 11 weeks -0.9 -4.46% N Hot flushes, scores, 12 weeks 1.8 9.94% N Hot flushes NR NR N Hot flushes (daytime) -0.3 0.66% N Hot flushes (nighttime) -0.2 -11.11% N -8.56% N¥ -23.48% Y -8.08% N¥ -22.82% Y Gabapentin, n=29 300mg/day (increased to 3 times per day) Diary 47 Age 55y (median) 12 weeks Hot flushes, scores, 6 weeks (principal end point) Acupuncture, n=25 twice per week for 4 weeks, then once per week for 8 weeks Sedatives 53 Age 51.1y (average) 5 weeks Joffe 201036 North Central Cancer Treatment Group Daily Vasomotor Symptom Diary Zolpidem 10mg/d and SSRI/SNRI, n=25 Placebo and SSRI and SNRI, n=28 Antihypertensive See SNRI antidepressants section, as all RCTs with antihypertensives (clonidine) were conducted head-to-head to venlafaxine Anticonvulsants Gabapentin Hot flushes, week 4 -0.66 300mg, n=139 420 Gabapentin Hot flushes, week 4 -2.02 Age 54y (average) 900mg, n=144 Pandya 200549 Placebo, n=137 8 weeks Gabapentin Hot flushes, week 8 -0.61 300mg n=139 Diary Gabapentin Hot flushes, week 8 -1.96 900mg n=144 50 -38.37 Biglia 2009 115 Gabapentin, n=31 Vitamin E, n=30 Hot flushes Age 50y (median) 900mg/day 800 IU/day (weekly), week 4 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 51 -41.25% NR 12 weeks Ahimahalle 201226 Diary Menopause Rating Scale (MRS) 120 Age 42.6, 42.8y (average) 8 weeks Clinical assessment See SNRI section for Bordeleau 2010 Menopause hormone therapy 3133 Age 52.7y Sismondi 2011 (average) (updated study of 2.75 years (median) 33 the LIBERATE trial) Kenemans 2009 (LIBERATE trial)12 Climacteric symptoms 3133 Age 52.5, 52.9y (average) 2.75 years (median) Hot flushes (weekly), week 8 -39.51 -42.46% Hot flushes (weekly), week 12 -43.63 -47.04% NR NR Gabapentin, n=60 300mg/day Megestrol acetate, n=60 40mg/day Hot flushes 1.8 18.61% Y Tibolone, n=1575 2.5mg/day Placebo, n=1558 Hot flushes, week 12 -0.97 -15.60% Y Tibolone, n=1575 Placebo, n=1558 Hot flushes, week 104 -0.89 -13.10% Y Tibolone, n=1556 2.5mg/day Placebo, n=1542 Hot flushes, week 12 -2.2 -35.71% Y Hot flushes/24h at 3 months NR -45% NR Hot flushes, week 12 (median KI score) -5 -23.91% NR Climacteric symptoms Frisk 2012 (update of Frisk 2008, HABITS trial)31 45 Age 54.1, 53.4y (average) 12 weeks Hot flush log book Frisk 2008 (substudy of Holmberg 2004, HABITS trial)51 45 Age 53 (average) 24 months Kupperman’s Index (KI) Hormone therapy, n=18 Estrogen/progesta gen for 24 months (asked to stop) Menopause hormone therapy , n=18 Estrogen/progesta gen for 24 months (asked to stop) Electroacupuncture, n=26 Electroacupuncture, n=26 30min twice a week for 2 weeks, then once a week Complementary Medicine and Therapy Psychological interventions Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 52 Mann 201229 96 Age 53.16, 54.07y (average 6 weeks (9 and 26 weeks follow-up) CBT, n=47 90min sessions Usual care, n=49 Hot Flush Rating Scale Duijts 201228 (per protocol analyses) 106 (CBT+Exercise) 109 (CBT) 104 (Exercise) 103 (Control) Age 47 (average) 12 weeks / 6 months Hot Flush/Night Sweats Frequency Rating Scale Hot flushes/week, week 9 3.18 8.38% N Hot flushes/week, week 26 1.03 5.80% N Night sweats/week, week 9 -3.99 -24.21% N Night sweat/weeks, week 26 -5 -27.04% N 0.91 3.41% N -2.54 -0.13% N -3.28 -24.05% N (sig only at 12 weeks) -2.35 -24.50% N 0.24 -5.95% N Total hot flushes and night sweats, week 9 Total hot flushes and night sweats, week 26 CBT + Exercise, n=30¶ 90min group sessions + 2.53h/week Hot flushes and Night sweats frequency scores (6months) Waiting list, n=103¶ CBT, n=46¶ Exercise, n= 38¶ Hot flushes and Night sweats frequency scores (6months) Hot flushes and Night sweats frequency scores (6months) Hypnotherapy Elkins 200838 60 Age 58.2, 55.8y (average) 5 weeks Hot Flash Relate Daily Interference Scale (HFRDIS) Hypnotherapy, n=30 50min 5 times a week Control, n=30 Hot flushes (interference) -4.3 -55.30% Y Acupuncture, n=31 15-20min once a Sham acupuncture, n=29 Superficial needle, Hot flushes, week 6 -1.1 -16.82% NR Acupuncture Bokmand 201325 94 Age 60, 62, 62y Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 53 (average) 5 weeks Subjective visual analyses scale (VAS) week Acupuncture, n=31 Sham acupuncture, n=29 Hervik 200956 59 Age 53.6, 52.3y (average) 10 weeks Kupperman’s Index (KI) Liljegren 201230 84 Age 58 (average) 5 weeks Acupuncture, n=30 30min sessions twice a week for 5 weeks, then once for the next 5 weeks Acupuncture, n=38¶ Twice a week 15-20min once a week No treatment, n=34 No treatment, n=34 Sham acupuncture, n=29 30min sessions twice a week for 5 weeks, then once for the next 5 weeks Sham acupuncture, n=36¶ Twice a week Numeric scale (010) Deng 200755 50 Age 55 (average) 4 weeks Acupuncture, n=33 Twice a week Sham acupuncture, n=17 Twice a week, superficial needle Diary Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Hot flushes, week 12 -1 -15.37% NR Hot flushes, week 6 -1.9 -27.49% NR Hot flushes, week 12 -1.9 -27.54% NR Hot flushes, week 6 -0.8 -10.67% NR Hot flushes, week 12 -0.9 -12.16% NR -4.2 -45.65% Y -6.1 -64.69% Y -1.6 -31.67% Y -3.2 -56.39% Y Hot flushes, week 3 -0.5 -2.68% N Hot flushes, week 6 -0.1 4.48%# N -1.2 -10.32% N -0.9 -3.17% N Hot flushes, day 7 0.7 4.91% NR Hot flushes, 6 weeks -0.1 -4.74% Hot flushes, day time- week 10, KI scores Hot flushes, day time- week 22, KI scores Hot flushes, night time – week 10, KI scores Hot flushes, day time- week 22, KI scores Night sweats, week 3 Night sweats, week 6 54 NR Nedstrand 200654 (updated study of Nedstrand 2005) Nedstrand 200553 38 Age 53y (average) 12 weeks Logbook Kupperman’s Index Visual Analog Scale (VAS) Symptom checklist Mood scale 38 Age 53y (average) 12 weeks Logbook and severity score See Menopause Hormone Therapies for Frisk Other therapies Relaxation therapy 150 Age 54.9, 55.4y (medians) Fenlon 200852 3 months Electro acupuncture, n=17¶ 30min twice a week for 2 weeks, then once a week for 10 weeks Acupuncture, n=17¶ Applied relaxation, n=14¶ 1 session per day, each done for 1520 times a day Applied relaxation, n=14¶ Carson 200937 0.4 -0.10% NR Hot flushes, 6 months 0.4 -0.72% NR Hot flushes, week 12 0.4 -0.1% NR Hot flushes, 6 months 0.4 -0.72% NR Hot flushes/week, month 1 (medians) -7 -19.52% Y Hot flushes/week, month 3 (medians) -5 -24.11% N Hot flushes (posttreatment, 8 weeks) -0.82 -18.56% Y Hot flushes (3 month follow-up) -1.35 -30.32% Y Night sweats (posttreatment, 8 weeks) 0.17 3.59% N Night sweats (3 month follow-up) 0.15 1.74% N Hot flushes scores NR 16.00% N 2008 and 2012 and SNRI section for Walker 2010 Relaxation therapy, n=61 1 hour one on one session, then 20min/day relaxation tape Control, n=64 Diary Hunter Menopause Scale See Acupuncture section for Nedstrand 2005 and 2006 Yoga 37 Age 54y (average) 8 weeks Hot flushes, week 12 Yoga, n=16 120min/day Wait list control, n=20 Daily menopausal symptoms, 0-9 scale Black cohosh Pockaj 200662 116 Age 56 (average) Black cohosh, n=58 Placebo, n=58 Matched to Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 55 9 weeks Diary 76 Age 18-<50; 50-60+y 2 months Jacobson 200161 Hernandez Munoz and Pluchino 200360 Diary Menopausal Symptom Index 136 Age 47, 46y (average) 5 years for tamoxifen, 12 months for black cohosh 20 mg Cimicifuga racemosa and rhizome extract standardized to contain 1 mg of triterpene glycosides Black cohosh/tamoxifen, n=26 1 tablet twice a day Black cohosh only , n=12 intervention Black cohosh with tamoxifen, n=90 20mg/day Usual care (tamoxifen), n=46 20mg/day Placebo/tamoxifen , n=28 1 tablet twice a day NR NR N NR NR N Hot flushes NR NR NR Hot flushes scores night sweats 0.1 -1.65% NR Hot flushes scores day sweats -0.1 -3.50% NR Hot flushes NR NR N Hot flushes NR NR N Hot flushes NR NR N Hot flushes and Night sweats Placebo only, n=10 Questionnaire Homeopathy 53 Age 51 (average) 16 weeks Thompson 200559 Measure Yourself Medical Outcome Profile (MYMOP) Menopausal symptoms questionnaire 83 Jacobs 200558 Age 54 (average) 1 year Diary and severity score Kupperman Menopausal Index Homeopathy, n=28 Dose not reported Homeopathy Combination (Hyland’s Menopause), n=30 1 tablet 3 times a day Homeopathy Single, n=26 Homeopathy Placebo, n=25 dose not reported, matched to homeopathy medication Placebo, n=27 1 tablet 3 times a day Homeopathy Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 56 (KMI) Combination Single Phytoestrogens, n=28¶ 114mg, 1 tablet/day Placebo, n=28¶ 1 tablet/day Hot flushes, Kupperman’s index -0.2 -1.01% N Placebo (rice), n=64 Matched to intervention Hot flushes - day 0.6 9.08% N Hot flushes - night 0.2 9.60% N Phytoestrogens Nikander 200365 62 Age 54y (average) 3 months Diary Kupperman’s Index Visual Analog Scale Van Patten 200264 123 Age 55.5, 54.9y (average) 12 weeks Isoflavones, n=59 90mg/day Diary MacGregor 200563 72 Age 51 (average) 12 weeks Isoflavines, n=33 70mg/day Placebo, n=35 Matched to intervention Hot flushes vasomotor score NR NR N Magnetic therapy, n=11 6 magnetic devices attached to skin for 72 hours (day 2 and 5), and 24 hours (day 4) Placebo, n=11 Matched to intervention Hot flushes 2.53 23.06% Y (in favour of placebo) Menopausal Symptom Score Magnetic therapy Carpenter 200257 15 Age 57.1y (average) 2 treatments periods of 3 days each with 10 day wash-out Diary Electronic Hot-flash Monitor (sternal skin conductance) HFRDIS Abbreviations CBT: cognitive behavioural therapy; HFNS: hot flushes and night sweats; HFRDIS: Hot Flash Related Daily Interference Scores; HT: hormone therapy; NR: not reported; N: no; Y: yes aThe units are those used by the study authors. † The number of participants who commenced treatment. If the authors did not state the number who commenced treatment, the number of participants assigned to the treatment was used. ŧ Results were significantly in favour of treatment following cross-over analyses; see section Selective serotonin re-uptake inhibitors: sertraline, fluoxetine and paroxetine Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 57 ¶Only data from participants who completed the trial were analysed (per protocol analyses); sample sizes reported are for those that completed the treatment. were not significantly different in their changes from baseline according to scores but were significantly different in their percentage changes from baseline. # Difference is negative for units but positive for percentages. ¥ Groups Table 5: Tools and scales used to measure vasomotor symptoms in 39 studies Study Assessment method, tool or scale Ahimahalle Biglia 201226 200950 Notes Clinical assessment Diary ‘Hot flush diary had been already validated in a series of previous publications’ Menopause Rating Scale (MRS) Boekhout 201145 Diary ‘This well validated diary was originally developed by the North Central Cancer Treatment group’ Bordeleau 201048 Diary ‘patients completed a validated prospective daily hot flash diary’ Bokmand 201325 Subjective Visual Analogue Scale (VAS) Buijs 200946 Diary/Questionnaire Hot Flash Related Daily Interference Scores (HFRDIS) Carpenter 200257 Diary Electronic Hot-flash Monitor (sternal skin conductance)* *‘Previous research supports the reliability and validity of this technology and this particular monitoring device’ Hot Flash Related Daily Interference Scores (HFRDIS) Carpenter 200744 Diary Electronic Hot-flash Monitor Hot Flash Related Daily Interference Scores (HFRDIS) Carson 200937 Diary Daily menopausal symptoms, 0-9 scale Deng 200755 Diary Duijts 201228 Hot Flush/Night Sweats Rating Scale Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 58 Study Elkins Assessment method, tool or scale 200838 Notes Hot Flash Related Daily Interference Scale (HFRDIS) Fenlon 200852 Frisk 2008 and 201231, 51 Diary Incidence Hunter menopause scale Distress measurement Logbook/diary ‘slightly modified version of the Kupperman's Index (KI) was used to assess climacteric symptoms’ Kupperman’s Index (KI) Hernandez Munoz 200360 Questionnaire Hervik 200956 Kupperman’s Index (KI) Jacobs 200558 Diary and severity score Score = Frequency x Severity Kupperman Menopausal Index (KMI) Jacobson 200161 Diary Menopausal Symptom Index Joffe 201036 North Central Cancer Treatment Group Daily Vasomotor Symptom Diary Liljegren 201230 Verbal 5 graded scales Kenemans 200912 Diary cards Sismondi 201133 Climacteric Symptoms Kimmick 200642 Diary ‘Hot flash assessment was performed using a modified version of Loprinzi 1994’ Hot flash score Loibl 200747 Loprinzi Questionnaire 200240 ‘developed by the North Central Cancer Treatment group’ Diary Questionnaire MacGregor Mann 200563 201229 Nedstrand 200553 Menopausal Symptom Score Hot Flush Rating Scale Logbook and severity score Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review ‘severity was graded from 0 to 3’ 59 Study Assessment method, tool or scale Nedstrand 200654 Notes Logbook Kupperman’s Index Visual Analogue Scale (VAS) Symptom checklist Mood scale Nikander 200365 Diary Kupperman’s Index Visual Analogue Scale Nunez 201324 Pandya 200549 Questionnaire related to hot flush interference, adapted from Hot Flash Related Daily Interference Scores (HFRDIS) Diary Pockaj 200662 Diary Stearns 200541 Diary and hot flash score Thompson 200559 Measure Yourself Medical Outcome Profile (MYMOP) ‘developed by the North Central Cancer Treatment group’ Validated patient-generated instrument that includes two self-rated symptom scores Menopausal symptoms questionnaire Van Patten 200264 Diary Walker 201035 Diary Wu 200943 Diary ‘Validated menopause diary’ Abbreviations: HFRDIS: Hot Flash Related Daily Interference Scores; MYMOP: Measure Yourself Medical Outcome Profile; VAS: Visual Analogue Scale; KI: Kupperman’s Index; MRS: Menopause Rating Scale. Figure 1. Forest plot of studies that assessed for vasomotor symptoms: Vasomotor outcome - Pharmaceutical interventions Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 60 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 61 Figure 2. Forest plot of studies that assessed for vasomotor symptoms: Vasomotor outcome - Complementary therapies Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 62 Figure 3. Forest plot of studies that assessed for vasomotor symptoms: Vasomotor outcome - Other therapies Forest plots ( Figure 1to Figure 3) illustrate the respective authors’ conclusions for all the RCTs that reported vasomotor symptoms (hot flushes and night sweats) as their primary outcome. In terms of producing the forest plot, the quality of reporting was poor or fair for most RCTs (e.g. no standard deviation or mean reported, only medians reported, low power of study, no data provided) and therefore not all data requirements could be populated. Hence the graphs represent the observations reported by all the RCTs and reflects their available data; it does not represent an accurate statistical calculation of the data for all the RCTs. Only 14 of the 39 RCTs reported standard deviations and are therefore accurately represented in this graph: Ahimahalle et al (2012), Kimmick et al (2006), Nunez et al (2013), Sismondi et al (2011), Bokmand et al (2013), Deng et al (2007), Duijts et al (2012), Elkins et al (2008), Liljegren et al (2012), Nedstrand et al (2005), Nedstrand et al (2006), Carpenter et al (2002), Thompson et al (2005, and Van Patten et al (2002). Further, not all studies compared groups statisticall (see Table 4 for more information). Significance is not represented in these Forest plots. Abbreviations EA: electro-acupunture; CBT: cognitive behavioural therapy; HF: hot flushes; HFNS: hot flushes and night sweats; NS: night sweats; wk: weak Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 63 3.3 Sleep disturbance Defining sleep disturbances The American Academy of Sleep Medicine defines sleep disturbance as "difficulty initiating sleep, difficulty maintaining sleep, waking up too early, or sleep that is chronically nonrestorative or poor in quality".74 Sleep problems can be both physiological and psychological in nature. They can influence factors like the perception of physical symptoms, tolerance of treatment measures, and quality of life.75 Joffe et al (2010)36 highlighted the association of hot flushes and sleep disturbances in breast cancer survivors, and that sleep disturbance associated with hot flushes was the primary reason that night time hot flushes were bothersome. The present systematic review uses the term sleep disturbance to include most aspects of poor quality of sleep, restless sleep, sleepiness, trouble sleeping, difficulty sleeping, interrupted sleep, unrefreshing sleep, and insomnia (mostly reported as part of quality of life). It excludes fatigue and tiredness, since these symptoms were measured separately from disturbed sleep in all randomized controlled trials assessed. Previous systematic reviews Two existing systematic reviews were identified that examined the effects of pharmacological or non-pharmacological treatment on sleep disturbances associated with menopausal symptoms in women after breast cancer.4, 5 Primary Evidence Base Nineteen RCTs (level II evidence) identified reported sleep disturbance outcomes during treatment for menopausal symptoms in women after breast cancer. The main characteristics and quality of these 19 studies are summarised in Table 6. Of these 19 RCTs, nine are of fair quality and 10 of poor quality in terms of reporting sleep disturbance as an outcome measure. Only two studies had sleep disturbances as a primary outcome measure 25, 31 where their main aim was to assess acupuncture treatment on sleep disturbance. All other studies reported sleep disturbance symptoms as a secondary outcome, or as an adverse event. Most of the studies used validated measures, such as the Medical Outcomes Survey (MOS), the Pittsburgh Sleep Quality Index (PSQI) and the Groningen SLEEP Quality scale amongst others (see Table 7). One study40 did not have a standardised measure for sleep disturbance and reported it as toxicity. Two studies47, 49 used a self- reported diary or symptom inventory to assess sleep disturbances, but they did not report the name of the measurement. Only one study reported the exclusion of patients previously diagnosed with a sleep disorder, such as apnea.36 Four studies mentioned sleep disturbance as part of their secondary outcomes but failed to report any data, and mentioned only if the intervention and the comparator were statistically significantly different.25, 41, 45, 48 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 64 Table 6. Sleep disturbance outcomes reported in 19 RCTs Population Author N, Age, Completed n Treatment, dose (n) Study Duration Sleep Disturbance Measure(s) Stat. Sig. between groups as per author (Y/N) Findings Comments / Quality of Reporting for Sleep Disturbance Outcomes Pharmaceutical Interventions SSRIs antidepressants Secondary outcome Change at week 5, sleep score increased by Sleep disturbance reported as part of QoL scale score Placebo, 11 N=116 Stearns 200541 Age=18-80 Completed= 107 P10, 9 Paroxetine 10mg/day (n=37); 20mg/day (n=38); all followed by 4 weeks of placebo 9 weeks MOS scale (sleep disturbance) P20, 8 All improved 10 points from baseline Y Mean change MOS Sleep scores increased by 10 points from baseline = better P10 vs Pb, -0.4, p=0.01(favouring P10) P20 vs Pb, -0.9 Loprinzi 200240 N=72 Age=18-49 Completed= 68 Fluoxetine 20mg/d (n=36) and placebo (n=36) 9 weeks Diary Improvement observed on paroxetine 10mg (P10)compared with baseline was statistically significantly better than the improvement observed with placebo (p=0.003) Poor quality of reporting There were fewer reports of trouble sleeping on the fluoxetine arm during the first randomized period (44% v 71%; p=0.03). No difference in fatigue between fluoxetine and placebo. Between group change not significant Secondary outcome Reported as toxicity Cross-over study N Only percentage change per arm given No other data reported Poor quality of reporting SNRIs antidepressants Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 65 Population Author Boekhout 201145 N, Age, Completed n Treatment, dose (n) Study Duration Sleep Disturbance Measure(s) N=102 Age= older than 18 years Completed= 80 Venlafaxine 75mg (n=41), or 0.1mg of clonidine (n=41), or placebo daily (n=20) 12 weeks GSQ scale Stat. Sig. between groups as per author (Y/N) Findings Comments / Quality of Reporting for Sleep Disturbance Outcomes Data not shown. Secondary outcome Severe/extreme (Sleepy), Worst Grade of Adverse Effects Reported: Reported as an adverse event N Venlafaxine 37% Clonidine 37% Placebo 25% Sleep quality was not significantly different between venlafaxine and clonidine groups Poor quality of reporting Secondary outcome Reported as an adverse event Venlafaxine N=322 Walker 201035 Age= 35 -77 Completed= 47 37.5mg/day/ and 75mg/night (n=22) 12 weeks Acupuncture 40 minutes session (n=25) National Cancer Institute Common Toxicity Criteria scale Adverse effect, number of people Acupuncture 0; Venlafaxine 7 N Estimates between venlafaxine vs. acupuncture were significantly different (P≤0.002), for all 18 adverse events, including difficulty sleeping Increasing severity of hot flushes and night sweats was also associated with increased difficulty sleeping Poor quality of reporting Buijs 200946 N=60 Venlafaxine Age=≤60 75mg (n=22) for 8 weeks, followed by 2 weeks wash-out Completed= 42 Frequency (%),Venlafaxine vs Clonidine 8 weeks Questionnaire on adverse events Clonidine Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Secondary outcome Week 2; 62% vs 81% Improvement in sleep observed using venlafaxine after 8 weeks Frequency of sleep disturbance for venlafaxine compared to baseline Disturbed sleep was often observed with clonidine Baseline 85% Y 66 Population Author N, Age, Completed n Treatment, dose (n) Study Duration Sleep Disturbance Measure(s) 0.05mg (n=20) for 8 weeks Stat. Sig. between groups as per author (Y/N) Findings at week 2: p=0.022 Comments / Quality of Reporting for Sleep Disturbance Outcomes Poor quality of reporting Week 8; 55% vs 75% Frequency of sleep disturbance between venlafaxine and clonidine at week 8: p=0.039 N=57 Carpenter 200744 Age= not reported, postmenopausal Venlafaxine 37.5mg/day or 75mg/day (n=23) or placebo (n=22) 14 weeks PSQI Percentage difference, between group change of 10.24% (p=0.096). Secondary outcome N High dose excluded n<10 per arm Fair quality of reporting Completed= 45 Secondary outcome Described as toxicity, side effect Venlafaxine Loibl 200747 N=121 37.5mg (n=31) or Age= 18 years or older Clonidine Completed= 64 Twice daily either 0.075mg (n=33) 4 weeks Self-reported diary Clonidine vs. Venlafaxine, between group change (%) Sleeplessness 1.30% (p>0.09) Restless sleep16% (p=0.073) N Hot flushes were accompanied by a variety of other symptoms (sleeplessness, tiredness, restless sleep) Restless sleep was more commonly reported by patients treated with clonidine but was not significantly different Poor quality of reporting Sedatives Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 67 Population Author N, Age, Completed n Treatment, dose (n) Study Duration Sleep Disturbance Measure(s) Stat. Sig. between groups as per author (Y/N) Findings Comments / Quality of Reporting for Sleep Disturbance Outcomes Secondary outcome Sleep changes did not differ substantially among the responders between groups N=53 Age=51 ± 8 y Joffe 201036 Completed =38 Excluded if previously diagnosed with a sleep disorder Zolpidem vs Placebo (PSQI) Zolpidem 10mg/day (n=25) or 5 weeks WASO and PSQI Placebo Baseline, 8.8 ± 4.2 vs 8.7 ± 4.5 At study end, 40% vs 14% N Baseline, 33.0 ± 15.1 vs 33.9 ± 15.9 p=0.035 10mg/day (n=28) Zolpidem vs Placebo (WASO) At study end, 40% reduced in zolpidem augmented responders (WASO) Fair quality of reporting Anticonvulsants Gabapentin Bordeleau 201048 N=66 Age= 39-80 Completed= 58 Pandya 200549 300mg/day (n=20)(increased to 3 times per day) Symptom experience diary (sleeplessness) 37.5mg/day for 1week, 75mg/day for 3 weeks (n=22) Gabapentin Age= 18 years or older 300mg (n=114) or 900mg (n=120) 3 times a day Completed= 347 14 weeks Venlafaxine N=420 Secondary outcome Subgroups: Arm1: venlafaxine followed by gabapentin Arm2: gabapentin followed by venlafaxine Cross-over trial N Data not shown. Improved sleep was observed while receiving the preferred patient drug in each of the two subgroups (p<0.01) Poor quality of reporting Between group change (% difference) 8 weeks Patient-report symptom inventory Placebo (n=113) Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Secondary outcome p=0.065 A criterion significance of p<0.01 was set. None of the groups met this criterion at week 4 or week 8 Week 8, 300mg; 4.56% Poor quality of reporting Week 4, 300mg; 13.10% Week 4, 900mg; 28.48% 68 N Population Author N, Age, Completed n Treatment, dose (n) Study Duration Sleep Disturbance Measure(s) Stat. Sig. between groups as per author (Y/N) Findings Comments / Quality of Reporting for Sleep Disturbance Outcomes Week 8, 900mg; 7.18% p=0.378 Secondary outcome Between group change (% difference) Gabapentin Biglia 200950 N=115 900 mg/day (n=31) Age=28-49 Vitamin E Completed= 61 800 IU/day (n=30) or Sleep quality was significantly improved in the gabapentin group Vitamin E vs. Gabapentin 12 weeks PSQI Y Week 4; -17.35% Week12; -23.87% p<0.05 The total score decreased by 21.33% After 12 weeks, 40% of the women observed an improvement in time to fall asleep and 13% in time staying asleep, while 16 % obtained fewer awakenings Fair quality of reporting Menopause hormone therapy Frisk 201231 N=45 (regional substudy of the HABITS study) Age=47-69 Completed= 30 Hormone replacement therapy (Menopause hormone therapy) Estrogen/progestagen for 24 months (n=11) (asked to stop) Electro-acupuncture (n=19) EA=3 months Menopaus e hormone therapy =2 years The Swedish version of WHQ sleep score WHQ sleep scores, mean values Primary outcome Menopause hormone therapy vs. EA Used the Swedish version of WHQ to assess disease specific HRQoL sleep scale Baseline; 0.29 vs. 0.32 6 months; 0.11, p=0.01vs 0.27, p=0.03 NR 12 months; 0.09, p<0.001 vs. 0.20, p=0.001 Fair quality of reporting 24 months; 0.09, p=0.03 vs. 0.12, p=0.02 Fahlen 201132 12 months EORTC QLQC30 is a HRQoL Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Mean values (SD), Menopause 69 All sleep parameters improved significantly from baseline to most measurement points in both groups Y Secondary outcome Population Author N, Age, Completed n Treatment, dose (n) (sub-group of the Stockholm trial) N=75 Oestradiol (Menopause hormone therapy) Age=57 ± 5.6 y Completed =48 Study Duration Sleep Disturbance Measure(s) questionnaire (insomnia) 2mg/daily in combination with different progestogens versus No treatment Stat. Sig. between groups as per author (Y/N) Findings hormone therapy vs. Control Comments / Quality of Reporting for Sleep Disturbance Outcomes Insomnia reported as part of quality of life, using the QoL symptoms scale Baseline; 64.10 (33.89) vs. 51.51 (33.69) Statistically significant difference over time between estradiol and no treatment, favouring estradiol (improvement of insomnia) 6 months; 29.49 (30.30) vs. 51.51(33.69) 12 months; 39.74 (32.69) vs. 46.97 (35.12) p=0.0002 Fair quality of reporting Sleep Quality outcome, changes in WHQ score (%) Tibolone vs. Placebo Substudy N=883 Sismondi 201133 (sub-study of the LIBERATE trial) Age= younger than 50, between 50-59 and older than 60 Completed= 883 Baseline, 0.649 vs. 0.664 Tibolone 2.5mg/day (n=438) Placebo 104 weeks, follow-up every year for 5 years WHQ (n=445) Week 26, −0.124 (−17.4%) vs. −0.071 (−10.0%) Week 52, −0.129 (−16.8%) vs. −0.079 (−10.3%) Secondary outcome Y Benefit with tibolone was clinically significant (change in score >0.100) for sleep quality Fair quality of reporting Week 78, −0.146 (−22.0%) vs. −0.071 (−9.6%) Week 104, −0.136 (−20.7%) vs. −0.044 (−3.5%) Secondary outcome Kenemans 200912 (LIBERATE trial) N=3133 Tibolone Age=40-70 2.5mg/day (n=1556) or Completed= 3098 Placebo (n=1542) 234 weeks, follow-up every year for 5 years Insomnia outcome WHQ Tibolone vs. Placebo, number during treatment (%) 59 (3.7%) vs. 76 (4.9%) N Insomnia was reported as an adverse event as part of psychiatric disorders Sleep problems data not shown No clinically meaningful differences were noted Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 70 Population Author N, Age, Completed n Treatment, dose (n) Study Duration Sleep Disturbance Measure(s) Stat. Sig. between groups as per author (Y/N) Findings Comments / Quality of Reporting for Sleep Disturbance Outcomes between the treatment groups for Insomnia Poor quality of reporting Complementary Medicines and Therapies Cognitive behavioural therapy CBT vs Usual care mean (SD) Secondary outcome Baseline, 0.63 (0.30)vs 0.72 (0.29) N=96 Mann 201229 Age=53 ± 8 y Completed= 80 Week 9, 0.37 (0.31)vs 0.65 (0.32) CBT 90 min sessions (n=47) 6 weeks Usual cancer care no treatment or dosage reported (n=49) WHQ for problem sleeping Week 26, 0.43 (0.37)vs 0.61 (0.34) Y Between group change (adjusted mean difference, SE) Week 9, –0.26 (0.07), p<0.05 Women in the CBT group reported statistically significant fewer sleep problems at week 9 and week 26 compared to those in the usual care group Fair quality of reporting Week 26, –0.16 (0.07), p<0.0001 Hypnotherapy N=86 Elkins 200838 Age= 18 years or older Completed= 60 Secondary outcome Hypnosis 5 weekly sessions of 50 min (n=30) 5 weeks MOS-sleep Between group change (% difference) Y Hypnosis vs. placebo, -41.81% Placebo (n=30, treatment not described). The difference between groups after treatment was statistically significant and had a large effect size Fair quality of reporting Yoga Mean values Yoga Carson 200937 N=37 Age=53 ± 9 y Completed= 120 min group classes (n=17) Wait list control (n=20) 8 weeks Daily diaries (daily menopausal symptoms Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Secondary outcome Yoga vs. Control Y Baseline; 3.82 vs 4.21 Post treatment; 3.29 vs 4.37 71 The yoga group showed significant improvements in sleep disturbance after last treatment compared to the Population Author N, Age, Completed n Treatment, dose (n) Study Duration 34 Stat. Sig. between groups as per author (Y/N) Sleep Disturbance Measure(s) Findings Comments / Quality of Reporting for Sleep Disturbance Outcomes scale) p=0.0071 controls 3 months follow-up Baseline; 3.80 vs 4.23 No statistically significant difference found at 3 month follow-up Follow-up; 3.01 vs 3.79 Fair quality of reporting p=0.1740. Acupuncture Primary outcome Acupuncture Bokmand 201325 N=94 Age=45-76 Completed= 94 15-20 min once a week for five consecutive weeks (n=31) Data not shown. 12 weeks VAS scale Sham acupuncture (n=29) Acupuncture vs. Sham acupuncture p=0.03 Acupuncture vs. No treatment p=0.009 Y Statistically significant improved sleep was shown among those treated with acupuncture compared to that receiving sham acupuncture and no treatment Poor quality of reporting No treatment (n=34). Other therapies See Biglia 2009 for vitamin E, under Anticonvulsants Abbreviations CBT: cognitive behavioural therapy; EA, electro-acupuncture; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; GSQ: Groningen Sleep Quality Scale; HRQoL: health-related quality of life; MOS: Medical Outcome Survey; NR: not reported; P10 or P20: paroxetine 10mg or 20mg; PSQI: Pittsburgh Sleep Quality of Life Score; QoL: quality of life; VAS: Visual Analogue Scale; WASO: Wake time After Sleep Onset; WHQ: Women’s Health Questionnaire. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 72 Table 7. Summary of sleep disturbance measures used in the 20 RCTs Measure Population Subscales Disease Specific Quality Scores Cited MOS N=523 116 items MOS core functioning and wellbeing Patients with neuropathic pain, restless leg syndrome, overactive bladder, rheumatoid arthritis, heart disease (congestive heart failure or recent myocardial infarction), diabetes, and hypertension. It has also been evaluated in the U.S. general population, Established validity, reliability and sensitivity All scales are scored so that a high score defines a more favorable health state Stearns 200541 N/A Questionable validity, reliability and sensitivity Varies according to the study Loprinzi 200240 Medical Outcomes Study76 MOS sleep scale survey instrument (12 items) Symptom Diary Menopausal women Varies according to the study Elkins 200838 Loibl 200747 Carson 200937 Bordeleau 201048 Likert scale77, 78 Any population Uses fixed choice response formats and are designed to measure attitudes or opinions. They can be five or seven point scales which is used to allow the individual to express how much they agree or disagree with a particular statement. N/A Questionable validity, reliability and sensitivity Varies according to the study Buijs 200946 GSQ The scale was evaluated on populations of depressed patients, This validated scale consists of 14 questions relating to sleep quality, to be N/A Established validity, reliability and sensitivity The scale rates from 0 to 14. Under normal conditions of an unrestricted and Boekhout 201145 Groningen Sleep Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 73 Quality Scale79 and shift workers answered with Yes (=1) or No (=0) National Cancer Institute Common Toxicity Criteria Scale80 Cancer patients 24 different adverse events categories. People with cancer Established validity, reliability and sensitivity Graded from 0 to 5. Zero being no adverse event and five being death related to adverse event. Walker 201035 PSQI 19 individual items generate 7 component scores (subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medication, daytime dysfunction). The sums of all the scores yields one global score Healthy and depressed individuals Established validity, reliability and sensitivity Each component score weighted equally on a 0-3 scale. The sum of the scores yield a global PSQI score, which ranges from 0 to 21, higher scores indicate worse sleep quality Carpenter 200744 Pittsburgh Sleep Quality of life Score81 Healthy subjects, n=52; depressed patients, n=54; sleep-disorder patients, n=64 WASO N=37, healthy subjects 12 items that evaluate Sleep quality, latency, ease of waking up, continuity General population Established validity, reliability and sensitivity Two factors, a sleepquality index (SQI) related to the initiation and maintenance of sleep, and a second factor related to difficulties waking-up and to whether sleep was recuperative and sufficient Joffe 201036 Menopausal women Subscale measuring sleep. Thirty-six symptoms were subjectively graded into a four-point scale N/A Established validity, reliability and sensitivity The patients recorded daily in log-books the numbers of times woken up/night and hours slept. Scores from 0 to 10 Frisk 201231 Wake Time After Sleep Onset undisturbed night’s sleep a score of 1 to 2 is found. A higher score (6 to 7) indicates a disturbed sleep. (part of the Karolinska Sleep Diary)82 WHQ Swedish version31 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 74 Joffe 201036 Biglia 200950 EORTC QLQ-C30 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire83 WHQ Women’s Health Questionnaire84, 85 HFRDIS Hot Flash-Related Daily Interference Scale 86 VAS N=23553 Cancer patients on clinical trials; Physical, role, cognitive, emotional, social functioning, fatigue, pain, nausea, and global health status, vulvovaginal symptoms subscale, sexual enjoyment subscale QLQ-BR23: Diseasespecific module for breast cancer Depressed mood (6 items), somatic symptoms (7 items), anxiety/fears (4 items), vasomotor symptoms (2 items), sleep problems (3 items), sexual behaviour (3 items), menstrual symptoms (4 items), memory/concentration (3 items), attractiveness (3 items) Changes women experience during menopause N=71 breast cancer survivors, N=63 agematch comparators Impact of hot flushes on 9 activities: work, social, leisure, sleep, mood, concentration, relationships, sexuality, enjoyment of life Impact of hot flushes after breast cancer Established validity, reliability and sensitivity Scores range 0-10, with higher scores indicating greater interference of hot flush on activity. Elkins 200838 N/A N/A N/A Questionable validity, reliability and sensitivity Rated 0 to 100 with higher scores indicating greater pain Bokmand 201325 Australia, N=401 N=850 women aged 45-65 in UK. Surgical menopause or Menopause hormone therapy excluded. Established validity, reliability and sensitivity Higher scores indicate better function/greater enjoyment. Fahlen 201132 Age 50-59: SF Mean 20.7(22.6); Enjoyment Mean 51.9 (26.8) Marsden 200139 Lower scores indicate better health. Sismondi 201133 Mean sexual behaviour score, aged 45-54: 0.28(0.30) Duijts 200928 Kenemans 200912 A meaningful clinically significant change on subscales: difference of 0.10-0.20. Visual Analogue Scale87 Abbreviations Established validity, reliability and sensitivity N/A: Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review not 75 available Pharmaceutical Treatments Antidepressants Selective serotonin re-uptake inhibitors: paroxetine and fluoxetine Stearns et al (2005)41 compared the effect of 10mg and 20mg/d paroxetine to placebo, and 10mg paroxetine versus 20mg paroxetine, for four weeks. The researchers used the Medical Outcomes Study Sleep Scale (MOS) to analyse their results. Sleep disturbance was analysed as part of the QoL scale scores, and it was reported at baseline and at week 5. The authors reported that the improvement observed with paroxetine 10mg was statistically significantly better than the improvement observed with placebo and that all groups had improvements of at least 10 points compared to baseline: however, MOS data at week 5 was not reported. Loprinzi et al (2002)40 compared 20mg/d of fluoxetine to placebo for four weeks and reported sleeplessness and trouble sleeping as toxicity. The fluoxetine arm had fewer reports of trouble sleeping during the first randomized period (44% v 71%; p=0 .03). When sleeplessness (reported as a toxicity) was compared in the two treatment cycles, (whether a patient was on placebo versus fluoxetine), there were no statistically significant findings. Serotonin noradrenaline re-uptake inhibitors: venlafaxine, and antihypertensive clonidine Boekhout et al (2011)45 compared 75mg/d of venlafaxine with 0.1mg/d of clonidine hydrochloride and placebo daily for 12 weeks. Levels of sleep quality were assessed at baseline, and after four and 12 weeks of treatment using the Groningen Sleep Quality Scale (GSQ). This scale included 14 questions and has not been validated in breast cancer trials but has been used previously in Dutch populations to determine sleep disturbance and sleep quality. The study did not report any statistical comparisons between venlafaxine, clonidine and placebo on sleep disturbance, and only reported that sleep quality was not significantly different between the venlafaxine and clonidine treatment groups. Bordeleau et al (2010)48 conducted a head-to-head cross-over trial comparing gabapentin (300mg increased to 900mg) with venlafaxine (37.5mg increased to 75mg). Patients were split into groups according to their preferred treatment and into subgroups which included patients that completed the 4 weeks of both treatment drugs (Subgroups, arm1: venlafaxine followed by gabapentin; arm2: gabapentin followed by venlafaxine). The study gave patients a symptom experience diary to record symptoms experienced during the treatment weeks and to rate them in an analog scale of 0 to 10. Data was not shown for sleeplessness, but a greater reduction in sleeplessness was reported while receiving the preferred patient drug in each of the two subgroups (p<0.01). There was no statistically significant difference between venlafaxine compared to gabapentin for sleep disturbance. Walker et al. (2010)35 investigated the effect of 37.5mg of venlafaxine versus acupuncture for 12 weeks. To measure sleep disturbance the study used the National Cancer Institute Common Toxicity Criteria scale. Difficulty sleeping was reported as an adverse event potentially due to treatment. The National Cancer Institute Common Toxicity Criteria scale showed that seven people presented difficulty sleeping in the venlafaxine group compared to none in the acupuncture group. Furthermore, the study concluded that increasing severity of hot flushes and night sweats was also associated with increased difficulty sleeping. Buijs et al (2009)46 investigated the effects of 75mg of venlafaxine or 0.05mg of clonidine for 18 weeks. A questionnaire of adverse events was used to assess the effect of the treatment versus comparator on sleep disturbance. Severity of sleep disturbance symptom was assessed on a four-point Likert scale, ranging from ‘‘not at all’’ to ‘‘very bothersome”. It reported an improvement in regards to sleep using venlafaxine, but no statistically significant difference was found for clonidine compared to baseline. When both drugs were compared at week 8, a statistically significant difference was found between venlafaxine versus clonidine, favouring venlafaxine (less disturbed sleep). Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 76 Carpenter et al (2007)44 investigated the effect of low and high dose (37.5mg and 75mg respectively) of venlafaxine for 6 weeks. The Pittsburgh Sleep Quality Index provided a global score ranging from 0 to 16, with scores ≥5 indicating poor sleep quality and high sleep disturbance. There were no significant treatment effects for the secondary outcome of sleep disturbance at either dose. Overall sleep quality did not improve with treatment compared with placebo. Loibl et al (2007)47 compared 0.075mg/day of clonidine or 37.5mg (twice a day) of venlafaxine for four weeks. Restless sleep and sleeplessness were considered toxic symptoms and participants were asked to note whether they were having these symptoms during each study week. Toxic effects were not graded. Data for sleeplessness (p>0.09) and restless sleep were reported (p=0.073) and they were not statistically significant. Restless sleep was more commonly reported by patients treated with clonidine, but was also not significantly different. There were no statistically significant differences found between venlafaxine and clonidine. Sedatives: zolpidem Joffe et al (2010)36 compared 10mg of zolpidem versus identically matched placebo for 5 weeks in women who were taking venlafaxine or other SSRIs/SNRIs. To objectively measure sleep disturbance the study used WASO, reduction in wake time after sleep onset of ≥15 min from baseline to study end, as well as the Pittsburgh Sleep Quality Index (PSQI) to measure the improvement in perceived sleep quality, with a score range of 0-21. It was reported that the levels of perceived sleep disturbance were high overall in the participants, reflecting poor sleep status, as well as reporting a moderate sleep disruption in patients. PSQI scores at study end indicated improved sleep for 40% of women treated with zolpidem compared to 14% with placebo. The study concluded that augmentation of SSRI/SNRI with zolpidem improved sleep in breast cancer survivors, but there was no statistically significant difference between zolpidem-augmented and placebo-augmented participants. Anticonvulsants: gabapentin Bordeleau et al (2010)48 investigated the effect of 300mg/day of gabapentin or 75mg/day of venlafaxine for 21 days and 3 days respectively. A greater reduction in sleeplessness was reported while receiving the preferred patient drug in each of the two subgroups (p<0.01), but no statistical difference was reported between groups. (Refer to SNRI section). Pandya et al (2005)49 investigated the effect of 300mg/day or 900mg/day of gabapentin versus placebo for 8 weeks. A patient-reported symptom inventory, modified from a measure created at the M D Anderson Cancer Centre, in the USA was used to assess the severity of ten symptoms, including sleep disturbance. A criterion significance of p<0.01 was set, but none of the analyses met this criterion at weeks 4 or 8. Biglia et al (2009)50 investigated the effect of 800 IU/day of vitamin E or 900mg/day of gabapentin for 12 weeks in women with breast cancer. To assess sleep quality, this study used the Pittsburgh Sleep Quality Index Score (PSQI). The study reported that sleep quality was statistically significantly improved in the gabapentin group compared to the vitamin E group from baseline (PSQI score reduction 21.33%, p<0.05). Menopause hormone therapy Frisk et al (2012)31 reported on sleep disturbances as part of the multicenter HABITS study. Electro-acupuncture (EA) and menopause hormone therapy were used as treatment options in women with a history of breast cancer and vasomotor symptoms. The HT group used a combination of oestrogen/progestagen therapy for 24 months, excluding tibolone. The EA group received treatment by a physiotherapist for 12 weeks. The Swedish version of the Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 77 women’s health questionnaire (WHQ) was used to measured sleep outcomes. The study reported that all sleep parameters improved significantly from baseline to most measure points in both groups but did not report on comparisons between treatment groups. Fahlen et al (2011)32 reported health related quality of life in a subgroup of women with breast cancer participating in the Stockholm trial. Daily 2mg oestradiol was administered in combination with different progestogens for six months. Fifty women in this study were on concomitant treatment with tamoxifen. The European organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was used to measure quality of life in cancer patients in clinical trials; it consisted of 30 items constituting five functional scales, including insomnia. The study reported statistically significant difference over time between oestradiol and no treatment, favouring estradiol (improvement of insomnia). Kenemans et al (2009)12 reported on the LIBERATE trial which included women with histologically confirmed breast cancer. Patients were given 2.5mg daily of tibolone or placebo for 234 weeks and followed up every year for 5 years. The WHQ was used to assess sleep disturbance as part of psychiatric disorders. The WHQ score showed a clinically meaningful improvement for sleep problems, but the data was not shown. Insomnia was considered an adverse event and the number of patients in each group with insomnia was recorded (tibolone: 3.7%; placebo: 4.9%). No clinically meaningful difference for insomnia was noted between the treatment groups. Furthermore no statistical significance was reported for insomnia or sleep problem. Sismondi et al (2011)33 undertook an updated analysis of the LIBERATE trial in a subset of 883 women, and reported outcome measures which investigated the safety of 2.5mg tibolone per day versus placebo in breast cancer survivors for a median of 2.75 years. To assess sleep quality the WHQ was used. The study reported that the benefit of tibolone was clinically and statistically significant for sleep quality compared to placebo (p<0.05). It also reported that the findings although significant for tibolone should be judged versus the main outcome of the trial. Showing that tibolone increased the risk of breast cancer recurrence, and its use in women with a known, past or suspected breast cancer will remain contra-indicated. Complementary medicine and therapy Psychological and physicial interventions Cognitive behavioural therapy Mann et al (2012)29 compared cognitive behavioural therapy (CBT) with the usual cancer care (no treatment name mentioned or dose) for 6 weeks. To measure sleep disturbance the WHQ was used for problem sleeping. Women in the CBT group reported fewer sleep problems from baseline compared to the usual care (between group change at week 9: 0.26, p<0.05; week 26: -0.16, p<0.0001). The study reported that the significant improvements in sleep after CBT are clinically important because difficulties with sleep are commonly reported by patients with breast cancer. Hypnotherapy Elkins et al (2008)38 investigated the effect of 5 weeks of hypnosis (weekly 50 min sessions, plus homework) compared to no treatment on sleep disturbance. Participants were assessed using the Medical Outcomes Study Sleep Scale (MOS) at baseline and after 5 weeks of treatment. The study reported that the difference between groups after treatment was statistically significant and had a large effect size, women who received the hypnosis intervention reported significant improvement in sleep. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 78 Yoga Carson et al (2009)37 compared yoga of awareness (120 min group classes) versus wait list controls for eight weeks, with a three month follow-up. Treatment outcomes were assessed via a brief daily diary measurement strategy (daily menopausal symptoms using 0-9 scale; the daily therapeutic processes and yoga practice 0-9 scale). The yoga group reported significant post-treatment improvements in sleep disturbance relative to the control group. Also post-treatment trends suggested that greater yoga practice was associated with less sleep disturbance. This was a pilot study and the findings provided preliminary evidence that the intervention may be helpful for improving sleep disturbance. Acupuncture Bokmand et al (2013)25 evaluated the effect of acupuncture on disturbed sleep in patients treated for breast cancer. All participants kept a protocol-specific logbook where they rated the extent of their symptoms on a subjective visual analog scale (VAS) from zero to ten. The study assessed the effect of acupuncture versus sham acupuncture and found that in the acupuncture group, patients reported lessened sleep disturbance than the other two groups (sham acupuncture and no treatment groups). There was a statistically significant difference from baseline between acupuncture compared to sham acupuncture (p=0.03), and no treatment (p=0.009). The authors concluded that genuine acupuncture had a statistically significant positive effect on sleep in women treated for breast cancer. Other therapies: Vitamin E Biglia et al (2009)50 investigated the effect of 800 IU/day of vitamin E or 900mg/day of gabapentin for 12 weeks, which is presented earlier in the section on anticonvulsants. It was reported that sleep quality significantly improved in the gabapentin group compared to the vitamin E group (PSQI score reduction: 21.33%, p<0.05). Evidence Summary: Sleep disturbances 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 was level II evidence from 19 RCTs (nine of fair quality and 10 of poor quality in terms of reporting sleep disturbance as an outcome measure) in a total of 4,387 women (who completed the study and whose scores were analysed for sleep disturbance). The patients in the RCTs were women with a history of breast cancer, high risk of breast cancer, or primary metastatic breast cancer (18-80 years). Among the19 RCTs, the following treatments were investigated: fluoxetine (one RCT), paroxetine (one RCT), venlafaxine (six RCTs), clonidine (two RCTs), gabapentin (two RCTs), zolpidem (one RCT), menopause hormone therapy (two RCTs), tibolone (two RCTs), CBT (one RCT), hypnotherapy (one RCT), yoga (one RCT), vitamin E (one RCT), and acupuncture (three RCTs). RCTs included sites from the UK, Denmark, USA, Netherlands, Germany, Canada, Sweden, Austria, and Italy. None of the included RCTs were conducted in Australia. Of the 19 RCTs, sleep disturbance was a primary outcome in only two of the trials. Only 16 reported sufficient data to allow interpretation of the findings. Two RCTs used SSRIs for the treatment of sleep disturbance. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 79 The evidence for the effectiveness of the various interventions for sleep disturbances is summarised in the Evidence Summaries below that are numbered for reference with the clinical practice guidelines developed from this systematic review. One RCT (with a low risk of bias) in women after breast cancer found that paroxetine (10 or 20 mg/d for 9 weeks) was associated with an improvement in sleep compared to placebo (Stearns 2005).41 One RCT (with a low risk of bias) in women after breast cancer found that there fewer reports on trouble sleeping with the fluoxetine (20 mg/d for 9 weeks) arm relative to baseline, but did not report between group differences for sleep disturbance compared to placebo (Loprinzi 2002).40 [Evidence Summaries #17] One RCT (with a moderate risk of bias) in women after breast cancer found no difference between venlafaxine 75 mg/d and placebo (Carpenter 2007).44 Three RCTs (one with a low risk of bias and two with a moderate risk of bias) in women after breast cancer compared venlafaxine versus clonidine (Boekhout 2011, Buijs 2009, Loibl 2007),45-47 and only one of the three studies found an improvement in sleep for venlafaxine compared to clonidine (Buijs 2009).46 One RCT (with a moderate risk of bias) in women after breast reported no statistical comparison between venlafaxine versus acupuncture (Walker 2010).35 [Evidence Summaries #18] One RCT (with a moderate risk of bias) in women after breast cancer receiving an SSRI or SNRI for vasomotor symptoms found an improvement in sleep disturbance with 5 weeks of zolpidem (10 mg/d) augmentation compared to placebo (Joffe 2010).36 [Evidence Summaries #19] One RCT (with a moderate risk of bias) in women after breast cancer reported that gabapentin (300mg/d or 900mg/d) had no effect on sleep compared to placebo (Pandya 2005).49 One cross-over RCT (with a moderate risk of bias) in women after breast cancer reported that gabapentin (900mg/d for 4 weeks) had no difference in sleeplessness compared to venlafaxine (75mg/d for 4 weeks, Bordeleau 2010).48 One RCT (with a moderate risk of bias) in women after breast cancer reported that gabapentin (900mg/d for 12 weeks) improved sleep quality compared to Vitamin E (800 IU/d for 12 weeks, Biglia 2009).50 [Evidence Summaries #20] One RCT (with a low risk of bias) in women after breast cancer found that tibolone (2.5mg/d) was associated with an improvement in sleep quality compared to placebo (LIBERATE study) (Sismondi 2011).33 An earlier analysis from the LIBERATE study reported insomnia as an adverse event, but did not report between-group differences (Kenemans 2009).12 One RCT (with a high risk of bias) in women after breast cancer found menopause hormone therapy (2mg of estradiol with different progestogens) improved sleep compared to no treatment (Fahlen 2011).32 One RCT (with a moderate risk of bias) in women after breast cancer found that menopause hormone therapy (for 24 months) and electro-acupuncture (for 12 weeks) improved sleep relative to baseline, but did not report between group differences (Frisk 2012).31 [Evidence Summaries #21] One RCT (with moderate risk of bias) in women after breast cancer found that CBT (90min per week for 6 weeks) significantly improved sleep compared to usual care (Mann 2012).29 One RCT (with moderate risk of bias) in women after breast cancer found that hypnotherapy (once a week for 5 weeks) improved sleep compared to no treatment (Elkins 2008). 38 [Evidence Summaries #22] One RCT (with moderate risk of bias) in women after breast cancer found that a yoga program significantly improved sleep compared to no intervention (Carson 2009).37 One RCT (with low risk of bias) in women after breast cancer found that acupuncture (for 15-20min once a week) significantly improved sleep compared to sham-acupuncture and no treatment groups but did not report between-group differences from baseline (Bokmand 2013).25 [Evidence Summaries #23] One RCT (with moderate risk of bias) in women after breast cancer found that gabapentin (900mg/d for 12 weeks) reduced the Pittsburgh Sleep Quality Index score (PSQI), compared Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 80 to Vitamin E (800 IU/d for 12 weeks) which had no effect on the PSQI score (Biglia 2009).50 [Evidence Summaries #24] Overall there is limited 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 evidence from one study each for improved sleep for the interventions: paroxetine, zolpidem (in women taking an SSRI or SNRI), tibolone, CBT, purposed design 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 (sleep disturbance was a secondary outcome in most of these studies) 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. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 81 3.4 Vulvovaginal symptoms Defining vulvovaginal symptoms The present systematic review uses the term “vulvovaginal symptoms” to 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 by 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). Previous systematic reviews No existing systematic reviews were identified that examined the effects of pharmaceutical therapy or complementary medicine or therapy on vulvovaginal symptoms associated with menopausal symptoms in women who had received breast cancer treatment. Primary Evidence Base Twelve RCTs (reported by 13 publications) were identified that reported vulvovaginal symptom outcomes during treatment for vasomotor symptoms in women after breast cancer treatment. The main characteristics and quality of these 12 RCTs with respect to vulvovaginal symptom outcomes are summarised in Table 8. Overall, the quality of these studies in assessing the effect of treatment on vulvovaginal symptoms was poor. Only one pilot study had vulvovaginal symptoms as a primary outcome measure39, with the main aim of assessing treatment (menopause hormone therapy) on sexuality. All other studies reported vulvovaginal symptoms as a secondary outcome or as an adverse event or side effect of treatment. Only one study24 reported the prevalence of sexual dysfunction in their study participants (n=25) and five studies7, 24, 32, 39, 46 reported whether participants were sexually active (the largest number of sexually active women was in the study by Lee et al (2011)34, with a total of 66 sexually active women). Additionally, only six studies24, 28, 39, 41, 45, 46 used a measure specifically designed to assess vulvovaginal symptoms (see Table 9). Studies used hot flush symptom diaries46, 48, study-specific measures33, 34, 39 or validated measures of quality of life32, 33, 38, 41 or depression40 to report vulvovaginal symptom outcomes. All studies were limited by inadequate reporting of results for vulvovaginal symptom outcomes. Consequently, there is a lack of consistent and reliable evidence regarding the effects of treatment on vulvovaginal symptoms associated with menopausal symptoms in women after breast cancer treatment. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 82 Table 8: Vulvovaginal symptom outcomes reported in 12 RCTs Author Number of subjects (N) Age Completed N Intervention N Study Duration Vulvovaginal symptom Measure(s) Findings Stat. Sig. between groups as per author (Y/N) Comments / Quality of Reporting for SF Outcomes 4 weeks, crossover 10 weeks ASEX Bupropion: Average(SD) N -SF secondary outcome Pharmaceutical interventions Antidepressants Nunez 201324 N=55 Age=49 Completed N=48 SA N=29 SD Bupropion Baseline 12.88(10.16); Final 11.52(9.50); Difference 1.36(SD=3.77) 150mg 2xday Placebo -only SA patients included in ASEX analyses (N=29) N=27 Baseline 12.83(10.30); Final 12.26(9.49); Difference 0.57(SD=3.41) -average scores below cutoff at baseline No sig. difference between groups (p=0.497). Sig. difference over time (p=0.003) -poor quality of reporting Placebo N=28 N=25 Loprinzi 200240 N=81 Age=18-49 Completed N=66 SA; NR SD; NR Stearns 200541 N=151 4 weeks, crossover 9 weeks BDI Fluoxetine 20mg daily N=40 “only 3 patients on the placebo arm had a decrease in libido in the fifth treatment week compared with baseline (nine with improved libido), whereas one patient in the fluoxetine arm had a decrease in libido (11 with improved libido)” (p. 1581) -short treatment duration N -SF secondary outcome -short treatment duration -single item on BDI is not a validated measure of SF -scores not reported Placebo -poor quality of reporting N=41 Completed 4 weeks, crossover Paroxetine 10mg or 20mg N=107 N=75 SA; NR Placebo -mean scores not reported SD; NR N=76 -poor quality of reporting Age=50-55 9 weeks MOS SPI Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review “At week 5, there were no significant statistical differences in the distribution of patients for either paroxetine dose vs placebo who experienced improvement or worsening” (p.6927) 83 N -secondary outcome -short treatment duration -categorised MOS scores difficult to interpret Author Number of subjects (N) Age Completed N Intervention N Study Duration Vulvovaginal symptom Measure(s) Findings Boekhout 201145 N=102 12 weeks SAQ Age=49 12 weeks Venlafaxine 75mg daily Completed N=41 “Vulvovaginal symptoms was not significantly different between venlafaxine and clonidine treatment groups” (p.3864) N=80 SA; NR Clonidine 0.1mg daily SD; NR N=41 Stat. Sig. between groups as per author (Y/N) N Comments / Quality of Reporting for SF Outcomes -SF secondary outcome -no SAQ results provided -poor quality of reporting Placebo N=20 Buijs 200946 N=60 Completed 8 weeks, crossover Venlafaxine 75mg daily N=40 N=30 SA; N=33 Clonidine 0.05mg daily Age=49 SD; NR Bordeleau 201048 N=66 18 weeks SAQ Symptom Diary N=30 Age=54.957.6 4 weeks, crossover Venlafaxine 75mg daily Completed N=32 N=58 SA; NR Gabapentin 300mg 3xday SD; NR N=34 14 weeks Symptom Diary Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review No sig. difference between groups on SAQ (mean scores not reported) As a side effect, the frequency of decreased sexual interest sig. reduced from baseline (n=68) to 2 wks (n=53; p=0.008) with venlafaxine and from 2 wks (n=53) to 8 wks (n=46, p=0.035) with clonidine : No comparison reported between groups of changes from baseline 20 answers on orgasm: Sig. more difficulty achieving orgasm with venlafaxine (approx. mean score 5) compared to gabapentin (approx. mean score 2, p=0.002) 25 answers on dryness/pain during intercourse (approx. mean score for venlafaxine and gabapentin 3, not sig.) 26 answers on lack of sexual interest (approx. mean score for venlafaxine and gabapentin 6, not sig.) 84 N -SF secondary outcome -no SAQ results provided N Y -diary not validated measure -poor quality of reporting -SF secondary outcome -short treatment duration -not validated measure of SF N N -small number of responses -mean scores illustrated in figure by patient preference (only able to approximate mean scores as they are not provided in text) Author Number of subjects (N) Age Completed N Intervention N Study Duration Vulvovaginal symptom Measure(s) Findings Stat. Sig. between groups as per author (Y/N) Mean symptom severity at baseline Comments / Quality of Reporting for SF Outcomes -poor quality of reporting Menopause hormone therapy Fahlen Subgroup 201132 N=75 (Stockholm trial) Age=57 N=38 Completed NR Control SA; Marsden 200139 Menopause hormone therapy 1 year QLQ-BR23 Menopause hormone therapy: mean values (SD) Sexual enjoyment: Baseline 48.48(22.92); 6mths 54.54(30.81); 12mths 66.67(21.08) N=37 SD; NR No sig. difference between groups on vulvovaginal symptoms or sexual enjoyment (only sexually active patients included in enjoyment) Age=56 -mean scores in normal range across time for both groups Control SF: Baseline 23.02(29.57); 6mths 30.16(29.16); 12mths 27.78(26.53) -SF secondary outcome -small number of sexually active women (<10 in control group) SF: Baseline 37.18(27.61); 6mths 37.18(27.21); 12mths 33.33(27.49) Menopause hormone therapy, N=11 Control, N=7 N=100 N -poor quality of reporting Sexual enjoyment: Baseline 57.14(14.02); 6mths 57.14(31.71); 12mths 52.38(37.80) Menopause hormone therapy N=49 Completed No treatment N=89 N=51 6 months SAQ SA; Menopause hormone therapy: median (range) -SF primary outcome -use of non-validated measure of vaginal symptoms (SS Vag) Sexual activity change: baseline 1-2(0>5); 3mths 0(-2 to 1); 6mths 0 (-2 to 1) (ns) Pleasure change: baseline 9(3-18); 3mths -0.5(-7 to 8); 6mths -0.5 (-10 to 10) (ns) N -errors in reporting of results in paper Menopause hormone therapy, N=29; Discomfort change: baseline 3(0-6); 3mths -1.5 (-5 to 4) (p=0.01); 6mths -1(-6 to 1) (ns) No Menopause hormone therapy -risk of BC recurrence No treat., N=24 Sexual activity change: baseline 1-2(0- -clinical significance not Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 85 N -conflicting findings on vaginal dryness (SAQ vs SS Vag) Author Number of subjects (N) Age Completed N Intervention N Study Duration Vulvovaginal symptom Measure(s) SD; NR Findings Stat. Sig. between groups as per author (Y/N) Comments / Quality of Reporting for SF Outcomes >5); 3mths 0(-2 to 1); 6mths 0(-2 to 1) (ns) reported Pleasure change: baseline 8(0-18); 3mths -1(-6 to 2); 6mths 0(-6 to 3) (ns) -fair quality of reporting Y Discomfort change: baseline 3(0-6); 3mths -1(-3 to 4) (p=0.01); 6mths 0(-3 to 4) (ns) “No sig. reduction in proportion of women complaining of vaginal dryness or severity of symptoms” (p. 89) SS Vag N Sismondi 2011 (LIBERATE trial)33 N=3098 Tibolone Total Mean Age=52.7 Vaginal Subgroup Vaginal N=1078 Subgroup WHQ Subgroup N=2144 N=438 WHQ Subgroup Placebo N=883 Vaginal Subgroup SA; NR N=1066 2.75 years SS Vag Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Vaginal dryness sig. improved at week 104 (treatment effect -0.18) with tibolone (p<0.0001), Tibolone: Mean(SD) Baseline 1.79; change -0.46(1.06) -25.7%; Placebo: Mean(SD) Baseline 1.85; change -0.29(1.00) -15.7% Sig. improvement in sexual behaviour with tibolone (p<0.05) Tibolone: change (%) Baseline 0.503; 26wks -0.160(-34.8%), 86 Y -SF secondary outcome -use of non-validated measure for vaginal symptoms -N’s not reported for sexual domain -risk of BC recurrence -poor quality of reporting Author Number of subjects (N) Age Completed N Intervention N SD; NR WHQ Subgroup Study Duration Vulvovaginal symptom Measure(s) Findings WHQ 52wks -0.183(-43.6%); 78wks -0.177(38.4%); -0.196(-39.3%) N=445 Stat. Sig. between groups as per author (Y/N) Y† Comments / Quality of Reporting for SF Outcomes Y -VAS primary outcome Placebo: change (%) Baseline 0.549; 26wks -0.062(-16.2%); 52wks -0.055(-14.0%); 78wks -0.023(-5.9%); 104wks -0.055(-12.9%) Vaginal gel Lee 201134 N=98 12 weeks Age=45 VAS pH-balanced gel: mean±SD VHI Dryness with pain Completed Vaginal topical pH balanced gel Vaginal pH N=86 N=44 VMI - pH balanced gel (SD): baseline 8.20±0.826; end 12wks 4.23±1.396, p<0.001, from baseline p=0.001 Sexually active; Placebo pH-gel, N=35 placebo, N=31 12 weeks N=42 SD; NR -fair quality of reporting - placebo (SD): baseline 8.11±0.955, end 12 wks 6.11±1.42, p=0.04, from baseline p=0.04 Dyspareunia: baseline 8.23±0.991; 12wks 5.48±1.095, p=0.040 VHI: baseline 15.78±3.710; 12wks 21.05±3.910, p<0.001 pH: baseline 6.49±1.085; 12wks 5.00±0.816, p<0.001 VMI: baseline 45.48±3.489, 12wks 51.18±3.753, p<0.001 Placebo Dryness with pain: baseline 7.92±0.895; 12wks 6.51±1.506 Dyspareunia: baseline 8.11±0.955; 12wks 6.11±1.421 VHI: baseline 14.27±3.740, 12wks Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 87 Author Number of subjects (N) Age Completed N Intervention N Study Duration Vulvovaginal symptom Measure(s) Findings Stat. Sig. between groups as per author (Y/N) Comments / Quality of Reporting for SF Outcomes Y -SF secondary outcome 16.98±3.875 VMI: baseline 46.42±3.713; 12wks 47.87±2.728 Complementary Medicine and Therapy Psychological and physical interventions Duijts 201228 N=422 CBT Age=48.2 N=109 Completed PE N=340 N=104 Compliant CBT+PE N=219 N=106 SA, NR Wait-list SD; NR N=103 6 months SAQ Sig. interaction between time and group for SAQ habit (p=0.27), see Figure 428, 88 ITT Analyses for SAQ habit: Mean(SD) CBT: baseline 0.34(0.78); 12 wks 0.54(0.79); 6 mths 0.47(0.69) PE: baseline 0.63(0.77); 12 wks 0.60(0.79); 6 mths 0.55(0.69) CBT+PE: baseline 0.44(0.78); 12 wks 0.53(0.79); 6 mths 0.75(0.69) Control: baseline 0.62(0.78); 12 wks 0.59(0.79); 6 mths 0.42(0.69) Between groups difference from baseline to 12 weeks: Mean change(SE) CBT: 0.24(0.16), p=0.134, effect size 0.31 PE: 0.01(0.17), p=0.969, effect size 0.01 CBT+PE: 0.12(0.16), p=0.443, effect size 0.15 Between groups difference from baseline to 6 months: Mean change(SE) CBT: 0.33(0.16), p=0.042, effect size 0.42 PE: 0.12(0.17), p=0.488, effect size 0.15 CBT+PE: 0.51(0.16), p=0.002, effect size 0.65 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 88 -dissimilar treatments -low compliance; CBT 42%; PE 36%; CBT+PE 30% -poor quality of reporting Author Number of subjects (N) Age Completed N Intervention N Study Duration Vulvovaginal symptom Measure(s) Findings Stat. Sig. between groups as per author (Y/N) Comments / Quality of Reporting for SF Outcomes N= 60 5 weeks 5 weeks HFRDIS -secondary outcome Hypnotherapy Completed N=30 N=51 No treatment SA; NR N=30 “Follow-up analyses of each item showed that all items were statistically significantly less interfering (p<0.05) for those in the experimental group, with the exception of an item asking about interference with sexuality (p=0.124)” (p.5024) N Age=55-58 Hypnotherapy Elkins 200838 -not validated measure of SF -does not control for placebo effect -poor quality of reporting SD; NR Note: where scores were not reported, the results are quoted from the original paper. NR, not reported; approx., approximate; SF, vulvovaginal symptoms; SA, sexually active; SD, sexual dysfunction; mths, months; wks, weeks; CBT, cognitive behaviour therapy; PE, physical exercise; ITT, intention-to-treat; ASEX, Arizona Sexual Experience Scale; BDI, Beck Depression Inventory; MOS SPI, Medical Outcomes Survey Sexual Problems Index; SAQ, Sexual Activity Questionnaire; EORTC QLQ-BR23, European Organisation for Research and Treatment of Cancer Quality of Life Breast Cancer Module; WHQ, Women’s Health Questionnaire; SS Vag, Study specific measure of vaginal dryness; VAS, Visual Analogue Scale; VHI, Vaginal Health Index; VMI, Vaginal Maturation Index; HFRDIS, Hot Flash Related Daily Interference Scale # reported clinically meaningful improvement for sexual behaviour but data not shown; †clinically meaningful difference reported Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 89 Table 9. Summary of measures used in 12 RCTs reporting vulvovaginal symptoms outcomes Measure Population Subscales Disease Specific Quality Scores (SD) Cited in current systematic review by ASEX N=107 control, N=58 psychiatric patients, US 5 global aspects of sexual dysfunction: drive, arousal, penile erection/vaginal lubrication, ability to reach orgasm, satisfaction from orgasm SSRI induced sexual dysfunction Established validity, reliability, sensitivity Total scores range from 5 to 30 with higher scores indicating greater sexual dysfunction. Norms not established. Suggested cutoff score >14 (Nunes, 2009) Nunez24 Psychiatric and normal populations Measures attitudes and symptoms of depression (single item on libido as a symptom of depression) Depression Established validity, reliability, sensitivity for Depression Cut-off scores indicating the severity of depressive symptoms vary depending of the version used (version not reported in Loprinzi) Loprinzi40 N=1852 women Measures any impairment to achieve sexual arousal or orgasm. Focus on current sexual problems, not changes in vulvovaginal symptoms due to illness. N/A Established validity, reliability, sensitivity High scores indicate greater sexual problems, range 0-100. Mean score for general population of women: 24.9(32.1) Stearns41 N=447 Women at high risk of developing BC, on tamoxifen trial, aged >35 years, in UK + N=81 women no family history of BC 1. Hormonal status (6 items). Not SA women complete section 2. SA women complete section 3. Breast cancer Established validity, reliability High scores indicate high pleasure (desire, enjoyment, satisfaction). Low score indicates low discomfort. Habit is single item, with values recorded on questionnaire. Boekhout45 Arizona Sexual Experience Scale89 BDI Beck Depression Inventory90-92 MOS SPI Medical Outcomes Survey Sexual Problems Index93 SAQ Sexual Activity Questionnaire94 2. Reasons for sexual inactivity (any that apply) 3. Vulvovaginal symptoms (10 items) desire, frequency, satisfaction, vaginal dryness, penetration pain Mean scores for ages 45-55: Pleasure 12.4(4.0), Menopause hormone therapy 11.1(4.1), Discomfort 2.8(1.3), Menopause hormone therapy 3.2(1.5), Habit 1.0(0.5), Menopause hormone therapy 0.9(0.5) Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 90 Buijs46 Marsden39 Duijts28 (Vistad) Symptom Diary N/A Frequency of side effects, including decreased sexual interest N/A Not an established measure of SF N/A Frequency of side effects, including difficulty achieving orgasm, dryness/pain in intercourse, lack of sexual interest EORTC QLQ-C30 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire83 SS Vag N=23553 Cancer patients on clinical trials; Australia, N=401 N/A Study specific measure of vaginal dryness WHQ Women’s Health Questionnaire84, 85 VAS Visual Analogue Scale VHI Vaginal Health Index Bordeleau48 Physical, role, cognitive, emotional, social functioning, fatigue, pain, nausea, and global health status. 3 items on sex: interest, activity (vulvovaginal symptoms subscale), enjoyment (sexual enjoyment subscale) QLQ-BR23: Diseasespecific module for breast cancer Established validity, reliability and sensitivity Higher scores indicate better function/greater enjoyment. 5 questions: if experience vaginal dryness, frequency, effect on sex life, extent of problem and distress. N/A Not an established measure of SF Higher scores indicate greater problem/distress Fahlen32 Age 50-59: SF Mean 20.7(22.6); Enjoyment Mean 51.9 (26.8)83 Individual rating of vaginal dryness Marsden39 Sismondi33 N=850 women aged 45-65 in UK. Surgical menopause or Menopause hormone therapy excluded. Depressed mood (6 items), somatic symptoms (7 items), anxiety/fears (4 items), vasomotor symptoms (2 items), sleep problems (3 items), sexual behaviour (3 items), menstrual symptoms (4 items), memory/concentration (3 items), attractiveness (3 items) Changes women experience during menopause Established validity, reliability and sensitivity N/A Dryness with pain (1 item), Dyspareunia (1 item) N/A Questionable validity, reliability and sensitivity87 Lower scores indicate better health. Mean sexual behaviour score, aged 45-54: 0.28(0.30) Sismondi33 A meaningful clinically significant change on subscales: difference of 0.100.20. Evaluated with regard to moisture, fluid volume, elasticity, epithelial integrity and pH according to methods of Robert Wood Johnson Medical School Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Buijs46 Rated 0 to 100 with higher scores indicating greater pain Lee34 Lee34 91 Vaginal pH Assessed with pH indicator strip VMI Calculated with a sum of percentages of superficial cells, intermediate cells, parabasal cells, assigned point values of 1.0, 0.6 and 0.2 respectively Vaginal Maturation Index HFRDIS Hot Flash-Related Daily Interference Scale86 N=71 breast cancer survivors, N=63 agematch comparators Impact of hot flushes on 9 activities: work, social, leisure, sleep, mood, concentration, relationships, sexuality, enjoyment of life Normal vaginal pH 3.8 to 4.5 Lee34 Impact of hot flushes after breast cancer Established validity, reliability and sensitivity BC, breast cancer; SA, sexually active; SF vulvovaginal symptoms; N/A not applicable; Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Lee34 92 Scores range 0-10, with higher scores indicating greater interference of hot flush on activity. Elkins38 Pharmaceutical interventions Antidepressants Atypical antidepressants: bupropion Nunez et al (2013)24 compared bupropion to placebo for four weeks and found that vulvovaginal symptoms significantly improved (within the normal range) over time (p=0.003) but not between groups (mean difference for bupropion 1.36, SD 3.77; placebo 0.57, SD 3.41), p=0.497). Analysis of variance was carried on the ASEX scores of 29 sexually active patients. These results suggest that bupropion neither caused nor treated loss of vulvovaginal symptoms but caution is needed when interpreting these findings due to the small sample size and short treatment duration. Selective serotonin re-uptake inhibitors: fluoxetine and paroxetine Loprinzi et al (2002)40 compared 20mg of fluoxetine to placebo for four weeks and reported that “only 3 patients on the placebo arm had a decrease in libido in the fifth treatment week compared with baseline (nine with improved libido), whereas one patient in the fluoxetine arm had a decrease in libido (11 with improved libido)” (p. 1581), suggesting that fluoxetine may not decrease libido (statistical and clinical significance not reported). However, they used a single item on the Beck Depression Inventory (BDI) to measure libido. While the BDI is a validated measure of depression, this individual item is not a validated measure of vulvovaginal symptoms. Additionally, the treatment duration may have been too short to assess the effect of fluoxetine on vulvovaginal symptoms (a medication otherwise known to cause sexual dysfunction in 8% Herman95 to 73% Piazza,96 of patients). Stearns et al (2005)41 investigated the efficacy of 10mg or 20mg of paroxetine compared to placebo. Stearns et al administered the MOS Sexual Problems Index and categorised scores as better (or worse) if the scores decreased (or increased) by at least ten points between baseline and week five. The authors reported that “at week five, there were no significant statistical differences in the distribution of patients for either paroxetine dose versus placebo who experienced improvements or worsening of MOS sexuality scores” (p.6927). This would suggest that paroxetine did not affect vulvovaginal symptoms, but treatment duration (four weeks) may be too short to assess the effect of paroxetine on vulvovaginal symptoms. Serotonin noradrenaline re-uptake inhibitors: venlafaxine Two studies45, 46 used the SAQ to compare the effect of venlafaxine and clonidine on vulvovaginal symptoms (for eight and 12 weeks, respectively). Both studies found no difference between treatments on vulvovaginal symptoms. However, the results were not adequately reported or compared to placebo, and the treatment duration may have been too short to adequately assess the effect on vulvovaginal symptoms. Bordeleau et al (2010)48 compared the effects of venlafaxine to gabapentin using a symptom diary. They reported that “more difficulty achieving orgasm was noted during venlafaxine use (p=0.002)” (p. 5150). However, only 20 women answered this question; there was no difference between treatment groups from baseline. Buijs et al (2009)46 also used a symptom diary to report the side effects of medication on vulvovaginal symptoms. They reported that the frequency of decreased sexual interest significantly reduced from baseline (n=68) to week two (n=53; p=0.008) with venlafaxine and from week two (n=53) to week eight (n=46, p=0.035) with clonidine. The findings of Buijs et al (2009)46 and Bordeleau et al (2010)48 are not directly comparable as they are measuring different aspects of vulvovaginal symptoms (libido and orgasm, respectively). Additionally, the clinical significance was not reported. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 93 Menopause hormone therapy Fahlen et al (2011)32 reported on a subgroup (N=75) of women in the Stockholm trial who completed the European Organization for Research and Treatment of Cancer Quality of Life Breast Cancer Module (EORTC QLQ-BR23). They reported that there were no statistically significant group by-time interactions on the subscales of vulvovaginal symptoms or sexual enjoyment. As items on the sexual enjoyment subscale should only be responded to by women who were sexually active, the sample may not have been large enough to detect differences (11 sexually active women in menopause hormone therapy group, seven in the control group). Additionally, mean scores reported by Fahlen et al (2011)32 were in the normal range83 at baseline, six and 12 months. Marsden et al (2001)39 stratified 100 postmenopausal women by tamoxifen use and randomly allocated them to receive hormone therapy (2mg valerate per day for women who had undergone hysterectomy or 2mg valerate plus levonorgestrel 75µg for twelve out of 28 days for those with an intact uterus) or no hormone therapy for six months. Participants completed the SAQ at baseline, and after three months and six months of treatment. No significant difference was found between groups on frequency of sexual activity or sexual pleasure. Sexual discomfort was statistically reduced after three months of treatment in the hormone therapy group (change in median discomfort score from baseline, -1.5, range -5 to 4) compared to no treatment (change in median discomfort score from baseline, -1, range -3 to 4, p=0.01). However, there was no difference between groups at six months, and they did not report whether the difference at three months was clinically significant. Marsden et al (2001)39 also included a study specific, non-validated measure of vaginal dryness (participants rated five items on a 10-point Likert scale) and found “no significant reduction in the proportion of women complaining of vaginal dryness or the severity of symptoms” (p. 89). The scores on the non-validated measure of vaginal dryness are not consistent with the validated SAQ discomfort scores, which includes items on vaginal dryness and pain/discomfort during sex. Sismondi et al (2011)33 reported secondary outcome measures of the LIBERATE trial which investigated the safety of 2.5mg tibolone per day versus placebo in breast cancer survivors for a median of 2.75 years. On a non-validated measure of vaginal dryness, “2144 patients showed a significant improvement at week 104 in the tibolone group compared to placebo (-0.46 versus -0.29, respectively, p<0.0001)” (p.369). A subset of 833 women completed the Women’s Health Questionnaire (WHQ; a validated quality of life measure, with an optional subscale measuring sexual behaviour with three items). The number of women who were sexually active and completed the sexual behaviour subscale was not reported. The mean sexual behaviour score significantly decreased from baseline (lower scores indicate better health) in the tibolone group compared to placebo (see Table 8 for change scores). Although this difference was considered clinically significant, the benefits of tibolone on vulvovaginal symptoms need to be balanced with the risk of breast cancer recurrence with tibolone treatment. Vulvo-vaginal treatments Lee et al (2011)34 evaluated the effect of vaginal pH-balanced gel on vaginal symptoms in women after breast cancer. Women rated vulvovaginal symptoms, pain and dyspareunia (only sexually active women were included in the dyspareunia analysis; pH-balanced gel, n=35; placebo, n=31) on a ten point, visual analogue scale (VAS). Other clinician assessed measures included the vaginal health index, vaginal pH and vaginal maturation index. A statistically significant treatment effect in favour of the pH-balanced gel compared to placebo was found on all measures, including when comparing changes from baseline (see Table 8). However, the reliability and validity of the VAS is not known, and the clinical significance was not reported. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 94 Complementary medicines and therapies Psychological and physical interventions Cognitive behavioural therapy and exercise Duijts et al (2012)28 evaluated the effect of CBT (six 90 minute weekly group sessions involving relaxation exercises and focus on hot flushes, night sweats, vaginal dryness, body image, sexuality and mood disturbance, plus “booster” session at week 12), physical exercise (individually tailored home-based exercise program consisting of 2.5-3 hours per week for twelve weeks), and CBT and physical exercise combined (as described above), compared to a wait-list control group. Vulvovaginal symptoms were measured by the SAQ as a secondary outcome measure. Intention-to-treat results indicated a significant difference between groups, with CBT plus physical exercise showing the greatest mean change (0.51, SE 0.16), p = 0.002, effect size = 0.65), followed by CBT alone (mean change 0.33, SE 0.16), p = 0.042, effect size = 0.42) on sexual habits (SAQ-H; high scores indicate a larger change in sexual activity) which was maintained at six months. However, mean scores remained below normative data88 for women aged 45–55 years (the mean age in Duijts study was 48.2 years28) (see Figure 4). However, the low levels of treatment compliance, (CBT, 42%; physical exercise, 36%; CBT plus physical exercise, 30%) may underestimate treatment effects. Figure 4. Mean Sexual Activity Questionnaire-Habit scores at baseline, 3 months and 6 months28, 88 1.20 1.00 Norm 0.80 HRT Norm Control 0.60 CBT 0.40 PE 0.20 CBT+PE 0.00 0 3 6 Norm= normal range for women 45-55 years; Menopause hormone therapy Norm=normal range for women aged 45-55 years on menopause hormone therapy; Control = Duijts et al control group; CBT= Duijts et al cognitive behavioural therapy group; PE= Duijts et al physical exercise group; CBT+PE=Duijts et al cognitive behavioural therapy plus physical exercise group. Hypnotherapy Elkins et al (2008)38 investigated the effect of hypnotherapy (five weekly 50 minute sessions, plus homework) compared to no treatment on hot flushes. Participants completed the Hot Flash Related Daily Interference Scale (HFRDIS) at baseline and after five weeks of treatment. Although the authors did not report the mean scores, they did indicate that there were no statistically significant differences between groups on interference of hot flushes on sexuality (p=0.124). Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 95 Yoga, acupuncture and magnetic therapy No RCTs were identified that reported the treatment effects of yoga, acupuncture or magnetic therapy on vulvovaginal symptoms (see Table 2: Menopausal symptoms and other outcomes reported in individual RCTs, including drug dosages and study risk of bias). There is only one RCT28 that investigated the treatment effects of a physical intervention (physical exercise) on vulvovaginal symptoms. Duijts et al (2012)28 reported the effect of CBT, PE or CBT+PE, on SAQ-Habit scores. This study is discussed under the psychological interventions section of the present systematic review, with results presented in Figure 4. In summary, the group undergoing CBT+PE showed the greatest change in sexual habits. However, the mean scores for all groups remained below normative data for the general population and for women on menopause hormone therapy. Considering the poor treatment compliance in the study by Duijts et al (2012)28, the benefits of physical exercise (with or without CBT) on vulvovaginal symptoms may be underestimated. Evidence Summary: Treatment of vulvovaginal symptoms associated with menopausal symptoms in women after breast cancer There was no level I evidence from systematic reviews that examined the effects of treatment on vulvovaginal symptoms associated with menopausal symptoms after breast cancer treatment. There is level II evidence from twelve RCTS (five with a low risk of bias, five with moderate risk of bias, two with high risk of bias; ten were of poor quality and two were of fair quality in reporting vulvovaginal symptoms outcomes). Amongst the RCTs, the following treatments were investigated: bupropion 1 RCT, fluoxetine 1 RCT, paroxetine 1 RCT, venlafaxine 3 RCTs, clonidine 2 RCT, gabapentin 1 RCT, Menopause hormone therapy 2 RCTs, tibolone 1 RCT, vaginal pH-balanced gel 1 RCT, CBT 1 RCT, PE 1 RCT, and hypnotherapy 1 RCT. RCTs included sites from the UK, USA, South America, Canada, Europe, and Korea (none were from Australia). The patients in the RCTs were women with a history of breast cancer, or at high risk of breast cancer, ductal carcinoma in situ or lobular carcinoma in situ who were experiencing hot flushes. The evidence for the effectiveness of the various interventions for treatment of vulvovaginal symptoms is summarised in the Evidence Summaries below that are numbered for reference with the clinical practice guidelines developed from this systematic review. Three RCTs (two with low and one with moderate risk of bias) in women after breast cancer reported no difference after 4-12 weeks of treatment with antidepressants: bupropion 300 mg/d (Nunez 2013)24, fluoxetine 20 mg/d (Loprinzi 2002)40, paroxetine 10-20 mg/d (Stearns 2005)41 on sexual function as measured by the ASEX, BDI single item, MOS SPI or SAQ, compared to placebo. One cross-over RCT (with a low risk of bias) in women after breast cancer found that neither venlafaxine (75mg/d for 8 weeks) nor clonidine (0.1mg/d for 8 weeks) had an effect on the Sexual Activity Questionnaire Scales (Buijs 2009). 6 One RCT (with a moderate risk of bias) in women after breast cancer found no differences in sexual function for venlafaxine (75mg/d for 12 weeks), clonidine (0.1mg/d for 12 weeks) or placebo (Boekhout 2011). 8 One RCT (with moderate risk of bias) in women after breast cancer reported increase in difficulty achieving orgasm for venlafaxine (75mg/d) compared to gabapentin (300mg/d or 900mg/d, Bordeleau 2010).48 [Evidence Summaries #25] One RCT (with a low risk of bias) in women after breast cancer found an improvement in sexual behaviour and vaginal dryness for tibolone (2.5 mg/d for 2.75 years) versus placebo (Sismondi 2011).33 Two RCTs (with a high risk of bias) in women after breast cancer found inconsistent effects of menopause hormone therapy on sexual enjoyment, sexual activity Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 96 and discomfort compared to no treatment control (Fahlen 2011, Marsden 2001).32, 39 [Evidence Summaries #26] One RCT (with a low risk of bias) in women after breast cancer found that 12 weeks treatment with a vaginal pH-balanced gel was associated with a statistically significant improvement in a range of vaginal symptoms, compared to placebo (Lee 2011).34 [Evidence Summaries #27] One RCT (with a moderate risk of bias) in women after breast cancer found that CBT alone or in combination with physical exercise improves sexual function compared with wait list controls (Duijts 2012).28 One RCT (with a moderate risk of bias) in women after breast cancer found that a 5 weeks course of hypnotherapy had no statistically significant effect on the impact of hot flushes on sexuality compared to no treatment control (Elkins 2008).38 [Evidence Summaries #28] Overall, there is insufficient evidence (for antidepressants) or limited evidence (for vaginal pH-balanced gel, CBT and CBT combined with exercise) on the effects of the interventions studied, in the treatment of vulvovaginal symptoms associated with menopausal symptoms in women who have received breast cancer treatment. Tibolone improves vulvovaginal symptoms, but increases the risk of breast recurrence. There is a need for more studies of high methodological quality. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 97 3.5 Psychological wellbeing Defining psychological wellbeing Living with the diagnosis and treatment of any chronic medical condition can be a source of psychological stress. Women who have received breast cancer treatment may be dealing with the shock of diagnosis and its implications, the side effects of treatment, alterations to body appearance, changes in social roles and functioning, and for some, declining heath and death.97 Additionally, women may be dealing with menopausal symptoms (treatment induced or otherwise), such as; hot flushes, night sweats, sleep disturbance, anxiety, changes in mood, and sexual difficulties. Younger women who have received breast cancer treatment may find menopausal symptoms more distressing than older women, due to issues around fertility and self-image. Consequently, many women with menopausal symptoms after breast cancer treatment may experience psychological and/or emotional difficulties. While episodes of intense, unpleasant and distressing emotions may be viewed as a natural response to difficult circumstances, they may become more persistent or severe enough to impact an individual’s life and functioning. When this occurs, an individual may meet diagnostic criteria for mental disorders, or mood disorders, such as anxiety or depression, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV, American Psychiatric Association9). Although, it is not possible to determine whether psychological or emotional distress is due to menopausal symptoms, breast cancer or other life factors, early identification and management of psychological distress is central to the provision of optimal care. The present systematic review uses the term “psychological wellbeing” to include clinical anxiety and depression (as defined in the DSM-IV), mood, and emotional wellbeing (distress that might be considered “appropriate sadness,” 10). 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 reviewed studies and the measures that they used. Psychological Wellbeing Existing systematic reviews No existing systematic reviews were identified that examined the effects of pharmaceutical therapy or complementary medicine or therapy on psychological or emotional wellbeing associated with menopausal symptoms in women after breast cancer treatment. Primary evidence base Twenty-four RCTs24, 27-29, 32, 33, 35-38, 40-48, 50, 52, 54, 59, 65 were identified that reported on psychological outcomes during treatment for menopausal symptoms in women after breast cancer treatment. The main characteristics and quality of these 24 RCTs are summarised in Table 10. Findings from these studies will be reported by the measured outcome; depression, anxiety, mood, emotional wellbeing. Overall, the quality of these studies in assessing the effect of treatment on psychological wellbeing was poor. Although 21 studies24, 27-29, 32, 33, 35, 36, 38, 40-46, 48, 50, 52, 54, 59 used a validated measure, only six 28, 32, 38, 41, 45, 59 used a measure Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 98 recommended for use in a breast cancer population (Love, 200497, see Table 11). Additionally, five studies37, 44, 47, 48, 65 did not use a validated measure at all: Nikander et al (2003)65 did not report the name of the measure used, Carpenter et al (2007)44used selected subscales from validated measures to create a study specific measure, and Loibl et al (2007)47, Bordeleau et al (2010)48 and Carson et al (2009)37 used a symptom diary to assess mood. Only one publication32 reported psychological distress (anxiety and depression) as a primary outcome measure (as part of a larger study, the Stockholm trial). Consequently, most studies contained methodological flaws that limit the assessment of treatment effect on psychological outcomes. For example, five studies28, 29, 36, 43, 44 excluded depressed patients; four studies24, 40, 48, 54 excluded prior use of anti-depressants (including St John’s Wort, for up to two years prior to study entry), and one study54 excluded prior use of anxiolytics. These exclusion criteria may have resulted in trial populations that are not clinically representative. Additionally, the treatment doses and durations may have been insufficient to elicit treatment effects on psychological outcomes. Although the TGA allows one to two weeks for duration of onset for most antidepressants (see Table 3), the World Health Organization98 recognizes that “it may be four to eight weeks before the full antidepressant effect occurs” (p.113) and other studies have indicated that eight to ten weeks are needed to see treatment effects on depression (Hiemke et al, 2000; Beique et al, 1999).99, 100 This may be particularly relevant for six studies in the current systematic review 24, 40, 41, 43, 47, 48 where an antidepressant was administered for only four weeks. When reported, the mean scores remained within the normal to borderline range, for all groups across time, except in two studies38, 59, where participants’ scores in both groups (treatment and control) remained above the cut-off for clinical depression38 and mild anxiety59. Consequently, there is a lack of evidence that treatment reduces depression or anxiety, or improves mood, emotional wellbeing associated with menopausal symptoms in women after breast cancer treatment. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 99 Table 10 Psychological wellbeing reported in 24 RCTs Author Population N Age Pharmaceutical Interventions Antidepressant Nunez N=55 201324 Age=49 Completed N=48 Depressed N=7 Excluded prior use of AD Loprinzi N=81 200240 Age=18-49 Completed N=66 Depressed N=44 Exclude AD <2 years prior Stearns 200541 N=151 Age=50-55 Completed N=107 Depressed N=32 Anxious N=11 Treatment N Study Duratio n Construct Measure Findings Stat. Sig. between groups as per author (Y/N) Comments/Quality 4 weeks, crossover Bupropion 150mg 2xday N=27 Placebo N=28 10 weeks Depression BDI “There was no statistically significant difference in BDI scores between groups or between different time points of the study.” (p.974) N -secondary outcome -short treatment duration -scores not reported -poor quality of reporting 4 weeks, crossover Fluoxetine 20mg daily N=40 Placebo N=41 9 weeks Depression BDI Mean(SD) Placebo/Fluoxetine Baseline, 12.7(8.66) Fluoxetine/Placebo Baseline, 10.5(8.29) Significance p=0.26 N -secondary outcome -short treatment duration -poor reporting of scores -mean scores in normal range at baseline -mean BDI changes presented in figure (numbers not provided) -poor quality of reporting N -secondary outcome -short treatment duration -10mg low dose for treating depression -mean scores in normal range at baseline -scores categorised by change, difficult to interpret -poor quality of reporting 4 weeks, crossover Paroxetine 10mg or 20mg N=75 Placebo N=76 9 weeks Depression Anxiety CES-D HADS-A “Trend” for lower scores/fewer depressive symptoms with fluoxetine (p=0.08) Depression: Mean (SE) Post-treatment scores, nr Paroxetine 10mg/Placebo Baseline, 16.4(2.5) Paroxetine 20mg/Placebo Baseline, 12.9(2.4) Placebo/Paroxetine 10mg Baseline, 11.7(1.7) Placebo/Paroxetine 20mg Baseline, 12.1(1.8) Significance Baseline, p=0.40 Anxiety: Mean (SE) Post-treatment scores, nr Paroxetine 10mg/Placebo Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 100 Author Population N Age Treatment N Study Duratio n Construct Measure Findings Stat. Sig. between groups as per author (Y/N) Comments/Quality N -secondary outcome -short treatment duration -mean scores in normal range at baseline -poor quality of reporting Y -secondary outcome -short treatment duration -excluded depressed participants -poor quality of reporting N -secondary outcome Baseline, 5.7(0.60) Paroxetine 20mg/Placebo Baseline, 6.7(0.85) Placebo/Paroxetine 10mg Baseline, 5.2(0.63) Placebo/Paroxetine 20mg Baseline, 5.2(0.78) Significance Baseline, p=0.40 Kimmick 200642 Wu 200943 Carpenter N=62 Age=53.9 Completed N=39 Depressed N=12 N=46 Age=55.8 Completed N=41 Depressed excluded N=84 6 weeks Sertraline 50mg N=33 Placebo N=29 4 weeks, crossover Sertraline 25mg – 100mg p/day N=24 Placebo N=22 39 in QOL analysis Sertraline N=20 Placebo N=19 6 weeks, 12 weeks 6 weeks Depression Emotional wellbeing CES-D FACIT No statistically significant difference in distribution of scores Mean(SD) Sertraline Baseline, 11.2(9.2); 6 weeks, 8.9(8.3); 12 weeks, 12.8(11.7) Placebo Baseline, 11.5(7.9); 6 weeks, 9.4 (7.4); 12 weeks, 7.9(6.8) Significance Baseline, p=0.49; 6 weeks, p=0.68; 12 weeks, p=0.10 Across all time points, mean scores were in the normal range Emotional wellbeing: Sertraline Mean(SD) Baseline, 20.8(2.6); week 6, nr Placebo Baseline, 20.8(3.2); week 6, nr Significance Baseline, p=0.778; week 6, p=0.041 Sertraline group showed statistically significant improvement in emotional wellbeing than placebo from week 1 to week 6 (p=0.041) 14 Emotional NAI Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Emotional wellbeing: 101 Author Population N Age Treatment N Study Duratio n Construct Measure 200744 Age=NR Completed N=55 Depressed and AD excluded weeks wellbeing (negative affect) Boekhout 201145 N=102 Age=49 Completed N=80 Depressed; NR 12 weeks Depression Anxiety HADS Buijs 200946 N=60 Age=49 Completed N=40 Depressed; NR 18 weeks Depression Zung Loibl 200747 N=80 Age>50 (61%) Completed N=64 Excluded current AD use crossover 37.5mg venlafaxine/ placebo N=64 or 75mg venlafaxine/ placebo N=20 12 weeks Venlafaxine 75mg daily N=41 Clonidine 0.1mg daily N=41 Placebo N=20 8 weeks, crossover Venlafaxine 75mg daily N=30 Clonidine 0.05mg daily N=30 4 weeks Venlafaxine 37.5mg 2xday N=40 Clonidine 0.075mg 2xday N=40 4 weeks Mood Bordeleau 201048 N=66 Age=54.957.6 4 weeks, crossover Venlafaxine 14 weeks Mood Findings Stat. Sig. between groups as per author (Y/N) Means(% change from baseline) Low dose Baseline, -0.02, placebo, 0.03(235), low dose, 0.03(-72), p=0.326 High dose Baseline, -0.02, placebo, 0.04(304), high dose, 0.02(206), p=0.872 No statistically significant effect at either dose “At week 12, the anxiety score (adjusted for baseline scores) was higher (increased anxiety) in the clonidine group than in the venlafaxine group (p=0.04), and the depression score was higher (increased depression) in the venlafaxine group than in the clonidine group (p=0.03)” (pp. 3864-3865) Comments/Quality -short treatment duration -excluded depressed participants -poor quality of reporting Y -secondary outcome measure -treatment duration -poor reporting of results -poor quality of reporting “After 8 weeks of venlafaxine the mean score improved from 45.7 to 40.7 (p=0.001). No change in mean Zung score was seen after 8 weeks of clonidine” (p.578) Y -secondary outcome -mean scores in borderline to normal range at baseline -poor reporting of results -poor quality of reporting Participant asked to note symptoms Baseline, p=0.81; week 4, p>0.1 Venlafaxine (n=31) frequency Baseline, 6(19.4%); week 4, 3(9.7%) Clonidine (n=33) Baseline, 7(21.1%); week 4, 5(15.1%) Significance Baseline, p=0.81; week 4, p>0.1 Y Symptom diary Venlafaxine associated with reduced mood changes (p<0.05) Y - secondary outcome -short treatment duration -not validated measure of mood -analysed with Chisquared test -p-value (two-sided)of <0.05 was considered statistically significant -poor quality of reporting -secondary outcome -short treatment duration -not valid measure Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 102 Author Walker 201035 Sedatives Joffe 201036 Population N Age Treatment N Completed N=58 Excluded use of AD§ <1year 75mg daily/ Gabapentin 300mg 3xday N=32 Gabapentin 300mg 3xday/ Venlafaxine 75mg daily N=34 12 weeks Venlafaxine 75mg daily (control) N=25 Acupuncture 30min weekly (study arm) N=25 N=50 Age=55 Completed N=33 Depression; NR N=53 Age=51.1 Completed N=38 Depression excluded 5 weeks AD with zolpidem 10mg N=25 AD with Placebo N=28 Study Duratio n Construct Measure Findings Stat. Sig. between groups as per author (Y/N) “Venlafaxine was associated with fewer negative mood changes than gabapentin (p=0.01)” (p.5150) 1 year Depression BDI-PC “The results of the ANOVA for secondary outcome measures showed a significant effect of time for BDI-PC (p<0.001. -poor resulting of results -poor quality of reporting N -secondary outcome -poor reporting of results -scores in normal range across all time points -poor quality of reporting N -secondary outcome -mean scores in normal range -poor quality of reporting Y -secondary outcome -poor quality of reporting There were no significant effects of group or significant interactions.” (p.637) 5 weeks Depression BDI Zolpidem: Mean ± SD Baseline, 9.1 ± 7.9 Placebo Baseline, 7.4 ± 5.6 Significance, p=0.60 No statistically significant difference between groups. Comments/Quality “Depressive symptoms were unchanged with treatment and did not differ by treatment assignment” (p.913) Anticonvulsants Lavigne N=420 201227 Age=55 Completed N=347 Depression, NR 8 weeks Gabapentin 300mg N=139 Gabapentin 900mg N=144 Placebo 8 weeks Anxiety STAI Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Mean, model adjusted mean change (SE) 300mg Gabapentin Baseline, 36.7(0.99); 4 weeks, -1.77(0.79); 8 weeks, -2.440(0.891) 900mg Gabapentin Baseline, 35.1(0.94); 4 weeks, -0.07(0.77); 8 weeks, -0.249(0.851) Placebo 103 Author Population N Age Treatment N Study Duratio n Construct Measure N=137 Findings Stat. Sig. between groups as per author (Y/N) Comments/Quality N -secondary outcome -scores in normal to borderline range throughout study -poor quality of reporting Y -secondary outcome -some analyses done on total, not subgroup -total WHQ score not reported -mean baseline scores in normal range Baseline, 35.9(0.99); 4 weeks, 1.06(0.82); 8 weeks, 2.140(0.909) Significance 4 weeks, p=0.005; 8 weeks, p=0.002 Gabapentin significantly reduced anxiety (300mg dose most effective) Menopause hormone therapy Fahlen Subgroup 201132 N=75 Stockholm Age=57 Trial Completed NR Depressed NR 1 year Menopause hormone therapy N=38 No treatment N=37 1 year Depression Anxiety HADS Depression: Mean(SD) Menopause hormone therapy Baseline, 4.74(3.86); 6 months, 2.93(2.93); 12 months, 2.85(3.05) No treatment Baseline, 4.90(3.77); 6 months, 3.81(2.84); 12 months, 4.24(3.19) Significance Over time, p<0.001; between groups, nr Anxiety: Mean(SD) Menopause hormone therapy Baseline, 7.52(5.12); 6 months, 5.16(3.59); 12 months, 5.00(4.49) No treatment Baseline, 7.85(5.23); 6 months, 6.40(3.80); 12 months, 5.45(3.30) Significance Over time, p<0.001; between groups, nr Sismondi 201133 N=3098 Age=52.7 Subgroup N=883 Depressed, NR 2.75 years Tibolone (2.5mg) N=438 Placebo N=445 Media n 2.75 years Depression Anxiety WHQ Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review No statistically significant difference between groups Depression: Changes in WHQ scores from baseline (%) Tibolone Baseline, 0.261; 26 weeks, -0.062¥(-29.5); 52 weeks, -0.051¥ (-18.6); 78 weeks, -0.064¥ (-27.4); 104 weeks, -0.050¥ (-22.9) Placebo 104 Author Population N Age Treatment N Study Duratio n Construct Measure Findings Stat. Sig. between groups as per author (Y/N) Baseline, 0.270; 26 weeks, -0.039(-10.4); 52 weeks, -0.024(-4.5); 78 weeks, -0.030(-6.5); 104 weeks, -0.028(-13.5) Significance ¥ Indicates statistically significant between groups, p<0.05 Statistical significant improvement in depression with Tibolone. Complementary Medicine and Therapy Cognitive behavioural therapy and exercise interventions Duijts 201228 N=422 6 weeks CBT 6 Age=48.2 N=109 months Completed 12 weeks PE N=340 N=104 Compliant CBT+PE N=219 N=106 Included Waitlist current AD N=103 use N=39 Depressed excluded Mann 201229 N=96 6 weeks CBT 26 Age=54 N=47 weeks Completed Usual Care Depression Anxiety HADS -poor quality of reporting Anxiety: Changes in WHQ scores from baseline (%) Tibolone Baseline, 0.312; 26 weeks, -0.073(-29.4); 52 weeks, -0.083(-30.9); 78 weeks, -0.075(-30.4); 104 weeks, -0.049(-28.2) Placebo Baseline, 0.316; 26 weeks, -0.056(-23.4); 52 weeks, -0.064(-24.5); 78 weeks, -0.058(-21.4); 104 weeks, -0.057(-21.2) Significance p nr No statistically significant difference in anxiety. N No statistically significant difference between groups. N -secondary outcome -dissimilar treatments -low compliance -scores not reported -poor quality of reporting Y -secondary outcome -CBT mean scores in normal range “No significant overall group differences over time were observed for psychological distress (HADS) data not shown” (p.4) Depression Anxiety WHQ Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Comments/Quality Depression: Mean(SD) CBT 105 Author Population N Age Treatment N N=88 Depression excluded N=49 Study Duratio n Construct Measure Findings Stat. Sig. between groups as per author (Y/N) Baseline, 0.23(0.26); 9 weeks, 0.13(0.16); 26 weeks, 0.13(0.19) Usual care Baseline, 0.31(0.27); 9 weeks, 0.28(0.24); 26 weeks, 0.28(0.26) Adjusted mean difference (SE) 9 weeks, -0.14(0.05); 26 weeks, -0.13(0.05) 95% CI 9 weeks, -0.23 to -0.06; 26 weeks, 0.22 to 0.05 Significance Baseline, nr; 9 weeks, p<0.01; 26 weeks, p<0.01 Comments/Quality -does not control for placebo effect -concurrent medication use -poor quality of reporting Anxiety: CBT Mean(SD) Baseline, 0.34(0.25); 9 weeks, 0.23(0.27); 26 weeks, 0.24(0.31) Usual care Baseline, 0.45(0.30); 9 weeks,0.40(0.33); 26 weeks, 0.39(0.31) Adjusted mean difference (SE) 9 weeks, -0.12(0.06); 26 weeks, -0.10(0.06) 95% CI 9 weeks, -0.24 to -0.01; 26 weeks, 0.21 to 0.01 Significance Baseline, nr; 9 weeks, p<0.05; 26 weeks, nr CBT improved depression, anxiety. Hypnotherapy Elkins 200838 N=60 Age=55-58 Completed N=51 Depression; NR 5 weeks Hypnotherapy N=30 No treatment N=30 5 weeks Depression CES-D Anxiety HADS-A Depression: Mean(SD) Hypnotherapy Baseline, 29.48(7.72); 5 weeks, 24.58(6.45) No treatment Baseline, 30.22(9.32); 5 weeks, 31.38(9.21) Significance Baseline, nr; 5 weeks, p=0.003; ƞp2=0.181 Anxiety: Mean(SD) Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 106 Y -secondary outcome -fair quality of reporting Author Population N Age Treatment N Study Duratio n Construct Measure Findings Stat. Sig. between groups as per author (Y/N) Comments/Quality N -secondary outcome -poor quality of reporting N -secondary outcome -difference between groups at baseline not tested (e.g. time since diagnosis 2.8 years in relaxation group vs 5.2 years EA group) -poor quality of reporting Hypnotherapy Baseline, 5.89(4.34); 5 weeks, 3.23(3.19) No treatment Baseline, 5.83(5.05); 5 weeks, 6.46(5.36) Significance p=0.004; ƞp2=0.171 Hypnotherapy improved anxiety and depression. Relaxation Fenlon 200852 Nedstrand 200654 N=150 Age=54.9, 55.5 Completed N=97 Depression; NR N=38 Age=53 Completed N=31 Excluded use of anxiolytic or AD 1 month Relaxation N=74 Control N=76 12 weeks Relaxation N=19 ElectroAcupuncture N=19 3 months Anxiety STAI Baseline mean(SD); median at one and three months post-treatment improvement Relaxation: State anxiety: baseline, 37(30-44); one month, -1; three months, 0 Trait anxiety: baseline, 40.5(34.2-48); one month, 0; three months, 1 Control: State anxiety: baseline, 35(27-48); one month, 0; three months, -2 Trait anxiety: baseline, 37(31.7-47); one month, 2; three months, 1 Median Difference (95% CI) State anxiety: one month, -1.0(-4.0, 2.0) p=0.51; three months, 2.0(-2.0, 5.0), p=0.31 Trait anxiety: one month, -1(-4, 1), p=0.24; three months, 1.0(-2.0, 3.0), p=0.72 6 months Psychologi cal wellbeing Mood SCL-90 Mood Scale (selected items) Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review No statistically significant difference between groups. Relaxation Mean(SD) Baseline, 108.4(19.3); week 12, 114.6(28.9); 6mth, 116.1(20.5) Electro-Acupuncture Baseline, 106.4(21.1); week 12, 106.5(19.2); 6mth, 112.0(23.2), p<0.05 Significance Between groups, p=0.55 107 Author Population N Age Treatment N Study Duratio n Construct Measure Findings Stat. Sig. between groups as per author (Y/N) Comments/Quality Y -secondary outcome -<10 participants in treatment arm at 3 months -included women taking AD or clonidine Emotional wellbeing: Relaxation Mean(SD) Baseline, 42.7(23.6); week 12, 21.4(18.2); 6mth, 19.7(14.2); p<0.0001 Electro-Acupuncture Baseline, 45.9(26.1); week 12, 29.7(21.1); 6mth, 33.1(27.4), p<0.0001 Significance Between groups, p=0.16 No statistically significant difference between groups. Yoga Carson 200937 Acupuncture Walker 201035 N=37 Age=54.4 Completed N=23 Included stabilized AD dose for >3 months Excluded serious psychiatric disorders <6mths 8 weeks Yoga N=17 Wait-list N=20 N=50 Age=55 Completed N=33 Depression; NR 12 weeks Venlafaxine 75mg daily (control) N=25 Acupuncture 30min weekly (study arm) N=25 1 year Depression BDI-PC No statistically significant difference between groups. N -secondary outcome -poor reporting of results -scores in normal range across all time points -poor quality of reporting 16 weeks 16 Depression HADS Depression: N -secondary outcome Other therapies Thompson N=53 3 months Mood Symptom diary Adjusted Means Yoga: Baseline, 3.17; week 8, 2.64 Baseline, 3.11; 3mth, 1.94 Waitlist control: Baseline, 3.51; week 8, 3.33 Baseline, 3.54; 3mth, 3.44 Significance Week 8, p=0.0954; 3mth, p<0.0001 Trend towards improved mood. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 108 Author Population N Age Treatment N Study Duratio n Construct 200559 Age=53.6, 51.6 Completed N=45 Depression; NR Homeopathy N=28 Placebo N=25 weeks Anxiety Measure Findings Stat. Sig. between groups as per author (Y/N) Mean(SD) Homeopathy Baseline, 6.1(3.9); 16 weeks, 5.6(3.3) Placebo Baseline, 5.4(3.6); 16 weeks, 4.6(3.1) Significance p=0.14 Comments/Quality -poor quality of reporting Anxiety: Mean(SD) Homeopathy Baseline, 9.2(3.9); 16 weeks, 8.1(3.3) Placebo Baseline, 8.7(3.6); 16 weeks, 7.4(3.1) Significance p=0.49 Nikander 200365 N=62 Age=54 Completed N=56 Depression N=7 3 months Isoflavonoids 114mg N=32 Placebo N=30 8 months (2 month washo ut before crossover Depression Anxiety “Establishe d indexes” No statistically significant difference between groups (statistically significant difference over time) Depression: Isoflavones: Mean ± SD Baseline, 5.7±4.5; 3 months, 4.4±4.2; change, 1.3±2.4, within groups, p=0.001 Placebo Baseline, 6.1±5.0; 3 months, 4.6±4.4; change, 1.5±2.9, within groups, p=0.001 Between groups, p=0.663 Anxiety: Isoflavones: Mean ± SD Baseline, 1.6±1.5; 3 months, 1.4±1.6; change, 0.2±1.5, within group, p=0.421 Placebo Baseline, 1.4±1.6; 3 months, 1.5±1.6; change, 0.1±1.8, within group, p=0.670 Between groups, p=0.370 No statistically significant difference between Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 109 N -secondary outcome -insufficient detail about measure “Established Index” -poor quality of reporting Author Population N Age Treatment N Study Duratio n Construct Measure Findings Stat. Sig. between groups as per author (Y/N) Comments/Quality groups. Note: scores are reported in individual symptom tables, where provided in the original papers. AD antidepressant; §includes St John’s Wort; EA, electro-acupuncture; Sig. significant; NR, not reported; BDI, Beck Depression Inventory; BDI-PC, Beck Depression Inventory-Primary Care; CES-D, Center for Epidemiologic Studies Depression Scale; HADS, Hospital Anxiety and Depression Scale; HADS-A: 7 items of anxiety subscale only administered; FACIT, Functional Assessment of Chronic Illness Therapy; HAM-D, Hamilton Rating Scale-Depression; STAI, Spielberger State-Trait Anxiety Inventory; WHQ, Women’s Health Questionnaire; SF36, Medical Outcomes Survey, Short-Form; NAI, Negative Affect Index; SCL-90, Symptom Checklist Note: when scores are not available, the results were quoted from the original paper #post-treatment * between groups as reported by the authors; NR, not reported; AD, antidepressant; BDI, Beck Depression Inventory; BDI-PC, Beck Depression Inventory – Primary Care; CES-D, Center for Epidemiologic Studies Depression Scale; HADS-D, Hospital Anxiety and Depression Scale (Depression subscale); WHQ, Women’s Health Questionnaire; SE, standard error; SD, standard deviation Note: where scores were not provided, the results section of the original paper has been quoted. *statistically significant difference between groups, as reported by the authors; HADS-A, Hospital Anxiety and Depression Scale-Anxiety subscale; STAI, Spielberger State/Trait Anxiety Index; WHQ, Women’s Health Questionnaire; nr, not reported; SE, standard error; SD, standard deviation; CI, confidence interval Note: where scores were not provided, the results were quoted from the original paper. SD, standard deviation; mth, month’s follow-up Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 110 Table 11 Measures used in RCTs assessing psychological wellbeing Measure BDI (5 versions) Beck Depression Inventory BDI-I (Beck 1961)90 BDI-IA (Beck 1979)91 Population Dimensions/Structure Disease Specific Quality Measures attitudes and symptoms of depression Depression Established validity, reliability and sensitivity. Psychiatric and normal populations 21 items: 16 items assess depressive cognitions and affects; 5 items measure somatic signs and symptoms BDI-II (Beck 1996)92 College students, psychiatric outpatients 21 items: Corresponds to DSMIV criteria for diagnosing depression BDI-PC (Beck 2000)101 Primary Care (AKA BDI-FS; FastScreen) General medical patients 7 items: sadness; loss of pleasure; suicidal ideation; pessimism; past failure; selfdislike, self-criticalness BDI-SF (Beck 1972)102 Short Form Screening tool for patients in general medical practice 13 items, 3 on somatic symptoms. CES-D Centre for Epidemiologic Studies Depression Scale103 General population FACIT Functional Assessment of Chronic Illness Therapy (Version 4)104 HADS Hospital Anxiety and Depression Scale105 Cancer patients and general population General medical outpatients Questionable use with medical populations because of somatic items. Depression in individuals with biomedical or substance abuse issues Depression Validated for use with primary care populations. 20 items: 8 items on affect; 4 items for depressive cognitions; psychomotor retardation, loss of appetite, sleep disturbance, interpersonal difficulty Depression 27 items measure 4 domains of QOL: physical, social/family, functional and emotional wellbeing A – Anxiety:7 items; general anxiety, panic Emotional Wellbeing Established validity, reliability and sensitivity. Moderate correlation with SF-36 and HADS. Not written to diagnostic criteria, does not indicate symptom severity. Established QOL measure Anxiety Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Established validity, reliability and sensitivity. Established validity, reliability and sensitivity. Anxiety scale more reliable than depression scale. Anxiety scale 111 Rating Scale / Norms & cut-off Varies, depending on version used. Higher scores indicate greater depression. Range: 0-63 Minimal: 0-9 Mild: 10-16 Moderate: 17-29 Severe: 30-63 Cut-off: ≥ 13 screening; ≥ 21 research criterion Range: 0-63 Minimal: 0-13 Mild: 14-19 Moderate: 20-28 Severe: 29-63 Range: 0-21 Minimal: 0-3 Mild: 4-8 Moderate: 9-12 Severe: 13-21 Range: 0-21 Minimal: 0-4 Mild: 5-7 Moderate: 8-15 Severe: ≥16 Range: 0-60, higher scores indicate greater depression. Cut-off score: ≥16 indicates depressed mood Cited Higher scores indicate better emotional wellbeing Wu43 Higher scores indicate greater severity. Non-case/normal: 0-7 Possible case/mild: 8 -10 Definite case/moderate: ≥11 Stearns41 Boekhout45 Fahlen32 Duijts28 Elkins38 Joffe36 Nunez24 Loprinzi40 Walker35 Walker35 Stearns41 Kimmick42 Elkins38 Measure Population Dimensions/Structure Disease Specific Quality D – Depression: 7 items; anhedonia (excludes somatic items) Depression recommended for use in breast cancer population. Rating Scale / Norms & cut-off Total distress/severe: ≥19 Cut-off of ≥5 recommended for BC population97 Cited Thompson59 Boekhout45 Fahlen32 Duijts28 Thompson59 Nedstrand54 (used selected items, in bold) Carpenter44 Mood Scale106 N=404 psychology students Six subscales: pleasantness, activation, tension, social orientation, social interaction motive, control Mood Established measure. NAI Negative Affect Index (study specific to Carpenter) N/A Conglomerate of anxiety, depression and other negative mood states Not an established measure of psychological outcomes Standardized scores. Note symptoms (study specific to Loibl) N/A “Calculated as combination of standardized scores on 4 measures: Profile of Mood States Short Form total mood disturbance score (excluding fatigue), the negative affect subscale of the Positive and Negative Affect Scale, the CESD and Ham-D” (Carpenter, p.126) “patients were asked to note whether they had any of the following symptoms: loss of appetite, mouth dryness, nausea, tiredness, constipation, restless sleep, nervousness, sweating, dizziness, mood disorder, diarrhoea, sleeplessness or other symptoms” (Loibl, p. 690) 40 items: 20 items current anxiety level (state); 20 items anxiety generally feel (trait) N/A Not an established measure of psychological outcomes Frequency of patients reporting symptoms Loibl47 Anxiety Established validity, reliability and sensitivity. Does not correspond to criteria for anxiety disorders. Total score range 20-80 General medical and surgical norms: State: 43, SD 14 Trait: 41, SD 13 Lavigne27 Fenlon52 13 items concerning mood, social behaviour, opinion of the future. “Anxiety and self-confidence were separately determined by means of specific questions” (p.1214) Depression Anxiety “Established index” Each item rated on scale of positive (0) to negative (3). Mild depression: 5-7 Moderate: 8-15 Severe: ≥16 Nikander65 STAI Spielberger State-Trait Anxiety Inventory 107 Study Specific “Established indexes” N/A Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 112 Measure Population Dimensions/Structure Disease Specific Quality SCL-90 Symptom Checklist108 Developed to assess drug trials on psychiatric outpatients General mental health, psychological wellbeing and distress Established reliability, controversial validity Symptom Diary N/A 90 items on 9 symptoms dimensions: somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, psychoticism. 3 global indices of distress: global severity index, positive symptom distress, positive symptom total. 18 symptoms, including nervousness and mood changes 10 symptoms including negative mood Depressed mood (6 items), somatic symptoms (7 items), anxiety/fears (4 items), vasomotor symptoms (2 items), sleep problems (3 items), sexual behaviour (3 items), menstrual symptoms (4 items), memory/concentration (3 items) Mood Not an established measure of psychological outcomes Changes women experience during menopause Established validity, reliability and sensitivity WHQ domain of depressed mood significantly correlates with SF-36 Mental Health scale 20 items: affective, psychological, somatic symptoms associated with depression. Depression Established reliability and validity. Does not correspond to DSM-IV WHQ Women’s Health Questionnaire84, 85 Zung Zung self-rating depression scale109 N=850 women aged 45-65 in UK. Surgical menopause or Menopause hormone therapy excluded. Rating Scale / Norms & cut-off Lower scores indicate better psychological wellbeing. Cited Scale range 0-10; higher scores indicate worse symptoms Bordeleau48 Scale range 0-9; higher scores indicate worse symptoms Lower scores indicate better health. Difference of 0.10-0.20 on subscales considered clinically meaningful. Cut-off of >0.43 on depressed mood has 87.5% correct classification of those considered at risk of clinical depression Higher scores indicate greater depression. Range: 20-80 Normal: 20-44 Mild: 45-59 Moderate: 60-69 Severe: ≥70 Carson37 Nedstrand54 (used selected items, in bold) Sismondi33 Mann29 Duijts28 DSM-IV, Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition; AKA, also known as; Ham-D, 17-item Hamilton Rating Scale-Depression; QOL, quality of life; BC, breast cancer Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 113 Depression and Anxiety Fifteen RCTs24, 28, 29, 32, 33, 35, 36, 38, 40-42, 45, 46, 59, 65 reported treatment effects on depression (see Table 10). None of the studies used an instrument recommended to measure depression in a breast cancer population.97 Four studies24, 35, 36, 40 used the BDI, a measure developed for psychiatric populations, which has not been validated for use in cancer patients, and contains somatic items which may elevate scores in physically ill patients. Four studies 28, 32, 45, 59 used the HADS-D (Depression subscale), a measure considered acceptable for detecting Major Depressive Disorder, but not Adjustment Disorder or Depressed Mood, and may miss a large proportion of distressed patients.97 Three studies38, 41, 42 used the CES-D, a measure that has been described as, “idiosyncratic” in “its assessment of symptom frequency rather than severity” (Love, 200497, p. 63). One study65 reported that they used an “established” measure, but did not indicate which measure they used. The limitations of the instruments used to measure depressed mood are important when interpreting the findings in the reviewed studies. Eleven RCTs27-29, 32, 33, 38, 41, 45, 52, 59, 65 reported treatment effects on anxiety (see Table 10), six28, 32, 38, 41, 45, 59 of which used a recommended measure for use in breast cancer populations. 97 To give an approximate overview of treatment effects on anxiety, scores (when reported on the HADS-A) are illustrated in Figure 5. Two studies27, 52 used the STAI, a measure specifically not recommended for use in breast cancer populations, as the scale measures aspects of personality factors that are not related to mood or distress.97 One study65 reported that an “established” measure was used, but not the name of the measure. It is important to consider the suitability of the instrument in measuring anxiety when interpreting the findings. Figure 6. Mean scores reported on Hospital Anxiety Depression Scale-Anxiety subscale <normal >definite case of anxiety Mean scores reported on HADS-Anxiety subscale at baseline and post-treatment (treatment dose and duration varies between studies). Scores on HADS-Anxiety range from 0-21, with higher scores indicating greater anxiety. Scores 0-7 indicate non-cases/normal range, scores 8-10 indicate possible case/mild anxiety. Note: scores were not reported in Boekhout45 and Duijts28. Boekhout45 and Elkins38 reported a statistically significant difference between groups. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 114 Pharmaceutical interventions Antidepressants Atypical antidepressants: bupropion Nunez et al (2013)24 investigated the effects of four weeks of bupropion (150mg twice per day) compared to placebo, on depression (measured with BDI scores), as a secondary outcome measure. Although scores were not provided, they reported that no statistically significant differences (between groups or time points) were found. Selective serotonin re-uptake inhibitors: fluoxetine, paroxetine, and sertraline Three studies40-42 compared the effect of an SSRI (20mg fluoxetine/d for four weeks; 10mg or 20mg paroxetine/d for four weeks; 50mg sertraline/d for six weeks, see Table 10) to placebo on validated measures of depression (BDI or CES-D) as a secondary outcome measure. At baseline, mean scores on the BDI 40 were in the mild range (placebo/fluoxetine, 12.7, SD 8.66; fluoxetine/placebo, 10.5, SD 8.29; scores 10-16 indicate mild depression), while scores on the CES-D41, 42 were in the borderline to normal range (see Table 10; cut-off score of ≥16 indicates depressed mood). None of the studies reported a statistically significant difference between groups after treatment. Stearns et al (2005)41 compared the effects of 10mg and 20mg of paroxetine to placebo for four weeks for anxiety and reported that there were no statistically significant differences in the distribution of HADS scores between groups (post-treatment scores not reported). Serotonin noradrenaline re-uptake inhibitors: venlafaxine Two studies45, 46 investigated the effect of venlafaxine compared to clonidine on depression (as a secondary outcome measure). Each study had a different treatment dose, duration and outcome measure, and consequently are not directly comparable (see Table 10). Boekhout et al (2011)45 reported that on the HADS “the depression score was higher (increased depression) in the venlafaxine group than in the clonidine group (p=0.3)” (p. 3865, scores not reported), while in contrast, Buijs et al (2009)46 reported that “after eight weeks of venlafaxine the mean Zung score improved from 45.7 to 40.7 (p=0.001)” (p. 578). Boekhout et al (2011)45 compared the effects of venlafaxine (75mg) to clonidine (0.1mg) on anxiety (HADS scores), as a secondary outcome measure. They stated “at week twelve, the anxiety score (adjusted for baseline scores) was higher (increased anxiety) in the clonidine group than in the venlafaxine group (p=0.04)” (pp. 3864 – 3865). Walker et al (2010)35 investigated the effect of 12 weeks of venlafaxine (75mg daily, control arm) to acupuncture (30 minutes per week, treatment arm) on depression, and followed participants for up to 12 months. The authors reported using the BDI-PC (scores range from 021; Beck, 2000); however, they then referenced the BDI-SF, and reported that scores ranged from 0-63. It is uncertain which version of the BDI they used, and which cut-off scores should be applied. Results of the BDI were illustrated in a figure, with scores remaining below twelve for all groups, across all time points. The authors reported a significant effect of time on depression (p<0.001), but no statistically significant difference between groups (p not reported). Sedatives: zolpidem Joffe et al (2010)36 compared the effect of five weeks of zolpidem to placebo (augmented with an SSRI/SNRI) on depression. Findings from the BDI-I were reported as a secondary Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 115 outcome measure, even though women with depression were excluded from participating in the study. Mean scores on the BDI remained in the normal range throughout the study (zolpidem, 9.1, SD ±7.9; placebo, 7.4, SD ±5.6; range for minimal symptoms, 0-9) and no statistically significant differences between groups were found (post-treatment mean scores and significance values were not provided). Anticonvulsants: gabapentin Lavigne et al (2012)27 investigated the effects of eight weeks of gabapentin (300mg or 900mg) compared to placebo on anxiety (using the STAI). Scores on the STAI range from 20 – 80 with higher scores indicating greater anxiety. At baseline, mean STAI scores were relatively low (300mg Gabapentin, 36.7, SE 0.99; 900mg Gabapentin, 35.1, SE 0.94; Placebo, 35.9, SE 0.99; see Table 10). After four weeks of treatment, the 300mg gabapentin group showed a significant mean change in STAI scores (-1.77, SE 0.79); 900mg gabapentin, -0.07, SE 0.77); placebo, 1.06, SE 0.82, p=0.005), which was maintained at eight weeks (-2.440, SE 0.891); 900mg gabapentin, -0.249, SE 0.851); placebo, 2.140, SE 0.909, p=0.002). Menopause hormone therapy Fahlen et al (2011)32 published depression scores (as measured on the HADS) from a subgroup of women (N=75) in the Stockholm trial that investigated the effect of menopause hormone therapy compared to no treatment. They reported a statistically significant difference over time (p<0.001), but not between groups (p not reported). However, the mean HADS scores in Fahlen et al (2011)32 (Menopause hormone therapy, baseline, 4.74, SD 3.86; 6 months, 2.93, SD 2.93; 12 months, 2.85, SD 3.05; No treatment, baseline, 4.90, SD 3.77; 6 months, 3.81, SD 2.84; 12 months, 4.24, SD 3.19) remained within the normal range (scores 0-7 are “non-cases”), for the duration of the study. The authors reported a statistically significant difference over time in anxiety (HADS-Anxiety scores, see Figure 6) (p<0.001), but not between groups (p not reported). However, the mean HADS-Anxiety scores (Menopause hormone therapy, baseline, 7.52, SD 5.12, six months, 5.16, SD 3.59, 12 months, 5.00, SD 4.49; No treatment, baseline, 7.85, SD 5.23, six months, 6.40, SD 3.80, 12 months, 5.45, SD 3.30; scores ≥8 indicate possible case/mild anxiety) remained in the normal range for both groups. Sismondi et al (2011)33 published the results from a subgroup of women (N=883) who completed the Women’s Health Questionnaire (WHQ) on the LIBERATE trial, comparing tibolone treatment to placebo. They reported that depressed mood significantly improved with tibolone treatment (Tibolone, baseline, 0.261; changes from baseline in WHQ scores at weeks: 26 weeks, -0.062(-29.5%, p<0.05); 52 weeks, -0.051(-18.6%, p<0.05); 78 weeks, -0.064(27.4%, p<0.05); 104 weeks, -0.050(-22.9%, p<0.05); Placebo, baseline, 0.270; changes from baseline in WHQ scores at weeks: 26 weeks, -0.039(-10.4%); 52 weeks, -0.024(-4.5%); 78 weeks, -0.030 (-6.5%); 104 weeks, -0.028 (-13.5%). However, mean scores at baseline were in the normal range (cut-off of >0.43 indicates depressed mood), and tibolone treatment may not have had a clinically meaningful benefit (difference of 0.10-0.20 on subscales scores is considered clinically meaningful) on depression. Sismondi et al (2011) reported no significant difference between groups on anxiety (tibolone, baseline, 0.312, change from baseline to week (per cent change): 26 weeks, -0.073(-29.4%), 52 weeks, -0.083(-30.9%), 78 weeks, 0.075(-30.4%), 104 weeks, -0.049(-28.2%); Placebo, baseline, 0.316, change from baseline to week (percentage change): 26 weeks, -0.056(-23.4%), 52 weeks, -0.064(-24.5%), 78 weeks, 0.058(-21.4%), 104 weeks, -0.057(-21.2%), p not reported). Additionally, the risk of breast cancer recurrence needs to be considered with tibolone treatment. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 116 Complementary medicines and therapies Psychological interventions Cognitive behaviour therapy Duijts et al (2012)28 compared the effects of six group sessions of CBT, 12 weeks of physical exercise or CBT plus physical exercise to a waitlist control group. They included the HADS as a secondary outcome measure. The authors reported that there was “no significant overall group differences over time observed for psychological distress (HADS)” (p. 4, results not reported). However, it is important to note that treatment compliance was poor (CBT, 42%, physical exercise, 36%, CBT plus physical exercise, 30%) which may have underestimated treatment effects in this study. Mann et al (2012)29 compared six weeks of group CBT (one 90 minute session per week) to usual care on depressed mood and anxiety, as measured on the WHQ (secondary outcome). The authors reported a significant improvement in depressed mood with CBT (baseline, 0.23, SD 0.26; 9 weeks, 0.13, SD 0.16; 26 weeks, 0.13, SD 0.19; Usual care, baseline, 0.31, SD 0.27; 9 weeks, 0.28, SD 0.24; 26 weeks, 0.28, SD 0.26; 9 weeks, p<0.01; 26 weeks, p<0.01). Additionally, mean scores remained within the normal range (cut-off of >0.43 indicated depressed mood) for both groups across time. The authors reported a significant improvement in anxiety with CBT at nine weeks (baseline, 0.34, SD 0.25, nine weeks, 0.23, SD 0.27; Usual care, baseline 0.45, SD 0.30, nine weeks, 0.40, SD 0.33; adjusted mean difference, 0.12, SE 0.06, p<0.05) but not at follow-up (26 weeks; CBT, 0.24, SD 0.31; Usual care, 0.39, SD 0.31; adjusted mean difference, -0.10, SE 0.06, p not reported). Hypnotherapy Elkins et al (2008)38 compared the effect of five weekly sessions of hypnotherapy (each 50 minute session included hypnotic induction, mental imagery, suggestions for relaxation, mental imagery for coolness, dissociation from hot flushes and positive imagery for the future) compared to no treatment, on CES-D scores and HADS anxiety scores. They reported a statistically significant effect of hypnotherapy on HADS and CES-D scores (baseline, 29.48, SD 7.72, 5 weeks, 24.58, SD 6.45) compared to no treatment (baseline, 30.22, SD9.32, 5 weeks, 31.38, SD 9.21, p=0.003). However, they did not control for placebo effects, and mean scores for both groups remained in the range indicative of depressed mood (cut-off score ≥16, with higher scores indicating greater symptoms). The authors reported that hypnotherapy significantly improved anxiety (baseline, 5.89, SD 4.34; five weeks, 3.23, SD3.19; no treatment, baseline, 5.83, SD 5.05, five weeks, 6.46, SD 5.36, p=0.004; scores ≥8 indicate possible case/mild anxiety), with a moderate effect size. However, the mean scores on the HADS remained within the normal range for both groups over time. Relaxation therapy Fenlon et al (2008)52 investigated the effect of twenty minutes per day of relaxation therapy compared to control for one month, using STAI scores as a secondary outcome measure. At baseline, mean state anxiety (relaxation therapy, 37, SD 30-44; control, 35, SD 27-48) and trait anxiety (relaxation therapy, 40.5, SD 34.2-48; control, 37, SD 31.7-47) were in the normal range (cut-off scores: state anxiety, 43, SD 14; trait anxiety, 41, SD 13; higher scores indicate greater anxiety). No statistically significant changes were reported in state or trait anxiety after one month of relaxation therapy or at three months follow-up (see Table 10). Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 117 Physical interventions: exercise and acupuncture Two studies28, 35 undertook head-to-head comparison of effects on depression: venlafaxine versus acupuncture,35 and CBT versus physical exercise.28 Both studies have previously been discussed in the SNRI section or CBT section of the present systematic review. In summary, neither study28, 35 found a statistically significant difference in anxiety between treatment groups. Yoga, and magnetic therapy No RCTs were identified that reported the treatment effects of yoga, or magnetic therapy on depression or anxiety. The impact of yoga on mood is discussed below (p.128). Other therapies Homeopathy Thompson et al (2005)59 investigated the effect of 16 weeks of homeopathy compared to placebo on HADS-D scores and HADS-Anxiety scores, as secondary outcome measures. For HADS-D scores at baseline, mean scores (Homeopathy, 6.1, SD 3.9; Placebo, 5.4, SD 3.6) for both groups were in the normal range (scores range from 0-7 for non-cases). Post-treatment, there were no statistically significant differences between groups (Homeopathy, 5.6, SD 3.3); Placebo, 4.6, SD 3.1, p=0.14), with scores remaining in the normal range. There is no evidence that homeopathy changed depression associated with menopausal symptoms in women after breast cancer treatment. HADS-Anxiety scores at baseline, mean scores for both groups (homeopathy, 9.2, SD 3.9; placebo, 8.7, SD 3.6; scores 8-10 indicate possible case/mild anxiety) indicated possible cases of mild anxiety. Post-treatment there was no statistically significant differences between groups, with scores remaining in the possible case/mild anxiety range for homeopathy (8.1, SD 3.3) and the normal range (7.4, SD 3.1) for placebo (p=0.49). There is no evidence that homeopathy changed anxiety associated with menopausal symptoms in women after breast cancer treatment. Phytoestrogens Nikander et al (2003)65 investigated the effect of three months of phytoestrogen (114mg isoflavonoid) compared to placebo. They reported that they used an “established measure” of depression but provided no further information (see Table 10). The authors stated that “phytoestrogen treatment had no effect on depression” (p. 1215). There is no evidence that phytoestrogen improves depression associated with menopausal symptoms in women after breast cancer. The authors reported that they used an “established index” of anxiety but provided no further information (see Table 10). The authors stated that “phytoestrogen treatment had no effect on anxiety” (p.1215). There is no evidence that phytoestrogen improves anxiety associated with menopausal symptoms in women after breast cancer. Mood and Emotional Wellbeing Four RCTs37, 47, 48, 54 were identified that reported treatment effects on mood (see Table 10). One study47 compared venlafaxine to clonidine, one48 compared venlafaxine to gabapentin, one54 compared relaxation to electro-acupuncture and one37 compared yoga to a wait-list control group. No RCTs investigated the effects of atypical anti-depressants, SSRIs, sedatives, menopause hormone therapy, or complementary therapies on mood. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 118 Three RCTs43, 44, 54 conceptualised psychological wellbeing as distinct from anxiety, depression or mood (see Table 10), herein grouped as emotional wellbeing. Wu et al (2009)43 investigated the effect of sertraline on emotional wellbeing, as measured on a validated quality of life measure (FACIT). Carpenter et al (2007)44 investigated the effect of venlafaxine (37.5mg or 75mg daily) on negative affect, “considered to be a conglomerate of anxiety, depression and other negative mood states” (p. 126, which they measured on a studyspecific index created by combining selected subscales from four validated measures. Nedstrand et al (2006)54 compared the effect of applied relaxation to electro-acupuncture on psychological wellbeing, as measured by selected subscales on the Symptom Checklist (SCL-90). No RCTs investigated the effects of sedatives, antihypertensives, anticonvulsants, menopause hormone therapy, or complementary therapies on emotional wellbeing, distinct from anxiety, depression or mood. Pharmaceutical interventions Antidepressants, anticonvulsants and antihypertensives Serotonin noradrenaline re-uptake inhibitor venlafaxine, antihypertensive clonidine and anticonvulsant gabapentin Loibl et al (2007)47 compared the effects of for four weeks of venlafaxine (37.5mg twice daily) to clonidine (0.075mg twice daily) on mood. Participants “were asked to note whether they were having one of the following symptoms during each study week,” including “nervousness” and “mood disorder” (p.690). The authors considered frequencies of nervousness and mood disorder as toxicity data which were analysed with a chi-squared test. “A p-value (two-sided) of <0.05 was considered statistically significant” (p.690). The authors indicated that “the frequency of patients reporting nervousness or moodiness was significantly less while taking venlafaxine compared with baseline (p=0.0013 and 0.05, respectively)” (p.691). However, the impact of clonidine over time from baseline was not reported. Additionally, the number of patients reporting symptoms of “moodiness” was small (baseline, clonidine, n=7, venlafaxine n=6, p=0.81; week 4; clonidine, n=5, venlafaxine, n=3, p>0.1). There was no statistically significant difference in mood between venlafaxine versus clonidine. Bordeleau et al (2010)48 compared the effects of four weeks of venlafaxine (75mg) to gabapentin (900mg) on mood. Participants were asked to complete a symptom diary, including negative mood changes. A total of 52 patients reported negative mood changes, with an average score of two (range 0-6 with higher scores indicating greater symptom severity) at baseline. Treatment with venlafaxine was associated with significantly fewer negative mood changes (p=0.01) than gabapentin. Mean scores were illustrated in a figure, with an approximate score of one after venlafaxine treatment. Although a statistically significant difference between groups was found in favour of venlafaxine, the clinical significance has not been established. Although two head-to-head studies47, 48 have indicated that venlafaxine may improve mood, it is not clear whether this is a clinically meaningful difference compared to clonidine or gabapentin treatment. Both studies reported low levels of negative mood at baseline, and conversely, none of the treatments increased negative mood. Additionally, mood was measured by asking participants to “note symptoms”47 or used a symptom diary48. Carpenter et al (2007)44 compared six weeks of low dose venlafaxine (37.5mg daily) to high dose venlafaxine (75mg daily) and placebo. They computed a negative effect index (as a secondary outcome measure) by combining selected subscales from four validated questionnaires (Profile of Mood States Short Form, Positive and Negative Affect scale, CES-D, and Ham-D). They reported “no significant treatment effects for secondary outcomes at either dose” (p.130). However, the treatment dose and duration may have been insufficient Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 119 to elicit treatment effects. Additionally, only nine participants received the high dose of venlafaxine at baseline, which may limit the statistical power of this study. Selective serotonin re-uptake inhibitors: sertraline Wu et al (2009)43 investigated the effect of four weeks of a flexible dose of sertraline (25100mg) versus placebo on emotional wellbeing, as measured on the Functional Assessment of Chronic Illness Therapy (FACIT, emotional wellbeing subscale). The authors reported a significant difference in emotional wellbeing from week 1 to week 6, with “the sertraline group showing better emotional wellbeing than the placebo group (p=0.041, p.372)”. However, the mean scores and the effect size were not reported. Complementary medicines and therapies Relaxation and electro-acupuncture Nedstrand et al (2006)54 compared the effect of applied relaxation (one 60 minute group session per week, in addition to daily home training) to electro-acupuncture (30 minutes per week) for 12 weeks, and at six month follow-up. Participants completed selected subscales (activation, pleasantness and tension) from the Mood Scale, and completed selected subscales (somatization, interpersonal sensitivity, depression, anxiety and hostility) on the Symptom Checklist. For Mood Scale, scores for both groups increased over time (see Table 10), with a statistically significant difference within the electro-acupuncture group. However, no statistically significant difference between groups was reported (p=0.55). Relaxation therapy and electro-acupuncture appear to be equally effective in increasing scores on activation, pleasantness and tension on the Mood Scale. However, they did not control for placebo effects or maturation. For Symptom Checklist, scores for both groups significantly decreased (from 42.7 to 19.7 in the relaxation group and from 45.9 to 33.1 in the electroacupuncture group, after six months, see Table 10), indicating better psychological wellbeing, over time. However, no statistically significant difference between groups was reported (p=0.16). Additionally, they did not control for placebo effects or maturation. Yoga Carson et al (2009)37 compared eight weeks of yoga (encompassing 40 minutes gentle stretching, 10 minutes breathing techniques, 25 minutes meditation, 20 minutes study of pertinent topics, 25 minutes group discussion) to a wait-list control group. Participants were asked to complete a symptom diary, including a rating of “negative mood” on a scale of 0-9 (higher scores indicate more negative mood). After eight weeks of treatment, there was a non-significant trend in favour of yoga (adjusted mean=2.64 vs waitlist adjusted mean=3.33, p=0.0954), which became statistically significant at three months follow-up (yoga adjusted mean=1.94 vs wait-list 3.44, p<0.0001; see Table 10). Evidence Summary There was no level I evidence from systematic reviews that examined the effects of treatment on psychological wellbeing, depression, anxiety, negative mood, and emotional wellbeing (distinct from anxiety, depression or mood) associated with menopausal symptoms in women after breast cancer. There is level II evidence from 24 RCTs with secondary outcome measures of depression, anxiety, negative mood, emotional wellbeing or mental Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 120 health. There is level II evidence from fifteen RCTs (five with low risk of bias, nine with moderate risk of bias and one with high risk of bias) with depression as a secondary outcome measure. Eleven RCTS (five with low risk of bias, five with moderate risk of bias and one with high risk of bias) with anxiety as a secondary outcome measure in a total of 2,474 women across all 11 studies. There is level II evidence from three RCTs (two with moderate risk of bias and one with high risk of bias) with emotional wellbeing 43, psychological wellbeing54 or negative affect44 as a secondary outcome measure, in a total of 168 women, across all three studies. Amongst the RCTs, the following treatments were investigated: bupropion (one RCT), fluoxetine (one RCT), paroxetine (one RCT), sertraline (two RCT), venlafaxine (six RCTs), clonidine (three RCTs), gabapentin (one RCT), zolpidem (one RCT), menopause hormone therapy (two RCTs), CBT (two RCTs), physical exercise (one RCT), hypnotherapy (one RCT), relaxation therapy (one RCT), acupuncture (one RCT), homeopathy (one RCT), and phytoestrogens (one RCT). No RCTs investigated the treatment effects of relaxation therapy, yoga, magnetic therapy, black cohosh, or vitamin E on depression. No RCTs investigated the effects of yoga, magnetic therapy, black cohosh, or vitamin E on anxiety. No RCTs investigated the effects of atypical antidepressants, SSRIs, sedatives, menopause hormone therapy, or alternative therapies on negative mood. The evidence for the effectiveness of the various interventions for psychological wellbeing is summarised in the Evidence Summaries below. Four RCTs in women after breast cancer found no statistically significant effect on depression compared to placebo for: bupropion (300mg/d for 4 weeks, RCT with a moderate risk of bias, Nunez 2013)24, fluoxetine (20mg/d for 4 weeks, RCT with a low risk of bias, Loprinzi 2002)40, paroxetine (10mg/d for 4 weeks, RCT with a low risk of bias, Stearns 2005) 41, and sertraline (50mg/d for 6 weeks, RCT with a moderate risk of bias, Kimmick 2006)42. Two of these RCTs found no effect on anxiety compared to placebo (Stearns 2005, Kimmick 2006).41, 42 One RCT (with a moderate risk of bias) in women after breast cancer found that the group treated with venlafaxine (75mg/d for 8 weeks) had a statistically significant improvement in depression compared to baseline, but no change was observed in the clonidine (0.05mg/d for 8 weeks) group compared to baseline (Zhung score, self-rating depression score) (Buijs 2009).46 One RCT (with a low risk of bias) in women after breast cancer found that venlafaxine had a statistically significant reduction in anxiety (75mg/d for 12 weeks) compared to clonidine (0.1mg/d) and a statistically significant increased depression in the venlafaxine group compared to the clonidine group (HADS scale), but did not report between-group differences from baseline (Boekhout 2011).45 One RCT (with a moderate risk of bias) in women after breast cancer found that venlafaxine (75mg/d for 12 weeks) and acupuncture (30 min twice/week for 4 weeks, then once/week for 8 weeks) had a similar statistically significant improvement in depression compared with baseline (Walker 2010). 35 One RCT (with moderate risk of bias) in women after breast cancer found that augmentation of an SSRI or SNRI with zolpidem (10mg/d for 5 weeks) had no statistically significant effect on depression compared to placebo (Joffe 2010).36 One RCT (with a moderate risk of bias) in women after breast cancer found no significant difference on emotional wellbeing for venlafaxine (37.5mg/d or 75mg/d for 6 weeks) compared to placebo (Carpenter 2007).44 One RCT (with a moderate risk of bias) in women after breast cancer found no statistically significant difference in mood between venlafaxine (37.5mg/twice per day) versus clonidine (0.075mg/twice per day for 4 weeks), but reported that venlafaxine significantly improved mood compared to baseline (Loibl 2007). 47 One RCT (with a moderate risk of bias) in women after breast cancer found a statistically significant reduction in negative mood between venlafaxine (75mg/d for 21 days) and gabapentin (900mg/d for 22days) (Bordeleau 2010).48 One RCT (with a moderate risk of bias) in women after breast cancer found a significant improvement on emotional wellbeing for sertraline (25-100mg/d for 4 weeks) compared to placebo, (Wu 2009).43 One RCT (with a moderate risk of bias) in women after breast cancer reported a significant reduction in anxiety for both gabapentin groups (300mg/d and 900mg/d for 4 and 8 weeks) compared to placebo; the Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 121 lower dose (300mg) was associated with the best treatment outcomes except for patients with high baseline anxiety. (Lavigne 2012).27 One cross-over RCT (with a moderate risk of bias) in women after breast cancer found that venlafaxine (75mg/d for 4 weeks) was associated with statistically significant fewer negative mood changes than gabapentin (900mg/d for 4 weeks, Bordeleau 2010).48 One RCT (with a low risk of bias) in women after breast cancer found a statistically significant improvement in depressed mood for tibolone (2.5mg/d for a mean of 2.5 years) compared to placebo, but found no statistically significant difference in anxiety between groups (WHQ score) (Sismondi 2011).33 One RCT (with a high risk of bias) in women after breast cancer found a statistically significant improvement for both depression and anxiety in the menopause hormone therapy group at 6 and 12 months compared to baseline, but only for the no menopause hormone therapy group for anxiety at 12 months; between group differences were not reported. (Fahlen 2011).32 One RCT (with a moderate risk of bias) in women after breast cancer reported no significant difference from baseline for psychological distress between cognitive behavioural therapy (CBT)) group versus physical exercise (PE) group, or CBT+PE combined compared to wait-list control group (HADS scale) (Duijts 2012).28 One RCT (with a moderate risk of bias) in women after breast cancer found a statistically significant improvement in depressed mood and anxiety after 6 weeks of group CBT compared to usual care (WHQ score) (Mann 2012).29 One RCT (with a moderate risk of bias) in women after breast cancer found a statistically significant improvement in depression and anxiety for hypnotherapy compared to no treatment (CES-D scales and HADS-A) (Elkins 2008).38 One RCT (with a low risk of bias) in women after breast cancer found no statistically significant difference on anxiety for relaxation therapy compared to no treatment control (Fenlon 2008).52 One RCT (with a high risk of bias) in women after breast cancer found improved mood with electro-acupuncture (EA) compared to baseline, but did not report between group differences for electro-acupuncture compared to applied relaxation (AR). Psychological wellbeing significantly improved for both treatment groups compared to baseline, but between group differences were not reported (Nedstrand 2006).54 One RCT (with a moderate risk of bias) in women after breast cancer found a significant improvement in mood between a yoga at 3 months follow-up compared to waitlist control (Carson 2009).37 One RCT (with a low risk of bias) in women after breast cancer found no statistically significant difference in depression or anxiety between homeopathy versus placebo (HADS scale) (Thompson 2005).59 One RCT (with a moderate risk of bias) in women after breast cancer found no statistically significant difference in depression or anxiety between phytoestrogens versus placebo (Nikander 2003).65 Overall, the quality of the 24 studies that measured treatment effects on psychological outcomes was poor. There is limited 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 would indicate that the interventions do not induce psychopathology (i.e. increase depression, anxiety, negative mood, or reduce emotional wellbeing or mental health). There is a need for more studies of higher methodological quality. Evidence Summaries were not developed for psychological wellbeing, in light of the poor quality of the studies: psychological wellbeing was measured as a secondary outcome and the dosages of psychotropic medications used were below that needed to treat depression or anxiety. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 122 3.6 Quality of life Defining Global Quality of Life Quality of life is a “complex construct for which there is no agreed definition” 110. When used in an everyday way, the term, “quality of life” can mean different things to different people 111. The Psycho-Oncology Co-operative Research Group (PoCoG) has defined health related quality of life as a multidimensional construct, referring “to the effects of disease and treatment as perceived and reported by the people affected by disease or disability themselves.” The present systematic review uses the term, “global quality of life” to refer to the overall wellbeing of an individual, including multiple domains such as; physical, cognitive, emotional and social functioning and wellbeing, work, and general health. Studies that have reported findings on the overall or global wellbeing or functioning of participants are included and discussed in this section of the systematic review. When subscales from a quality of life measure were used to assess vulvovaginal symptoms or psychological outcomes (such as emotional wellbeing or mental health), the study is included in the appropriate symptom section. Previous systematic reviews No existing systematic reviews were identified that examined the effects of pharmaceutical therapies or complementary medicine or therapy on global quality of life associated with menopausal symptoms in women after breast cancer. Primary Evidence Base Eleven RCTs (Nunez, Loprinzi, Stearns, Kimmick, Joffe, Fahlen, Frisk, Fenlon, Thompson, MacGregor, Carpenter)24, 31, 32, 36, 40-42, 44, 52, 59, 63 were identified that reported the outcome of global quality of life during treatment of vasomotor symptoms in women after breast cancer treatment. The main characteristics and quality of these 11 RCTs with respect to global quality of life are summarised in Table 12. Overall, the quality of these studies in assessing the effect of treatment on global quality of life was poor. Only one study (MacGregor et al 2005)63 reported quality of life as a primary outcome measure. The remaining 10 studies reported quality of life as a secondary outcome measure, and frequently quality of life scores were not clearly presented. Most studies are limited by small sample size (and hence insufficiently powered for QOL measures), and short treatment duration (possibly subject to recall bias due to short time between QOL assessments). One study24 (Nunez et al 2013) did not report any scores at baseline or posttreatment, but stated that there were no statistically significant differences between groups. Two studies40 (Loprinzi et al 2002; Stearns et al 200541) did not provide post-treatment scores. Three studies40, 44, 59 (Loprinzi et al 2002; Thompson et al 2005; Carpenter et al 2007) did not clearly indicate how they measured global quality of life, or used a single item from a validated measure. Table 13 provides an outline of the different quality of life measures use in the eleven RCTs. Due to the variety of measures used, and poor reporting of results, it was not possible to conduct a meta-analysis of global quality of life scores. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 123 Table 12 Global quality of life outcomes reported in 11 RCTs Author Population N Age Treatment N Study Duration Measure Findings Stat. Sig. between groups as per author (Y/N) Comments/Quality 10 weeks EORTC QLQ-C30 “No statistically significant difference in QOL scores between groups or between different time points” (p.974) N -secondary outcome Age=49 4 weeks Bupropion 150mg 2xday, crossover Completed Bupropion/Placebo N=48 N=27 Pharmaceutical interventions Antidepressants Nunez 201324 N=55 -post-treatment mean scores not reported -poor quality of reporting Placebo/Bupropion N=28 Loprinzi 200240 N=81 Age=18-49 Completed N=66 4 weeks Fluoxetine 20mg daily, crossover 9 weeks Fluoxetine/Placebo Uniscale global QOL N=40 Placebo/Fluoxetine Mean score at baseline 91 (on scale of 0-100). After 5 weeks of treatment, groups differed by one point in favour of fluoxetine (p=0.51, mean scores not reported). After cross-over, fluoxetine group showed “modest improvement” of 4 points (p=0.07, mean scores not reported) (p.1581). N -secondary outcome -short treatment duration -high QOL at baseline (mean score 91/100) -post-treatment mean scores not reported N=41 -poor quality of reporting Stearns 200541 N=151 Age=50-55 Completed N=107 4 weeks Paroxetine 10mg or 20mg daily, crossover 9 weeks EuroQOLLRS Baseline mean scores (SD): N -secondary outcome Paroxetine 10mg/placebo = 79.7(3.2) -short treatment duration Paroxetine 10mg /Placebo Paroxetine 20mg/placebo = 82.8(2.7) - post-treatment mean scores not reported N=37 Placebo/Paroxetine 20mg = 82.7(2.2) Paroxetine 20mg/Placebo “Scores improved or remained the same with treatment in all arms, including placebo, and the distribution of patients was similar among all treatment arms” (p=0.72) (p.6927). N=38 Placebo/Paroxetine 10mg = 83.8(2.4) Placebo/Paroxetine 10mg Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 124 -categorisation of scores difficult to interpret -poor quality of reporting Author Population N Age Treatment N Study Duration Measure Findings Stat. Sig. between groups as per author (Y/N) Comments/Quality 12 weeks FACT-B Sertraline: Mean(SD) N -secondary outcome measure N=39 Placebo/Paroxetine 20mg N=37 Kimmick 200642 N=62 6 weeks Sertraline Age=53.9 50mg, crossover Completed Sertraline/Placebo N=39 N=33 Baseline, 119.4(18.7); 6wks, 126.4(19.7); 12wks, 117(18.5) -short treatment duration Placebo: Mean(SD) -poor quality of reporting Placebo/Sertraline Baseline, 122.1(14.4); 6wks, 120.6(12.3); 12wks 124.2(15.5) N=29 Significance Baseline, p=0.65; 6wks, p=0.32; 12wks, p=0.88 Sedatives Joffe 201036 N=53 Age=51.1 Completed N=38 5 weeks AD with zolpidem 10mg 5 weeks QOLI Zolpidem Y N=25 Baseline, M=51.6±29.8; week 5 percentile score change, 14.7±22.4 AD with placebo Placebo N=28 Baseline, M=60.7±35.5; week 5 percentile score change, -10.7±27.2 -secondary outcome -per protocol analyses -Wilcoxon rank sum test to detect “change” on QOLI scores -higher dropout in placebo group Significance -poor quality of reporting Baseline, p=0.31; week 5, p=0.01 Menopause hormone therapy Fahlen 201132 Subgroup N=75 Age=57 Completed N=57 Menopause hormone therapy 1 year EORTC QLQ-C30 Menopause hormone therapy: Mean(SD) N=38 Baseline, 61.73(22.91); 6mths, 72.84(23.41); 12mths, 75.31(21.37) Control Control: Mean(SD) N=37 Baseline, 66.27(19.98); 6mths, 65.48(21.62); Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 125 N -subgroup of Stockholm Trial -significance values not reported -poor quality of reporting Author Population N Age Treatment N Study Duration Measure Findings Stat. Sig. between groups as per author (Y/N) Comments/Quality N -subgroup of HABITS trial 12mths 67.46(23.11) Significance p not reported (not significant) Frisk 201231 N=45 12 weeks 2 years Age=54.1, 53.4 EA EA N=26 N=7 2 years Menopause hormone therapy Completed N=18 Menopause hormone therapy N=18 PGWB Authors report statistically and clinically significant changes from baseline to all time points in both EA and menopause hormone therapy groups. However, no statistically significant difference between groups: 12 months (p=0.466, n=31) or 24 months (p=0.193, n=18). -ITT analyses not reported -n <10 after 18 months -different treatment durations for each group -poor quality of reporting N=11 Complementary medicines and therapies Relaxation Fenlon 200852 N=150 1 month Relaxation Age=54.9, 55.5 N=74 Completed 12 weeks FACT-ES Relaxation N Baseline, M=170; 1mth median change, -0.38; 3mths median change -5.2 Control -QOL decreasing with time in both groups -fair quality of reporting Control N=76 N=97 Baseline, M=168, 1mth median change, -0.33; 3mths median change -3.5 Significance 1mth, p=0.94; 3mths p=0.62 Electro-acupuncture Frisk 201231 N=45 12 weeks 2 years Age=54.1, 53.4 EA EA N=26 N=7 2 years Menopause hormone therapy N=11 Completed N=18 Menopause hormone PGWB Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Authors report statistically and clinically significant changes from baseline to all time points in both EA and Menopause hormone therapy groups. However, no statistically significant difference between groups: 12 months (p=0.466, n=31) or 24 months (p=0.193, n=18). 126 N -subgroup of HABITS trial -ITT analyses not reported -n <10 after 18 months -different treatment durations for each group Author Population N Age Treatment N Study Duration Measure Findings Stat. Sig. between groups as per author (Y/N) Comments/Quality 16 weeks EORTC QLQ-C30 Homeopathy: Mean(SD) N -secondary outcome therapy N=18 Other therapies Thompson 200559 N=53 16 weeks Homeopathy Age=53.6, 51.6 N=28 Completed Placebo Placebo: Mean(SD) N=25 Baseline, 4.6(1.2) N=45 MacGregor 200563 N=72 Age=51 Completed N=68 Carpenter 200257 N=15 Age=57.1 Completed N=11 Baseline, 4.3(1.4) -possibly reporting single item on EORTC QLQ-C30, and not global/overall QOL health score -poor quality of reporting Adjusted Difference = -0.1 (95% CI, -0.7 to 0.6), p=0.85 12 weeks Isoflavines 70mg daily 12 weeks EORTC QLQ-C30 No statistically significant differences between groups (p=0.844). N N=36 -primary outcome measure Placebo -results displayed in figure, approx. score of 68 across time N=36 -poor quality of reporting 3 days Magnetic Therapy, crossover Magnetic/Placebo 16 days HFRDIS Placebo: Mean(SD) (single item) Baseline, 2.64(3.35); Day 5, 1.45(1.92) N=6 Placebo/Magnetic N=5 N -overall QOL score from single item on HFRDIS -analyses conducted on small sample (n=11) Magnetic: Mean(SD) Baseline, 1.45(1.69); Day 5, 1.09(1.30) Significance -overall QOL measured on single item of HFRDIS p=0.13 -poor quality of reporting AD, antidepressant; EA, electro-acupuncture; QOL, quality of life; wks, weeks; mths, months; yrs, years; M, mean; SD, standard deviation; N, number; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; EuroQOL LRS, European Quality of Life Linear Rating Scale; QOLI, Quality of Life Inventory; FACT-B, Functional Assessment of Cancer Therapy-Breast; FACT-ES, Functional Assessment of Cancer Therapy-Endocrine Subscale; HFRDIS, Hot Flash-Related Daily Interference Scale; PGWB, Psychological and General Wellbeing Index Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 127 Table 13 Summary of quality of life measures used in the Quality of Life and Mental health RCTs Measure Population Dimensions/Structure Disease Specific Modules Quality Rating Scale Norms & Cut-off (SD) EORTC QLQ-C30 N=23553 Cancer patients on clinical trials; Physical, role, cognitive, emotional, social functioning, fatigue, pain, nausea, and global health status QLQ-BR23: Diseasespecific module for breast cancer Established validity, reliability and sensitivity Range 0-100 with higher scores indicating better QOL European Organization for Research and Treatment of Cancer Quality of Life Questionnaire112 Australia, N=401 Global QOL: BC aged <50 years Mean=61.3(24.5) Median=66.7 Cited in the current systematic review by Nunez 201324 Fahlen 201132 Thompson 200559 MacGregor 200563 BC aged 50-59 years Mean= 63.3(24.4) Median=66.7 (Scott et al 2008)83) EuroQOL-LRS 0-100 Stearns 200541 Higher scores indicate better QOL Kimmick 200642 European Quality of Life-Linear Rating Scale113 FACT Cancer patients. Functional Assessment of Cancer Therapy General population norms developed in Queensland, N=2727 (Janda et al 2009)104 HFRDIS Hot Flash-Related Daily Interference Scale86 Breast cancer patients, N=71; Comparators, N=63 Physical wellbeing, social/family wellbeing, emotional wellbeing, functional wellbeing (FACT-G) + symptom specific subscale (e.g. FACT-B or FACT-ES) FACT-B: Breast specific subscale (37 items) Established validity, reliability and sensitivity FACT-ES: Endocrine specific subscale (55 items: FACT-B+ES) Impact of hot flushes on 9 activities: work, social, leisure, sleep, mood, concentration, relationships, sexuality, enjoyment of life. 1 item on overall QOL Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Impact of hot flushes after breast cancer BC Mean=122.09 (Fallowfield et al 1999)114 Higher scores indicate better QOL Fenlon 200852 BC Mean=177.64 (Fallowfield et al 1999)114 Established validity, reliability and sensitivity 128 Range 0-10, with higher scores indicating greater interference of hot flush on activity. Carpenter 2002 (only used single item)57 Measure Population Dimensions/Structure Disease Specific Modules Quality Rating Scale Norms & Cut-off (SD) PGWB US population 6 subscales: anxiety, depressed mood, positive wellbeing, selfcontrol, general health and vitality (22 items) N/A Established validity Range 0-110: higher scores indicate greater wellbeing Psychological and General Wellbeing Index115 Cited in the current systematic review by Frisk 201231 BC aged 50-60 years Mean=73.2(17.0) Community 50-60 years Mean=79.1(17.5)116 QOLI Quality of Life Inventory117 Various clinical settings, N=3927 Health, work, recreation, friendships, love relationships, home, self-esteem, standard of living (positive psychology test Measure of life satisfaction, wellbeing, positive psychology and positive mental health Established validity, reliability and sensitivity Range 0-100 Joffe 201036 Very low: 0-37 Low: 37-43 Average: 43-58 High: 58-77 SF-36 Medical Outcomes Study Heath Survey Short Form118 General population 36 items: includes mental health, physical health, pain, role limitations. SF-12 Medical Outcomes Study Health Survey Short Form Uniscale global QOL General population 12 items from SF-36. Summary mental and physical health scores. N/A Single item global score Mental health, physical functioning N/A Established validity, reliability and sensitivity. Emphasises functional health. Mental health items do not measure loss of enjoyment or anxious preoccupation. Claimed to be as robust as SF36. Normative data: raw scores are transformed to a scale of 0-100. Higher scores indicate better health. Questionable validity, reliability and sensitivity Range 0-100 Abbreviations QOL, quality of life; N/A, not applicable; AUST, Australian; BC, breast cancer Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 129 Carpenter44 Buijs46 Bordeleau48 Biglia50 Duijts28 Mann29 Walker35 Loprinzi 200240 Pharmaceutical interventions Antidepressants Atypical antidepressants: bupropion Nunez et al (2013)24 evaluated the effect of bupropion compared to placebo on EORTC QLQ-C30 scores, as a secondary outcome measure. No statistically significant differences (between groups or time points) were found. The authors did not report the EORTC QLQ-C30 scores, preventing any interpretation of their findings. Selective serotonin re-uptake inhibitors: sertraline, fluoxetine and paroxetine Three RCTs (Loprinzi et al 2002; Stearns et al 2005; Kimmick et al 2006)40-42 investigated the effects of an SSRI (fluoxetine, paroxetine, sertraline, respectively) versus placebo, and reported the outcome of a quality of life measure after treatment as a secondary outcome. Loprinzi et al (2002)40 used a uniscale instrument that asked participants to rate their global quality of life on a scale ranging from 0 to 100. The reporting of results was poor and it was not clear what scores on the scale indicated. The authors stated that at baseline the average score was 91. The authors reported that after five weeks of treatment the fluoxetine and placebo groups differed by one point (p=0.51, mean scores not reported). After crossover, the “quality of life showed a relative improvement trend for fluoxetine over placebo by four points” (p=0.07, mean scores not reported). However, the difference between groups was not statistically significant. Stearns et al (2005)41 compared the effects of four weeks of paroxetine (10mg or 20mg) to placebo. They included the EuroQOL Linear Rating Scale (EuroQOL-LRS) as a secondary outcome measure. They classified scores as better (or worse) if the score increased (or decreased) by at least ten points between baseline and week five. This classification of scores made it difficult to interpret their results, which were reported to have “improved or remained the same with treatment in all arms, including placebo, and the distribution of patients to better, same or worse was similar among all treatment arms” (p.6927). Kimmick et al (2006)42 investigated the effects of six weeks of sertraline to placebo. Participants completed the Functional Assessment of Cancer Therapy for patients with breast cancer (FACT-B), a quality of life measure with a breast cancer specific subscale. Mean scores are displayed in Table 12. No significant differences between groups were found at baseline, after six weeks of treatment or at follow-up (twelve weeks). Sedatives: zolpidem Joffe et al (2010)36 investigated the effect of an antidepressant (SSRI/SNRI) combined with zolpidem or placebo on sleep in 53 women. The Quality of Life Inventory (QOLI) was administered for a secondary outcome measure. At baseline, mean scores for the placebo group were in the high range (60.7, SD±35.5), while mean scores for the zolpidem group were in the average range (51.6, SD±29.8), with no statistically significant difference between groups (p=0.31). Amongst study completers (n=38), QOLI percentile scores improved by 14.7 (SD±22.4) points with zolpidem augmentation and decreased by 10.7 (SD±27.2) points with placebo. The authors reported that “augmentation with zolpidem improved quality of life more than augmentation with placebo (p=0.01)” (p. 913). Menopause hormone therapy Two studies (Fahlen et al 2011; Frisk et al 2012)31, 32 investigated menopause hormone therapy, and reported the outcomes of a quality of life measure. Fahlen et al (2011) 32 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 130 published the findings from a subgroup of 75 women who participated in the Stockholm trial, and completed the EORTC QLQ-C30 measure. Although the authors reported a statistically significant difference within groups over time (scores improved over time for both groups, p<0.05), there was no statistically significant difference between groups (p not reported). Additionally, the mean scores reported in Fahlen (range from 61.73 - 75.31, see Table 12) were comparable to breast cancer norms for women aged 50-59 years (mean=63.3; SD=24.4, Scott et al83, see Table 13). Similarly, Frisk et al (2012)31 published the findings from a subgroup of women who participated in the HABITS trial. Forty-five women were randomly allocated to receive 12 weeks of electro-acupuncture (EA, n=27) or two years of menopause hormone therapy (n=18). Eighteen women completed the Psychological and General Wellbeing Index (PGWB) at seven different time points, up to two years (see Table 14). The authors reported a statistically and clinically significant improvement within groups, with no statistically significant difference between groups at one year (p=0.466, n=31) or two years (p=0.193, n=18). These observations suggest that menopause hormone therapy and electro-acupuncture are both effective at improving global quality of life. Table 14 Psychological and General Wellbeing scores reported in Frisk et al 2012 (p.720)31 Time (months) Menopause hormone therapy group EA group n n Total PGWB p (IQR 25th-0.75th pct) Total PGWB (IQR 25th-0.75th pct) Baseline 18 75 (59-88) 19 78 (54-89) NR 3 18 90 (62-97) 19 79 (68-93) NR 6 18 88 (70-98) 18 79 (58-94) NR 9 18 81 (74-94) 16 83 (74-95) NR 12 17 93 (86-97) 14 85 (74-95) 0.466 18 11 92 (74-98) 8 83 (76-96) NR 24 11 86 (84-96) 7 80 (76-96) 0.193 Data presented as median (IQR 25th-0.75th pct) as in Frisk et al 2012 (p.720)31; EA, Electroacupuncture, NR, between groups p not reported Although quality of life significantly improved for all groups in the two studies (Fahlen et al 2011; Frisk et al 2012),31, 32 mean scores remained within the normal range. Complementary medicine and therapies Relaxation therapy Fenlon et al (2008)52 investigated the effect of relaxation therapy (20 minutes per day for 1 month) to no treatment on the FACT-ES, a quality of life measure with an endocrine specific subscale. At baseline, the mean scores for both groups (relaxation = 170; control = 168) was below the normative breast cancer mean score (177.64, Fallowfield et al 114; see Table 13). Frisk et al (2012)31 found that both menopause hormone therapy and electro-acupuncture had a significant improvement in health related quality of life from baseline. The authors Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 131 mentioned that because of the risk of breast cancer recurrence, menopause therapy is not recommended for women that have menopausal symptoms due to breast cancer treatment. Acupuncture and electro-acupuncture One study reported the effects of electro-acupuncture (EA) compared to menopause hormone therapy, as part of the HABITS trial (Frisk et al 2012).31 As this study compared EA with menopause hormone therapy, the findings are discussed in the menopause hormone therapy section of the present systematic review. In summary, there were no statistically significant differences between groups in PGWB scores. Yoga No RCTs were identified that reported the effects of exercise or yoga on global quality of life. Other therapies Homeopathy Thompson et al (2005)59 investigated the effect of 18 weeks of homeopathy compared to placebo on quality of life, as a secondary outcome measure. Although Thompson et al (2005)59 indicated that they reported the mean “overall quality of life” scores (homeopathy=4.3; placebo=4.6) on the EORTC QOL-C30 “plus Breast module” (p.14). The authors found no statistically significant differences in global quality of life between homeopathy versus placebo. Phytoestrogens MacGregor et al (2005)63 investigated the effects of 12 weeks of isoflavine (70mg daily) compared to placebo on quality of life, as a primary outcome measure. The authors reported no statistically significant differences between treatment group versus placebo on global quality of life scores, as measured by the EORTC QOL-C30 (p=0.844). Scores were illustrated in a figure, with an approximate mean score of 68 across all time points. This mean score is in the normal range for breast cancer patients aged 50-59 years (M=63.3, SD=24.4, Scott et al (2008)83), which may underestimate the treatment effects of isoflavines on global quality of life. Magnetic therapy Carpenter et al (2002)57 investigated the effect of three days of magnetic therapy compared to placebo. A single item on the Hot Flash-Related Daily Interference Scale (HFRDIS) was used to report the overall quality of life. Although a single item is not considered a valid measure of a multi-dimensional construct of global quality of life, no statistically significant differences were found in overall quality of life between magnetic therapy versus placebo. Defining Mental health The present systematic review uses the term “mental health” to describe quality of life as measured by the SF-36 and the SF-12 survey form (see Table 13). The SF-36 contains five items that create a mental health subscale, which when combined with three other subscales Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 132 (vitality, social functioning, and role-emotional) creates a mental health composite score. Scores range from 0-100, with higher scores indicating better mental health (see Table 13). Seven RCTs28, 29, 35, 44, 46, 48, 50 (see Table 15) included a quality of life measure, the Medical Outcomes Study Health Survey Short Form (SF-36 or SF-12), as a secondary outcome measure. To provide an approximate guide of the findings, the mean scores (when reported) are illustrated in Table 15. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 133 Table 15 Summary of seven RCTs measuring mental health Author Treatment Stat. Sig. between groups as per author (Y/N) Finding Pharmaceutical interventions Antidepressants Carpenter 200744 6 weeks Venlafaxine N Baseline, 86.41 Low dose (37.5mg) Buijs 200946 Placebo, 89.95(4%) vs Low dose, 90.93(5%), High dose (75mg) p=0.365, Effect size, -0.15, 95% CI for Effect size, (-0.48, 0.18) Placebo p=0.194, Effect size, -0.31, 95% CI for Effect size (-0.81, 0.18) 8 weeks Venlafaxine Placebo 92.00(6%) vs High dose, 93.73(8%) N Venlafaxine, 82 vs Clonidine, 78 Clonidine p nr (0.05mg) 4 weeks Venlafaxine N Gabapentin (900mg) 12 weeks Venlafaxine Mean MHC score “At baseline the mean mental component summary score was 48.2±11.7. Overall mean scores increased by less than two points on either treatment, and there was no statistically significant differences between venlafaxine and gabapentin with regard to the scores obtained after 4 weeks of treatment” (p.5151) (75mg) Walker 2010^35 MHS scores, Mean Baseline, 79 (75mg) Bordeleau 2010#48 Mental health score, Mean (% change from baseline) N MenQol and BDI-PC “There were no significant effects of group or significant interactions. Thus, both groups had similar changes over time in each outcome measure. (pp. 637-638). Both groups exhibit significant improvements in mental health from pre to post treatment.” (75mg) Acupuncture (30mins) Anticonvulsants Biglia 2009#50 12 weeks Y Gabapentin (300mg) Mean MHC scores Gabapentin Baseline, 60.64; 4 weeks, 68.28, absolute change, -7.64, p<0.05; 12 weeks, 68.96, absolute change, -8.32, p<0.05 Vitamin E 800IU Vitamin E “In the group of women receiving vitamin E, the evaluation of total scores of SF-36 after 4 and 12 weeks of treatment did not show any modification as compared to pre-treatment values” (p.315) Complementary medicines and therapies Cognitive behavioural therapies Duijts 201228 6 weeks CBT, N “No significant overall group differences over time were observed for the remaining scales of the SF-36 (data not Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 134 Mann 201229 12 weeks PE, shown)” (p.4) on intent-to-treat analyses. 