Non hormonal interventions for hot flushes in women with a history of breast cancer
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The aim of the review is to assess the effectiveness of non hormonal therapies for improving hot flushes in patients with breast cancer.
Primary Objective:
To examine the effectiveness of non‐hormonal treatments for relieving hot flushes in women with breast cancer compared to placebo or no treatment group.
Secondary Objectives:
To determine adverse effects of non‐hormonal treatments
To evaluate the impact on quality of life of non‐hormonal treatments versus control or placebo.
Background
Worldwide, breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer mortality in women. Annually, more than a million women are diagnosed with this condition and 370000 die. (Ferlay 2001)
Women with breast cancer experience a myriad of symptoms. Vasomotor symptoms (hot flushes) may be experienced as a consequence of natural menopause, but in this group, hot flushes are more commonly caused by either breast cancer treatment with endocrine therapy or chemotherapy‐induced ovarian suppression (Day 1999, Ganz 1998). The frequency and intensity of treatment‐induced symptoms are greater than those associated with natural menopause (McPhail 2000). Postmenopausal tamoxifen users are 2.6 times more likely to experience severe hot flushes than nonusers. These vasomotor symptoms, particularly if intense, may interfere with normal habits, disrupt sleep and affect quality of life (Carpenter 1998). Additionally, they may compromise long‐term compliance with breast cancer therapy (Love 1991).
Estrogens and progesterone promote epithelial growth and differentiation of breast cancer cells. Cellular concentration of estrogen receptor (ER) or progesterone receptor (PR) are demonstrated in approximately 60% of these tumors and these are therefore considered to be hormonally responsive (Allegra 1980) Endocrine therapy aims to interfere with the sexual steroids regulatory pathways, particularly estrogens, and can be achieved by several means including ovarian ablation, drugs that block estrogen receptor (ER), i.e. tamoxifen, or drugs that block peripheral conversion from adrenal androgens to estrogens, i.e. Aromatase inhibitors.
Endocrine therapy is an alternative for hormone receptor positive breast cancer at different stages. The role of endocrine therapy is well established in patients with metastatic breast cancer (Kiang 1977, Mouridsen 1978). In patients with resectable early‐stage breast cancer, it is used as an adjuvant therapy to prolong disease‐free survival (EBCT 1998, EBCT 1996). There is some evidence supporting the administration of endocrine therapy in non‐resectable tumors to reduce their size and make them resectable.
In postmenopausal women, hormonal replacement therapy relieves menopausal symptoms to a large extent, but concern about long term safety limits its use to the shortest possible period (Rossouw 2002, Chlebowski 2003, Beral 2003). Given the known proliferative effects of estrogens on breast cancer, estrogen replacement is not recommended in this group. Progestational agents are also effective in relieving menopausal symptoms, but uncertainties exist about its safety. Theoretical concerns and in‐vitro data suggest that progestational agents may unfavorably affect prognosis (Hofseth 1999).
Some alternatives to hormonal therapy for hot flushes include selective serotonin reuptake inhibitors (SSRI's) ( Stearns 2000, Stearns 2003), Neuroendocrine agents such as clonidine (Pandya 2000), gabapentin (Guttuso 2003) and alternative medicine compounds (Taylor 2002). There is no clear evidence on the effectiveness of different non hormonal interventions in the treatment of vasomotor symptoms in women with breast cancer. This review aims to address this issue.
Objectives
The aim of the review is to assess the effectiveness of non hormonal therapies for improving hot flushes in patients with breast cancer.
Primary Objective:
To examine the effectiveness of non‐hormonal treatments for relieving hot flushes in women with breast cancer compared to placebo or no treatment group.
Secondary Objectives:
To determine adverse effects of non‐hormonal treatments
To evaluate the impact on quality of life of non‐hormonal treatments versus control or placebo.
Methods
Criteria for considering studies for this review
Types of studies
All randomized controlled trials assessing the effects of non hormonal interventions.
Types of participants
-
Women of any age suffering from hot flushes or night sweats due to endocrine therapy for breast cancer.
