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TAMOXIFEN
     
 
How it works

In around 60 per cent of cases breast cancer cells contain receptors for the female sex hormone oestrogen.
Oestrogen is produced mainly from the ovary in women prior to the menopause, but after the menopause substantial amounts are still produced in the adrenal glands, which sit above the kidneys, and in the fat tissue of the body. The oestrogen circulates through the bloodstream and reaches any breast cancer cells where ever they may be in the body, stimulating them to divide and grow.
Doctors have known for many decades that they can inhibit the growth of breast cancer by lowering the amount of oestrogen in the bloodstream. Initially this was done by removing the ovaries, in pre-menopausal women, or by removing the adrenal glands or the pituitary gland in women after the menopause.
In the 1960s people began experimenting with new hormonal agents which inhibited oestrogen from binding to the oestrogen receptor on breast cancer cells. The most important of these drugs, and the one that has seen most clinical testing, is tamoxifen.
Tamoxifen is a very interesting drug. Its molecular shape is very similar to oestrogen itself, and the various tissues in the human body that require oestrogen for their functioning respond to it in different ways. Some of them, like the lining of the uterus, and the cells of the skeleton, confuse it with oestrogen itself, and in these tissues tamoxifen has what is termed an "oestrogenic " action. Breast cancer cells, however, see it as an anti-oestrogen. It binds to the oestrogen receptor, and prevent oestrogen from having its normal stimulatory activity on the breast cancer cell. Deprived of this necessary stimulus to make them divide and grow, the breast cancer cells arrest. In some cases they seem to subsequently die, possibly under the influence of the body's immune system.





How to take it

Tamoxifen should be taken daily in a dose of 20 milligrams, or as prescribed by your doctor. Normally, we recommend that be taken after breakfast, but some women prefer to take it in the evening. It doesn't seem to matter in terms of its effectiveness. You should try to be fairly careful to take it every day, but, if you do forget one day, don’t panic: simply resume the following day. Should you forget, and take two tablets, it is quite safe. If you forget in the morning, and remember that evening, it is quite OK to take it then.
It is fine to take tamoxifen with your other medications.




Does tamoxifen interfere with my other medications?

Tamoxifen can very much increase the potency of warfarin, a drug used to thin the blood. This may result in dangerous bleeding. You should not take tamoxifen if you are already taking warfarin unless strictly under medical supervision. There are no other known serious drug interactions.




Does the brand matter?

There are several “look-alike” cheaper brands than the original one which is branded “Nolvadex”. There is no difference between the brands in the effectiveness or side-effects.



What are the side-effects of tamoxifen?

Generally speaking, tamoxifen causes few side-effects, and it is very rare that patients have to stop it because of an adverse reaction.
There are two very important, but rare, side-effects which deserve special attention:

1. Tumours of the lining of the womb ("endometrium")
Very rarely, the use of tamoxifen has been associated with cancers of the lining of the womb, technically called uterine carcinoma, or endometrial adenocarcinoma. The risk is around three per 1000 woman-years for women taking tamoxifen. Whenever you are confronted with these sort of risk figures, you should always compare them to what the risk would be without tamoxifen. In the general community there is a risk of around one per 1000 woman-years in getting cancer of the lining of the uterus.
The fact is that this has to be compared to the benefit that tamoxifen offers in both preventing recurrence of breast cancer, and also preventing the occurrence of a new primary breast cancer. For a woman who has had breast cancer, the risk of getting a second new quite separate primary breast cancer is around one per cent per annum. This means, that of 100 women who have had previous breast cancer, every year, one of those women will get a new primary breast cancer, often, but not always, in the other breast. Tamoxifen reduces the risk of this by between one third and one half. This is a benefit far greater than the risk posed by the very rare incidence of cancer of the womb.
Cancer of the womb occurs more commonly in women over the age of 50. In most cases, it presents early with vaginal bleeding. This is why it is most important to report to your doctor early any instance of unusual vaginal bleeding. What do I mean by unusual? Well, in women who are past the menopause, any instance of vaginal bleeding is unusual. In women before the menopause, it has to be distinguished from normal menstruation. Most women can tell when they are having a normal period by their other symptoms, such as breast tenderness, and pelvic discomfort. However, if you are in any doubt you should talk to your doctor.
However, it is most important not to panic if you do develop vaginal bleeding while taking tamoxifen. The reason is, because tamoxifen acts like oestrogen on the lining of the womb, it is very common for it to cause a build-up of the normal lining of the womb, which occasionally is shed, a bit like a normal period. In more than 90 per cent of cases, vaginal bleeding in women taking tamoxifen is completely benign. However, the only way to be absolutely certain is to see your doctor, who will probably arrange for a uterine biopsy to be performed. Nowadays, this is a simple rooms procedure which does not require a general anaesthetic. There are occasions, though, when your doctor may wish to perform a dilatation and curette under general anaesthetic.
2. Deep venous thrombosis ("DVT") and pulmonary embolism ("clots in the lungs").
Rarely, tamoxifen may increase the stickiness of the cells in the blood which cause the blood to clot. These cells are called platelets, and they are a normal necessary part of stopping you from bleeding when, for example, the skin is wounded. However, when they're made more sticky, they can sometimes clump and cause clots in the veins of the legs. This is called deep venous thrombosis. In serious cases, these clots may migrate to the lungs. This is known as pulmonary embolism. If untreated, pulmonary embolism may be fatal. The risk of pulmonary embolism in women taking tamoxifen is around 0.75 per 1000, compared to 0.25 per 1000 in women not taking the drug.
In women who are fit and active, there seems to be very little risk over and above what occurs in the general population. There are several circumstances, however, when the risk is substantially greater. These include:
- Smoking
Smoking increases the risk of deep venous thrombosis, and women taking tamoxifen should not smoke.
- A previous history of venous thrombosis.
If you have previously had clots in the veins of the leg you should tell your doctor before you start taking the tamoxifen.
- Long-distance travel
People embarking on long aeroplane journeys are at an increased risk of venous thrombosis. This risk is probably enhanced if you are taking tamoxifen.
My advice is:
- MOST IMPORTANT: Do all the exercises in the back of the airline magazine at least one set hourly
- Walk around plane at reg intervals
- Keep well hydrated - cabin air is very drying. Buy bottled water AFTER security (or they'll confiscate it). Economy Class never give enough water
- Minimal alcohol (because it dehydrates)
- No sleeping tablets (in case you fall asleep in one position)
- THERE IS NO NEED to stop tamoxifen before or during travel
- There is no benefit of aspirin
- Ask your doctor about pre-flight Clexane if you have a past history of deep vein thrombisis or other clotting
- Other elective surgery.
Should you require surgery for any other reason, you should tell your surgeon and anaesthetist, and if you are going to be immobilised for a day or more after the operation, you should cease your tamoxifen for one week prior to the operation. Your surgeon may recommend the use of other special medicines to prevent venous thrombosis. Once you are active again, you should recommence the tamoxifen.
- Prolonged immobilisation. If you are immobilised for any length of time, for example, after a serious ankle strain or breaking a bone, you should follow the same advice as that for a elective surgery. In any of these circumstances it is best to seek advice from your own doctor..