6 weeks CBT + 12 weeks PE Per-protocol analyses indicated significant differences on MHS and MHC scores in favour of CBT+PE. 6 weeks CBT vs Usual care Y Mean MHS(SD) CBT Baseline, 67.57(17.89); 9 weeks, 74.63(14.22); 26 weeks, 70.70(19.24) Usual care Baseline, 62.52(17.37); 9 weeks, 66.46(14.20); 26 weeks, 64.5(16.06) Adjusted mean difference (SE) 9 weeks, 6.03(2.95); 26 weeks, 3.86(2.96) 95% CI 9 weeks, 0.24 to 11.81; 26 weeks, -1.94 to 9.65 Significance Baseline, nr; 9 weeks, p<0.05; 26 weeks, NR Note: when scores were not reported, the results of the original paper were quoted. #Mental health component score, ^MenQOl and BDI-PC, SF-12; CBT, cognitive behaviour therapy; PE, physical exercise; NR, not reported; MHS, Mental Health Subscale score; MHC, Mental Health Composite score; SD, standard deviation; SE, standard error; CI, confidence interval; ES, effect size Figure 5 Mean scores reported on Short Form-36 mental health Mean scores reported on SF-36 mental health at baseline and post-treatment (treatment dose and duration varies between studies). Scores on SF-36 range from 0-100, with higher scores indicating better mental health. Note: scores were not reported in Walker 35 and Duijts28. Bordeleau48 and Biglia50 reported mental health component score (all other studies report mental health subscale scores). Biglia was the only study that reported a statistically significant difference between groups. Pharmaceutical interventions Antidepressants Selective noradrenaline re-uptake inhibitors: venlafaxine, and antihypertensive clonidine Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 135 Four head-to-head studies35, 44, 46, 48 compared 75mg of venlafaxine to low dose venlafaxine (37.5mg), clonidine (0.05mg), gabapentin (900mg) and acupuncture (12 weeks; see Table 15). None of the studies found a statistically significant difference between groups on mental health scores. Anticonvulsants: gabapentin Biglia et al (2009)50 compared the effect of gabapentin (900mg daily) to vitamin E (800IU daily) for 12 weeks. The authors reported a “significant increase in the mental health component score of 13.72% (absolute change -8.32; 95% CI -13.78 to -2.86; p<0.05) at the end of the treatment period as compared to the baseline week” with gabapentin (p.314). The vitamin E group “did not show any significant modification as compared to pretreatment values” (p.315). Bordeleau et al (2010)48 compared gabapentin and venlafaxine and the study is described above under the section serotonin noradrenaline re-uptake inhibitors. Complementary medicines and therapies Psychological and physical interventions Cognitive behavioural therapy and exercise Duijts et al (2012)28 compared the effects of six weeks of cognitive behaviour therapy (CBT) to twelve weeks of physical exercise (PE) or CBT+PE to a waitlist control group. On intentionto-treat analyses, the authors reported that there was “no significant overall group differences over time observed for … scales of the SF-36 (data not shown)” (p. 4). Mann et al (2012)28 compared six weeks of group CBT (one 90 min session per week) to usual care on mental health, as measured by the SF-36 (secondary outcome). The authors reported a significant improvement in mental health with CBT (from 67.57 to 70.70 at 26 week, see Table 15). However, it is important to note that participants were concurrently taking medication (including menopause hormone therapy, SSRIs, gabapentin and clonidine), which may have confounded these results. Evidence Summary 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 eleven RCTs (five with low risk of bias, four with moderate risk of bias and two with high risk of bias) with quality of life as a secondary outcome measure, in a total of 812 women across all studies. Among the RCTs, the following treatments were investigated: bupropion (one RCT), fluoxetine (one RCT), paroxetine (one RCT), sertraline (one RCT), zolpidem (augmented with SSRI/SNRI) (one RCT), menopause hormone therapy (two RCTs), electro-acupuncture (one RCT), relaxation therapy (one RCT), magnetic therapy (one RCT), homeopathy (one RCT), and isoflavones (one RCT). No RCTs investigated the effect of venlafaxine, clonidine, gabapentin, vaginal gel, cognitive behaviour therapy, physical exercise, hypnotherapy, yoga, black cohosh, or vitamin E on global quality of life associated with menopausal symptoms in women after breast cancer. The evidence for the effectiveness of the various interventions on global quality of life is summarised in the Evidence Summaries below. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 136 Four RCTs in women after breast cancer found no statistically significant effects on global quality of life versus placebo for: bupropion (300mg/d for 4 weeks, RCT with a moderate risk of bias, Nunez 2013)24; fluoxetine (20mg/d for 4 weeks, RCT with a low risk of bias, Loprinzi 2002)40; paroxetine (10mg/d for 4 weeks, RCT with a low risk of bias, Stearns 2005)41; on sertraline (50mg/d for 6 weeks, RCT with a moderate risk of bias, Kimmick 2006).42 One RCT (with a moderate risk of bias) in women after breast cancer found a statistically significant improvement in global quality of life between SSRI/SNRI augmented with zolpidem (10mg/d) compared to SSRI/SNRI with placebo. One RCT (with a moderate risk of bias) in women after breast cancer found a statistically significant improvement in global quality of life for menopause hormone therapy at 6 and 12 months compared with baseline, but there were no significant differences in changes from baseline between menopause hormone therapy and no treatment control (Fahlen 2011).32 One RCT (with a high risk of bias) in women after breast cancer found that menopause hormone therapy (for 24 months) and electro-acupuncture (for 12 weeks) were equally effective at improving health related quality of life (Frisk 2012).31 One RCT (with a low risk of bias) in women after breast cancer found no significant improvement in global quality of life between relaxation therapy compared to no treatment control (Fenlon 2008).52 Three RCTs (two with a low risk of bias and one with a moderate risk of bias) in women after breast cancer found no statistically significant difference in global quality of life between treatment groups versus placebo for: homeopathy (Thompson 2005)59; phytoestrogens (MacGregor 2005)63; or magnetic therapy (Carpenter 2002).57 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 studied significantly reduce global quality of life. There is a need for more studies of higher methodological quality. Mental health There is no level I evidence from systematic reviews that examined the effects of treatment on mental health associated with menopausal symptoms in women after breast cancer. There is level II evidence from seven RCTs, all with moderate risk of bias, on 893 women across all seven studies. Amongst the RCTs, the following treatments were investigated: venlafaxine (four RCTs), clonidine (one RCT), gabapentin (two RCTs), CBT (two RCTs), physical exercise (one RCT), acupuncture (one RCT), and vitamin E (one RCT). No RCTs investigated the effects of atypical antidepressants, SSRIs, sedatives, or menopause hormone therapy on mental health. The evidence for the effectiveness of the various interventions on mental health is summarised in the Evidence Summaries below. One RCT (with a moderate risk of bias) in women after breast cancer found no statistically significant differences in SF36 mental health subscale score between venlafaxine (37.5mg/d or 75mg/d) compared to placebo (Carpenter 2007).44 One RCT (with a moderate risk of bias) in women after breast cancer found no statistically significant differences between venlafaxine (75mg/d) and clonidine (0.05mg/d, Buijs 2009).46 One RCT (with a moderate risk of bias) in women after breast cancer found no statistically significant differences between venlafaxine (75mg/d) and gabapentin (900mg/d, Bordeleau 2010).48 One RCT (with a moderate risk of bias) in women after breast cancer found a statistically significant improvement in mental health score and menopausal specific quality of life for venlafaxine Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 137 (75mg/d)and acupuncture (30min/twice a week), with no significant differences between groups (Walker 2010).35 One RCT (with a moderate risk of bias) in women after breast cancer found a significant improvement in the SF36 mental health score with gabapentin (900mg/d) compared to baseline. The study did not report between group differences from baseline (Biglia 2009). 50 One RCT (with a moderate risk of bias) in women after breast cancer found no statistically significant improvement in mental health score between CBT alone or in combination with physical exercise compared to wait list controls (Duijts 2012).28 One RCT (with a moderate risk of bias) in women after breast cancer found a statistically significant improvement in mental health score for CBT compared to usual care (Mann 2012).29 Overall, there is limited evidence on the effects of the interventions studied to improve mental health 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 associated with menopausal symptoms in women after breast cancer treatment, there is no evidence that treatment has an adverse effect on mental health. Evidence Summaries were not developed for Global Quality of Life and mental health, in view of the poor quality of the studies: quality of life and mental health were reported as secondary outcomes and the dosages of psychotropic medications used were below that needed to treat mental health conditions. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 138 3.7 Breast cancer recurrence Breast cancer recurrence is a serious potential adverse effect of menopause hormone treatments, hence the recommendation in many clinical practice guidelines to exercise caution with prescribing menopause hormone therapies to women with a history of breast cancer or that menopause hormone therapies are contraindicated (see section 3.10 International guidelines and recommendations, p154). There was no level I evidence from systematic reviews that focused on the recurrence of breast cancer in women previously treated for breast cancer and have been administered with menopause hormone treatments. Among the RCTs comprising the Primary Evidence Base, three trials investigated menopause hormone treatments and included breast cancer recurrence as an outcome (Table 16): two on “hormone replacement therapy” (Menopause hormone therapy) (Holmberg et al 2004,11 which has sub-studies by Frisk et al 2008 and 2012, and von Schoultz et al 2005,13 which has a sub-study by Fahlen et al 201132) and one on tibolone by Kenemans et al (2009)12 and its update by Sismondi et al (2011).33) The HABITS trial (Holmsberg et al 2004)11 reported on 345 women with a previous breast cancer who were using Menopause hormone therapy for menopausal symptoms. After a median follow-up of 2.1 years, the risk of a new breast cancer event was higher in the Menopause hormone therapy group compared with the no- Menopause hormone therapy group (RH 3.5; 95% CI 1.5, 8.1). The result remained unchanged when adjusted for use of Menopause hormone therapy before diagnosis (yes vs no), use of tamoxifen (yes vs. no) and hormone receptor status (positive vs negative or unknown). The majority of the events were local recurrences or distant metastases. The Stockholm trial (von Schoultz et al 2005)13 reported on 359 women who had been diagnosed with early-stage breast cancer and were randomised to either Menopause hormone therapy or no-Menopause hormone therapy. After a median follow-up of 4.1 years, no significant differences in breast cancer recurrence were observed between the two groups. Both the Stockholm trial and the HABITS trial 11, 13 were terminated early due to the perceived increased risk of breast cancer recurrence following menopause hormone therapy. Only the HABITS trial reported an increased risk of breast cancer recurrence following menopause hormone therapy. However the Stockholm trial was still closed early. Differences between the two trials included that the HABITS trial had a higher proportion of lymph-node-positive patients and a lower proportion of patients on adjuvant tamoxifen compared to the Stockholm trial. Also the trials differed in the treatment protocols used, with the Stockholm trial minimising the use of combined oestrogen and progestogen.13 A third study, the LIBERATE trial (Kenemans et al 2009)12 analysed 3,098 breast cancer patients with vasomotor symptoms randomised to either tibolone (n=1,556) or placebo (n=1,542), with breast cancer recurrence (including contralateral breast cancer) as the primary endpoint. After a median follow-up of 3.1 years, 15.2% of women on tibolone had a breast cancer recurrence compared with 10.7% on placebo (intention-to-treat analysis: HR 1.40, 95% CI 1.14, 1.70, p=0.01; per-protocol analysis: 16.7% versus 11.4% respectively, HR 1.44, 95% CI 1.16, 1.79, p=0.0009). When analysed by location of recurrence, results were only statistically significant for distant recurrence (p=0.007), rather than local (p=0.122) or contralateral (p=0.305) recurrence. The overall incidence of breast cancer recurrence was more likely in lymph-node-positive patients and oestrogen-receptor-positive patients (however it was noted that the study was not powered to assess effectiveness in different sub-groups). Users of aromatase inhibitors at baseline (6.5% of ITT population) had a higher risk of recurrence than tamoxifen users (67% of ITT population) (HR 2.42; 95% CI 1.01, 5.79; p=0.047 versus HR 1.25; 95% CI 0.98, 1.59; p=0.076). In the subgroup of patients who were not on tamoxifen, aromatase inhibitors, or GnRH analogues at trial entry (26.7% of the ITT population) the HR was 1.73; 95% CI 1.18, 2.53; p=0.005. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 139 In addition, three RCTs reported on breast cancer recurrence in their study participants, but did not analyse the data further.29, 58, 61 The RCT investigating CBT (Mann et al 2012)29 reported one participant in each group (CBT and usual care) experienced recurrence of breast cancer. The RCT assessing homeopathy (Jacobs et al 2005)58 reported four participants withdrew from the study because of cancer recurrence (three from the combination treatment arm and one from the placebo arm) but did not explicitly state this was breast cancer recurrence. The RCT into black cohosh (Jacobson et al 2001) 61 reported one case of breast cancer recurrence in a participant receiving black cohosh and who was on tamoxifen. Evidence summary: Breast cancer recurrence There was no level I evidence from systematic reviews for the recurrence of breast cancer in women who have received breast cancer treatment and were administered menopause hormone treatments. Three RCTs, which investigated menopause hormone therapy, reported on breast cancer recurrence as an outcome. One trial on menopause hormone therapy (HABITS) (Holmsberg et al 2004)11 and another on tibolone (LIBERATE) (Kenemans et al 2009)12 reported a statistically significant increase of breast cancer recurrences in patients who had menopause hormone therapy. Due to the increased risk of recurrence, the Swedish HABITS and Stockholm trials were terminated early. The third RCT (the Stockholm trial) (von Schoultz et al 2005)13 did not report a significant increase in breast cancer recurrence but was still terminated early. One RCT (with a high risk of bias) in women after breast cancer found that menopause hormone therapy (sequential or continuous combined oestrogen/progestogen) was associated with a significantly higher rate of new breast cancer events compared with no treatment, resulting in the early termination of this study (Holmberg et al 2004).11 One RCT (with a high risk of bias) of menopause hormone therapy (combined oestradiol/medroxyprogesterone) in women after breast cancer was terminated early due to safety concerns related to breast cancer recurrence (von Schoultz 2005).13 One RCT (with a low risk of bias) in women after breast cancer found that tibolone (2.5 mg/d) was associated with a significantly higher rate of new breast cancer events compared with no treatment (Kenemans et al 2009).12 [Evidence Summaries 29] While menopause hormone therapy is effective in reducing vasomotor symptoms in women who have received breast cancer treatment, there is evidence for increased risk of breast cancer recurrence. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 140 Table 16: RCTs that assessed for breast cancer recurrence Author, year (Trial name) Holmberg, 200411 Symptom/Impact Specific Outcome Breast cancer recurrence New breast cancer events Breast cancer recurrence Breast cancer recurrence Breast cancer recurrence Breast cancer recurrence HABITS Von Schoultz, 200513 Stockholm trial Sismondi, 201133, LIBERATE Intervention Number of recurrences Hormone replacement therapy Local 11 Contralateral 5 Distant 10 Comparator Number of recurrences Non-hormone replacement therapy Local 2 Contralateral 1 Distant 5 Hormone therapy Number of breast cancer recurrence Overall 11 Local 5 Contralateral 3 Distant 3 Tibolone Percentage of patients with breast cancer recurrence Any recurrence 15.2% Local 3.1% Contralateral 1.6% Distant 11% Non-hormone therapy Number of breast cancer recurrence Overall 13 Local 5 Contralateral 3 Distant 5 Placebo Percentage of patients with breast cancer recurrence Any recurrence 10.7% Local 2.1% Contralateral 1.1% Distant 7.8% Difference Hormone replacement therapy vs non- hormone replacement therapy RH 3.5; 95% CI 1.5-8.1; p-value not reported Hormone therapy vs non-hormone therapy No significant difference between groups Tibolone vs Placebo HR (95% CI) Any recurrence HR Kenemans, 1.40 (95% CI 1.14-1.70) 200912 p=0.01+ Local HR 1.42 (95% CI 0.91-2.21) p=0.122# Contralateral HR 1.387 (95% CI 0.742-2·594) p=0.305# Distant HR 1.378 (95% CI 1.092-1.740) p=0.007+ Abbreviations CI: confidence interval; SD: standard deviation; HR=hazard ratio; #Not statistically significant; +Statistically significant; HABITS=hormone replacement therapy after breast cancer – is it safe?; NR=not reported; RH=relative hazard Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 141 3.8 Adverse events A range of adverse events were reported by the trials that form the Primary Evidence Base. Initially, it was intended to systematically extract this data from the published trials, but adverse events were reported inconsistently and sample sizes across the trials were typically small. Thus the Primary Evidence Base cannot be relied on for data regarding adverse events. As a result, it was decided to identify pharmaceuticals that may be used by women who have been treated for breast cancer, including the pharmaceutical interventions assessed by the Primary Evidence and other pharmaceutical agents women were likely to be administered as part of their ongoing breast cancer treatment (excluding chemotherapy agents). Information was sourced from the Therapeutic Goods Administration 66 of Australia(TGA)-approved product information sheets, which in turn are based on large registration trials. It should be noted that these large trials are in broader, general populations and were not limited to our target population of women with a history of breast cancer. The indications, contraindications, common side effects (that is, side effects occurring with an incidence of at least 10% of the trial population administered the drug), drug interactions and precautions are presented in Table 17. In addition to the pharmaceuticals listed in Table 17, the vaginal gel assessed by Lee et al (2011)34 was associated with some minor complications such as irritation and itching, but none of the reported complications were significantly different from the placebo gel. Among complementary medicines and therapies, the key systematic review by Rada et al (2010)4 reported that the studies they included did not find differences between the interventions and placebo in the incidence of adverse effects for vitamin E and homeopathy. However, study sample sizes were small and thus such conclusions are not reliable; further, Rada et al (2010) stated that the overall quality of reporting of adverse effects in the RCTs they included in their systematic review was low. Rada et al also reported acupuncture was associated with minor adverse effects such as slight bleeding or bruising at the needle site, although the RCTs by Bokmand et al (2013)25, Liljegren et al (2012) 30 and Walker et al (2010)35 reported no major adverse events in relation to acupuncture. Mann et al (2012) also reported no major adverse events in relation to CBT.29 The CEPO/L’Espérance (2013)5 systematic review also reported mild gastrointestinal effects with phytoestrogens. Evidence summary: Adverse events Adverse events were poorly and inconsistently reported by the Primary Evidence Base; therefore the present systematic review has presented data from the Therapeutic Goods Administration regarding safety of pharmaceuticals commonly used by women who have had breast cancer, including the pharmaceuticals assessed by the Primary Evidence Base. Key side effects for antidepressants, which are the largest group of non-hormonal interventions assessed in this systematic review, include nausea, insomnia and gastrointestinal effects. For the anticonvulsants (gabapentin and pregabalin), key side effects are dizziness and drowsiness. In addition, complementary medicines and therapies may also have adverse effects, such as bleeding and bruising with acupuncture and gastrointestinal effects with phytoestrogens. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 142 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 Generic name (brand names) Indications Contraindications Common side effects Drug interactions Breast cancer Pregnancy or lactation Hot flushes Headache Nausea Rash Weakness Joint stiffness/arthritis Drugs metabolised by cytochrome P450 1A2, 2C8/9, 3A4 Tamoxifen Nicotine dependence Seizure disorders CNS tumour Abrupt withdrawal from benzodiazepines or alcohol Bulimia or anorexia nervosa Monoamine oxidase inhibitors Insomnia Headache Dry mouth Gastrointestinal disturbance May interact with drugs known to affect the CYP2B6 isoenzyme Drugs which require activation by CYP2D6 (e.g. tamoxifen) may have reduced efficacy Sweating Drowsiness Dry mouth Nausea Drugs that prolong the QT interval Selegiline Pimozide Serotonergic drugs Dizziness Sedation Orthostatic hypotension Dry mouth Antihypertensive agents Nonsteroidal anti-inflammatory drugs can reduce the therapeutic effect of clonidine Tricyclic antidepressants or -receptor blocking effects Anastrozole Arimidex Anastrol Anzole Arianna Bupropion Clorprax Prexaton Zyban Citalopram Celapram Celica Ciazil Cipramil Talam Major depression Hypertension Migraine prophylaxis Menopausal flushing Clonidine Catapres Monoamine oxidase inhibitors Linezolid Pimozide Congenital long QT syndrome Bradyarrhythmia Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 143 Precautions/Comments Bupropion is associated with a dose-related risk of seizures, therefore the recommended dose must not be exceeded Care should be taken with beta-blockers, antiarrhythmics, antidepressants, and antipsychotics Clinical worsening and suicide risk associated with psychiatric disorders Special care should be exercised in treating patients who have a history of depression or who have advanced cerebrovascular disease Generic name (brand names) Indications Contraindications Common side effects Drug interactions Precautions/Comments Major depression Monoamine oxidase inhibitors Insomnia Nausea Dry Mouth Constipation Fatigue Dizziness Headache Monoamine oxidase inhibitors Caution advised for CNSactive drugs Other agents that affect the serotonergic neurotransmitter system (including triptans, SSRIs, other SNRIs etc.) Clinical worsening and suicide risk associated with psychiatric disorders The development of syndromes like serotonin syndrome (SS) or Neuroleptic Malignant Syndrome (NMS) may occur Major depression Social anxiety disorder General anxiety disorder Obsessive compulsive disorder Hypersensitivity to citalopram, Escitalopram or any of the excipients Monoamine oxidase inhibitors Pimozide Nausea Headache Insomnia Diarrhoea Monoamine oxidase inhibitors serotonergic agents Pimozide Clinical worsening and suicide risk associated with psychiatric disorders Oestrogen receptorpositive breast cancer Pregnancy or lactation Hot flushes, Sweating Fatigue, Insomnia Nausea, Headache Serum alkaline phosphatase increase and lymphocyte decrease No formal drug interaction studies have been carried out Should not be co-administered with oestrogen-containing products as these would negate its pharmacological action Desvenlafaxine Pristiq Escitalopram Cilopam-S Escilupin Escital Escitalup Escicor Esipram Esitalo Lexam Lexapro Loxalate Exemestane Aromasin Exaccord Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 144 Generic name (brand names) Fluoxetine Prozac Lovan Zactin Gabapentin Gantin Gabacor Gabaran Neurontin Nupentin Letrozole Femara Femolet Fera Gynotril Letrosyn Megestrol acetate Megace Indications Contraindications Common side effects Drug interactions Major depression Obsessive compulsive disorder Premenstrual dysphoric disorder Monoamine oxidase inhibitors Should not be used in combination with Pimozide Insomnia Anxiety and nervousness Tryptophan, Warfarin, Pimozide, Serotonergic drugs Drugs metabolised by cytochrome P450 3A4/2D6 Highly protein bound drugs Tamoxifen may have reduced efficacy Epilepsy Neuropathic pain Hypersensitivity to gabapentin Fatigue Drowsiness Dizziness Ataxia Cimetidine Antacids may reduce gabapentin bioavailability Hormone receptor positive breast cancer in postmenopausal women Premenopausal endocrine status Pregnancy Lactation High cholesterol Hot flushes Increased sweating Joint pain Fatigue There is minimal data on the interaction between Letrozole and other drugs. Metabolism of Letrozole may be influenced by drugs known to affect the CYP3A4 and CYP2A6 enzymes. Palliative treatment of recurrent inoperable or metastatic carcinoma of the breast As a diagnostic test for pregnancy Weight gain No information is available regarding interactions with food, alcohol or other drugs Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 145 Precautions/Comments Clinical worsening and suicide risk associated with psychiatric disorders Antiepileptic drugs, including gabapentin, increase the risk of suicidal thoughts or behaviours in patients taking these drugs for any indication Use with caution in patients with a history of thromboembolic disease or diabetes mellitus Generic name (brand names) Paroxetine Aropax Extine Paxtine Roxet Roxtine Indications Contraindications Common side effects Major depression Obsessive compulsive disorder Panic disorder Social anxiety disorder Monoamine oxidase inhibitors Should not be used in combination with Pimozide or Thioridazine None occurring with an incidence of at least 10% Epilepsy Neuropathic pain Galactose intolerance Lapp lactase deficiency Glucose-galactose malabsorption Major depression Social anxiety disorder Premenstrual dysphoric disorder Obsessive compulsive disorder in children Monoamine oxidase inhibitors Pimozide Breast cancer Pregnancy Pregabalin Lyrica Sertraline Elva Sertra Sertracor Setrona Tralen Traxor Xydep Zoloft Tamoxifen Genox Nolvadex Tamosin Tamoxen Drug interactions Precautions/Comments Medicines that interfere with haemostasis (NSAIDs, aspirin, warfarin etc.) Clinical worsening and suicide risk associated with psychiatric disorders Drugs affecting hepatic metabolism Drugs metabolised by cytochrome P450 3A4/2D6 Serotonergic drugs Tamoxifen may have reduced efficacy Dizziness and drowsiness Fatigue Tremor Nausea Insomnia Drowsiness Hot flushes Nausea and vomiting Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Pregabalin undergoes negligible metabolism in humans and is unlikely to produce pharmacokinetic interactions. Pimozide Drugs that prolong the QT interval Serotonergic drugs Medicines that interfere with haemostasis Drugs highly bound to plasma proteins Drugs metabolised by CYP enzymes Coumarin type anticoagulants Cytotoxic agents Rifampicin CYP2D6 inhibitors Fluoxetine and Paroxetine 146 Antiepileptic drugs, including gabapentin, increase the risk of suicidal thoughts or behaviours in patients taking these drugs for any indication The development of syndromes like serotonin syndrome (SS) or Neuroleptic Malignant Syndrome (NMS) has been reported An increased incidence of endometrial changes including hyperplasia, polyps and cancer and uterine sarcoma (mostly malignant mixed Mullerian tumours) has been reported Generic name (brand names) Testosterone AndroForte 5 Andoderm Axiron Reandron Sustanon 250 Testogel Indications Contraindications Common side effects Drug interactions Precautions/Comments Male hypogonadism Male testosterone deficiency Suspected carcinoma of the prostate or breast (in men) Pregnancy and lactation Administration site reactions Insulin Anticoagulants Corticosteroids Oxyphenbutazone Cyclosporin Androgens may accelerate the progression of sub-clinical prostate cancer and benign prostatic hyperplasia Menopause symptoms Bone mineral density loss Known, suspected or history of breast cancer Estrogen-dependent malignant tumours Pregnancy and lactation Venous thromboembolism, thrombophilic disorders, arterial thromboembolic disease Liver disease Porphyria None occurring with an incidence of at least 10% May enhance the effect of anticoagulants CYP3A4 substrates CYP3A4 inducing compounds St John’s Wort Climacteric symptoms Pregnancy and lactation Known, suspected or history of breast cancer None occurring with an incidence of at least 10% CYP3A4 inducers or inhibitors St John’s Wort Antihypertensive agents Tibolone Livial Xyvion Oestrogen-dependent neoplasia Vaginal oestrogen Premarin Abnormal genital bleeding Venous thromboembolism, Arterial thromboembolic disease, Severe uncontrolled hypertension Liver dysfunction Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 147 Tibolone increases the risk of ischaemic stroke from the first year of treatment Increases the risk of stroke The use of unopposed oestrogens in women with an intact uterus has been associated with an increased risk of endometrial cancer Generic name (brand names) Venlafaxine Altven Efexor-XR Elaxine SR Enlafax XR Indications Contraindications Common side effects Drug interactions Major depression General anxiety disorder Social anxiety disorder Panic disorder Monoamine oxidase inhibitors Headache, Nausea Insomnia, Drowsiness Dizziness, Weakness Constipation Sweating Nervousness Drugs that prolong the QT interval Monoamine oxidase inhibitors Other agents that affect the serotonergic neurotransmitter system (including triptans, SSRIs, other SNRIs etc.) St John’s Wort Headache CNS depressants Imipramine Hepatic enzyme inhibitors and inducers Insomnia Zolpidem Dormizol Somidem Stildem Stilnox Zolpibell Sleep apnoea Myasthenia gravis Severe hepatic insufficiency Severe pulmonary insufficiency Children under 18 years of age *Common side effects defined as occurring with an incidence of at least 10% Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 148 Precautions/Comments Clinical worsening and suicide risk associated with psychiatric disorders The development of a potentially lifethreatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reaction may occur Continuous long-term use of Zolpidem is not recommended and should not exceed four weeks 3.9 Ongoing trials A search for ongoing trials was conducted in July 2014 to identify any additional studies which addressed the inclusion criteria. The search included RCTs only and excluded any completed trials. Eight trials were identified. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 149 Table 18. Ongoing trials as of July 2014 Trial name Study design Participants Intervention Control Location NCT01908270, Germany Completion Outcomes measured Status Interventional, Randomised, SingleBlind trial http://clinicaltrials. gov/show/NCT019 08270 Women diagnosed with breast cancer (Stage I-III); completed surgical therapy, adjuvant radiotherapy and chemotherapy; and have a score of 5 or greater on the Menopausal Rating Scale Yoga Usual care This study has recently been completed Menopausal symptoms The recruitment status of this study is unknown because the information has not been verified recently Not provided Menopause Rating Scale 12 weeks, weekly 90minute intervention Yoga postures, breathing, relaxation, and meditation Patients continue usual care by their practitioner Women diagnosed with breast cancer (stage I or II); completed surgery therapy; postmenopausal; experiencing vasomotor symptoms Menopause hormone therapy No Menopause hormone therapy N=2,800 – 3,000 Drug: conjugated estrogens Women diagnosed with breast cancer; completed treatment (exception of endocrine therapy); menopausal symptoms Internet-based cognitive behavioural therapy Minimal intervention control group This study is currently recruiting participants Sexuality problems Women diagnosed with breast cancer; endocrine therapy; climacteric symptoms Acupuncture Self-care N=210 Chinese traditional psychological The recruitment status of this study is unknown because the Greene climacteric scale between the 5th and 6th session of acupuncture at 14 weeks after N=40 NCT00079248, UK Interventional, Randomised Clinical Trial http://www.clinic altrials.gov/ct2/sh ow/NCT00079248? term=breast+canc er+%2B+menopau sal+symptoms&ra nk=4 NCT02091765, Netherlands http://www.clinic altrials.gov/ct2/sh ow/NCT02091765? term=breast+canc er+%2B+menopau sal+symptoms&ra nk=16 NCT01275807, Italy http://www.clinic altrials.gov/ct2/sh Interventional, Phase 3, Prospective, Randomized, one intervention group, study Biological: therapeutic progesterone Offered advice on non-hormonal Menopause hormone therapy alternatives Intimacy problems N=160 Interventional, Phase 4 Randomized, Open, Controlled Study Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 150 Trial name Study design Participants Location ow/NCT01275807? term=breast+canc er+%2B+menopau sal+symptoms&ra nk=52 Intervention Control Completion Outcomes measured medicine: 10 acupuncture sessions support, physical exercise, diet, selfcare groups Status information has not been verified recently randomization and at 3 and at 6 month after randomization for both arms Greene's score as measure for severity of menopausal symptoms Change in the number of hot flushes NCT01900418, US Interventional, Randomised, Single Blind Study http://www.clinic altrials.gov/ct2/sh ow/NCT01900418? term=breast+canc er+%2B+menopau sal+symptoms&ra nk=83 Women diagnosed with breast cancer (stage I-III); endocrine therapy; mild joint pain/symptoms Active Comparator: Walking - Walk with Ease No Intervention: Wait list control Wait list control receiving the active intervention 6 weeks later. N=80 This study is currently recruiting participants Self-reported walking Self-reported fatigue Self-reported joint stiffness Pain Lower extremity pain and function Quality of life Beliefs about engaging in exercise Self-efficacy to manage joint pain Engagement in Physical Activity Helplessness Adverse event Feasibility Tolerability NCT00156416, US http://clinicaltrials. gov/show/NCT001 56416 Interventional, randomised, feasibility, single blind, pilot, Study Women diagnosed with breast cancer (stage I or II) and amenorrhea secondary to breast cancer treatment; menopausal symptoms: hot flushes Mindfulness Meditation 8 meditation sessions N=60 (estimated) Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Attention control group: offered meditation training after completion of the intervention and follow up phases 151 The recruitment status of this study is unknown because the information has not been verified recently Sleep Concurrent validity of three hot flush measures Trial name Study design Participants Intervention Control Location NCT01246427, France Completion Outcomes measured Status Interventional, randomised, doubleblind study http://clinicaltrials. gov/show/NCT012 46427 Women diagnosed with histologically proven nonmetastatic breast cancer; receiving adjuvant hormonal therapy for at least 1 month; hot flushes. N=138 (estimated) Homeopathic Drug: BRN01 2 tablets every morning and every evening during 8 to 10 weeks. Each patient will receive 1 set of 5 treatment boxes (60 tablets/box) Placebo 2 tablets every morning and every evening during 8 to 10 weeks. Each patient will receive 1 set of 5 treatment boxes (60 tablets/box) This study is ongoing, but not recruiting participants Evaluation of BRN01 efficacy in reducing hot flash score after 4 weeks of treatment Evaluation of BRN01 efficacy in reducing the hot flash score after 8 weeks of treatment Evaluation of the mean daily intensity and frequency of hot flushes during the run-in period and on the 4th and 8th weeks of treatment in both arms Evaluation of quality of life in both arms Evaluation of patient satisfaction with the treatment and with the management of hot flushes Evaluation of treatment tolerance Evaluation of patient compliance NCT00497458, Australia http://clinicaltrials. gov/ct2/show/rec ord/NCT00497458 Interventional, phase 2, randomised, double blind study Women diagnosed with breast cancer; undergone a total mastectomy, a lumpectomy or a quadrantectomy for primary breast cancer; +/-chemo, +/radiotherapy; developed arthralgia and associated joint symptoms; have commenced anastrozole therapy within the previous 6 months; postmenopausal whether induced by surgery, radiotherapy, or by being Arimidex plus testosterone Arimidex plus placebo Arimidex 1mg plus testosterone 40 or 80 mg once a day Arimidex 1 mg plus placebo Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review The recruitment status of this study is unknown because the information has not been verified recently Reduces arthralgia and associated joint symptoms as indicated by the change in hand or large joint pain from baseline to 3 months using a 100mm visual analogue scale for pain Has acceptable safety and tolerability profile with particular reference to androgenic adverse events including acne, hirsutism, and alopecia 152 Trial name Study design Participants Intervention Control Location Completion Outcomes measured Status naturally amenorrhoeic Impacts the bone resorption marker CTx N=90 (estimated) Impacts serum HDL, LDL Trg, total Chol Impacts serum levels of oestrogens, androgens and sex hormone binding globulin levels Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 153 3.10 International guidelines and recommendations The following international guidelines that included recommendations relevant to the research questions were identified from guideline websites: CG80 Early and locally advanced breast cancer: Diagnosis and treatment (NICE) 119 Management of Early Breast Cancer (New Zealand Guidelines Group, 2009) 120 Scientific support of the College of Oncology: update of the national guidelines on breast cancer (Cardoso et al, 2012)121 Management of Gynecologic Issues in Women With Breast Cancer (The American College of Obstetricians and Gynecologists, 2012)122 Hormone Therapy and Breast Cancer (The Society of Obstetricians and Gynaecologists of Canada, 2009)123 American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Menopause (Goodman et al 2011)124 AGO Recommendations for Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer. Update 2011 (Thomssen et al 2011)125 EMAS clinical guide: Low-dose vaginal estrogens for postmenopausal vaginal atrophy (Rees et al 2012)126 Adolescent and Young Adult Oncology (Coccia et al 2012, Journal of the National Comprehensive Cancer Network).127 Clinical practice guidelines for the care and treatment of breast cancer: 14. The role of hormone replacement therapy in women with a previous diagnosis of breast cancer. (Pritchard et al 2002)128 Supportive care after curative treatment for breast cancer (survivorship care): Resource allocations in low- and middle-income countries. A Breast Health Global Initiative 2013 consensus statement. (Ganz et al 2013)129 Key relevant recommendations are reported below. See Appendix H: Summary of key points from international guidelines for detailed summaries of guidelines’ recommendations. Clinical practice guidelines NICE clinical guideline 80: Early and locally advanced breast cancer: Diagnosis and treatment (National Institute for Health and Care Excellence, 2009) 119 NICE published the above clinical guideline in the UK. For managing menopausal symptoms in women with breast cancer, they recommend: 1.13.8 Discontinue hormone replacement therapy (HRT) in women who are diagnosed with breast cancer. 1.13.9 Do not offer HRT (including oestrogen/progestogen combination) routinely to women with menopausal symptoms and a history of breast cancer. HRT may, in exceptional cases, be offered to women with severe menopausal symptoms and with whom the associated risks have been discussed. 1.13.10 Offer information and counselling for all women about the possibility of early menopause and menopausal symptoms associated with breast cancer treatment. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 154 1.13.11 Tibolone or progestogens are not recommended for women with menopausal symptoms who have breast cancer. 1.13.12 the selective serotonin re-uptake inhibitor antidepressants paroxetine and fluoxetine may be offered to women with breast cancer for relieving menopausal symptoms, particularly hot flushes, but not to those taking tamoxifen. 1.13.13 Clonidine, venlafaxine and gabapentin should only be offered to treat hot flushes in women with breast cancer after they have been fully informed of the significant side effects. 