-
Women of any age suffering from hot flushes or night sweats due to menopause secondary to chemotherapy for breast cancer, with or without concomitant endocrine therapy.
-
Women of any age suffering from hot flushes or night sweats due to menopause and who have a past history of breast cancer, precluding the use of hormonal treatments.
Endocrine therapy includes:
-
Ovarian ablation (chemical or surgical)
-
Selective Estrogen Receptive Modulator (SERM) such as tamoxifen or fulvestrant .
-
Aromatase inhibitors
Chemotherapy includes:
-
Any chemotherapy able to induce chemical ovarian ablation with vasomotor symptoms.
Types of interventions
Any non hormonal therapy administered for at least one month. Non hormonal therapy is defined as those treatments which are known not to have proven or supposed hormonal activity,
For example:
Pharmacological agents such as:
-
Vitamin E
-
Neuroendocrine agents: Clonidine, Ergotamine‐phenobarbital‐belladona, Gabapentin, Veralipride
-
Selective Serotonine Reuptake Inhibitors (SSRIs): Venlafaxine, Paroxetine, Sertraline, Fluoxetine, Mirtazapine, Trazodone
Non‐pharmacological:
We will include complementary or alternative therapies such as meditation, yoga, ayurveda, aromatherapy, acupuncture, magnetic therapy, applied relaxation, biofeedback, hypnosis and behavioural treatments (breathing exercises like paced respiration, aerobic exercise), compared to placebo or non‐treatment control group.
Types of outcome measures
-
Hot flushes are defined as a sudden sensation of heat/sweat centered on the face and upper chest.
Primary outcomes:
-
Frequency of event (hot flushes or night sweats) or
-
Severity of event as reported through validated instruments such as patients' diaries or other well‐validated methodology
Secondary outcomes:
-
Risk of recurrence of breast cancer and/or survival.
-
Any side effects of non hormonal therapies for hot flushes.
-
Any effect not listed as an outcome and reported as a side effect by the authors.
-
Health related quality of life as measured by any validated generic or condition‐specific instrument.
Search methods for identification of studies
All reports describing randomized controlled trials of non‐hormonal treatment for hot flushes in women receiving endocrine therapy for breast cancer will be obtained using the search strategy of the Breast Cancer CRG. For the search on the specialised register, the following search terms will be used: "hot flush", "hot flushes", "hot flash", "hot flashes", "vasomotor symptoms", "non‐hormonal therapy", "non hormonal therapy", "selective serotonin reuptake inhibitors", (SSRI, Fluoxetine, Sertraline, Paroxetine, Citalopram, Venlafaxine, Mirtazapine, Trazodone), Neuroendocrine agent (Gabapentine, Clonidine, Veralipride, Methyldopa), Vitamin E .
In addition to a search of the specialised register, the following databases will be searched: MEDLINE, EMBASE, CINAHL, PsycInfo, Bioabstracts, CENTRAL, LILACS. For this purpose additional search terms may be used ie. "endocrine therapy", "alternative therapy", "breast cancer" , "psychotherapy". Hand searches in relevant journals will be done. Reference lists of included trials, conference abstracts and relevant review articles will also be searched.
Data collection and analysis
1.Study Selection.
Only randomised controlled trials that assess the effects of non hormonal intervention in breast cancer patients will be included. The titles and abstracts found through the search strategy defined above will be scanned by (GM) and (JC) to select those potentially eligible. If one of the 2 reviewers has doubt about the eligibility, the full text paper will be reviewed. The full‐text paper of all potentially eligible studies will be assessed independently by (DC) and (GAR). A third reviewer (LML or TP) will resolve any discrepancies.
2.Assessment of Methodological Quality
(GAR) and (DC) will independently assess the methodological quality of the studies selected. Discrepancies will be resolved by a third reviewer (LML). Each study will be graded as A (low risk of bias), B (moderate risk of bias) or C (high risk of bias) according to the allocation score described below.
