Drug treatment (systemic therapy)

When are drugs used?

Surgery alone was used to treat breast cancer until it became clear that some cancers had spread to other parts of the body by the time surgery was performed. After such surgery, untreated cancer cells grew in the parts of the body that they had spread to and this caused symptoms and problems in these areas.

Studies have now shown that women with early breast cancer who receive drug treatment or systemic therapy after surgery to treat cells that have spread have a better outcome, with a longer survival and fewer recurrences.

Drug treatments in common usage for breast cancer include:

• hormone therapy

• chemotherapy

• newer targeted biologic treatments such as trastuzumab.

The same drugs are used to shrink cancers before surgery (sometimes called neoadjuvant therapy), after surgery as adjuvant therapy (treatment given in addition to surgery and radiotherapy) and to treat breast cancer that has returned or spread.

Choosing treatments for individual patients is not straightforward. It is usually a balance of weighing up the benefits compared with the side effects. When deciding on a particular treatment the following factors need to be considered:

• the risk of the cancer returning

• the likely benefits of the treatment

• the risks and side effects of the treatment

• the general health of the patient

• the views of the patient.

Hormone therapies

Why is oestrogen important?

The hormones oestrogen and progesterone play an important part in the control of growth and development of the normal breast. At puberty these hormones increase in amount and are responsible for the development of the breast. During pregnancy as hormone levels increase, growth of breast tissue allows production of milk.

As well as controlling the activity of normal cells, oestrogen is also involved in controlling the activity of cancer cells. About three-quarters of breast cancers contain receptors for oestrogen and/or progesterone within the cells.

Many breast cancers are dependent on oestrogen and progesterone for their growth and removal of oestrogen can stop cancer cells growing and cause them to die.

It is now routine to test breast cancers for oestrogen receptors (ERs, where E is for estrogen – the American spelling) and progesterone receptors (PgRs) (see page 81). Some tumours do not have any oestrogen receptors and are referred to as ER negative and therefore not dependent on hormones.

Both premenopausal and postmenopausal women produce oestrogen. In premenopausal women the major source of oestrogen is the ovaries. The brain controls the amount of oestrogen that the ovaries produce by producing a hormone called luteinising hormone-releasing hormone (LHRH).

The LHRH stimulates a gland under the brain, known as the pituitary gland, to produce hormones that then stimulate the ovaries to produce oestrogen.

In postmenopausal women male hormones, which are produced from a gland that sits on the kidneys, called the adrenal gland, are converted to oestrogen in fat, muscle, liver, breast tissue and even within breast cancers.

The conversion from male to female hormones is through an enzyme called aromatase. There are now very specific drugs that block this enzyme and they are called aromatase inhibitors.

How do hormone treatments work?

Hormonal treatments work by either:

• blocking the action of oestrogen or

• preventing the production of oestrogen.

These treatments are very effective and generally produce fewer side effects when compared with chemotherapy. Women whose tumours are ER negative do not benefit from these treatments.

As well as reducing the risk of cancer returning, these drugs are also effective at reducing the development of new breast cancers. There are a variety of hormone treatments including:

• removal of the ovaries

• suppression of the ovaries

to reduce oestrogen production in premenopausal women.

Removal of the ovaries

The ovaries can be removed by an operation (oophorectomy) or radiotherapy can be given to the ovaries, which stops them functioning. The easiest way of removing the ovaries is via keyhole surgery using a laparoscope. The problem with surgical oophorectomy is that it produces a permanent and rapid onset of menopausal symptoms.

Nevertheless it is effective and is particularly important for women who have BRCA-1 or BRCA-2 gene mutations who are at increased risk of breast and ovarian cancer. Removal of the ovaries in these women dramatically reduces their chance of getting both ovarian and breast cancer. If women with gene mutations have had a breast cancer, oophorectomy reduces the chance of the cancer returning.

Suppression of the ovaries

LHRH agonists

Drugs have been developed that stop production of the hormones that stimulate the ovaries to produce oestrogen. These drugs are given by monthly injection and their medical name is luteinising hormone-releasing hormone agonists.