1.13.14 Soy (isoflavone), red clover, black cohosh, vitamin E and magnetic devices are not recommended for the treatment of menopausal symptoms in women with breast cancer.” (pp20-21). In addition: 1.2.3 All patients with breast cancer should be offered prompt access to specialist psychological support, and, where appropriate, psychiatric services.” (p11) Specific psychological concerns are not detailed and the psychological issues are not necessarily due to menopausal symptoms. Scientific support of the College of Oncology: update of the national guidelines on breast cancer. KCE reports 143C (Cardoso et al, 2012)121 This update was published in Belgium and states: “Menopausal hormonal replacement therapy is contraindicated in women with breast cancer (level of evidence1B)”. “Psychological support should be available to all patients diagnosed with breast cancer (level of evidence1A)”. The update did not state whether the psychological support was specifically in relation to menopausal symptoms. Management of Early Breast Cancer (New Zealand Guidelines Group, 2009) 120 The New Zealand guidelines state: “Cognitive behavioural therapy should be available for women with early breast cancer experiencing an anxiety disorder or depression (level of evidence A)” “Psychosocial support should be available to all women with early breast cancer (level of evidence A)”. This support is not directed specifically at psychosocial issues related to menopausal symptoms. Management of Gynecologic Issues in Women With Breast Cancer (The American College of Obstetricians and Gynecologists, 2012)122 This Practice Bulletin from the US noted that the incidence of chemotherapy-induced amenorrhea was 53 to 89% and that the hormone profile of a premenopausal woman who has had surgically induced menopause (for example, from bilateral salphingooophorectomy and/or hysterectomy) is similar to that of a postmenopausal woman. Recommendations for the management of menopausal symptoms in women who have received treatment for breast cancer were not restricted to women with treatment-induced Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 155 menopause. The Practice Bulletin made the following recommendations that are related to the Research Question: “SSRIs and SNRIs have both been shown to be safe and to reduce the severity of hot flushes in patients with breast cancer, although caution must be used when using these agents in conjunction with tamoxifen. Gabapentin and clonidine are other options for management of hot flushes (Level A: based on good and consistent scientific evidence). Non-hormonal methods should be considered first-line treatment for vaginal atrophy in women with a history of hormone-sensitive breast cancer (Level C: based primarily on consensus and expert opinion).” The Bulletin also discussed lifestyle changes to manage bone loss and non-hormonal treatments for vasomotor symptoms and vaginal atrophy. Hormone Therapy and Breast Cancer (The Society of Obstetricians and Gynaecologists of Canada, 2009)123 This Guideline from Canada contains a section on menopausal symptoms in breast cancer survivors, but not specifically on women with treatment-induced menopause or menopausal symptoms. It highlights that 30,000 premenopausal women in North America who are diagnosed with breast cancer experience chemotherapy-induced ovarian failure. Also, over 2.5 million breast cancer survivors in North America have an unsatisfactory quality of life “because alternative [non-hormonal] approaches to relieving vasomotor symptoms remain largely unsatisfactory” (pS23) The Society of Obstetricians and Gynaecologists of Canada recommends: “Health care providers should clearly discuss the uncertainty of risks associated with HT [hormone replacement therapy] after a diagnosis of breast cancer in women seeking treatment for distressing symptoms. (IB)” (pS24). American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Menopause (Goodman et al 2011)124 This set of guidelines was developed in the US and is not specifically focused on women with breast cancer, but does make recommendations regarding managing menopause in women at risk of or with a history of breast cancer: “The FDA has recommended that MHT (menopause hormone therapy) should generally not be prescribed to women with ...Current, past or suspected breast cancer” (p6). “For women who cannot or do not wish to use estrogen for control of severe vasomotor symptoms, lifestyle changes should be implemented first. If pharmacologic therapy is needed, the most effective non-oestrogen class of agents is the antidepressants. Venlafaxine is probably the most beneficial in this class. If antidepressants are not tolerated or cannot be used, then clonidine or megestrol may be considered, although side effects may occur more frequently with these agents. Gabapentin can be considered as a promising new therapeutic option, although both long-term efficacy and safety remain to be substantiated. Data on most nutritional supplements are limited by the lack of placebo-controlled trials and by existing trials that have generally shown no differences in results between such therapy and placebo. Because soy may have some estrogen agonist properties, long-term safety issues, especially in patients with breast cancer, remain of concern for high-dose therapy. A healthful diet that incorporates some soy protein seems reasonable (Grade C)” (p20). Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 156 AGO Recommendations for Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer. Update 2011 (Thomssen et al 2011).125 This set of guidelines is from Germany. “A major issue is the use of hormonal therapy (HRT) for postmenopausal symptoms. Available data suggests that the use of HRT should be avoided [level evidence 2aB, Arbeitsgemeinschaft Gynäkologische Onkologie ++]” (p312). EMAS clinical guide: Low-dose vaginal estrogens for postmenopausal vaginal atrophy (Rees et al 2012)126 The set of UK guidelines focuses on the use of topical oestrogen in women with menopause in general, not specifically women with breast cancer. It includes a section on topical estrogens after breast cancer and states: “There are safety concerns about topical estrogens in postmenopausal women taking adjuvant aromatase inhibitors because of systemic absorption and non-hormonal lubricants and moisturisers should be considered first line” (p173). Adolescent and Young Adult Oncology (Coccia et al 2012, Journal of the National Comprehensive Cancer Network. This set of guidelines from the US focuses on young people with cancer. In relation to breast cancer, they state: “Fertility is a major concern for young women receiving chemotherapy for breast cancer and HL. Among young women treated with adjuvant chemotherapy for breast cancer, the risk for chemotherapy-related amenorrhea and premature menopause is significantly higher for those with newly diagnosed breast cancer treated with chemotherapy who are older than 35 years. In a cohort study of 518 female survivors of HL diagnosed between 14 and 40 years of age, those who were older (22–39 years of age) at first treatment had a higher risk for developing premature menopause after treatment compared with younger patients (14– 21 years). Similarly, the risk of developing premature ovarian failure is also higher among young women receiving chemotherapy and RT for HL, irrespective of their age at treatment (38% for those diagnosed between 30 and 40 years of age; 37% for those diagnosed between 9 and 29 years of age)” (p1134). Clinical practice guidelines for the care and treatment of breast cancer: 14. the role of hormone replacement therapy in women with a previous diagnosis of breast cancer. (Pritchard et al 2002)128 Relevant recommendations are: “Routine use of HRT (either estrogen alone or estrogen plus progesterone) is not recommended for women who have had breast cancer” (p1018) “Postmenopausal women with a previous diagnosis of breast cancer who request HRT should be encouraged to consider alternatives to HRT. If menopausal symptoms are particularly troublesome and do not respond to alternative approaches, a wellinformed woman may choose to use HRT to control these symptoms after discussing the risks with her physician. In these circumstances, both the dose and the duration of treatment should be minimized” (p1019). Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 157 Supportive care after curative treatment for breast cancer (survivorship care): Resource allocations in low- and middle-income countries. A Breast Health Global Initiative 2013 consensus statement. (Ganz et al 2013)130 This consensus statement has a multinational focus on public health policy recommendations for breast cancer survivors in low- and middle-income countries. The statement makes recommendations on resource allocation rather than clinical treatment recommendations for the individual patient. Comprehensive recommendations are made in terms of health professional education (women’s reproductive health through to psychosocial screening methods), patient and family education (awareness of the effects of treatment and lifestyle modification issues through to adherence to endocrine therapy and sexual health issues), health professionals’ awareness and management of patients’ psychosocial aspects of survivorship, health professionals’ and patient and family education regarding management of women’s reproductive health issues and monitoring of cancer recurrence and adherence to therapies. For more detailed information from this consensus statement, refer to Appendix H: Summary of key points from international guidelines. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 158 4 Discussion In an Australian study by Hickey et al (2010)3, vasomotor symptoms, sleeping difficulties, loss of interest in sex and fatigue were the most common and severe menopausal symptoms reported by women with breast cancer. The treatment of menopausal symptoms in women who have previously been treated for breast cancer is confounded in that systemic hormone replacement therapies are generally contraindicated in this group14 and published clinical practice guidelines and position statements mostly state they are contraindicated or advise caution if administering them. Further, if vasomotor symptoms have been induced by breast cancer treatments, they are often more severe than in women experiencing “natural” menopause.14, 21 This systematic review was conducted to evaluate evidence for treating menopausal symptoms in women who have received treatment for breast cancer. It spans level I and level II evidence from studies published between January 2001 and January 2014 and includes 45 studies (40 RCT cohorts with five sub-studies and updated analyses) which comprise this systematic review’s Primary Evidence Base. Twenty-six of these studies were included in five previously published systematic reviews4-8 published between January 2001 and January 2014, with the other 19 studies (Recent RCTs) mostly published after the systematic reviews (Table 1). The outcomes investigated were vasomotor symptoms (hot flushes and night sweats), sleep disturbances, vulvovaginal symptoms, psychological wellbeing, global quality of life and breast cancer recurrence. Adverse events were also noted. Vasomotor symptoms were the main focus of the evidence identified, with 39 studies in the Primary Evidence Base (level II evidence) evaluating vasomotor symptoms as a primary outcome. Level I evidence was only available for vasomotor symptoms. The Primary Evidence Base assessed other menopausal symptoms (sleep disturbance, vulvovaginal symptoms, psychological wellbeing and global quality of life) mostly as secondary outcomes. However, two RCTs assessed breast cancer recurrence as their primary outcome. The Primary Evidence Base assessed a large range of interventions for vasomotor symptoms: antidepressants (venlafaxine, sertraline, fluoxetine, bupropion), anticonvulsants (gabapentin), antihypertensives (clonidine), zolpidem, menopause hormone therapies, CBT, physical exercise, relaxation, acupuncture and electro-acupuncture, yoga, herbal medicines (black cohosh, phytoestrogens and isoflavones), homeopathy and magnetic therapy. Vasomotor symptoms were the primary outcome for most of these studies and the quality of reporting for this outcome was high overall. Of all the interventions, venlafaxine was the better studied pharmaceutical treatment, with seven RCTs. 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, CBT, CBT combined with exercise, purposed design hypnotherapy and yoga; limited evidence for acupuncture and short-term relaxation therapy; and evidence for no effect, or no consistent effect, of bupropion, fluoxetine, sertraline, zolpidem augmentation of SSRIs or SNRIs, black cohosh, homeopathy, phytoestrogens, or magnetic therapy. It should be noted that tibolone is associated with increased risk of breast cancer recurrence. This systematic review defines sleep disturbance as including most aspects of poor sleep quality but excludes fatigue and tiredness. There is no level I evidence examining interventions for sleep disturbances associated with menopausal symptoms in women after breast cancer. The Primary Evidence Base contains 20 RCTs (level II evidence) that reported on sleep disturbance, of which only two reported on it as a primary outcome and the rest as a secondary outcome. There is limited 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 evidence from one study each for improved sleep for the interventions: paroxetine, zolpidem (in women taking an SSRI or SNRI), tibolone, CBT, purposed design hypnotherapy, yoga and acupuncture, compared to placebo. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 159 However, these studies were of fair or poor quality in terms of reporting sleep disturbance as an outcome measure (sleep disturbance was a secondary outcome in most of these studies) 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 issues are common in women who have received treatment for breast cancer. An Australian study of 1,011 breast cancer patients131 reported that overall, 70% of women experienced vulvovaginal symptoms problems and these were significantly more common in women who had become postmenopausal since breast cancer diagnosis, were experiencing vasomotor symptoms or had used aromatase inhibitors. In the present systematic review, 13 studies (from 12 RCT cohorts) in the Primary Evidence Base assessed vulvovaginal symptoms, but only one assessed vulvovaginal symptoms as a primary outcome.39 The other studies assessed vulvovaginal symptoms as a secondary outcome or in terms of adverse effects of the treatment. The quality of assessing and reporting of vulvovaginal symptoms was poor and results were also confounded in that study samples did not necessarily include sufficient numbers of sexually active women. There is insufficient evidence (for antidepressants) or limited evidence (for vaginal pH-balanced gel, CBT and CBT combined with exercise) on the effects of the interventions studied, in the treatment of vulvovaginal symptoms associated with menopausal symptoms in women who have received breast cancer treatment. Tibolone improves vulvovaginal symptoms, but increases the risk of breast recurrence. There is a need for more studies of high methodological quality. Psychosocial issues are of great importance in women with a history of breast cancer, although it is not possible to determine whether psychological issues were due to menopausal symptoms alone or due to breast cancer itself and its associated stressors. Howard-Anderson et al systematic review (2012)132 concluded that the mental domains of quality of life were most severely affected in younger women with breast cancer (women who were 50 years old or younger), with anxiety over the future and fear of cancer recurring being key concerns for this group. This review did not specifically exclude women who were not menopausal or postmenopausal, nor exclude women who not experiencing menopausal symptoms. Depressive symptoms were more common, especially in the youngest women, compared to women of similar ages without cancer.132 This systematic review includes depression, anxiety, mood, emotional wellbeing and mental health in its definition of psychological wellbeing. There was no level I evidence to support the effect of treatments for any of these outcomes but 24 RCTs (level II evidence) measured depression, anxiety, mood, emotional wellbeing and mental health as secondary outcomes, with only one reporting anxiety and depression as primary outcomes.32 As a result, quality of assessing and reporting of these outcomes was poor. Overall, there is limited evidence on the effects of the interventions studied on psychological wellbeing associated with menopausal symptoms in women after breast cancer. However, these studies also indicated that the interventions assessed do not induce psychopathology or worsen current psychological status. Also, for some studies the participants’ levels of depression or anxiety were in the normal range at baseline and remained so throughout the trial, or the study design had excluded depressed participants. Another conundrum is that the dosages and duration of use for drugs interventions in these studies were primarily for the control of vasomotor symptoms and thus – in the case of the antidepressants which should reduce depressive symptoms – the dosages were below what was needed to manage depression and/or were not used for long enough for a clinical effect on depression to occur. Overall, if these treatments at the dosages assessed by the Primary Evidence Base are effective in controlling vasomotor symptoms, while they may not improve psychological wellbeing, there was also no evidence to support them being contraindicated in terms of psychological wellbeing. This systematic review defines global quality of life as the overall wellbeing of an individual as measured by an overall scale. It does not include quality of life outcomes that have only been measured by specific subscales of an overall quality of life measure. Eleven RCTs in the Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 160 Primary Evidence Base measured global quality of life as a secondary outcome but the quality of reporting was poor. For example, post-treatment scores were not reported by two of the RCTs and three did not clearly state how they measured global quality of life or used only one item from a validated measure. Further, there was great heterogeneity in the measures used to assess global quality of life (Table 13). 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 studied significantly reduce global quality of life. Similarly, there is limited evidence on the effects of the interventions studied to improve mental health associated with menopausal symptoms in women after breast cancer treatment, and there is no evidence that treatment has an adverse effect on mental health. There is a need for more studies of higher methodological quality. Menopause hormone treatment is an effective and standard treatment for vasomotor symptoms, but one of the main concerns regarding their use in women previously treated for breast cancer is the potential for the recurrence of breast cancer. This has led to the interest in non-hormonal therapies and interventions for menopausal symptoms for this population of women. There was no level I evidence from the systematic reviews that focused on the recurrence of breast cancer. While menopause hormone therapy is effective in reducing vasomotor symptoms in women who have received breast cancer treatment, there is evidence for increased risk of breast cancer recurrence. Adverse events were poorly and inconsistently reported by the Primary Evidence Base and so this data was not extracted. This systematic review presents the drug safety profile 66 of pharmaceuticals commonly used by women with a history of breast cancer, including those pharmaceuticals assessed by the Primary Evidence Base (Table 17). Antidepressants were the largest class of drugs assessed by the Primary Evidence base and their main side effects were nausea, insomnia and gastrointestinal effects. For the anticonvulsants (gabapentin and pregabalin), key side effects are dizziness and drowsiness. Aside from pharmaceuticals, complementary medicines and therapies may also have adverse effects, such as bleeding and bruising in acupuncture and gastrointestinal side effects with phytoestrogens. There are limitations within the Primary Evidence Base of the present systematic review. Some interventions were searched for, but no RCTs in the breast cancer population were identified (see section 3.1.4 Interventions for which no relevant studies were identified); although they may have been studied through single arm studies, or were studied in the general population beyond only women with a history of breast cancer. Vasomotor symptoms were the primary menopausal symptom investigated by the majority of the studies in the Primary Evidence Base, with the other symptoms assessed as secondary outcomes. Consequently, studies were powered for vasomotor symptoms and used drug dosages chosen for efficacy in treating vasomotor symptoms and not for the secondary outcomes. Thus, studies were insufficiently powered to detect a difference for the secondary outcomes and drug dosages and durations of treatment may not have been sufficient to elicit a significant effect for outcomes other than vasomotor symptoms. Some interventions were also only supported by a single RCT within the Primary Evidence Base. Further, statistical differences and clinically meaningful differences are not identical and most studies do not report on whether an intervention produced clinically useful improvements in symptoms. For example, Wyrwich et al (2008) 133 conducted an RCT in a general population of postmenopausal women and reported that a treatment (in this case, desvenlafaxine) was considered satisfactory by women if it reduced moderate to severe hot flushes by an average of 1.64 flushes during the day. Overall, this systematic review captures level II evidence for the treatment of vasomotor symptoms (hot flushes and night sweats) in women previously treated for breast cancer. There has been a particular focus in the evidence for alternatives to menopause hormone therapies, due to concerns regarding breast cancer recurrence. There is level II evidence for the efficacy of: paroxetine, venlafaxine, clonidine, gabapentin, tibolone, CBT, CBT combined with exercise, purposed design hypnotherapy and yoga; and limited evidence for acupuncture and short-term relaxation therapy; but their clinical efficacy and impact needs Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 161 to be considered. However, other menopausal symptoms (sleep disturbances, vulvovaginal symptoms, psychological wellbeing and global quality of life) were mostly assessed as secondary outcomes. The quality and consistency of their assessment and reporting has been poor. Further studies with larger study samples and greater methodological rigour are needed to assess treatments for vulvovaginal symptoms, psychological wellbeing and global quality of life. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 162 5 Appendix A: Literature databases searched Database Results / retrievals PubMed 2,313 Medline (OVID) 1,826 Embase (OVID) 1,179 PsycInfo (OVID) 306 Cochrane 8 CINAHL 381 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 163 6 Appendix B: Search strategy Breast cancer Breast cancer* Breast neoplasm* Breast carcinoma Studies extracted will not be restricted by the therapies for breast cancer the participants may have received, such as endocrine therapy, endocrine treatment, tamoxifen, aromatase inhibitors, GnRH analogues and bilateral salphigo-oophorectomy. However, any therapies reported by studies will be recorded. Menopause symptoms Menopause Fatigue Vaginal dryness Hot flushes Disrupted sleep Vaginal atrophy Hot flushes Sleep disturbance Osteoporosis Night sweats Dyspareunia Osteopenia Vasomotor symptoms Vulvovaginal atrophy Bone mineral density loss Loss of libido Atrophic vaginitis Mood disturbance Psychosocial symptoms Psychosocial Depression Psycholog* Psychosexual Mental* Psychiatr* Distress Mental health Mood disturbance Anxiety Mental stress Quality of life Treatments Oestrogen Homeopathy Hypnosis Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Ayurveda 164 Estrogen Estradiol Estriol Estrone Antidepressant Chinese herbs Cognitive behavioural therapy Aromatherapy Cognitive behavior therapy Hypnotherapy Antihypertensive Black cohosh Psychotherapy Magnetic therapy Venlafaxine Phytoestrogens Paroxetine Biofeedback Hormone replacement therapy Yoga Fluoxetine Breathing exercises (paced respiration) Selective serotonin reuptake inhibitor Relaxation therapy Sertraline Isoflavones Serotonin norepinephrine reuptake inhibitor Vaginal moisturizers/lubricants Counselling Soy Gabapentin Exercise Ergotaminephenobarbitalbelladonna Red clover Clonidine Bisphosphonate Veralipride Cimicifuga racemosa Acupuncture Vitamin D Mirtazapine Tibolone Vitamin E Calcium Trazodone Bioidentical hormone therapy Meditation Physical activity Selective noradrenaline reuptake inhibitor Pregabalin Stellate ganglion block Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 165 7 Appendix C: Inclusion and exclusion criteria and decision algorithms For abstracts where the reviewers disagreed whether to include for full text review, a discussion was held to come to a consensus. Abstracts were rejected if they did not mention breast cancer and menopause, or if they were commentaries, book reviews or from dissertations. Guidelines and position statements were included in the guidelines and recommendations section. Table 19. Algorithm for including-excluding by abstract One reviewer Other reviewer Final decision Include Include Include Include Query Include Include Exclude Reviewer who originally included to double check abstract to determine whether to happy to exclude, if not then include Include Background Include Background Background Background* Background Query Background* Background Exclude Background* Query Query Excel query spreadsheet reviewed to qualify reasons for ‘query’ – if no clear information that paper was of interest to review these were excluded unless they were marked as: - A systematic review - A CPG - Additional Issues - Prominent Australian authors In which case they were included or grouped for further assessment Query Exclude As per Query/Query assessment above Query/Background Exclude Checked for relevance for either Background* or excluded Complete mix of Include, Query, Background, Exclude Include to check full text Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 166 Background papers were sourced if published from 2010/2011 onwards or were particularly relevant to Australian context such as published by prominent Australian authors Papers potentially relevant for the following sections were marked separately and sourced for further assessment: Clinical practice guidelines Ongoing trials Additional issues (i.e. psychosocial issues associated with menopause in younger women) Following discussion with the working group, the following types of articles were excluded: Papers on treatment of cancer-related fatigue in general rather than fatigue caused from induced menopause Papers on treatment of cancer-related anxiety/depression in general rather than caused from menopause/induced menopause (Note: general papers suggesting association between menopause and anxiety/depression were sourced to evaluate relevance for additional issues section.) Papers investigating interventions to improve side effects of radiotherapy (such as fatigue, but with no mention of menopause) Papers reporting the overall effects of physical or psychosocial interventions such as exercise, yoga counselling etc. in breast cancer patients in general (usually quality of life), rather than specifically for menopausal symptoms Papers on the use of dietary/herbal remedies to treat menopausal symptoms, however with no mention of breast cancer patients/treatment Papers reporting the effects of interventions on bone mineral density/osteoporosis in breast cancer patients, with no mention of menopause Papers discussing breast cancer and menopause in general, including mention of use in BC survivors, unless clearly a primary trial or systematic review Papers which contain mixed populations of other cancers as well as breast cancer, unless results are clearly stratified by type of cancer. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 167 8 Appendix D: Flowchart for inclusion-exclusion of articles Figure 6 Inclusion and exclusion of articles 4,157 citations identified through electronic databases From internet web searches, 11 guidelines/position statements 3,135 excluded based on title and abstract (round 1) 156 background 194 citations for full text review 672 abstracts/titles queried and for 2nd review 563 excluded based on title and abstract (round 2) 56 background papers 247 full text articles for review 155 excluded based on full text review 2 “CPGs”, reviews 8 ongoing trials (as of July 2014) 9 other 5 published systematic reviews covering 26 RCTs that met inclusion criteria (and 15 RCTs that were excluded) 15 RCTs, 1 sub-study and 3 updates published after the 5 systematic reviews [7 comparative studies, 29 single arm studies] Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 168 9 Appendix E: Additional RCTs From Updated Search (January 2014 – November 2015) 9.1 Methods The following search strategy was used, with the aim of subsequently informing the development of Recommendations or Practice Points in the Guideline, management of menopausal symptoms in women who have received breast cancer treatment. The key change to the ‘PICO’ (population, intervention, comparator, outcomes) criteria from the original search in the Cancer Australia Systematic Review 134, to the proposed search in the current Literature Review, is the broadening of the patient population: from women experiencing menopausal symptoms after breast cancer, to a more general population of women experiencing menopausal symptoms. Moreover a re-run of the original search was performed to include Level I and II studies that had been published from January 2014 to October 2015 which had not been included in the original search. All other aspects of the PICO criteria were identical to the original search. Inclusion criteria English language. Published from January 2014 to November 2015. Meta-analyses, reviews and systematic reviews of RCTs, were included. No direct restriction was applied regarding age: results available for age ranges, as reported by studies, are included in the results of the systematic review. No restrictions were made regarding symptom types experienced by the participants. All original key treatments or interventions were included in the search. No direct restriction was applied regarding type of cancer treatments received by participants: for studies that report the types of cancer treatments their participants have undergone, this was noted in the results of the systematic review. Population Women who are undergoing or who have completed treatment for breast cancer and who are experiencing one or more menopausal symptoms as defined below. Outcome measures The types of outcomes measured were identical to the original search: improvement/reduction of menopausal symptoms, including; vasomotor symptoms (hot flushes and/or night sweats), sleep disturbances, sexual functioning including vaginal dryness, psychological wellbeing, global quality of life, breast cancer recurrence and adverse events. The Working Group agreed a priori that information related to vasomotor symptoms was of the highest priority in the context of this additional search. Consequently, if evidence was identified for one intervention, vasomotor symptoms, but not for other outcomes, then additional literature searching was not undertaken. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 169 Intervention / Comparator Anti-depressants; bupropion, paroxetine, fluoxetine, venlafaxine Sedatives; zolpidem Anti-hypertensives; clonidine Anti-convulsants; gabapentin Vaginal gels Phytoestrogens Vitamin E Non-pharmaceutical interventions (complementary medicines and therapies): Physical interventions, such as exercise, yoga Psychological interventions, such as cognitive behavioural therapy, hypnotherapy Relaxation therapies Acupuncture Magnetic therapy Black cohosh Homeopathy. Modifications to methodology In consultation with working group members, the systematic literature search was updated to include RCTs not identified in the primary search. These included RCTs from January 2014 to November 2015. The primary search for evidence was restricted to Systematic reviews and Meta-analysis (level I evidence). For all interventions where no Systematic reviews and Meta-analysis were identified in the target population, a broader search was undertaken to include RCTs (level II evidence). Exclusion criteria Articles were excluded if they met any of the following criteria: Dissertations, which therefore were not published in a peer-reviewed journal. Not published in the English language. Published before January 2014. Interventions were not for the purpose of treating menopausal symptoms. Outcomes were not the outcomes described above in the inclusion criteria. Not indexed in PubMed, Medline, Embase, PsycInfo, Cochrane Database or CINAHL. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 170 Literature search Electronic database search The following electronic databases were searched: PubMed Medline (OVID) Embase (OVID) PsycInfo (OVID) Cochrane CINAHL Key terms for conducting the searches were developed with input from the working group members. The databases searches were conducted in January 2014 (Appendix A: Literature databases searched and Appendix B: Search strategy). The searches from PubMed, Medline, PsycInfo, Embase, Cochrane and CINAHL (total of 400 citations) were combined into a single Endnote library and duplicate citations were removed. From these only 17 citations made the inclusion criteria. Inclusion-exclusion of articles Two reviewers independently reviewed the 333 citations. 6. An initial review by title yielded 262 citations for abstract review. 7. Review by abstract resulted in 35 citations for full text review. 8. Review by full text yielded 5 systematic reviews published from 2014 to 2015 and 4 RCTs, in a breast cancer population. Details of inclusion and exclusion criteria and the reviewers’ decision algorithm are presented in Appendix C: Inclusion and exclusion criteria and decision algorithms and Appendix D: Flowchart for inclusion-exclusion of articles. Data extraction Data extraction for each included paper was completed by one reviewer and verified by a second reviewer for accuracy. The data extracted from each paper included study characteristics such as population, interventions, study design and study outcomes, as well as risk of bias assessment. Risk of bias The inherent risk of bias in the study design was assessed using criteria based on NHMRC guidance, for systematic reviews and RCTs.23 For systematic reviews the following items were considered: whether an adequate search strategy and appropriate inclusion criteria were used, Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 171 whether quality assessment was performed whether results were summarised and data pooled appropriately; and whether any heterogeneity was explored. For RCTs the following items were considered: the method of treatment assignment (randomisation method, blinding) and minimisation of selection bias (intention-to-treat analysis, follow-up), whether outcome assessment was standardised, whether baseline characteristics were balanced between groups; and whether the study was adequately powered to detect differences in the outcomes investigated. A reviewer then made a judgement as to whether the risk of bias of a study was high, moderate or low. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 172 9.2 Results The present literature review describes the findings of the additional 4 randomised control trials (RCTs) that reported outcomes of various interventions on menopausal symptoms in a breast cancer population (seeTable 22). Findings from the RCTs by menopausal symptom: vasomotor symptoms sleep disturbance, and sexual function. A summary of each RCT is provided in Table 23 Table 21. Table 20 Key menopausal symptoms reported in the 4 additional RCTs Individual trial reference Intervention Vasomotor symptoms Sleep Vulvovagin Psychol Globa l QOL disturban al ogical ce symptoms Wellbei Adverse events Risk of Bias** ● Moder ate ● Low ● Moder ate ● Low ng Cramer et al 2015135 Yoga and meditation (90min/day for 12 weeks) Goetsch et al 2015* 136 Lidocaine (4% aqueous lidocaine for 3min, twice per week) Mao et al 2015*137 Electroacupuncture (twice per week/2 weeks, once per week/6 weeks) ● ● ● ● ● Gabapentin (300mg/day for 3 days, 900mg/day for a total of 8 weeks) Mathews et al 2014138 Cognitive behavioural therapy for insomnia ( ● ● ● *Goetsch et al 2015 and Mao et al 2015 have published the same studies in different journals (Mao et al 2015; Goetsch et al 2014)136, 139, on this systematic review, we have relied on the latest study data to report on their results. **The risk of bias in the randomised control trials was assessed using the following questions: (1) Was the study design appropriate for the research question? (2)Did the study test a stated hypothesis? Did the study methods address the most important potential source of bias? Was the study adequately powered? (3) Was the process of treatment allocation truly random? Were participants and researchers ‘blinded’ to participants’’ treatment group? (4) Were outcomes assessed objectively? Were the statistical analyses performed correctly? Were all participants’ data analysed in the group to which they were randomly allocated? (5) Were participants followed up for a sufficient length of time and important losses to follow-up reported? Were adverse events reported? Were there any conflicts of interest? Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 173 Table 21 Summary of 4 RCTs (level II) reporting the effects of high priority interventions in women after breast cancer treatment Study characteristics Population Intervention/s (dose) Comparator/s Outcomes of interest Results Yoga (Hatha) and meditation (90min/day for 12 weeks) Usual care Total menopausal symptoms (MRS) Yoga vs Usual care (mean ± SD, 95% CI, p) at week 12 Cramer et al (2015)135; yoga and meditation N = 40 Mean age = 49.2 Duration = 12 weeks Follow-up = 3 months Peri- and postmenopausal women experiencing at least mild menopause symptoms (value of at least 5 points in MRS) FACT-B FACIT-F HADS MRS: 11.6 ± 7.2 vs 18.7 ± 8.0, -5.6 p=0.004ᶧ FACT-B: 113 ± 20.5 vs 102.1 ± 14.8, 12.5 p=0.002ᶧ FACIT-F: 48.8 ± 11.1 vs 37.0 ± 8.7, 6.0 p=0.010ᶧ HADS: Anxiety; 11.4 ± 1.9 vs 11.2 ± 1.8, -0.13 p=0.772 Depression; 8.5 ± 1.5 vs 8.8 ± 2.4, -0.7 p=0.182 Authors’ conclusion: “Yoga combined with meditation can be considered a safe and effective complementary intervention for menopausal symptoms in breast cancer survivors. The effects seem to persist for at least 3 months.” Goetsch et al (2015)136; lidocaine N = 46 Mean age = 55 Peri- and postmenopausal women that complain of moderate or severe 4% aqueous lidocaine (to the vulval vestibule for 3 minutes before vaginal Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Saline control Dyspareunia (numeric rating scale) - pain with intercourse score 174 Blinded phase – 1 month, Study characteristics Population Intervention/s (dose) Duration = 1 month dyspareunia for at least 6 months penetration) Follow-up = 2 months Comparator/s Outcomes of interest Results The Sexual Function Questionnaire (scores in 6 domains of sexual function) Saline and silicone users (71%) noted a 38% reduction in pain: median pain score, 5.3; p<0.007ᶧ The Female Sexual Distress Score-Revised (emotional distress regarding sex) Lidocaine and silicone users (73%) had 87.5% less pain: median pain score, 1.0; p<0.001ᶧ Authors’ conclusion: “Breast cancer survivors with menopausal dyspareunia can have comfortable intercourse after applying liquid lidocaine compresses to the vulvar vestibule before penetration.” Mao et al (2015)137; electro-acupuncture and gabapentin N = 120 Mean age = 52.3 Duration = 8 weeks Peri- and postmenopausal women with at least 2 hot flushes per day Electro-acupuncture ( or gabapentin (900mg/day for 8 weeks) Sham acupuncture or placebo Change in the hot flush composite score (HFCS) EA vs SA vs PP vs GP – mean (SD) Baseline: 15.5 (9.4) vs 13.1 (9.6) vs 15.2 (10.7) vs 13.2 (7.7) Follow-up = at week 12 and 24 Change from baseline at week 8: -7.4 (8.1) vs -5.9 (5.9) vs -3.4 (6.5) vs -5.2 (4.9), p<0.001ᶧ Change from baseline at week 12: -4.4 (6.3) vs -5.0 (6.3) vs -3.5 (6.3) vs -4.0 (7.2), p<0.001ᶧ Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 175 Study characteristics Population Intervention/s (dose) Comparator/s Outcomes of interest Results Change from baseline at week 24: -8.5 (10.3) vs -6.1 (4.5) vs -4.6 (7.8) vs -2.8 (7.2), p<0.001ᶧ Authors’ conclusion: “Acupuncture produced larger placebo and smaller nocebo effects than did pills for the treatment of hot flashes. EA may be more effective than GP, with fewer adverse effects for managing hot flashes among breast cancer survivors; however, these preliminary findings need to be confirmed in larger randomized controlled trials with long-term follow-up.” Mathews et al (2014)138; cognitive behavioral therapy for insomnia N = 60 Mean age = 52 Duration = Follow-up = 3 and 6 months Peri- and postmenopausal women with a WASO greater than 30 minutes three or more nights per week, and a score of 8 in the Insomnia Severity Index (ISI) Cognitive behavioral therapy for insomnia (CBIT, 30min to 60 min weekly, for 6 weeks) Behavioral placebo treatment (BPT) Sleep disturbance: Insomnia - ISI (perceived insomnia severity score) EORTC QLQ-C30 Difficulty sleeping (sleep-wake diary; sleep efficiency and latency) WASO TST Baseline vs Change from week 1 to 6 Sleep efficiency (%) CBTI: 79.09 vs 9.39 BPT: 79.92 vs 5.99 p=0.046ᶧ, effect size comparison week 1-6: 0.34 Sleep latency (minutes) CBTI: 36.79 vs –20.73 BPT: 25.46 vs –7.97 p=0.002ᶧ, effect size comparison week 1-6: 0.48 WASO (minutes) CBTI: 38.25 vs –20.38 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 176 Study characteristics Population Intervention/s (dose) Comparator/s Outcomes of interest Results BPT: 40.84 vs –12.12 p=0.18, effect size comparison week 1-6: 0.26 TST (minutes) CBTI: 394.16 vs –0.37 BPT: 382.7 vs 30.96 p < 0.0001ᶧ, effect size comparison week 1-6: 0.67 Awakenings (per night) CBTI: 2.46 vs –0.68 BPT: 2.84 vs –0.78 p=0.81, effect size comparison week 1-6: 0.13 Authors’ conclusion: “Nurse-delivered CBTI appears to be beneficial for BCSs’ sleep latency/efficiency, insomnia severity, functioning, sleep knowledge, and attitudes more than active placebo, with sustained benefit over time.” ᶧ Statistically significant: p<0.05. Abbreviations: CI = confidence interval; EA = electro-acupuncture; EORTC QLQ-C30 = European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire–Core 30; FACIT-F = functional assessment of chronic illness therapy; FACT-B = functional assessment of cancer therapy-breast; GP = gabapentin; HF = hot flushes; HADS = hospital anxiety and depression scale; HFCS = hot flush composite score; MRS = menopause rating scale; PP = placebo pill; RR = event rate ratios; SA = sham acupuncture; SD = standard deviation; SGA = stellate ganglion blockade; TA = true acupuncture; TST = total sleep time; VMS = vasomotor symptoms; WASO = wake after sleep onset. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 177 Summary of results Four RCTs reported the effect of one or more interventions on vasomotor symptoms. The findings from each of these reviews is summarised in brief according to the primary outcomes assessed per study. Vasomotor symptoms Cramer et al (2015) compared the effect of 90 minutes per day Hatha yoga and meditation with usual care, for 12 weeks. The researchers used the menopause rating scale to measure total menopausal symptoms (somatovegetative, psychological, urogenital) to analyse their results. Fatigue was analysed using the functional assessment of chronic illness therapyfatigue scale, HADS was used to analyse anxiety and depression, and quality of life was analysed using the functional assessment of cancer therapy-breast scale. All patient characteristics were reported at baseline. The intention to treat analysis showed that women in the yoga group reported significantly lower total menopausal symptoms compared with the usual care group at week 12 (mean difference, 25.6; 95% confidence interval, 29.2 to 21.9; p=0.004). Moreover at week 12, the yoga group reported less somatovegetative, psychological, and urogenital menopausal symptoms; less fatigue; and improved quality of life (all p<.05). Minor adverse events were reported in the yoga group by six women (31.5%) none of them were serious. At 3 months follow-up all effects persisted except for psychological menopausal symptoms. Therefore yoga and meditation appeared to be a promising intervention to relieve menopausal symptoms in women after breast cancer treatment. Granted, further studies are required with longer follow-ups and control groups that regulate for nonspecific effects.135 Mao et al (2015) compared the effect of Electro-acupuncture or Gabapentin with Sham acupuncture or placebo, for 8 weeks. The researchers used the hot flash composite score (HFCS) as measured by the Daily Hot Flash Diary, where the participants reported their hot flash frequency and severity daily, starting from baseline. By week 8 (end of the intervention), acupuncture produced a significantly greater placebo effect than did pills, with the SA group having a significantly lower HFCS than the PP group (p=0.035). Compared with PP, EA also had improvement in hot flashes (p=0.005), whereas GP showed nonsignificant improvement (p=0.085). The authors reported the differences among treatment groups in the HFCS score (p<0.001 for time and treatment interactions. Participants in the active treatment groups (EA and GP) experienced 47.8% and 39.4% improvement in hot flashes, respectively, compared with baseline. Placebo participants in the SA and PP groups experienced 45.0% and 22.3% improvement, respectively. No serious adverse events were reported, no worsening of lymphedema or infection was reported in the acupuncture group. The gabapentin and placebo pill group reported mild adverse events only (dizziness, headaches, dry mouth, and drowsiness). One of the limitations of this study was that it was not powered to examine the efficacy or the long term use of acupuncture versus gabapentin, therefore it cannot be concluded that continued drug therapy would not be beneficial in the long term. The authors reported that acupuncture was associated with higher placebo effects and lower nocebo effects, showing promising results in reducing hot flushes, but these results were preliminary and further studies with larger population size and longer follow-up are warrant.137 Sleep disturbances Mathews et al (2014) compared the effect of cognitive behavioral therapy for insomnia (CBTI) on sleep improvement, daytime symptoms, and quality of life (QOL) in breast cancer survivors (BCSs) after cancer treatment. The researchers reported that sleep efficiency and latency improved more in the CBTI group than the BPT group; the difference was maintained Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 178 during follow-up (p=0.003). Moreover the authors reported that the CBTI group reduced the minutes to fall asleep by 20.73 minutes from baseline to week 6 compared to the BPT group (7.97 minutes, p=0.007), this was also maintain during follow-up (p=0.0005). Women in the CBTI group had less subjective insomnia, greater improvements in physical and cognitive functioning, positive sleep attitudes, and increased sleep hygiene knowledge. No group differences in improvement were noted relative to quality of life (QOL), fatigue, or mood. The authors concluded the clinical significance of the results, since the women in the CBTI group increased their sleep efficacy from 79% to 90% at follow-up. This study increased awareness of sleep disturbances in patients with cancer, and the implications on patients and nurses. It encourages the contribution and participation of nurses in research studies that build on the science that leads to evidence-based recommendations and policies. This study suggested that CBTI is a promising intervention for insomnia, but further research that replicate these findings are necessary and would increase the generalisability of the results to other cancer types and ethnic groups. Furthermore additional studies that test the effectiveness of the interventions using a varying treatment modality, such as cost analysis, are warrant. 