Internal Validity:
1) Was the assigned treatment adequately concealed prior to allocation?(see below)
2) Were the outcomes of patients who withdrew or were excluded after allocation described and included in an "intention to treat" analysis?
3) Were the outcome assessors blind to assignment status?
4) Were the treatment and control group comparable at entry?
5) Were the subjects blind to assignment status following allocation?
6) Were the treatment providers blind to assignment status?
7) Were the care programs, other than the trial options, identical?
8) Were the withdrawals <20% of the study population
Allocation Score (criterion 1 above)
Score A
-
Some form of centralized randomization scheme, such as having to provide participant details by phone to receive treatment group allocation
-
A scheme controlled by a pharmacist.
-
In a pharmaceutical study, sequential administration of pre‐numbered or coded containers to enrol participants.
-
An on‐site computer system, given that allocations are in a locked unreadable file which can be accessed only after inputting participant details.
-
Assignment envelopes, provided that they are sequentially numbered, sealed, and opaque.
-
Other combinations which appear to provide assurance of adequate concealment.
Score B
-
Assignment envelopes, without description of adequate safeguards
-
Use of a "list" or "table"
-
Flip of a coin
-
A trial in which the description suggests adequate concealment, but other features are suspicious ‐ for example, markedly unequal controls and trial groups
-
Stated random, but unable to obtain further details
Score C
-
Alternation.
-
Case record numbers, dates of birth, day of the week, or any other such approach.
-
Any allocation procedure transparent before assignment, such as an open list of random numbers.
Other aspects of study quality including the extent of blinding (if appropriate), whether groups were comparable at baseline, the extent of losses to follow‐up, non‐compliance, whether the outcome assessment was standardized, and whether an "intention to treat" analysis was undertaken, will be assessed using the standard checklist defined in the Cochrane Reviewers' Handbook 4.2.0. This information will be presented in a table describing the included studies and will provide a context for discussing the relevance of the results. Furthermore it will be used in a number of sensitivity analyses (see below)
3.Data Collection
The data from included studies will be extracted independently by (GAR) and (DC) using forms designed by the review group. Discrepancies will be resolved by discussion. For each included study, information regarding the methods of the study (as per quality assessment checklist), the participants (age range, eligibility criteria), the nature of the interventions, and data relating to the outcomes specified above will be collected. Where possible, authors will be approached to provide missing data.
4. Analysis
Statistical analysis will be performed in accordance with the guidelines for statistical analysis developed by the Cochrane Collaboration.
Heterogeneity between the results of different studies will be examined qualitatively by inspecting the distribution of point estimates for the effect measure and the overlap in their confidence intervals on the forest plot. Quantitatively, a formal statistical test will be use to check for heterogeneity (Q statistic). Where appropriate a pooled effect measure will be computed. It is planned to pool results by types of interventions (i.e. neuroendocrine agents, SSRIs, vitamins, non‐pharmacological interventions). Results will not be pooled when the statistical test for heterogeneity reveals a p value < 0.05
For dichotomous data, results for each study will be expressed as a relative risk with 95% confidence intervals and combined for meta‐analysis when appropriate with RevMan 4.2 using a fixed effects model with the Mantel‐Haenszel method in the primary analysis.
For continuous data, results from each study will be expressed as a weighted mean difference (WMD) with 95% confidence intervals and combined for meta‐analysis. If outcomes are measured in different ways, the standardized mean difference (SMD) will be used. Meta‐analytic methods for continuous data assume that the underlying distribution of the measurements is normal. Where data are clearly skewed and results are reported in the publication as median and range with non parametric tests of significance, the results will also be reported in the Other Data section of the review.
If enough studies are found we plan to perform a number of subgroup analyses to identify possible sources of heterogeneity. These hypotheses will consider:
-
Endocrine therapy vs. chemotherapy induced menopausal symptoms.
-
Type, doses and duration of intervention.
Furthermore, it is planned to perform a number of one‐way sensitivity analyses on results to look at the possible contribution of:
-
Differences in quality of studies depending on randomization concealment and blinding.