They can be used for women with early breast cancer, as treatment after surgery or for women with advanced breast cancer. The effects of these changes are usually reversible when the drug is stopped.

Many women find that their periods do not return immediately when they stop these drugs and it can take many months or even years for periods to return.

The chance of you getting your periods back depends on your age and what other treatment you have had.

These drugs are currently being investigated in women with ER-negative cancers (tumours that are not sensitive to oestrogen) who are having chemotherapy

to try to protect the ovaries from the effects of chemotherapy. The hope is that, by switching off the ovaries, there will be less damage by the chemotherapy and this may allow women to maintain their fertility even after chemotherapy.

The most common drug and the only one licensed for breast cancer is goserelin (Zoladex). There are other drugs available including buserelin (Prostap). The other drugs are used mainly in prostate cancer but, as they have an identical action to goserelin, doctors occasionally prescribe them for breast cancer.

Goserelin is given as a monthly injection into the lower abdomen, into the fat under skin below the umbilicus (belly button). There is a three-monthly injection available but it is not always effective in women with breast cancer for the whole three-month period and is used mainly in men with prostate cancer.

LHRH agonists, when used in early breast cancer, are usually given for between two and five years to premenopausal women and can be given as an alternative to chemotherapy or after chemotherapy. They are often combined with other drugs such as tamoxifen or an aromatase inhibitor.

Drugs that interfere with the actions of hormones

Antioestrogens

Rather than stopping the production of oestrogen these drugs stop oestrogen getting to the oestrogen receptors where it works. These are often called antioestrogens.

The most common of these drugs is tamoxifen. Fulvestrant is another antioestrogen, which is occasionally used. Tamoxifen is a drug that has been widely used and has proved to be enormously successful for the treatment of women with ER-positive breast cancer in all ages and at all stages. The tamoxifen is taken as a once-daily tablet.

Tamoxifen

Tamoxifen given for five years to women with early breast cancer has been shown to reduce significantly the risk of recurrence and deaths from breast cancer, as well as the risk of developing a new cancer in the opposite breast.

Not all women who take tamoxifen benefit from it and one possible reason is that there is variation in how individuals handle tamoxifen when it gets into the body. Tamoxifen is converted after it has been absorbed to a more active antioestrogen. Some individuals convert more of the tamoxifen to the active form than others. Tests are being developed – those who are low converters get less benefit because they don’t produce enough of the active form of tamoxifen for it to be effective. Low converters could then be given alternative drugs.

Tamoxifen is equally effective in pre- and postmenopausal women and in the latter it can be sequenced with the new aromatase inhibitors. Schedules include two years of tamoxifen followed by three years of an aromatase inhibitor or five years of tamoxifen followed by five years of an aromatase inhibitor.

Although tamoxifen has antioestrogen effects in the breast, in many other parts of the body its actions are similar to those of oestrogen. This has some benefits in that it preserves bone strength in postmenopausal women and lowers cholesterol, possibly reducing the risks of heart attack.

Side effects of tamoxifen

As it acts like oestrogen, it has some of the problems and complications that are seen in women who take hormone replacement therapy (HRT). The side effects of tamoxifen include:

• hot flushes

• vaginal discharge or irritation

• weight gain: randomised studies have not shown that women on tamoxifen gain more weight but weight gain is commonly reported by breast cancer patients on this drug

• increased joint pains

• eye problems: tamoxifen can slightly increase the risk of cataracts and another condition called iritis

• increased risk of deep venous thrombosis and pulmonary embolus (blood clots in the leg that can travel to the lungs); this is rare and the risk is thought only to be in postmenopausal women

• increased risk of developing endometrial cancer (cancer of the womb) in postmenopausal women; this type of cancer is rare but tamoxifen increases the likelihood that a woman will get endometrial cancer by about two to three times. For this reason any woman who develops vaginal bleeding on tamoxifen should be investigated.

