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What can be done to treat menopausal symptoms in breast cancer patients?

silvia jansen/istockphoto.comAround 80 per cent of women diagnosed with breast cancer are over 50 years of age so many are likely to be menopausal. Many will have the classic vasomotor symptoms of hot flushes and sweats (see Panel 1) and may already be on hormone replacement therapy to help control them. However, with the diagnosis of breast cancer, these women will be taken off HRT pending tissue tumour study results.

Panel 1: Menopause

When a woman is at the end of her reproductive phase, she will go through the menopause — her ovarian function declines and then stops. This can occur anytime between the ages of 45 and 55 years, with a median age of 51 years.1

Around 75 per cent of women who go through the menopause struggle with vasomotor symptoms. The exact mechanisms are not understood, but it is thought that negative feedback via the hypothalamus affects the thermoregulatory centre, resulting in the classic hot flushes and sweats. Other symptoms include sleep deprivation (due to night sweats), a cluster of emotional symptoms, including irritation and depression, and bladder, sexual and bleeding problems.

Generally women who feel that menopausal symptoms are adversely affecting their quality of life, will see their GP, who will perform a risk-benefit analysis for hormone replacement therapy. HRT is linked with an increase in breast cancer risk,2 and women will be advised about the monitoring needed, including self examination and having a mammogram every three years between the ages of 50 and 70 years.

Furthermore, HRT is likely to be avoided in women prescribed anti-oestrogen therapy as their ongoing breast cancer treatment to reduce cancer recurrence (see Panel 2). Typical anti-oestrogens include tamoxifen and the aromatase inhibitors (anastrozole, letrozole and exemestane).

Panel 2:Breast cancer treatment

Acute phase A patient presents with symptoms (eg, a lump, inverted nipple, discharge from the nipple, swelling in the armpit) which are investigated. With a diagnosis of breast cancer, the breast cancer team will make an assessment of tumour stage and grade, and a prognosis. Management in the acute phase can include chemotherapy, radiotherapy (in combination or alone) and surgery (eg, mastectomy and removal of ovaries with or without hysterectomy — the latter may considered for women who have completed their family and where there is a need to reduce all possible endogenous oestrogen exposure).

Survivorship After acute treatment, women with breast cancer enter the survivorship phase, where they will live with their diagnosis and where ongoing adjuvant treatment aims to reduce risk of recurrence.

If tumour tissue studies show that a woman’s cancer was oestrogen receptor positive, she will be prescribed tamoxifen or an aromatase inhibitor, which act as anti-oestrogens. Tamoxifen is a selective oestrogen receptor modulator which occupies oestrogen receptors in the breast.

Aromatase inhibitors act predominantly by blocking the conversion of androgens to oestrogens but they do not inhibit ovarian oestrogen synthesis and should not be used for premenopausal women.

Women with human epidermal growth factor-2 (HER2) positive receptor status are prescribed trastuzumab (Herceptin).

Side effects The likelihood of hot flushes and sweats is higher with tamoxifen. Typically with aromatase inhibitors, patients will also complain of joint aches and pains. The Herceptin summary of product characteristics lists hot flushes as a very common side effect.3

In postmenopausal patients, risk of osteoporosis is high due to ageing and oestrogen deficiency. This risk is further increased in breast cancer patients prescribed aromatase inhibitors and they will need to be assessed for bone sparing therapy (eg, bisphosphonates) and advised on lifestyle interventions. Patients with early invasive breast cancer should have a baseline dual energy X-ray absorptiometry (DEXA) scan if they are starting aromatase inhibitor therapy, if they have treatment induced menopause or if they are starting ovarian ablation or suppression therapy.4 Because tamoxifen can help protect bone mineral density, NICE states that patients with early invasive breast cancer who are started on this drug will not require a baseline DEXA scan, regardless of pre-treatment menopause status.

