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Management of menopausal
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received breast cancer treatment
Systematic review
February 2016
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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
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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
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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
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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
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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
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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.
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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).
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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.
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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
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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
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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
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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
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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
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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. Requires a sophisticated computer-based scoring system.
Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review
219
SF-12
MOS Health Survey Short Form – 12. Looks promising but needs further validation with breast cancer
patients.
Management of menopausal symptoms in women who have received breast cancer treatment. Systematic review
220
16
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