138 Vulvovaginal symptoms and sexual function Goetsch et al (2015) compared the effect of either saline or 4% aqueous lidocaine applied either to the vulvar vestibule for 3 minutes before vaginal penetration for estrogen-deficient breast cancer survivors with severe penetrative dyspareunia. On the first month (blinded phase) 41 participants (89%) completed the full study. The researchers reported that the saline and silicone lubricant users who tried intercourse (71%) noted a 38% reduction in pain (median score, 5.3; p<0.007). In comparison, users of lidocaine and silicone lubricant who attempted intercourse (73%) had 87.5% less pain (median pain score, 1.0; p<0.001). In contrast Sexual Function Questionnaire scores at baseline and after the interventions were not different for women using aromatase inhibitors or selective estrogen receptor modulators compared with nonusers. Moreover, Sexual Distress scores diminished significantly for both interventions after 4 weeks and again significantly after 12 study weeks. Due to the sever dyspareunia at baseline of the participants and the significant reduction in vulval pain and sexual distress, the quality of life of the participants improved greatly. Further studies with larger population size need to be conducted, as well as confirmatory studies to confirm the reproduction of results.136 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 179 10 Appendix F: Study characteristics of RCTs not included in the 5 previously published systematic reviews Table 22 and Table 23 describe the study characterists of the 19 Recent RCTs. The study characteristics of the five previously published systematic reviews are provided in Table 25 (Appendix J: Additional tables of interest). Table 22. Study characteristics of Recent RCTs of pharmaceutical therapies for menopausal symptoms in women after breast cancer Recent RCTs are those that were not included in the five previously published systematic reviews Author, year (Trial name) Design, location Risk of bias Patient population Menopause status Age Intervention vs comparator Dosages Patient numbers n by group Total N Outcomes assessed Average duration of treatment and follow-up RCT - phase II, Brazil Women with a history of breast cancer Pre-menopausal n=34 (69.4%) Post-menopausal n=15 (30.6%) 49 (33-71) years (median) Bupropion crossed over to placebo vs Placebo crossed over to bupropion Bupropion n=24, Placebo n=25 N=55 (48 completed study) Hot flushes, daily diary on hot flushes - For seven days in Weeks 1 (baseline), 5, and 10. Psychosocial symptoms (depression), Beck depression inventory (BDI) ranging from 0 to 3. Quality of life, EORTC QLQC30 was used to assess quality of life through 36. The score for each topic ranges from 1 to 4. Sexual dysfunction, Arizona Sexual Experience Scale (ASEX) – scale that included five questions Each question has five response options ranging from 1 to 6. 10 weeks No follow-up Bupropion Nunez, 2013 24 Moderate risk of bias Both at baseline Bupropion dose of one of 150mg tablet a day for 3 days and then one tablet twice a day for the remainder of the four weeks) Placebo, after one week wash-out patients received doses same as bupropion. Venlafaxine Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 180 Author, year (Trial name) Walker, 2010† 35 Design, location Risk of bias Patient population Menopause status Age Intervention vs comparator Dosages Patient Outcomes assessed Average numbers duration of n by group treatment and Total N follow-up See under Acupuncture section, see Table 23. Study characteristics of Recent RCTs of complementary medicines and therapies for menopausal symptoms in women after breast cancer. RCT, USA Women with or at high risk of breast cancer with hot flushes and awakenings Pre/perimenopausal n=8(15.1%) 51.1 (SD 7.6) years (mean) Venlafaxine (or other SSRI/SNRI) + zolpidem vs Venlafaxine (or other SSRI/SNRI) + placebo Zolpidem Joffe, 2010 36 Moderate risk of bias Natural menopause = 21 (39.6%) 5 weeks of treatment with double-blinded zolpidem 10 mg or identical matched placebo orally at bedtime. For women not already taking an SSRI/SNRI openlabel venlafaxine 75 mg each day was initiated concurrent with the doubleblinded randomization to zolpidem or placebo and administered throughout the 5-week trial. Surgical menopause = 14 (26.4%) Chemotherapyinduced menopause = 8 (15.1%) GnRH agonistinduced menopause = 2 (3.8%) Gabapentin Ahimahalle, 2012† 26 RCT, Iran High risk of bias Women with breast cancer, younger than 50 years, with hot flushes and concurrently receiving chemotherapy and tamoxifen NR Venlafaxine + zolpidem n=25, Venlafaxine + placebo n=28 Gabapentin 42.8 (SD 4.6) years (mean) Gabapentin vs Megestrol acetate Megestrol 42.6 (SD 4.3) years (mean) 40mg of megestrol acetate twice daily and 300mg of gabapentin once daily for a period of 8 weeks Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 181 N=53 (38 completed study) Gabapentin n=60, Megestrol n=60 N=120 Psychosocial symptoms (mood /depression), was assessed using the Beck Depression Inventory (BDI). It ranges, 0-63, where a higher score indicates greater symptom burden. Sleep problems, It was measured using the PSQI, score range, 0-21, where higher scores indicate greater perceived sleep disturbance. A PSQI score greater than 5 distinguishes good from poor sleepers. Quality of life was measured by the Quality-of-Life Inventory (QOLI). Hot flushes were assessed subjectively with the 7-day North Central Cancer Treatment Group Daily Vasomotor Symptom Diary. 5 weeks of treatment, no follow-up Hot flushes The clinical assessment of hot flushes was performed base on its frequency, severity and duration. It was classified as mild, moderate and severe. 8 weeks of treatment, no follow-up Author, year (Trial name) Design, location Risk of bias Patient population Menopause status Age Intervention vs comparator Dosages Lavigne, 2012 27 RCT, USA Women with breast cancer NR G300mg 56 (SD 8.7) years (mean) Gabapentin 300mg (G300mg) Gabapentin 900mg (G900mg) vs Placebo Moderate risk of bias G900mg 55 (SD 8.7) years (mean) Placebo 54 (SD 7.4) years (mean) Gabapentin 300 mg daily, gabapentin 900 mg daily, measured at 4 and 8 weeks Patient numbers n by group Total N Gabapentin 300mg n=139, Gabapentin 900mg n=144, Placebo n=137 N=420 Outcomes assessed Psychosocial symptoms (anxiety) were measured using the Spielberger State-Trait Anxiety Inventory (STAI) at baseline, 4 and 8 weeks. The STAI yields a single summary score for current anxiety (‘‘state’’ anxiety) ranging from 20 to 80, with higher scores representing greater anxiety. Average duration of treatment and follow-up 8 weeks, no follow-up Pain was measured at baseline using a 10-point scale, ‘‘0’’ = ‘‘pain not present’’ to ‘‘10’’ = ‘‘pain as bad as you can imagine it could be.’’ Menopause hormone therapy (hormone replacement therapies) Frisk 201231 (update of Frisk 2008,51 HABITS substudy) RCT, Sweden Moderate risk of bias Women with a history of breast cancer and vasomotor symptoms Menopause (years): Menopause hormone therapy 7.4 vs EA 6.2 Menopause hormone therapy 53.4 (47-69) years (mean) EA 54.1 (4367) years (mean) Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Electro-acupuncture vs Menopause hormone therapy Menopause hormone therapy n=11 vs Electroacupuncture n=7 The Menopause hormone therapy group was treated with sequential or continuous combined estrogen/progestagen therapy for 24 months. In the EA group, treatment was given by a physiotherapist for 12 weeks. N=18 182 Health related quality of life (HRQoL) Hot flushes/day and night Sleep disturbances 24 months Author, year (Trial name) Design, location Risk of bias Patient population Menopause status Age Intervention vs comparator Dosages Holmberg, 2004 11 RCT, Scandinavia NR HABITS High risk of bias Women who had previously completed treatment for Tis up to stage II breast cancer Menopause hormone therapy mean 55.5 (42-75) years (average) Menopause hormone therapy vs No- Menopause hormone therapy Fahlen, 2011 32 RCT, Sweden Sub-study of Stockholm trial High risk of bias Breast cancer survivors Post-menopause = 100% NoMenopause hormone therapy mean 55.0 (40-74) years (average) 57.0 ± 5.6 (4266) years (average) Patient numbers n by group Total N Menopause hormone therapy n=174, NoMenopause hormone therapy n=171 Women were exposed to oestrogens, or combination of Menopause hormone therapy, or tibolone, or no exposure to Menopause hormone therapy N=434 (345 completed the study) Menopause hormone therapy vs No hormone treatment Menopause hormone therapy n=38 (Tamoxifen (n=25), No tamoxifen (n=13)) , No hormone treatment n=37 (Tamoxifen (n=25), No tamoxifen (n=12)) Patients in the treatment group received 2 mg estradiol daily in combination with different progestogens, for a year. N=75 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 183 Outcomes assessed Breast cancer recurrence Adverse events, for several reasons, the steering committee of the HABITS trial judged the data to be mature enough to strongly indicate that exposure to Menopause hormone therapy conveys an unacceptable risk in the HABITS trial. Anxiety and Depression (HADS), it consists of 14 items, seven assessing anxiety and seven assessing depression. On a four-point scale from 0 (‘no problem’) to 3. Quality of life (EORTC QLQ C-30, EORTC QLQ-BR 23 - physical, role, emotional, cognitive, social functioning, insomnia, fatigue, global quality of life, body image), It consists of 30 items constituting five functional scales and nine symptom scales. Vulvovaginal symptoms and enjoyment (EORTC BR-23 scale), higher scores indicates better functioning. They were all assessed over one year of treatment. Average duration of treatment and follow-up 2 years of treatment, median follow-up 2.1 years 1 year treatment. Follow-up at 6 months and 12 months, after randomization Author, year (Trial name) Design, location Risk of bias Patient population Menopause status Age Intervention vs comparator Dosages Von Schoultz, 2005 13 RCT, Sweden Postmenopausal early-stage breast cancer survivors Post-menopause = 100% Menopause hormone therapy 56.9 (42-69) years (median) Menopause hormone therapy vs No- Menopause hormone therapy Stockholm trial High risk of bias NoMenopause hormone therapy 57.5 (44-70) years (median) Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Patient numbers n by group Total N Menopause hormone therapy n=175, NoMenopause hormone therapy n=184 Patients <55 years in the Menopause hormone therapy group, 2 mg of cyclic oestradiol for 21 days with the addition of 10 mg of medroxyprogesterone acetate for the last 10 days, followed by 1 week with no treatment. The spacing out was of 2 mg of estradiol for 84 days with the addition of 20 mg of medroxyprogesterone acetate for the last 14 days, followed by 1 week with no treatment. Patients that had a hysterectomy in the Menopause hormone therapy group, 2 mg of estradiol valerate daily. N=378 (359 completed study) 184 Outcomes assessed Breast cancer recurrence, end points in these calculations were loco regional recurrence, distant metastasis, contralateral breast cancer, or death attributed to breast cancer. All analyses were done on an intent-to-treat basis, that is, patients were analysed according to their allocated treatment. Average duration of treatment and follow-up Median follow-up 4.1 years Author, year (Trial name) Design, location Risk of bias Patient population Menopause status Age Intervention vs comparator Dosages Sismondi, 2011 33 RCT, International Women with a history of breast cancer 52.7 (28-75) years (average) Tibolone vs Placebo LIBERATE Low risk of bias Time since menopause Tibolone =median 3.6 (035) years Tibolone group <50 years, 34.3% 2.5mg of tibolone daily Placebo=median 3.5 (0-40) years Patient numbers n by group Total N Tibolone n=1575, Placebo n=1558 N=3133 Placebo group <50 years, 33.1% Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 185 Outcomes assessed Hot flushes assessed using diary cards during 14 days before the baseline visit. The women filled in the daily Diary Cards during the first three months of the trial. Sleep problems was assessed using the Women’s Health Questionnaire (WHQ). Psychosocial symptoms (anxiety & mood) Quality of life was assessed using the Women’s Health Questionnaire (WHQ). Sexual dysfunction was assessed using the Women’s Health Questionnaire (WHQ). Vaginal symptoms Mean vaginal dryness scores were calculated on the basis of individual ratings at baseline and at week 104. Average duration of treatment and follow-up Median duration of treatment, 2.75 years Author, year (Trial name) Design, location Risk of bias Patient population Menopause status Age Intervention vs comparator Dosages Kenemans, 2009 12 RCT, International Low risk of bias Time since menopause T = mean 6.2 (6.3) years P = mean 6.2 (6.5) years Mean 52.87(SD 7.3) years (average) Tibolone (T) vs Placebo (P) LIBERATE Postmenopausal women younger than 75 years of age Tibolone group <50 years, 32.3% Randomly assigned to either tibolone 2.5 mg daily or placebo in a one-to-one ratio. Patient numbers n by group Total N Tibolone n=1556, Placebo n=1542 N=3148 (3098 completed study) Placebo group <50 years, 30.4% Marsden, 2001 39 RCT, UK High risk of bias Postmenopausal women with a confirmed diagnosis of stage I or II breast cancer Time since menopause in years (range): Menopause hormone therapy 7 (1-25) vs No treatment 5 (0-23) Menopause hormone therapy 58 (45-82) years (median) No treatment 55 (43-66) years (median) Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Menopause hormone therapy vs No treatment Menopause hormone therapy n=51, No treatment, n=49 The Menopause hormone therapy prescribed was oestradiol valerate 2 mg/day continuously in hysterectomised women, or the same oestrogen plus levonorgestrel 75 mg for 12 out of 28 days in those with an intact uterus. N=100 186 Outcomes assessed Breast cancer recurrence, including contralateral breast cancer, and was analysed in the intention-totreat (ITT) and per-protocol populations. Overall mortality, analysis done by fitting the Cox proportional hazard model stratified by (pooled) country, to obtain an estimate and a two-sided 95% CI for the hazard ratio (HR). ‘Safety outcomes’, an independent data and safety monitoring board (DSMB) assessed the safety of the participants by reviewing unblinded data every 6 months. Health-related quality of life was assessed at weeks 13, 26, 52, 78,104, and annually thereafter, using the nine domains in the WHQ in a subgroup of patients. Quality of life, sexual activity and vaginal dryness were assessed at baseline and at 3 and 6 months using the self-administered EORTCQLQ C30, the Sexual Activity Questionnaire and a study specific measure to determine the prevalence and severity of vaginal dryness. Average duration of treatment and follow-up Median duration of treatment, 3.1 years 6 months treatment, follow-up at 3 and 6 months Author, year (Trial name) Design, location Risk of bias Patient population Menopause status Age Intervention vs comparator Dosages Patient numbers n by group Total N Outcomes assessed RCT, South Korea Breast cancer survivors who experienced menopause after chemotherapy or endocrine therapy Mean duration of menopause, pH balanced gel=18.18 months pH Balanced gel 45.86 years (average) Vaginal topical pHbalanced gel vs Placebo Vaginal topical pHbalanced gel n=44, Placebo n=42 Adverse effects including endometrial thickening and ovarian cyst formation were measured. Vaginal symptoms were measured according to the VAS for vulvovaginal dryness with pain and dyspareunia. The VAS was rated from 0 to 10.0 on the 10-cm bar by the participant. Average duration of treatment and follow-up Vaginal gel Lee, 2011 34 12 weeks of treatment, participants Low risk of were bias randomly Placebo =18.45 Placebo Patients were randomly assigned months 44.98 years administered vaginal topical between (average) pH-balanced gel or N=98 (86 November placebo three times per completed 2007 and week for 12 weeks. trial) November 2008 and were followed until April 2009 Abbreviations CBT: cognitive behavioural therapy; NR: not reported; SD: standard deviation; SSRI/SNRI: Serotonin norepinephrine re-uptake inhibitors/selective serotonin re-uptake inhibitors; RCT: randomised controlled trial. †Head-to-head trials investigating various pharmacological/non-pharmacological interventions, trials are categorised according to primary intervention investigated. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 187 Table 23. Study characteristics of Recent RCTs of complementary medicines and therapies for menopausal symptoms in women after breast cancer Recent RCTs are those that were not included in the five previously published systematic reviews Author, year (Trial name) Design, location Risk of bias Patient population Menopause status RCT, USA Breast cancer survivors with hot flushes NR Age Intervention comparator vs Patient numbers n by group Total N Outcomes assessed Average duration of treatment and followup Hot flushes, daily hot flush diary for 1 week before any treatments, HFRDIS. Sleep problems, MOS-Sleep Scale. Psychosocial symptoms (anxiety, depression & mood), HADS-A scale. The measures were done at the beginning and at the end of the study. 5 weeks of treatment Hypnotherapy Elkins, 2008 38 Moderate risk of bias Hypnotherapy 55 years 10 months (average) Control 58 years, 2 months (average) Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Hypnotherapy vs No treatment Hypnosis intervention condition were scheduled for five weekly sessions, each to last approximately 50 minutes Hypnotherapy n=27, No treatment n=24 N=60 (51 completed study) 188 Author, year (Trial name) Design, location Risk of bias Patient population Menopause status Age Women with primary breast cancer, younger than 50 years, experiencing treatmentinduced menopause. Who had received adjuvant chemotherapy and/or hormonal therapy Premenopausal at diagnosis =100% 48.2(SD 5.6) years (average) <50 years, 100% Intervention comparator vs Patient numbers n by group Total N Outcomes assessed Average duration of treatment and followup CBT n=109, PE n=104, CBT + PE n=106, Waitlist controls n=103 Hot flushes and Night sweats, HF/NS frequency rating and HF/NS–problem rating. Psychosocial symptoms (psychological distress), assessed by HADS; and generic HRQoL, as assessed by the 36-Item Short Form Health Survey (SF-36. Quality of life was assessed by QLQ-BR23. Sexual dysfunction, assessed by the SAQ Other outcomes (body image & urinary symptoms), assessed by the BFLUTS-36; body image, as assessed by the four-item subscale of the European Organisation for Research. 12 weeks, 6 months Cognitive Behavioural Therapy Duijts, 2012† 28 RCT, Netherlands Moderate risk of bias Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review CBT or Physical exercise (PE) or Cognitive Behavioural Therapy + physical exercise N=422 vs Wait-list controls The CBT, six weekly group sessions of 90 minutes each, was including relaxation exercises. A booster at 6 weeks after completion. The PE program was a 12-week, individually tailored, homebased, selfdirected exercise program of 2.5 to 3 hours per week. 189 Author, year (Trial name) Design, location Risk of bias Patient population Menopause status Age Intervention comparator Mann, 2012 29 RCT, UK Breast cancer patients with problematic hot flushes and night sweats after breast cancer treatment Before diagnosis CBT Premenopausal n=24(51%) Perimenopausal n=9(19%) Postmenopausal n=12(25%) CBT 53.16(SD 8.10) years (average) CBT+ usual care vs Usual care Usual care 54.05 (SD 7.76) years (average) CBT, one 90 min session a week for 6 weeks, and included psychoeducation, paced breathing, and cognitive and behavioural strategies to manage HFNS. Assessments were done at baseline, 9 weeks, and 26 weeks after randomisation. 54.4(SD 7.5) years (average) Yoga of Awareness program vs Wait-list controls Moderate risk of bias Usual care Premenopausal n=24(49%) Perimenopausal n=8(16%) Postmenopausal n=16(33%) vs Patient numbers n by group Total N Outcomes assessed Cognitive behavioural therapy + usual care n=47, Usual care n=49 Hot flushes and Night sweats, 2week diary to be updated on a daily basis to record HFNS frequency, assessed at week 9 and 26. Psychosocial symptoms assessed using the WHQ which comprised of 37 items. It used a 4-point scale rate. Quality of life, The General Health Survey Short Form 36 (SF-36). Adverse events, the trial data management committee reviewed adverse events and assessed whether they were related to the intervention. N=96 Average duration of treatment and followup 26 weeks of treatment. 9 weeks and 26 weeks assessment. Yoga Carson, 2009 37 RCT, USA Moderate risk of bias Breast cancer survivors with hot flushes NR Patients were then randomly assigned to either start the yoga program immediately (yoga group) or 6 months later (wait-list control group). The intervention consisted of eight weekly 120-min group classes. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Yoga of Awareness program n=17, Waitlist controls n=20 N=37 190 Hot flushes, Night sweats, Sleep problems, Psychosocial symptoms (mood); the daily menopausal symptoms was used, using 0–9 scale, over 24h. Other outcomes (pain) 8 week program. Follow-up up to 3 months after treatment Author, year (Trial name) Design, location Risk of bias Patient population Menopause status Age Intervention comparator vs Acupuncture 60(46-75) years (average) Acupuncture vs Sham-acupuncture vs No treatment Patient numbers n by group Total N Outcomes assessed Average duration of treatment and followup Acupuncture n=31, Shamacupuncture n=29, No treatment n=34 Hot flushes, logbooks (VAS) were filled in 3 days after each treatment, and 6 and 12 weeks after the final acupuncture treatment. Sleep problems, Their sleep disturbances were rated “yes” or “no” at the same time points. Adverse events 5 weeks of treatment. Follow-up at week 6 and week 12 Exercise Duijts, 2012† 28 See under Cognitive Behavioural Therapy section Acupuncture Bokmand, 2013 25 RCT, Denmark Low risk of bias Women treated for breast cancer with hot flushes and disturbed night sleep NR Shamacupuncture 62(43 – 72) years (average) Acupuncture for 15-20 min once a week for five consecutive weeks. N=94 No treatment 62(45 – 75) years (average) Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 191 Author, year (Trial name) Design, location Risk of bias Patient population Menopause status Age Intervention comparator Liljegren, 2012 30 RCT, Sweden Breast cancer patients treated with adjuvant tamoxifen suffering from hot flushes and sweating True acupuncture Pre-menopausal n=9(21%) Perimenopausal n=5(12%) Postmenopausal n=28(67%) True acupuncture 58(6.8) years (average) True acupuncture vs Control acupuncture Control 58(9.3) years (average) Treated for 20 min twice a week for 5 weeks. Moderate risk of bias Frisk 201231 Moderate of bias vs Patient numbers n by group Total N Outcomes assessed True acupuncture n=38, Control acupuncture n=36 Hot flushes and Sweating, measured at week 6 after treatment, recorded by the patient at the first treatment, at week 6, and at week 18. Adverse events N=84 (74 completed study) Control Pre-menopausal n=14(33%) Perimenopausal n=4(10%) Postmenopausal n=24(57%) Electroacupuncture vs Menopause hormone therapy Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 192 Average duration of treatment and followup 5 weeks of treatment. Follow-up at week 6 and week 18 Author, year (Trial name) Design, location Risk of bias Patient population Menopause status Age Intervention comparator Walker, 2010† 35 RCT, USA Breast cancer patients on tamoxifen or arimidex that had completed chemotherapy NR 55 (35-77) years (median) Acupuncture vs Venlafaxine Moderate risk of bias vs Venlafaxine 37.5 mg orally at night for 1 week, 75 mg at night for the remaining 11 weeks. Acupuncture, twice per week for the first 4 weeks, once per week for the remaining 8 weeks. Patient numbers n by group Total N Outcomes assessed Acupuncture n=25, Venlafaxine n=25 Hot flushes, diary measuring the severity of hot flushes. Psychosocial symptoms (mental health), Beck Depression Inventory-Primary Care. Adverse events, National Cancer Institute Common Toxicity Criteria scale. Quality of life, MenQOL. All compared at 12 weeks, and observed after 1 year. N=50 Average duration of treatment and followup 12 weeks of treatment, 1 year (post treatment) Abbreviations CBT: cognitive behavioural therapy; NR: not reported; SD: standard deviation; SNRI/SSRI: Serotonin norepinephrine re-uptake inhibitors/selective serotonin re-uptake inhibitors; RCT: randomised controlled trial. †Head-to-head trials investigating various pharmacological/non-pharmacological interventions, trials are categorised according to primary intervention investigated Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 193 11 Appendix G: Search strategies for international guidelines and conference abstracts Table 24: Search for international guidelines and conference abstracts Portal Website Key words American Society of Clinical Oncology http://www.asco.org Guideline searched: Notes categories Supportive Care Quality of Life No relevant guidelines and Survivorship Treatment-related Issues Breast Cancer San Antonio Breast Cancer Symposium http://www.sabcs.org Menopause Guidelines International Network http://www.g-i-n.net/ breast menopause No relevant guidelines cancer Management of gynecologic issues in women with breast cancer. American College of Obstetricians and Gynecologists.122 Hormone therapy and breast cancer. In: Menopause and osteoporosis update 2009. Society of Obstetricians and Gynaecologists of Canada.123 breast psychosocial cancer No relevant guidelines breast psychosexual cancer No relevant guidelines cancer 1 guideline119 National Institute for Health and Care Excellence (NICE) http://www.nice.org.uk/ breast menopause NHMRC guideline portal http://www.nhmrc.gov.au/ Cancer section No current guidelines on breast cancer Mental health section Psychosocial Clinical Practice Guidelines: Information, Support and Counselling for Women with Breast Cancer: RESCINDED Breast cancer onwards) No additional relevant guidelines National Guidelines Clearinghouse http://www.guideline.gov/ Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review (2001 194 Portal Website Key words Notes Menopause treatment New Zealand Guidelines Group (NZGG) Scottish Intercollegiate Guideline Network (SIGN) Cancer Care Ontario http://www.health.govt.nz/aboutministry/ministry-healthwebsites/new-zealand-guidelinesgroup http://www.sign.ac.uk/ https://www.cancercare.on.ca/ and No additional relevant guidelines Cancer section 1 citation for breast cancer120 Mental health section No relevant guidelines Cancer section No relevant guidelines Mental health section No citations Support care section No relevant guidelines Survivorship section No relevant guidelines Psycho-oncology section No relevant guidelines National Comprehensive Cancer Network (NCCN) http://www.nccn.org/professionals /default.aspx Australasian Menopause Society http://www.menopause.org.au/ Endocrine Society https://www.endocrine.org/ Breast menopause North American Menopause Society http://www.menopause.org/ Breast cancer 3 abstracts from the 2012 and 2013 Annual Meeting141-143 American Society for Reproductive Medicine http://www.asrm.org/?vs=1 Breast cancer No relevant titles International Menopause Society http://www.imsociety.org/ British Society Menopause No relevant guidelines Cites Cancer Australia’s resource “Sexual wellbeing for women with breast cancer”140 cancer No relevant citations No relevant guidelines or position statements http://www.thebms.org.uk/ IMS Recommendations and Position Papers and Consensus Statements No relevant titles Breast cancer No relevant titles Consensus Statements No relevant statements Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 195 Portal Website Key words Notes Google http://www.google.com.au Breast cancer and treatment induced menopause guidelines. First 20 citations retrieved and reviewed; 2 abstracts included.144, 145 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 196 12 Appendix H: Summary of key points from international guidelines Guidelines located through database searches The following two guidelines were identified through database searches but on review by full text, were excluded. Hickey, M., C. Saunders, A. Partridge, N. Santoro, H. Joffe and V. Stearns (2008). "Practical clinical guidelines for assessing and managing menopausal symptoms after breast cancer." Ann Oncol 19(10): 1669-1680.146 o This paper is a narrative review. Lea, R., E. Bannister, A. Case, P. Levesque, D. Miller, D. Provencher, V. Rosolovich, O. Society of and C. Gynaecologists of (2004). "Use of hormonal replacement therapy after treatment of breast cancer." Journal of Obstetrics & Gynaecology Canada: JOGC 26(1): 49-60147 o The information in this set of guidelines has been superseded. NICE clinical guideline 80: Early and locally advanced breast cancer: Diagnosis and treatment (National Institutefor Health and Care Excellence 2009)119 Country: UK Patient groups covered: “Women with newly diagnosed invasive adenocarcinoma of the breast of clinical stages 1 and 2. This is where the primary tumour is less than 5 cm in maximum diameter and there is no sign of spread beyond the breast and axillary lymph nodes. Women with invasive adenocarcinoma of the breast of clinical stage 3. This includes primary tumours which may be larger than 5 cm in diameter (and includes inflammatory carcinoma). Men with newly diagnosed invasive adenocarcinoma of the breast of clinical stages 1, 2 and 3. Women with newly diagnosed DCIS. Women with Paget's disease of the breast.” (p24) “1.2 Providing information and psychological support 1.2.1 All members of the breast cancer clinical team should have completed an accredited communication skills training programme. 1.2.2 All patients with breast cancer should be assigned to a named breast care nurse specialist who will support them throughout diagnosis, treatment and follow-up. 1.2.3 All patients with breast cancer should be offered prompt access to specialist psychological support, and, where appropriate, psychiatric services.” (p11) “Menopausal symptoms Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 197 1.13.8 Discontinue hormone replacement therapy (HRT) in women who are diagnosed with breast cancer. 1.13.9 Do not offer HRT (including oestrogen/progestogen combination) routinely to women with menopausal symptoms and a history of breast cancer. HRT may, in exceptional cases, be offered to women with severe menopausal symptoms and with whom the associated risks have been discussed. 1.13.10 Offer information and counselling for all women about the possibility of early menopause and menopausal symptoms associated with breast cancer treatment. 1.13.11 Tibolone or progestogens are not recommended for women with menopausal symptoms who have breast cancer. 1.13.12 The selective serotonin re-uptake inhibitor antidepressants paroxetine and Fluoxetine may be offered to women with breast cancer for relieving menopausal symptoms, particularly hot flushes, but not to those taking tamoxifen. 1.13.13 Clonidine, venlafaxine and gabapentin should only be offered to treat hot flushes in women with breast cancer after they have been fully informed of the significant side effects. 1.13.14 Soy (isoflavone), red clover, black cohosh, vitamin E and magnetic devices are not recommended for the treatment of menopausal symptoms in women with breast cancer.” (pp20-21) Management of Gynecologic Issues in Women With Breast Cancer (The American College of Obstetricians and Gynecologists, 2012)122 Country: USA Patient groups: all women who had received or were receiving treatment for breast cancer. “Clinical Considerations and Recommendations How should the risk of osteoporosis be evaluated in breast cancer survivors, and what treatments are useful for those found to be at increased risk? Osteoporosis risk assessment in patients with breast cancer should include an assessment of clinical risk factors and BMD testing and monitoring (89). First-line pharmacologic options approved by the FDA for the prevention and treatment of osteoporosis include the bisphosphonates and raloxifene. Women also should be counseled about lifestyle changes to reduce the risk of bone loss and osteoporotic fractures. Osteoporosis presents a challenge in the long-term management of breast cancer survivors. Bone health is adversely affected by many of the cancer treatment modalities, including chemotherapy, ovarian suppression, and aromatase inhibitors, which all result in lower estrogen levels, more bone loss, and increased risk of fracture (7, 90–92). In patients with breast cancer, most discussions related to osteoporosis relate to management of women taking aromatase inhibitors. Bone loss is most rapid in premenopausal women undergoing ovarian suppression and taking aromatase inhibitors. In addition, in a large population-based study, hip fractures and falls were increased after a diagnosis of breast cancer, which suggests a disease and non–treatment-related risk of fracture. The American Society of Clinical Oncology recommends BMD monitoring by dual energy Xray absorptiometry to assess and manage bone loss in patients with breast cancer at high risk of osteoporosis (93). Because almost 80% of fractures occur in women with normal BMD or osteopenia, it is important to assess clinical risk factors of fracture such as advanced age, estrogen deficiency, postmenopausal use of aromatase inhibitors, history of fracture, family history of osteoporosis, chronic corticosteroid use, low body mass index, inadequate physical activity, cigarette smoking, and excessive alcohol consumption (93–95). The World Health Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 198 Organization has devised a multivariate model that uses BMD and risk factors of fracture to calculate a 10-year probability of any major osteoporotic fracture and is available on-line (www.sheffield.ac.uk/FRAX/). Pharmacologic options for the prevention and treatment of bone loss include bisphosphonates and raloxifene. There are several randomized controlled trials with data showing that bisphosphonates, which inhibit osteoclasts and prevent bone reabsorption, can prevent or reduce bone loss for women taking aromatase inhibitors (96). To reduce the risk of osteoporosis in high-risk patients, bisphosphonates may be administered to patients during long-term treatment with aromatase inhibitors. The 2009 National Comprehensive Cancer Network Task Force report recommends that pharmacologic therapy should be considered for women with breast cancer who have T scores between -1.5 and -2.0 (89). The task force suggested that health care providers strongly consider initiation of pharmacologic treatment in women with T scores less than -2.0 or with a 10-year fracture risk greater than 20% for a major fracture or 10-year hip fracture risk greater than 3%. Monitoring should annually occur for patients with cancer whose bone loss risks significantly change or who undertake a major therapeutic intervention; otherwise, patients with cancer with elevated fracture risks should be monitored every 2 years (97). There is clinical and preclinical evidence that the bisphosphonates may have antitumor activity in addition to protecting and treating bone loss. Although the mechanism is not clearly known, the bisphosphonate most frequently used in patients with breast cancer, zoledronic acid, is thought to affect angiogenesis, induce tumor apoptosis, affect tumor migration, disrupt bone deregulation, and possibly reduce disseminated tumor cells in the bone marrow (98). Very rare adverse effects associated with the long-term use of these drugs have been suggested but not yet confirmed, including atypical femur fractures and osteonecrosis of the jaw (99, 100). Raloxifene has been shown to have estrogen-like activity in the prevention of bone loss and is approved by the FDA for the prevention and treatment of osteoporosis. In the Multiple Outcomes of Raloxifene Evaluation trial, it was shown to significantly reduce the risk of vertebral fracture relative to placebo (101). Although generally well tolerated, the adverse effects of raloxifene include vasomotor symptoms (hot flushes and night sweats) and an increased risk of thromboembolic events (36, 102). Women with or at risk of osteoporosis should be counseled about lifestyle changes to reduce the risk of bone loss and osteoporotic fractures, such as weight-bearing and musclestrengthening exercises to reduce the risk of fractures and falls, increasing vitamin D and calcium intake, cessation of smoking, reducing alcohol intake, and fall-prevention strategies (103). Because vitamin D is an important cellular regulator and many women are deficient, 25-hydroxyvitamin D levels should be assessed in all patients with breast cancer. What therapies are useful in the treatment of vasomotor symptoms in breast cancer survivors? Treatments for vasomotor symptoms include lifestyle alterations, alternative and complementary therapy, and pharmacologic agents. A variety of low-dose antidepressants or gabapentin can be used to manage vasomotor symptoms. The use of hormonal therapy is generally contraindicated in patients with breast cancer. Safety and efficacy data on herbal treatments are unclear, and more data are needed on the efficacy of lifestyle changes and alternative therapies. The safety of estrogen or estrogen and progestin HT for the treatment of vasomotor symptoms in breast cancer survivors is unknown, and randomized controlled trials initiated in the 1990s were terminated early when findings indicated increases in breast cancer recurrence (104). This is still a controversial area because a large quantitative review of published data that evaluated the use of menopausal HT in women with a history of breast cancer showed that HT was not associated with an increased risk of cancer recurrence, cancer-related mortality, or total mortality. Women using HT had a decreased chance of Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 199 recurrence (OR, 0.5; 95% CI, 0.2–0.7) and cancer-related mortality (OR, 0.3; 95% CI, 0.0–0.6) compared with nonusers (105). Given the controversial reports, the use of HT is generally contraindicated in patients with hormone-positive breast cancer, and the need for safe and effective non-hormonal treatments for vasomotor symptoms in patients with breast cancer has accelerated research in this area (106, 107). Nonhormonal pharmacologic treatments that have been investigated for the treatment of vasomotor symptoms include SSRIs, SNRIs, and gamma-aminobutyric acid analogs. Overall, most of these treatments are not as effective as HT, but they do offer some relief for symptomatic hot flushes (108). In trials evaluating the efficacy of the SNRI venlafaxine for the treatment of hot flushes, the most effective dose has been much lower than the typical treatment dose for depression (109, 110). In a number of randomized controlled trials, significant reduction in hot flushes among breast cancer survivors using venlafaxine was seen. The optimal balance between effectiveness and adverse effects (most commonly, dry mouth, nausea, constipation, and poor appetite) appears to be a dose of 75 mg, with larger doses associated with an increased likelihood of adverse effects with no further clinical benefit (111). Other trials have evaluated low doses of the SNRI desvenlafaxine and the SSRIs paroxetine, fluoxetine, and citalopram, which have all showed a benefit in reducing vasomotor symptoms compared with placebo (22). However, there is some significant concern that the use of pure SSRIs, in women taking tamoxifen may interfere with tamoxifen metabolism and thus block the drug’s therapeutic benefit. This interference with tamoxifen appears to be less severe or nonexistent for SNRIs such as venlafaxine (89, 112). Gabapentin, a gamma-aminobutyric acid analog used as an anticonvulsant and in managing neuropathic pain in patients with breast cancer, has shown a benefit for the management of vasomotor symptoms at low doses. In a meta-analysis of four trials, gabapentin users had a significantly greater reduction in hot flushes (weighted mean difference=23.72 [95% CI, 16.46–30.97]; P<0.001), although adverse effects like dizziness were common (113). It also has been shown to improve sleep quality, which is a problem for many patients with breast cancer (114). Pregabalin, a newer compound that works similarly to gabapentin, also has demonstrated effectiveness in treatment for hot flushes in randomized controlled trials (115). It is important to note that none of these drugs has FDA approval for the treatment of vasomotor symptoms. Investigations of many herbal products have been contradictory, and there is little information regarding the long-term effect of these products for women with a history of breast cancer (108, 116, 117). Of the herbal products, probably the best studied is black cohosh, which has shown mixed results. Although older, lower-quality studies suggested a benefit for the treatment of vasomotor symptoms, recent randomized controlled trials in menopausal women have not shown a benefit compared with placebo (118, 119). There are less data regarding the use of black cohosh specifically in women with breast cancer. However, a recent prospective observational trial of patients with breast cancer who were taking tamoxifen did find a statistically significant improvement in hot flushes with black cohosh (120). Trials that have evaluated the efficacy and safety of soy products in the treatment of vasomotor symptoms in patients with breast cancer have found that soy, purported to have estrogen-like activity, is not beneficial for the treatment of vasomotor symptoms (121), which is also the case for women experiencing natural menopause (117, 122). Because safety data are also lacking, many oncologists advise breast cancer survivors to avoid the use of soy products. Lifestyle and behavioral changes to reduce vasomotor symptoms include paced-breathing, relaxation techniques, environmental modifications, and dietary changes (123). Many patients with breast cancer also look to complementary modalities, such as acupuncture. In a 2009 review, five of six randomized controlled trials found no benefit for acupuncture compared with sham or placebo acupuncture in postmenopausal women (124). Another review that analyzed the use of acupuncture in patients with breast cancer also did not show an overall benefit for reducing vasomotor symptoms compared with placebo (125). A Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 200 recent 12-week randomized controlled trial found acupuncture and venlafaxine equally effective for the treatment of vasomotor symptoms; however, adverse effects were more common in the venlafaxine group (126). In a Cochrane review that evaluated nonpharmacological therapies, including homeopathy, acupuncture, and relaxation therapy, for the treatment of vasomotor symptoms, only relaxation therapy seemed to show a benefit (127). A Cochrane review of exercise for menopausal vasomotor symptoms found insufficient evidence to determine the effectiveness of exercise for the treatment of vasomotor symptoms, or whether it is any more effective than HT or yoga (123). Many other complementary modalities are being evaluated for the treatment of vasomotor symptoms in patients with breast cancer and