At the Northwick Park Breast Cancer and Menopause Unit, it has been agreed that patients with tamoxifen side effects seriously affecting their quality of life can be referred for reassessment by their oncologist, with a view to considering alternatives for breast cancer recurrence risk reduction.

When a woman’s HRT is stopped (see below), menopausal symptoms can return. In addition, either breast cancer treatment — tamoxifen or the aromatase inhibitors — can themselves cause hot flushes and night sweats as side effects. Moreover, surgery and radiotherapy can also affect ovary function, causing menopause to begin earlier than expected or triggering menopausal symptoms.

Pharmacists may be approached by women in the survivorship phase for advice to help with control of menopausal type symptoms. Management plans can combine both pharmacological and non-pharmacological treatments.

Stopping HRT

Breast cancer treatment is not a complete contraindication for HRT. For postmenopausal patients to be prescribed aromatase inhibitors National Institute for Health and Clinical Excellence guidelines4 state that although HRT is not recommended, in exceptional circumstances it may be used by women with early stage cancer with severe menopausal symptoms, as long as the woman has been fully informed about the associated risks. For patients on tamoxifen, continuing HRT may be a more acceptable clinical decision due to its anti-oestrogenic activity on breast tissue. Any decision to use HRT for a woman on tamoxifen, or with non-hormone sensitive tumours, should include full discussion of risks and benefits with patient.

For most patients, however, a decision will be made to stop HRT, often along with any local oestrogen replacement therapy (see later) and it is important to counsel these patients about possible breakthrough vasomotor symptoms. Tibolone and progestogens are not recommended as alternatives to oestrogen-containing HRT for treating menopausal symptoms in breast cancer patients.4,5

Although it is generally advised that HRT is stopped immediately (particularly if surgery or other treatment is imminent), if time allows, it is possible (and kinder) for the patient to be weaned off HRT slowly before starting drug treatment for breast cancer, for example, halving the dose for a month before stopping. Slow weaning can allow rebound vasomotor symptoms to be managed more effectively.

Non-hormonal treatments

Non-hormonal treatments may be prescribed for menopausal symptoms in women with breast cancer and in the survival phase. These include clonidine, selective serotonin receptor inhibitors, venlafaxine (a serotonin noradrenaline receptor inhibitor; SNRI) and gabapentin (see summary in Panel 3).

Panel 3: Treatment options for symptoms*

Clonidine 50µg tablets bd, increasing to 75µg dose bd after two or three weeks. Also available in a transdermal formulation.

Paroxetine 10mg od. Increasing dose offers no further benefit. Other SSRIs can be prescribed, but the Nelson meta-analysis6 recommends paroxetine as the first-line choice in the SSRI group. Interaction between SSRIs and tamoxifen, so avoid if possible in women with breast cancer prescribed tamoxifen [see main text].

Venlafaxine 37.5mg on, increasing to 75mg od (long-acting formulation) after two weeks. Use of a long acting once daily dose may help alleviate the side effect of nausea

Gabapentin 300mg on for two weeks, then 300mg bd for two weeks then a maintenance dose of 300mg tds. If drowsiness is troublesome, the total dose can be given at night.7

*Clonidine is licensed for control of menopausal symptoms but the other agents in this Panel are not. However, there is an evidence base for prescribing.6,8,9

Tamoxifen interactions

The efficacy of tamoxifen therapy for the treatment of breast cancer varies widely among individuals. Plasma concentrations of its active metabolite, endoxifen, are associated with the cytochrome P450 (CYP) 2D6 genotype.
Some SSRIs, such as paroxetine and fluoxetine, are known to inhibit CYP2D6.10 Venlafaxine is thought to be a less potent inhibitor. Jin et al have demonstrated that the plasma endoxifen concentration was slightly reduced in women taking venlafaxine whereas it was reduced substantially in subjects who took paroxetine.10 Therefore, when prescribing an SSRI or SNRI, consideration needs to be given to this interaction, which may result in lowered tamoxifen efficacy.
A recent trial where women with breast cancer and on tamoxifen, and who were also taking citalopram, reported no adverse recurrent breast cancer outcome with the use of citalopram over three years.11,12
Interactions between CYP2D6 polymorphisms and other drugs that are CYP2D6 inhibitors may also be associated with altered tamoxifen activity.