Women should avoid becoming pregnant while they are taking tamoxifen because the effects on the baby are unknown. Women should use barrier forms of contraception because tamoxifen is a drug that has been shown to increase the likelihood of women getting pregnant – similar drugs to tamoxifen are used to treat infertility.

Fulvestrant

Fulvestrant is given as an injection into the buttock once a month. Studies are trying to find the best dose to use and are currently investigating higher doses – two injections every two weeks for the first month and then two injections monthly rather than the current once-a-month one-injection schedule that is in common use.

Fulvestrant is considered a ‘pure’ antioestrogen and does not have the same side effects as tamoxifen on the endometrium (lining of the womb) and does not seem to increase the risk of blood clots.

Aromatase inhibitors

These drugs interfere with the conversion of male hormones to female hormones. They are effective only in postmenopausal women and should not be used in premenopausal women. By reducing oestrogen production to extremely low levels, aromatase inhibitors deprive cancer cells of oestrogen, which results in the cancer cells dying and the cancer shrinking.

The aromatase inhibitors in common use are extremely specific and very effective and include anastrozole, letrozole and exemestane:

• Anastrozole in a dose of one milligram a day taken orally has been investigated extensively in both adjuvant treatment (treatment given in addition to primary therapy) to postmenopausal women and treatment of metastatic breast cancer (cancer that has spread). It appears to be somewhat more effective than tamoxifen.

• Letrozole given orally in a dose of two and a half milligrams per day has been shown to be considerably more effective than tamoxifen in metastatic breast cancer. Studies in early breast cancer have also suggested that it is more effective than tamoxifen when used as adjuvant therapy. Letrozole is widely used in women with large ER-positive breast cancers to shrink the cancer before surgery or to make a cancer that is not initially suitable for surgery operable. Studies have also shown that after five years of tamoxifen women who then take letrozole do better than those women who have no further treatment.

• Exemestane is the least commonly used of the aromatase inhibitors but is a very effective drug. The dose is 25 milligrams per day given orally. It can work in cancers that are resistant to letrozole or anastrozole. One study showed that women who took tamoxifen for two to three years and then switched to exemestane did much better than those women who continue on tamoxifen for five years. 

Side effects of aromatase inhibitors

These drugs are generally well tolerated. It is likely that they all have slightly different side effects and, because a woman has side effects with one drug, it does not mean that she will get the same side effect with another aromatase inhibitor.

Hot flushes

Studies have tended to show that there are slightly fewer hot flushes with aromatase inhibitors than there are on tamoxifen.

Vaginal dryness

As there is no oestrogen present this can cause vaginal problems. Although dryness can be treated by local creams including oestrogen creams, the amount of oestrogen in these creams needs to be extremely low because studies have shown that some oestrogen preparations given vaginally can result in significant levels of oestrogen in the bloodstream.

Muscle and joint pains

These appear to be much more common with the aromatase inhibitors than with tamoxifen.

Fatigue

Some women do complain of feeling tired on these drugs.

Increased rates of fractures

As these drugs stop oestrogen production and oestrogen is important for bones, women who take these drugs have a slightly increased risk of bone fracture. Women who are taking these drugs for a long time should have their bone density checked and, if the bones are thin (osteoporotic), treatment with a bisphosphonate (bone-strengthening drug) is usually effective at strengthening the bones. Bisphosphonates can be taken with the aromatase inhibitors, so it is not necessary to stop this treatment even if osteoporosis develops.

Treating hot flushes in women on tamoxifen or aromatase inhibitors

Hot flushes tend to improve with time but can be extremely troublesome, particularly if they occur at night in association with night sweats. Wearing cool cotton clothing can help.

Megestrol acetate is a drug that acts in the body like the natural female hormone progesterone and can be effective in hot flushes. It is used at a low dose (20 mg daily) and is effective in controlling hot flushes in about 80 per cent of women.

There is no evidence that megestrol acetate increases the risk of recurrence of breast cancer and it certainly improves quality of life for women with hot flushes.

Drugs used to treat depression, including venlafaxine and fluoxetine, have been shown to be somewhat effective in hot flushes but fluoxetine may act by making tamoxifen less effective so caution is required.