postmenopausal women in general, including stellate ganglion blocks, yoga, and hypnosis. Efficacy data currently are limited, but research into these and other complementary therapies is growing. What therapies are useful for treating vaginal atrophy in breast cancer survivors? Vaginal dryness and atrophy are common gynecologic issues in patients with breast cancer. It is estimated that 20–40% of patients with breast cancer have severe vaginal dryness that affects libido (32, 128). Vaginal dryness is a particular problem in young patients with breast cancer and one of the biggest predictors of vulvovaginal symptoms (129, 130). Given the increasing use of aromatase inhibitors, which suppresses all peripheral estrogen, reports of vaginal dryness and sexual dysfunction are even more common (84). Tamoxifen use also has been associated with vaginal dryness and decreased sexual satisfaction (131). Treatment options for vaginal dryness and atrophy have been limited because there are little data on the safety and efficacy of the traditional topical hormonal therapies in patients with breast cancer. However, many women have found non-hormonal vaginal lubricants and moisturizers to be effective in managing vaginal dryness (132, 133), and small studies of vaginal moisturizer compared with placebo in patients with breast cancer have shown a benefit (134). There are many studies that have demonstrated the success of local hormonal therapies for vaginal dryness in postmenopausal women, but the variable rates of estrogen absorption raise safety concerns for patients with breast cancer. This has led to the use of local hormonal therapies for which rates of systemic absorption are thought to be quite low. The estradiol vaginal ring, a silastic vaginal ring that slowly releases estradiol-17b without significant systemic absorption (135), is frequently used in patients with breast cancer; however, there are no randomized controlled trial data assessing its safety. A recent small study evaluated the use of vaginal estriol cream and found improvement in symptoms for women taking aromatase inhibitors (136). In postmenopausal women, estradiol-17b vaginal suppositories have been associated with improvement in vaginal dryness comparable with the use of conjugated equine estrogen vaginal cream (137). However, a small study showed that the use of estradiol tablets in women taking aromatase inhibitors was associated with increases in circulating estradiol after 2 weeks of use, leading the authors to conclude that estrogen suppositories might interfere with the estrogen-suppression efficacy of aromatase inhibitors, and thus, their use should be avoided in this population (22, 138). Given the lack of data to determine whether transient increases in estradiol are clinically significant, and whether the effects of long-term exposure pose increased risk, non-hormonal methods should be considered first-line treatment for vaginal atrophy in women with a history of hormone-sensitive breast cancer (139). Short-term use of hormonal methods may be considered for women with severe or refractory symptoms in whom other options have failed, following appropriate counseling with their oncologists about the potential risks. There are a lack of safety data evaluating testosterone supplementation for the treatment of vaginal dryness and vulvovaginal symptoms in patients with breast cancer, and most studies that have evaluated testosterone have also included the use of estrogen, which typically is Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 201 contraindicated in this population. A placebo-controlled trial of transdermal testosterone alone in patients with breast cancer did not show an improvement in vulvovaginal symptoms (140). A small Phase I/II study that evaluated the use of either 150-microgram testosterone cream or 300-microgram testosterone cream found an improvement in dryness for women taking aromatase inhibitors without an increase in systemic estradiol or testosterone levels (141). However, the largest randomized trial of testosterone versus placebo showed a nonstatistically significant increased risk of breast cancer in the testosterone group (142). Overall, the relationship between testosterone supplementation and general breast cancer risk is not clear, and the FDA has yet to approve testosterone supplementation to treat sexual dysfunction in women, in part, due to a lack of breast safety data.” Scientific support of the College of Oncology: update of the national guidelines on breast cancer. KCE reports 143C (Cardoso et al, 2012)121 This set of guidelines was developed in Belgiuim. The recommendations it makes that are related to the Research Questions are: “Physical training including specific exercises for cancer-related fatigue can be recommended after treatment for breast cancer (level of evidence 1A) Menopause hormone replacement therapy is contraindicated in women with breast cancer (level of evidence1B) Psychological support should be available to all patients diagnosed with breast cancer (level of evidence1A)” (p44) Management of Early Breast Cancer (New Zealand Guidelines Group, 2009)120 “Psychosocial support should be available to all women with early breast cancer (level of evidence A)” “Cognitive behavioural therapy should be available for women with early breast cancer experiencing an anxiety disorder or depression (level of evidence A)” “Women who are osteoporotic and on adjuvant endocrine therapy which enhances loss of bone density or who have undergone premature treatment-induced menopause should receive a bisphosphonate (level of evidence A)” “Women who are osteopenic and on adjuvant therapy which enhances loss of bone density, or who have undergone premature treatment-induced menopause should be considered for a bisphosphonate, especially in the presence of other risk factors: prior nontraumatic fracture, aged over 65 years, family history, tobacco use, low body weight (level of evidence C)” “Women with premature menopause due to chemotherapy, ovarian function suppression or oophorectomy and postmenopausal women receiving adjuvant therapy with an aromatase inhibitor should have bone density monitored at least every 2 years following a baseline DXA (dual energy X-ray absorptiometry) scan of the spine and hip (level of evidence C)” “Frequency of bone mineral density monitoring should be tailored to the individual. If baseline T-score >-1.0 further monitoring of bone density may not be necessary (level of evidence)” “A woman with early breast cancer at risk of bone mineral loss should be provided with appropriate advice for good bone health. This includes, but is not limited to: • a healthy diet • cessation or continuing abstinence from smoking Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 202 • maintenance of a healthy body mass index • regular exercise • calcium • adequate vitamin D levels (level of evidence C)” “It is known that very young women (i.e., aged under 35 years) are less likely to experience permanent menopause as a result of chemotherapy” (p111). “Assessment of menopausal status Measurement of oestrogen and gonadotrophin levels is recommended before initiating treatment with an AI if there is a chance that a woman is still premenopausal (e.g., it is less than one year since her last menstrual period). Particular care is required for younger women just post chemotherapy or on tamoxifen, as amenorrhoea can occur when normal premenopausal ovarian oestrogen production is present. As tamoxifen leads to elevated gonadotrophin levels even in premenopausal women, it is important to be sure that oestrogen levels are postmenopausal, indicating that ovarian oestrogen production is no longer occurring, in order to be sure that use of an AI is appropriate and will be effective at further suppressing oestrogen production. As ovarian function can cease temporarily after chemotherapy, levels should be rechecked probably about three monthly for the first year after completion of chemotherapy if AIs are to be used in this group. Note most trials have excluded this group from AI therapy. In elderly patients, a patient profile of risk factors for various adverse effects should be considered to decide between different endocrine treatment options. For example, in the presence of comorbidities such as osteoporosis, tamoxifen may be preferred, whereas in the presence of risk for thromboembolic disease, an AI may be preferred” (p122). “Although they are often used in metastatic disease, bisphosphonates have also been used in the adjuvant setting in order to prevent treatment-induced osteoporosis and to reduce the risk of developing osseous metastases.” (p127) American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Menopause (Goodman et al 2011)124 Country: US Population: Women undergoing menopause This set of guidelines focuses on managing menopause in general. Statements specifically relating to women with a history of or at risk of breast cancer are as follows: “R8. Long-cycle therapy with use of a progestagen for 14 days every 3 months may be considered, in an effort to reduce breast exposure to progestagens, despite lack of definitive assessment of efficacy (Grade B; BEL 2). R9. Amenorrhea may be achieved by using a low dose of a progestagen administered continuously (daily) in conjunction with estrogen. Because recent studies suggest adverse breast outcomes with continuous progesterone exposure, this form of therapy is not recommended (Grade D; BEL 2). R13. Phytoestrogens, including soy-derived isoflavonoids, result in inconsistent relief of symptoms. Because these compounds may have estrogenic effects, women with a personal or strong family history of hormone-dependent cancers (breast, uterine, or ovarian), thromboembolic events, or cardiovascular events should not use soy-based therapies (Grade D; BEL 1).” Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 203 AGO Recommendations for Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer. Update 2011 (Thomssen et al 2011)125 Country: Germany. Population: patients with primary and metastatic breast cancer. This set of guidelines states: “A major issue is the use of hormonal therapy (HRT) for postmenopausal symptoms. Available data suggests that the use of HRT should be avoided [level evidence 2aB, Arbeitsgemeinschaft Gynäkologische Onkologie ++]” (p312). EMAS clinical guide: Low-dose vaginal estrogens for postmenopausal vaginal atrophy (Rees et al 2012)126 Country: UK Population: Women undergoing menopause and with vaginal atrophy. “Topical estrogens after breast cancer Vaginal dryness is commonly reported in women receiving adjuvant endocrine and chemotherapy for breast cancer. While topical estrogens are effective there are safety concerns in postmenopausal women taking adjuvant aromatase inhibitors because of systemic absorption. Thus a study in 7 postmenopausal women using aromatase inhibitors and estradiol 25mcg tablets found that serum estradiol levels rose from baseline levels ≤5 pmol/l consistent with aromatase inhibitor therapy to a mean 72 pmol/l at 2 weeks. By 4 weeks this had decreased to 35 pmol/l in the majority (median 16 pmol/l) although significant further rises were seen in two women. Vaginal estriol and lower doses of estradiol (12.5 mcg) seem to result in lower serum levels. Of note these studies were of short duration with a limited sample size and no long-term safety data are currently available. Data with low dose oestrogen are scant. However, in view of these concerns, non-hormonal lubricants and moisturisers should be considered first line” (pp172-173)” Menopause and Osteoporosis Update 2009 (Society of Obstetricians and Gynaecologists of Canada 2009) Journal of Obstetrics and Gynaecology Canada Volume31 Number 1 supplement 1123 Country: Canada Population: Women undergoing menopause. Chapter 4 focuses on hormone therapy and breast cancer. It recommends: “1. Health care providers should periodically review the risks and benefits of prescribing HT to a menopausal woman in light of the association between duration of use and breast cancer risk. (IA) 2. Health care providers may prescribe HT for menopausal symptoms in women at increased risk of breast cancer with appropriate counselling and surveillance. (IA) 3. Health care providers should clearly discuss the uncertainty of risks associated with HT after a diagnosis of breast cancer in women seeking treatment for distressing symptoms. (IB)” (pS24) In addition, it states: Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 204 “Women who wish to consider HT for improved quality of life after a diagnosis of breast cancer should understand that a definitive answer to the question of when HT will influence prognosis is lacking. The results of observational studies, which are fraught with potential biases, have been reassuring; however, a single RCT suggested that HT had an adverse effect on recurrence rates. Alternative, non-hormonal agents exist for the treatment of many menopausal symptoms (e.g., SSRIs for hot flushes and topical estrogen for urogenital atrophy). If these options are unsuitable and quality of life is seriously impaired, then individual women with a low risk of tumour recurrence may still wish to explore the option of HT” (ppS23-S24). Adolescent and Young Adult Oncology (Coccia et al 2012, Journal of the National Comprehensive Cancer Network)127 Country: US Population: Young people with cancer “Fertility is a major concern for young women receiving chemotherapy for breast cancer and HL. Among young women treated with adjuvant chemotherapy for breast cancer, the risk for chemotherapy-related amenorrhea and premature menopause is significantly higher for those with newly diagnosed breast cancer treated with chemotherapy who are older than 35 years. In a cohort study of 518 female survivors of HL diagnosed between 14 and 40 years of age, those who were older (22–39 years of age) at first treatment had a higher risk for developing premature menopause after treatment compared with younger patients (14– 21 years). Similarly, the risk of developing premature ovarian failure is also higher among young women receiving chemotherapy and RT for HL, irrespective of their age at treatment (38% for those diagnosed between 30 and 40 years of age; 37% for those diagnosed between 9 and 29 years of age)” (p1134). Clinical practice guidelines for the care and treatment of breast cancer: 14. the role of hormone replacement therapy in women with a previous diagnosis of breast cancer. (Pritchard et al 2002)128 Country: Canada Population: Women with a previous diagnosis of breast cancer Relevant recommendations include: “Routine use of HRT (either estrogen alone or estrogen plus progesterone) is not recommended for women who have had breast cancer” (p1018). “Postmenopausal women with a previous diagnosis of breast cancer who request HRT should be encouraged to consider alternatives to HRT. If menopausal symptoms are particularly troublesome and do not respond to alternative approaches, a well-informed woman may choose to use HRT to control these symptoms after discussing the risks with her physician. In these circumstances, both the dose and the duration of treatment should be minimized” (p1019). Alternative treatments to HRT discussed were: “Vaginal dryness and local menopausal symptoms can be significantly reduced with the use of K-Y Jelly and Replens (level II evidence)” (p1019) “Hot flashes can be treated with a variety of non-hormonal therapies: • Vitamin E: A placebo-controlled trial demonstrated that vitamin E (800 IU/d) achieved a statistically significant reduction in hot flashes over placebo (level I evidence). However, this Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 205 reduction may have been due in part to a placebo effect, since the decrease amounted to 1 hot flash per person per day. • Clonidine: In a placebo-controlled trial, clonidine reduced the frequency of hot flashes by about 15% compared with placebo (level I evidence), but it was associated with a statistically significant amount of toxicity. At the study’s end patients did not prefer clonidine over placebo. • Venlafaxine (Effexor): Low doses of venlafaxine (37.5 mg in a sustained-release preparation) substantially reduced the frequency of hot flashes and was well tolerated in a randomized trial (level I evidence). • Soy phytoestrogens: A recently completed placebo controlled trial did not show that soy protein significantly reduced the severity or frequency of hot flashes when compared with placebo (level I evidence). • Other compounds: Compounds such as black cohosh and Bellergal (a combination of belladonna, ergotamine and phenobarbital) have been used, but these have not undergone placebo-controlled trials to illustrate benefits and toxicities. • Megestrol acetate: A placebo-controlled trial that evaluated a low dose of the progestational agent megestrol acetate demonstrated a reduction in the frequency of hot flashes by about 80% (level I evidence). The therapy was well tolerated in this short-term double-blind, crossover clinical trial, and women significantly preferred megestrol acetate over the placebo. However, many animal and in vitro studies have shown that progestational agents may increase or accelerate breast cancer development or progression, and progesterone has been clearly identified as a cause of breast cancer in women. As with estrogen, there are no good data to demonstrate whether low doses of megestrol acetate in women with a previous diagnosis of breast cancer increase or decrease the risk of recurrence, or have no effect. Progestational agents should be regarded with the same degree of caution as estrogen when recommending treatment to patients with a previous diagnosis of breast cancer” (p1020). Supportive care after curative treatment for breast cancer (survivorship care): Resource allocations in low- and middle-income countries. A Breast Health Global Initiative 2013 consensus statement. (Ganz et al 2013)130 Country: Multinational Population: Breast cancer survivors in low- and middle-income countries. Breast cancer survivors are defined as “patients who have entered the posttreatment phase after initial surgery, with or without chemotherapy and/or radiation (i.e., 6 months of curative treatment)” (p607). The definition of low- and middle-income countries was not provided. This consensus statement was produced by an expert panel and focuses on public health policy recommendations in terms of resource allocations for supportive care for women after curative treatment for breast cancer in low- and middle-income countries. The consensus statement categorises resource allocations into basic, limited, enhanced and maximal, defined as follows (p607): Basic: “Core resources or fundamental services absolutely necessary for any breast health care system to function; basic-level services are typically applied in a single clinical interaction.” Limited: “Second-tier resources or services that are intended to produce major improvements in outcome, and are attainable with limited financial means and modest infrastructure; limited-level services may involve single or multiple clinical interactions.” Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 206 Enhanced: “Third-tier resources or services that are optional but important; enhanced-level resources should produce further improvements in outcome and increase the number and quality of therapeutic options and patient choice.” Maximal: “High-level resources or services that may be used in some high-income countries, and/or may be recommended by breast care guidelines that do not adapt to resource constraints. They should be considered lower priority than those resources or services listed in the basic, limited, or enhanced categories on the basis of extreme cost and/or impracticality for broad use in resource-limited environments; to be useful, maximal-level resources typically depend on the existence and functionality of all lower-level resources.” Panel recommendations relevant to menopausal symptoms in women who have received treatment for breast cancer are as follows, with key relevant recommendations in bold: Health professional education (pp608-9): o “At basic levels of resource allocation, health professional education should include education about breast cancer recurrence and second primary cancers, and recognition and management of physical/clinical complications of long-term treatment, including women’s health issues (e.g., reproductive health, early menopausal symptoms, body image). It should include awareness and recognition of psychosocial complications of treatment, and lifestyle modifications to reduce cancer risk and improve quality of life. o “At limited levels, health professional education should include awareness of patient characteristics associated with increased risk for depression, anxiety or distress, and long-term psychosocial complications. Education should include sexual health issues. At enhanced levels, health professional education should include methods for psychosocial screening.” Patient and family education (p609): o “At basic levels of resource allocation, patient and family education should include discussions on breast cancer recurrence and second primary cancers and symptoms to report. Patient and family education should include discussions on persistent or late-effects of treatment (e.g., lymphedema, fatigue, insomnia, and pain), symptoms to report, and management strategies, including the appropriate use of complementary and alternative medicine. Women’s health issues (early menopause, body image), and psychosocial problems (e.g., depression, emotional distress, and changing roles at home and work), and lifestyle modifications (e.g., diet and exercise), should be included. o “At limited levels, education should include the importance of follow-up scheduling, adherence to endocrine therapy, and sexual health issues. Patient and family education should be culturally appropriate; partners should be included, as appropriate.” Psychosocial aspects of survivorship (p610): o “At basic levels of resource allocation, health professionals should consider (through observation, dialogue, and other appropriate means) psychosocial problems of breast cancer survivors, and refer patients to peer support by trained peer volunteers, as appropriate. Patient and family education regarding survivorship issues should be offered. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 207 o “At limited levels, psychosocial assessment, including assessment for depression, should be available, with referrals for emotional and social support as indicated. o “At enhanced levels, patients should be screened for depression and psychological distress by mental health specialists and referred for psychosocial counseling as appropriate. Pharmacotherapy for depression and distress, based on available research and clinical practice guidelines (CPGs), should be available. Social services, including employment, financial, and legal counseling, should be available. o “At maximal levels, coordinated mental health care by a psychiatrist, psychologist, or social workers could be considered.” Women’s health issues (p611): o “At basic levels of resource allocation, patient and family education on women’s health issues (e.g., early menopause and body image) should be available. o “At limited levels, treatment of menopausal symptoms with behavioral strategies (e.g., efforts to modify or reduce core body temperature) and topical agents (e.g., non-hormonal vaginal moisturizers) is recommended. Patient and partner education on sexual health should be available. o “At enhanced levels, pharmacotherapy to manage menopausal symptoms should be available, and could include antidepressants and complementary therapies; these should be administered based on clinical practice guidelines and available research. Breast reconstruction for asymmetry to address body image concerns should be provided, as needed. Bone-modifying agents (e.g., bisphosphonates) should be available for women who may be at increased risk for osteopenia and osteoporosis due to premature menopause. o “At maximal levels, clinical assessment and tailored interventions to reduce menopausal symptoms and improve vulvovaginal symptoms could be considered.” Monitoring (p611): o “At basic levels of resource allocation, monitoring for cancer recurrence or second primary cancers with review of systems and physical examination should be part of follow-up care. o “At limited levels, monitoring for adherence to endocrine therapy should be provided.” o The context for recommending monitoring for adherence to endocrine therapy is that side effects (for women with ER-positive breast cancer) include vaginal discharge, arthralgia and hot flushes, which may result in women stopping their medication if they do not receive reinforcement or non-hormonal supportive care interventions. “At maximal levels, genetic counseling and screening for high-risk cancers should be considered.” Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 208 13 Appendix I: Abbreviations ASEX Arizona Sexual Experience Scale BDI, BDI-SF, BDI-I Becks Depression Inventory BFLUTS-36 Bristol Female Lower Urinary Tract Symptoms CBT Cognitive behavioural therapy CEPO Comité de l’évolution des pratiques en oncologie CI Confidence interval CPG Clinical practice guideline DASS Depression Anxiety Stress Scale DSM-IV Diagnostic and Statistical Manual for Mental Disorders IV EORTC QLQ-C30 European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire EORTC BR-23 European Organisation for Research and Treatment of Cancer Breast Cancer Module EuroQoL-LRS European Quality of Life Linear Rating Scale FACIT Functional Assessment of Chronic Illness Therapy FACT-B Functional Assessment of Cancer Therapy – for patients with breast cancer FACT-ES Functional Assessment of Cancer Therapy-Endocrine Subscale GSQ Groningen Sleep Quality Scale HABITS Hormone replacement therapy after breast cancer - is it safe? (Trial name) HADS Hospital Anxiety and Depression Scale HAM-D Hamilton Rating Scale for Depression HF/NS Hot Flushes/Night Sweats HFRDIS Hot Flash Related Daily Interference Scores HR Hazard ratio HRT Hormone replacement therapy, menopause hormone therapy HRQoL Health Related Quality of Life ITT Intention-to-treat KI Kupperman’s Index LIBERATE Livial Intervention following Breast cancer: Efficacy, Recurrence, And Tolerability Endpoints MHC Mental Health Composite Score MHS Mental Health Subscale Score MOS Medical Outcomes Survey MOS-SPI Medical Outcomes Survey – sexual problems index MYMOP Measure Yourself Medical Outcome Profile NAI Negative Affect Index NHMRC National Health and Medical Research Council NR Not reported NS Not significant PE Physical exercise Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 209 PGWB Psychological and General Wellbeing Index PoCoG Psycho-Oncology Co-operative Research Group POMS Profile of Mood States PSQI Pittsburgh Sleep Quality Index QOLI Quality of Life Inventory RCT Randomised controlled trial RH Relative hazard SAQ-H Sexual Activity Questionnaire-Habits score SCL-90 Symptoms Checklist-90 SF-36 Medical Outcomes Study Short Form – 36 SNRI Serotonin noradrenaline (norepinephrine) re-uptake inhibitors SSRI Selective serotonin re-uptake inhibitors STAI Spielberger State Trait Anxiety Inventory VAS Visual Analogue Scale VHI Vaginal Health Index VMI Vaginal Maturation Index WASO Wake time After Sleep Onset WHQ Women’s Health Questionnaire Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 210 14 Appendix J: Additional tables of interest 14.1 Study characteristics of the five previous systematic reviews Table 25. Characteristics of the five previously published systematic reviews Systematic review Population L’Espérance 20135 CEPO review Women with breast cancer (patients treated with tamoxifen) and breast cancer survivors experiencing hot flushes Intervention/Comparison Non-hormonal therapy versus placebo. Cochrane review Pharmacological agents, tamoxifen, SNRIs and SSRIs (venlafaxine, paroxetine, fluoxetine, sertraline, citalopram); antihypertensive (clonidine) and anticonvulsants (gabapentin, pregabalin), vitamin E, antidepressants (venlafaxine, paroxetine, fluoxetine, citalopram). Secondary outcomes: o mild-moderate side effects o health-related quality of life o not significant impact on quality of life Non-pharmacological agents , natural health products (flaxseed, isoflavones, phytoestrogens, black cohosh, St. John’s wort) o no adverse effects o vulvovaginal symptoms In some studies, non-hormonal therapies were tested against each other, without and with the use of placebos (crossover studies). o severe adverse effects (hysterectomy and breast cancer recurrence – black cohosh) Non-hormonal therapy vs placebo Primary outcome: hot flushes Non-hormonal therapy included: Secondary outcomes: recurrence of breast cancer or survival; side-effects; health-related quality of life - Women with a history of breast cancer and experiencing hot flushes Primary outcome: frequency and severity of hot flushes. Non-hormonal therapy included: - Rada 2010 4 Outcomes - Pharmacological agents (vitamin E, clonidine, gabapentin, veralipride, SSRIs and SNRIs) - Non-pharmacological agents (acupuncture, magnetic therapy, applied relaxation, homeopathy). Compounds with possible estrogen-like mechanisms were excluded (plant phytoestrogens, black cohosh and tibolone) Dos Santos 2010 8 Women with breast cancer, undergoing treatment and/or surgery. This systematic review looked at studies that have also populations of adults with any Acupuncture versus ‘placebo’ acupuncture. Primary outcome: hot flushes. Acupuncture included: Secondary outcome: fatigue, pain, dyspnea, psychological wellbeing, range of motion, lymphoedema, and emesis. Traditional acupuncture or electrical stimulation acupuncture. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 211 Systematic review Population Intervention/Comparison type of cancer. Outcomes In the Tukmachi study acupuncture was given with lifestyle and diet advice. Frisk et al study used electrical stimulation acupuncture versus hormone therapy. Acupuncture versus acupressure was researched by Molassiotis et al. Lee 2009 7 Women with breast cancer. Acupuncture versus sham acupuncture. Women with breast cancer undergoing adjuvant estrogen-antagonist treatment. Acupuncture included Women with breast cancer who suffer from severe vasomotor symptoms. Women with breast tamoxifen or arimidex. Post-menopausal cancer. cancer women with receiving breast Electro acupuncture, acupuncture. traditional acupuncture Primary outcome: mean change on hot flushes frequency. and classic Secondary outcomes: minor adverse effects (slight bleeding or bruising at the needle site), vasomotor syndrome. Acupuncture versus other therapies. Other therapies included: Hormone replacement therapy, antidepressant, venlafaxine, applied relaxation. Other forms of acupuncture, such as laser acupuncture were excluded, as well as studies with no clinical data. Abstracts and dissertations were included in this systematic review. Chao 20096 Women diagnosed with breast cancer at any stage and undergoing treatments such as surgery, radiotherapy, chemotherapy, hormonal therapy or palliative treatment for metastatic breast cancer. Stimulation of acupuncture point by any modality versus controls. Any modality included: Manual needling, needling combined with electric stimulation (electro acupuncture), wrist band stimulation, magnet stimulation, lasers or heat with burning herbs (moxibustion), applying pressure to the acupoint (acupressure), treating the whole body by acupoints in the ears only. Controls included: Hormone replacement therapy, sham acupuncture, relaxation programme, acupressure P6 at acupoint S13, intravenous injected dexa, and mental support, intramuscular injected drug, magnetic devices. Reports only available as abstracts and trials with other than breast cancer diagnosis were excluded from this systematic Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 212 Primary outcome: lower frequency of daily hot flush (clinically related outcome variable such as symptom scores) Secondary outcomes: Improvement in quality of life (nausea, vomiting, shiver, headache pain), reduction in acute emesis, shock sensation and tingling, vasomotor syndrome, lymphoedema (condition-specific or generic health status outcomes). Systematic review Population Intervention/Comparison Outcomes review. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 213 14.2 RCTs excluded from this systematic review’s Primary Evidence Base Table 26: RCTs included by published systematic reviews but excluded from Cancer Australia’s primary evidence base Individual trial reference Intervention CEPO 20135 Rada 20104 Dos Santos 20108 Lee 20097 Chao 20096 Reason not included Barton 2010 Citalopram Only 31-37% had breast cancer history Kalay 2007 Citalopram No mention of breast cancer in abstract. Full text does not report participants as having a history of breast cancer. Loprinzi 2000 Venlafaxine Walker 2008 Acupuncture vs Venlafaxine Published before 2001 Published as an abstract. Walker 2010,35 which was included, is the full paper for this abstract Goldberg 1994 Clonidine Published before 2001 Pandya 2000 Clonidine Published before 2001 Loprinzi 2007 Gabapentin (Phase III trial) J Clin Oncol 25(3) 308-312 No mention of breast cancer in the abstract, but CEPO review reports 78-84% had breast cancer history and both arms had gabapentin. The results were not stratified by breast cancer status. This trial was not netted in our original search Loprinzi 2010 Pregabalin 35-44% had breast cancer history Fenlon 1999 Relaxation therapy Davies 2001 Acupuncture Hervik 2008 Acupuncture Published before 2001 Was not netted in our original search and is not indexed in PubMed or Medline. The author was also not indexed in Scopus and the paper is a poster abstract Was not netted in our original search, because this study is the same as Hervik 200956 Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 214 Individual trial reference Intervention CEPO 20135 Rada 20104 Dos Santos 20108 Lee 20097 Chao 20096 Reason not included which is included in the primary evidence base, but was dated differently Pruthi 2012 Flaxseed Only 50% had breast cancer history Quella 2000 Phytoestrogens Published before 2001 Al-Akoum 2009 St. John’s wort No mention of breast cancer in the abstract. Full text article reports combining participants with and without a history of breast cancer and results were not stratified. Barton 1998 Vitamin E Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review Published before 2001 215 Data from RCTs excluded from Primary Evidence Base, as reported on by published systematic reviews: Vasomotor symptoms These are supplementary notes that do not appear in the main body of the systematic review and refer to the evidence supported by RCTs that were excluded from the Primary Evidence Base (Table 1). Antidepressants The CEPO/L’Esperance review reported that citalopram significantly improved hot flushes compared with placebo5 in two RCTs (Barton 2010, Kalay 2007). Antihypertensives Both systematic reviews reported that clonidine significantly improved hot flushes compared with placebo4, 5 in one RCT (Pandya 2000). The Rada 2010 review 4 also included another, older, RCT of transdermal clonidine (Goldberg 1994) which also reduced hot flushes compared with placebo. Anticonvulsants Pregabalin significantly improved hot flushes compared with placebo5 in one RCT (Loprinzi 2010). Acupuncture Davies 2001 was cited by Lee et al. 20097: true acupuncture was not significantly different to sham acupuncture regarding hot flushes. Other Rada 20104 reported vitamin E (one RCT by Barton 1998) had no significant effect on hot flushes. CEPO/L’Esperance 20135 reported abnormal sweating was more common on placebo than St. John’s wort (Al-Akoum 2009). Rada 20104 reported that one study on relaxation therapy (Fenlon 1999) showed no significant benefit. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 216 15 Appendix K: Properties of some psychological screening instruments Diagnostic criteria for mental disorders, or mood disorders, such as anxiety or depression, as defined in the Diagnostic and Statistical Manual of Mental Disorders. Table 27. Diagnostic and Statistical Manual of Mental Disorders IV9: Criteria for Mood Disorders Criteria for Major Depressive Episode A. B. C. D. E. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. 1. Depressed mood most of the day, nearly every day, as indicated by either subjective report, (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). Note: In children and adolescents, can be irritable mood. 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observations made by others). 3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. 4. Insomnia or hypersomnia nearly every day. 5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). 6. Fatigue or loss of energy nearly every day. 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick). 8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others). 9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or specific plan for committing suicide. The symptoms do not meet criteria for a Mixed Episode. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). The symptoms are not better accounted for by Bereavement. Criteria for Dysthymic Disorder A. B. C. D. E. F. G. H. Depressed mood for most of the day, for more days than not, as indicated either by subjective account or observation by others, for at least 2 years. Presence, while depressed of two (or more) of the following: 1. Poor appetite or overeating. 2. Insomnia or hypersomnia. 3. Low energy or fatigue. 4. Low self-esteem. 5. Poor concentration or difficulty making decisions. 6. Feelings of hopelessness. During the 2-year period of the disturbance, the person has never been without the symptoms in criteria A and B for more than 2 months at a time. No Major Depressive Episode has been present during the first 2 years of the disturbance. There has never been a Manic Episode, a Mixed Episode, or a Hypomanic Episode and criteria have never been met for Cyclothymic Disorder. The disturbance does not occur exclusively during the course of a chronic Psychotic Disorder, such as Schizophrenia, or Delusional Disorder. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). The symptoms cause clinically significant distress of impairment in social, occupational, or other important areas of functioning. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 217 Criteria for Adjustment Disorders A. The development of emotional or behavioural symptoms in response to an identifiable stressor(s) occurring within 3 months of the onset of the stressor(s). B. These symptoms or behaviours are clinically significant as evidenced by either of the following: 1. Marked distress that is in excess of what would be expected from exposure to the stressor. 2. Significant impairment in social or occupational (academic) functioning. C. The stress-related disturbance does not meet the criteria for another specific Axis I disorder and is not merely an exacerbation of a pre-existing Axis I or Axis II disorder. D. The symptoms do not represent Bereavement. E. Once the stressor (or its consequences) has terminated, the symptoms do not persist for more than an additional 6 months. Specify if: Acute: if the disturbance lasts less than 6 months. Chronic: if it lasts for 6 months or longer. Adjustment disorder with anxiety in which the stressor is a serious general medical condition Diagnostic Decision Tree for Depressive Disorders in DSM-IV Depression is challenging phenomenon, because it can occur on a spectrum from sadness to major psychiatric disorder. Mood change in response to a life threatening illness can also be considered a normal reaction to an abnormal event. Thus, the definition of depression used to categorise patients’ responses will affect the estimate of prevalence. In psychiatry, the following algorithm is usually applied to determine the appropriate DSM-IV diagnosis for a depressive episode: Does the distress meet the criteria for one or more Major Depressive Episodes? • If yes, then the diagnosis is Major Depressive Disorder. Does the distress not meet criteria for Major Depressive Episode? • If yes, and is greater than two years mood duration, then the diagnosis is Dysthymic Disorder. Is it less than two years mood duration? • If yes, then the diagnosis is Depressive Disorder not otherwise specified. Consider the research criteria: Minor Depressive Disorder. Is the distress a response to an identifiable stressor? • If yes, then the diagnosis is Adjustment Disorder with Depressed mood, or Mixed Anxious and Depressed mood. N.B., Both the criteria and the diagnostic decision tree are adapted from: American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders: DSM-IV, 1994.97 Criteria for Anxiety Disorder Due to a General Medical Condition A. B. Prominent anxiety, Panic Attacks, or obsessions or compulsions predominate in the clinical picture. There is evidence from the history, physical examination, or laboratory findings that the disturbance is the direct physiological consequence of a general medical condition. C. The disturbance is not better accounted for by another mental disorder (e.g. Adjustment Disorder With Anxiety) in which the stressor is a serious general medical condition). D. The disturbance does not occur exclusively during the course of a delirium. E. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. Specify if: With Generalized Anxiety: if excessive anxiety or worry about a number of events or activities predominates in the clinical presentation. Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review 218 With Panic Attacks: if Panic Attacks predominate in the clinical presentation. With Obsessive-Compulsive Symptoms: if obsessions or compulsions predominate in the clinical presentation. Love97 conducted a literature review of psychological screening instruments used in breast cancer research. The following tables (from Love, pp. 62-6497) summarise the measures identified as being suitable, not suitable, or suitable for a specific application in a breast cancer population (only measures used in the studies reported in the present systematic review are described below): Table 28. Suitable screening tools to measure psychological distress in breast cancer patients (Love, pp. 62-63)97 Application Comments To detect depression in a clinical setting BDI-SF is a short but valid scale for assessing severity of depression. It correlates well with the full BDI scale and is freely available. However, three of the items refer to somatic symptoms. To detect anxiety in a clinical setting The HADS anxiety subscale appears to be a reliable measure of anxious mood and related symptoms. It does not confound anxiety disorder with personality and state manifestations of anxiety. To form part of a research project concerning distress in women with breast cancer. BDI-PC is a short scale and is validated as a screening tool for depression in primary care patients. It excludes somatic items and correlates with the BDI-II but it needs to be validated with a breast cancer patients. It needs to be purchased. Table 29. Screening tools not considered suitable for researching psychological distress in breast cancer patients (Love, p. 63)97 BDI Beck Depression Inventory. A well-established measure of depressive symptom severity but the somatic items are likely to be problematic in chemotherapy and radiotherapy settings. BDI-II Beck Depression Inventory – II. A recently developed version of the BDI that has not been validated for breast cancer populations and needs to be purchased. BDI-PC Beck Depression Inventory – PC. A promising version of the BDI-II for screening primary care patients. It is not validated for use with cancer patients and needs to be purchased. CES-D Centre for Epidemiological Studies-Depression. Although it is well established in epidemiological research, it is less commonly used in cancer studies and its assessment of symptom frequency rather than severity is idiosyncratic. STAI State-Trait Anxiety Inventory. The two scales assess aspects of anxiety that are not necessarily related to mood disorder and distress. The trait scale taps into personality factors and the state scale assesses current affective experience. Table 30. Screening tools considered suitable for specific applications (Love, p. 64) 97 BDI-SF Beck Depression Inventory – Short Form. It is suitable for depression only and possibly contaminated by three somatic items. It is freely available. HADS Hospital Anxiety and Depression Scale. Only the anxiety subscale can be considered valid as the depression subscale performs poorly when compared with operationally defined syndromes of depression. Combined with other scales, such as the BDI-SF, it might prove suitable. SF-36 MOS Health Survey Short Form – 36. 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