Local oestrogen replacement therapy

In menopause, local oestrogen therapy can be prescribed for relief of vaginal dryness and painful intercourse — symptoms of atrophy. However safe use for breast cancer patients has not been studied within randomised controlled trials of long duration.
With aromatase inhibitors, both local oestrogen therapy and systemic HRT are stopped. With tamoxifen, some consultants will allow vaginal oestrogen therapy. Current clinical consensus is that local oestrogen replacement therapy could be used as long as high levels of systemic absorption are avoided. Estring, a vaginal oestrogen ring, can be used for up to two years without resulting in high sustained systemic absorption warranting co-prescribed progestogen for endometrial protection,13 but this formulation has not been tested in breast cancer patients. For patients with tissue tumour studies suggesting oestrogen receptor negative status, Vagifem (10µg estradiol vaginal tablets) or the low potency Ovestin or Ortho-Gynest oestrogen vaginal creams (0.1 per cent and 0.01 per cent estriol, respectively) could be considered. It should be noted that these formulations are licensed for short duration use by postmenopausal women in the UK but in clinical practice have been used for longer periods based on longer duration licences outside the UK.

For patients taking aromatase inhibitors and who have severe symptoms, consideration may be given to switching to tamoxifen, which, unlike aromatase inhibitors, does not seem to cause much vaginal atrophy.

Alternatives to HRT

The evidence base for most alternative strategies to HRT is weak and adoption of lifestyle and self care options4,14 should be based on the knowledge that many have not been tested by rigorous study designs. However, these form an important part of holistic management plans. Patients can be given advice on weight reduction or maintenance, smoking cessation, caffeine reduction, stress management, both weight-bearing and toning exercise, and on environmental control (eg, avoiding heat).

Patients may benefit from counselling, which ideally should be personalised and address realistic expectations. This might include psychotherapy and psychosexual therapy.

There are numerous alternative therapies, with examples cited in the literature including reflexology, massage, acupuncture (which has some evidence base, but survivors of breast cancer who have had axillary surgery should be advised to avoid acupuncture to the particular arm), aromatherapy (NICE has advised some caution with this), hypnotherapy and homoeopathy.4,15 Patients wishing to try any of these should be advised to consult a qualified, regulated practitioner.

Herbal treatments should not be recommended for use by breast cancer patients on aromatase inhibitors and caution is advised with use of these supplements in all breast cancer patients because all have some oestrogenic activity and safety data for use in these patient groups is not available.16 NICE has stated that soy isoflavones, red clover, black cohosh, vitamin E and magnetic devices are not recommended for treating menopausal symptoms.4,14–16

Advice should be culturally sensitive. For example, phyto-oestrogens can form a large part of the diet in certain ethnic groups. These patients can be advised to continue with what may be considered to be normal levels of dietary intake, but it is not known if it is safe for breast cancer patients to take phyto-oestrogen supplements.

Non-hormonal vaginal lubricants or moisturisers, such as Replens (a bio-adhesive vaginal moisturiser), Astroglide, Durex Sensilube and Sylk, may be recommended for patients with vaginal symptoms if local oestrogen replacement therapy is not acceptable. KY Jelly is a vaginal lubricant that is often recommended but some patients find it messy to use.

About the author

Nuttan Tanna is pharmacist consultant, womens health and older people, at the NW London Hospitals NHS Trust. She is the co-author of prescribing guidelines used by the trust’s joint breast cancer and menopause symptom clinic, available from nuttantanna@nhs.net.

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Citation: The Pharmaceutical Journal URI: 11108035

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