A drug called gabapentin has been shown recently to improve hot flushes.

Although some women take soy (containing phyto­oestrogens) and believe that this improves hot flushes, there is concern that some soy products contain substantial amounts of oestrogen-like substances so these products are not therefore generally recommended for treating hot flushes in women with breast cancer.

Studies have shown no consistent benefit from vitamin E and evening primrose oil.

Clonidine is very occasionally effective but is not a very pleasant drug to take and it is rarely worth trying.

THINK SHOULD BE A HEADING HERE

Studies of giving HRT to women have shown that it increases the risks of the cancer coming back, so it is not advised to give HRT to women with hormone-sensitive breast cancer.

Tibolone (Livial) is a drug that has oestrogen-like effects but is not actually an oestrogen. It does reduce hot flushes associated with tamoxifen but similar to HRT it increases the risk of cancer returning and so its use is not advised in women with breast cancer taking tamoxifen.

Most women take tamoxifen and a few younger premenopausal women who still have regular periods will be advised to take tamoxifen combined with LHRH agonist.

Studies in younger women have investigated whether combining an LHRH agonist with an aromatase inhibitor is better than combining it with tamoxifen. It looks as though combining LHRH agonists with tamoxifen or the aromatase inhibitor anastrozole is equally effective.

Postmenopausal women

In postmenopausal women the choices are tamoxifen or the aromatase inhibitors. The current options are:

• five years of tamoxifen

• five years of an aromatase inhibitor

• two to three years of tamoxifen followed by two to three years of an aromatase inhibitor

• five years of tamoxifen followed by three years of an aromatase inhibitor

• two years of an aromatase inhibitor followed by three years of tamoxifen.

Deciding which treatment you should have depends on your general health and the risk of the cancer returning. If you have had a deep venous thrombosis or pulmonary embolus in the past, tamoxifen is not suitable and you will receive an aromatase inhibitor.

Most women will now receive an aromatase inhibitor either immediately after surgery or after two to five years of tamoxifen.

Increasingly patients who have taken tamoxifen for two to three years are being switched to an aromatase inhibitor because studies have shown that this reduces cancer recurrence.

Nowadays most women who finish five years of tamoxifen will be advised to take an extra five years of treatment with letrozole because this not only reduces the chances of recurrence but also improves survival of women whose nodes were initially involved by cancer.

Chemotherapy after surgery (adjuvant chemotherapy)

Chemotherapy drugs are poisons that kill rapidly growing cells. Adjuvant chemotherapy is given to destroy any cancer cells that have escaped from the breast or the lymph glands to other parts of the body.

Even if all scans show that there is no evidence of any spread, it is known that in some women there are small groups of cancer cells that are undetectable and if these cancer cells are left untreated they can eventually cause problems. Chemotherapy can be given before or after surgery. When it is given after surgery, it is usually given immediately after surgery and before radiotherapy.

Chemotherapy and hormone therapy are not usually given together because chemotherapy is active against dividing or growing cells and hormone therapy switches off the growth of cells.

If you are to have chemotherapy and hormone therapy then the hormone therapy treatment will start after you have completed your chemotherapy.

Will I have chemotherapy?

The decision as to whether you have chemotherapy is based on:

• the size of the tumour

• whether the lymph nodes are involved

• the grade of the tumour

• the hormone receptor status of the tumour (ER

Intravenous chemotherapy

Sometimes chemotherapy is given before surgery, either to slow the growth of tumours that are growing rapidly or to shrink larger tumours. Chemotherapy, when given after surgery, usually starts before radiotherapy. Chemotherapy usually starts between three and four weeks after surgery, giving your body some time to recover from the effects of the operation.

Chemotherapy is most often given into a vein in your arm as a session of treatment, usually over a few hours. This is followed by a rest period usually of a few weeks, which allows your body to recover from any side effects of the treatment.

Generally you are more likely to receive chemotherapy if:

• your tumour is large (over two centimetres)

• your lymph nodes are involved

• the tumour is grade 3 (see page 212)

• if the cancer is HER2 positive (see page 212)

• you are aged under 50 years

• the tumour is ER negative (see page 138). If you have one or more of these features it is likely that you will be a good candidate for chemotherapy. Although chemotherapy is slightly more effective in ER-negative cancers, it is also effective in ER-positive cancers and further reduces the chances of the cancer coming back above and beyond that achieved with hormone therapy alone.

Benefits of chemotherapy

The benefit from chemotherapy depends partly on the risk of the cancer returning. Higher-risk women are more likely to get a benefit than lower-risk women.

Part of the effectiveness of chemotherapy in younger women is that it brings forward the age of menopause and so the ovaries stop producing oestrogen at a younger age than if no chemotherapy had been used.

Although chemotherapy appears to be effective in women of all ages its greatest benefit appears to be in younger women.

How is chemotherapy given?

Most women who receive chemotherapy will receive a combination of drugs. These are given as intravenous injections three weeks apart (a cycle). A course commonly consists of four, six, eight or even twelve cycles.

Commonly used drugs include anthracyclines, which have been shown to be one of the most effective types of drug in breast cancer; the most commonly used anthracyclines are doxorubicin (Adriamycin – A) and epirubicin (E). The anthracyclines are often combined with cyclophosphamide (C) and 5­

fluorouracil (F) as CAF or FEC (the initials of the drugs).

Other drugs in common use are the combination of cyclophosphamide, methotrexate and 5-fluorouracil, known as CMF.

Recently chemotherapy drugs called taxanes have been introduced in cancer treatment. They are derived from the bark of yew trees and there are two common agents in use: paclitaxel (Taxol) and docetaxel (Taxotere).

These drugs are used in women with metastatic breast cancer, but they are also used in some women with early breast cancer. The results from large studies of these drugs show a benefit in high-risk women so they are becoming increasingly used as part of adjuvant chemotherapy regimens.

Capecitabine is an oral drug that works similarly to 5-fluorouracil and is generally well tolerated; it has the obvious advantage of being in tablet form. Capecitabine is being tested after surgery and can be used either alone or in combination with other drugs in patients whose cancer has spread.

Commonly used regimens include the following:

• FEC: 5-fluorouracil, epirubicin and cyclophosphamide for six cycles

• CAF: cyclophosphamide, Adriamycin (doxorubicin) and 5-fluorouracil for four or six cycles

• Epi-CMF: three or four cycles of epirubicin or epirubicin followed by three or four cycles of CMF

• ACT: four cycles of doxorubicin (Adriamycin) and cyclophosphamide followed by three or four cycles of a taxane

• TAC: a taxane combined with doxorubicin (Adriamycin) and cyclophosphamide for six cycles

• AC: four cycles of Adriamycin (doxorubicin) and cyclophosphamide.

Other combinations are also used.

Chemotherapy before surgery (neoadjuvant chemotherapy)

Chemotherapy can also be given as initial treatment for larger or locally advanced breast cancers to shrink them down before surgery. This is known as neoadjuvant chemotherapy.

The advantages of neoadjuvant chemotherapy are that:

• a large tumour that would require a mastectomy to remove it may shrink sufficiently to allow lumpectomy or breast-conserving surgery

• if the cancer is locally advanced and not suitable for operation, the chemotherapy can make it operable

• if the tumour does respond and there is no cancer left after chemotherapy, this indicates that the long-term outlook is likely to be good

• if the drugs used are not effective, treatment can be changed.

Side effects of chemotherapy

Chemotherapy drugs are active against all dividing cells so tissues such as bone marrow, hair follicles, and the lining of the gut and bladder are all affected by chemotherapy and this explains why it causes unpleasant side effects. There are now treatments to combat most of these side effects.

Bone marrow suppression

Most chemotherapy drugs reduce the production of blood cells in the bone marrow. There are different types of cells in the blood and these include:

• white cells, which help fight off infection

• red cells, which carry oxygen round the body

• platelets, which are important for blood clotting.

If the production of any of these is markedly reduced by the chemotherapy, this could result in the problems listed below. If you develop any of these problems you should contact your doctor and get some advice.

A lowered resistance to infection

You will have blood counts taken before every cycle of chemotherapy. If your white count is low the chemotherapy may be put off, the dose may be reduced or you may be given a drug to stimulate white cell production.

The lowest levels of white count occur about seven to ten days after a dose of chemotherapy. It is very important if you feel hot or unwell and have any flu-like symptoms, including signs of fever, to contact the hospital immediately because these are signs of an infection.

If this happens, you usually have to go into hospital and receive antibiotics. If this happens for subsequent courses of chemotherapy a drug to stimulate your bone marrow to produce white cells can be given or the dose of the drug can be lowered to stop this happening again.

Anaemia (deficiency of red blood cells)

You can feel tired, lethargic, and dizzy and breathless if you are anaemic. If you are very anaemic this can be treated by a blood transfusion. Another option is to give you a drug called erythropoietin, which stimulates your bone marrow to produce more red cells.

Bruising/bleeding

Signs of a low platelet count include nosebleeds, bruising and unexplained bleeding. This can occur between cycles of chemotherapy and is a consequence of the effect of the chemotherapy on the production of platelets which play an important role in blood clotting.

Nausea and vomiting

These are very upsetting side effects and the doctors and nurses who give chemotherapy will work very hard at trying to prevent them. Anti-sickness medication will be started before you get chemotherapy and will continue for a few days afterwards. Even if you are feeling well you should take the medication because prevention is better than cure.

Sore mouth and mouth ulcers

This is a common complication of chemotherapy particularly after anthracyclines. It is important that you take great care about oral hygiene. Brush with a soft toothbrush and use mouthwashes after meals. Some people also complain of a dry mouth. You should avoid any major dental work while you are having chemotherapy.

Hair loss

This is almost inevitable with certain drugs including the anthracyclines and the taxanes. Scalp cooling can help reduce this but to be effective needs to be applied some time before chemotherapy is started and kept on for some time after it finishes.

There are two methods available to cool the scalp: one is to wear a ‘cold cap’ which is a cap containing gel that is cooled in the deep freeze; the second method blows very cold air on to your scalp.

Hair loss usually starts about two to three weeks after the first cycle of chemotherapy and by the second cycle most women will have lost all their hair.

Eyelashes, eyebrows and other body hair are also often affected. You should be fitted for a wig before chemotherapy begins.

Most women cope well with hair loss and find that it is not as bad as they thought it was going to be. Once your chemotherapy stops your hair will grow again but, when it comes in, it may be permanently softer and curly.

Premature menopause

Chemotherapy damages growing tissue including the ovaries and women who have chemotherapy are likely to have the menopause at a younger age. Even if your periods do not start after you have completed chemotherapy, it does not mean that you are postmenopausal.

In some women there is a gap of many months after the end of chemotherapy before menstruation returns. Chemotherapy will reduce the chances of you being able to become pregnant in the future.

If you are thinking of having children it is important to discuss this with your doctor before you start chemotherapy. There are ways of storing eggs or part of the ovary to try to get round this problem. Ongoing studies are looking at whether LHRH analogues can protect the ovaries from the effects of chemotherapy.

Although most women stop their periods during chemotherapy, it is important to realise that there is a small chance of you becoming pregnant while on chemotherapy, so you need to ensure that you take precautions and use barrier methods of contraception.

Fatigue

All chemotherapy causes women to be fatigued and tired. This is the side effect that women complain of most. It is important to realise that during chemotherapy you will not be able to do the things that you could before.

It does not mean, however, that you should stop going out. You may need to cut down on the amount that you would normally do but you should take regular exercise. Because you tend to do less this may cause weight gain so regular exercise (swimming or walking) will help to limit the weight that you might gain during treatment and will also improve your energy levels.

The problem with fatigue is that it often continues even after you have finished your chemotherapy and in some women it can last for many years.

Diarrhoea

Some women develop this but it can usually be controlled by medication.

Constipation

This is the most common side effect of the drugs given to stop sickness. It is important that you keep drinking and eat a well-balanced diet when you are having chemotherapy because this is the best way to stop this problem.

Thrombosis and pulmonary embolus

Women who have chemotherapy are at slightly increased risk of these complications. If you have any leg swelling or any breathlessness you should report this to your doctor immediately.

Problems with veins

Chemotherapy is given through the veins in the back of the hand. If you have had removal of all the axillary nodes from one side, chemotherapy is usually given into the opposite hand.

Once you inject chemotherapy into a vein, it damages the vein. This can result in the vein becoming sore and/or hardened and the blood stops flowing in the vein. This settles down over a few weeks.

Chemotherapy is usually given via a drip and it is important to ensure that the chemotherapy does not leak out from the vein into the tissues. Chemotherapy is given by experienced nurses and doctors who are aware of this problem.

Damage to your heart

Doxorubicin (Adriamycin) and to a lesser extent epirubicin can damage the heart if given in high doses. Doctors are aware of this and calculate carefully the dose so that you are unlikely to develop this problem. Sometimes before chemotherapy a heart scan is performed to check how effectively your heart is pumping.

A particular problem has been found in women given a combination of anthracyclines and the drug trastuzumab (Herceptin – see below). If you are getting this combination you will have a heart scan before treatment and you will also have regular scans during treatment to make sure that no damage develops.

Cystitis

Some drugs, especially cyclophosphamide, can cause irritation of the bladder (cystitis). This is usually prevented by drinking regular fluids.

Damage to nerves

The taxanes can cause damage to nerves of the hands and feet and this can cause pain, tingling or numbness. Report this to your doctor if this develops.

Redness of the hands and feet

5-Fluorouracil given intravenously and oral capecitabine (Xelda) can cause the palms of the hands and the soles of the feet to become red and sore.

Skin and nail changes

You may develop dry and flaky skin on your hands and feet after several cycles. Your skin will also be more sensitive to sunlight with a tendency to sunburn. Your nails can become discoloured.

Red urine

Epirubicin is red and you may notice that your urine is red for up to 24 hours after each injection

Dizziness/hot flush

These can sometimes occur when cyclophosphamide is injected.

Temporary taste changes

These can occur throughout treatment. Sharp and spicy foods often taste better than bland foods! Some patients lose their sense of taste.

Trastuzumab

Trastuzumab (Herceptin) is a newer type of drug that is given to women whose cancers have a lot of receptors for HER2 on the surface of their cancer cells. These cancers are known as HER2 positive. HER2 is a growth factor that combines with other members of the HER family (HER1, -3 or -4) to cause cancer cells to grow (see page 81).

Trastuzumab is a particular type of drug known as a monoclonal antibody and the antibody binds to the HER2 on the surface of the cancer cell and stops it combining with other members of the HER group, which it does to keep the cancer cells active. Trastuzumab stops the cell growing and then the cancer cells eventually die.

Women who have cancers that are HER2 positive tend to have faster-growing cancers. Giving trastuzumab after surgery together with chemotherapy for early breast cancer significantly reduces the chances of the cancer returning (by up to 50 per cent).

Trastuzumab can also be given before surgery combined with chemotherapy and is very effective in shrinking down large HER2-positive breast cancers before surgery.

It is an expensive treatment. It is licensed to be given only at the same time as or after chemotherapy. Trastuzumab is given after surgery for one year. For women whose cancer has spread but is controlled by trastuzumab the drug is continued while the cancer is under control, which in some women is for more than five years. Trastuzumab can be given at the same time or after chemotherapy.

Side effects

Trastuzumab can affect the heart particularly when combined with anthracycline chemotherapy (see page 152). For this reason you will have a heart scan before and during treatment. If the scan shows that the function of the heart has been affected, you may need to discontinue the drug for a period. The heart function usually picks up again to allow completion of the whole course, which consists of 17 injections 3 weeks apart.

Occasionally patients have an allergic reaction to trastuzumab. If this happens it does so shortly after starting the injection and is very treatable. After the first few injections you can usually have the rest of the course at home. There are very few other side effects. It is a new generation of targeted therapies and is very safe and very effective.

Lapatanib

This is a new drug that can be taken in tablet form, and is also effective against HER2-positive cancers. It can be effective when trastuzumab has stopped working. Studies are under way to find out how it can most effectively be incorporated into treatment plans.

Pertuzumab

This is another monoclonal antibody that targets HER1, HER2 and HER3, and is currently undergoing clinical trials.

Bisphosphonates

These are drugs that inhibit bone resorption and are used in the treatment of osteoporosis. Early trials suggested that women with breast cancer who took bisphosphonates after surgery had a small but significant improvement in survival. More recent trials with a new more potent drug, zoledronate, which is given by a 15-minute infusion every few months, have confirmed the benefit of these drugs in improving survival. Further studies have been performed and the results of these are awaited.

If they confirm the benefit, then it is likely that these drugs will become part of the routine treatment after surgery for certain groups of women. The length of time that the treatment needs to continue is still being assessed. Bisphosphonates reduce the bone loss associated with the use of the aromatase inhibitors. Patients taking an aromatase inhibitor should be considered for a dual energy X-ray absorptiometry (DEXA) scan to check bone density. Those with osteoporosis at diagnosis or who have major bone loss during treatment should be considered for bisphosphonate therapy. Oral bisphosphonates are available but are not always easy to take and can cause heartburn. A major potential side effect is damage to the jawbone but this is very rare and occurs only in patients who have dental problems, where the bone has been damaged or is left uncovered after dental surgery or infection.

Immunotherapy

Stimulating the body to kill the cancer through activating the body’s immune system has been a goal of treatment for many years. Drugs are in trials and vaccines against cancers are being developed. As yet, none of the attempts to stimulate the immune system has proved very effective.

PARP inhibitors

When a cell divides and forms two cells, the genetic material in the cell has to be copied. The body has three mechanisms to check that the cells produced are perfect copies. In BRCA-1 and BRCA-2 gene carriers, a faulty gene for one of three mechanisms is inherited from either the mother or the father. In each cell there are two copies of each gene. If the normal copy of the BRCA-1 or BRCA-2 gene becomes faulty, then the gene does not function.

Thus if your BRCA-1 or BRCA-2 genes are faulty, you are much more likely to produce a faulty copy each time that a breast cell divides. Some but not all the faults that are not detected because of loss of BRCA-1 or BRCA-2 result in the development of a breast cancer. When they divide, cancer cells are much more likely to copy abnormally and produce faulty copies, but these are usually picked up and repaired.

In a woman or man with a cancer who is a BRCA-1 or BRCA-2 carrier, the knocking out of one of the other mechanisms for checking that cell copies are perfect results in the cancer cells having only one of the three checking mechanisms. As the cancer cells divide abnormally and the faults are no longer repaired, the cancer cells produced have so many faults that they die. The drugs that knock out one of the other checking mechanisms are called PARP inhibitors. They are currently undergoing clinical trials but show great promise in patients with cancer who are BRCA-1 or BRCA-2 carriers, and also in triple-negative breast cancer.

Other new drugs

There are lots of other drugs being studied in clinical trials (see next chapter).

KEY POINTS

• Drugs used to treat breast cancer include hormone treatments, chemotherapy and new biologic therapies

• Hormone treatments act on the main female hormone oestrogen which in most breast cancers stimulates them to grow

• The most commonly used hormone treatment has been tamoxifen and this is usually given for about five years

• Aromatase inhibitors are used alone or together in sequence with tamoxifen in postmenopausal women with hormone receptor-positive breast cancers

• Side effects of hormone treatment include menopausal symptoms, tiredness and joint pains

• Chemotherapy kills rapidly growing cells

• Treatments are usually given by injection with six to eight doses or cycles being given every three weeks

• Side effects of chemotherapy include reduced resistance to infection, sickness, hair loss and tiredness

• Trastuzumab is effective in the 15 to 20 per cent of women whose cancers are HER2 positive