Marion
"I developed some vaginal bleeding about 6 months after I'd been on tamoxifen. My GP assured me that this was nearly always due to a benign thickening of the lining of the womb, but that a simple biopsy would sort it out. My gynaecologist did this in her rooms - it wasn't very different from having a Papsmear. The results are all clear and I am carrying on with the tamoxifen. I haven't had any more problems at all."



Other side-effects of tamoxifen

This section contains some details about less serious reported side-effects of tamoxifen. However, I want to stress to you that tamoxifen is one of the safest drugs and one of the most widely used in the whole cancer field. Most of my patients, like Jill (not her real photo) do not know that they are taking it.
Nausea
About 10 to 15 per cent of women experience some nausea when first taking tamoxifen. Should this occur, my advice is that the first thing you do is to take the drug in the evening, preferably after supper when retiring. Often, after 10 to 14 days, the nausea subsides. It may be helpful to take some anti-nausea medication during this period, such as Stemetil, or Maxolon, always under the supervision of your own doctor. In some cases it is necessary to cease the tamoxifen for a week or two and then to try recommencing it at half dose. Again, this should only be done under the supervision of your doctor.
Hot flushes.
Hot flushes, (sometimes called hot flashes), are a common symptom of the menopause and they are commonly made worse by taking tamoxifen. They are caused by hormones released from the pituitary gland which cause dilatation of blood vessels in the skin of the face and upper body. This is accompanied by a hot prickly sensation and the strong desire to stand in front of an air conditioner, or remove clothing! They are more common at night when they might disturb sleep. In some women they are severe enough to disturb the ability to work and may severely inhibit quality of life. They can last for months to years, but the severity generally decreases rather than increases with time.
Simple measures may help to ease hot flushes, including wearing several layers of thin clothing which can be removed if necessary, and sleeping in an air-conditioned room, or one with a ceiling fan.
Natural products containing plant oestrogens are heavily promoted by health food stores and pharmacies as being of benefit in easing hot flushes. These products include Promensil and Remifem. However, properly conducted clinical trials have failed to show any evidence that these products are of benefit in reducing the symptoms of the menopause. None of the "natural" oestrogens are of proven safety in women who have had breast cancer.
Two drugs that have been shown to reduce the severity of hot flushes are venlafaxine and medroxyprogesterone acetate ("Provera"), in a dose of between 10 and 50 mg daily, and tibolone ("Livial"). These drugs must only be used under the advice of your doctor. Whilst there is some evidence that the blood pressure table Clonidene may reduce hot flushes, I have never seen it work, and most of my colleagues are sceptical about it.
Certain antidepressants like venlafaxine (Efexor) have been shown to reduce hot flashes. However, tamoxifen should not be taken with "Specific Serotonin Reuptake Inhibitor" (SSRI) antidepressant medication unless under specific medical advice. This includes Prozac, Efexor, Aropax, Zoloft and many others. These drugs may interfere with the activation of tamoxifen in the liver, reducing its effectiveness.
Of course, there is one sure fire way to reduce hot flushes and that is the use of hormone replacement therapy. However, I am personally loathe to recommend this to women who have a history of breast cancer unless they have menopausal symptoms that are disabling. In women who had breast tumours that were not hormone receptor positive, some specialists feel relaxed about using HRT for short periods. The hormonal agent tibolone ("Livial") is weakly oestrogenic, and might therefore be the best one to choose in the first instance. Again, I must stress that any such endeavour should be done under careful medical advice and with the full knowledge of your breast cancer specialist.
The newer anti-oestrogens letrozole ("Femara")and its partner drug anastrozole ("Arimidex")  have a much lower incidence of side effects like hot flushes but these drugs cannot be used in women who are premenopausal or perimenopausal.
For additional information on the management of hot flushes ("hot flashes"), CLICK HERE

Vaginal irritation dryness and discharge.
Vaginal irritations and dryness may be relieved by the use of local oestrogen containing pessaries. The best of these is probably oestriol ("Ovestin"). This should be used twice weekly at first, then weekly Of, under strict medical supervision.
Bone density
After the menopause it is common for there to be a gradual reduction in bone density due to slow leaching of calcium from the skeleton. Paradoxically, tamoxifen reduces this problem in women after the menopause, but seems to exacerbate it in women who are still having periods. The best advice for all women on tamoxifen is that they have regular weight- bearing exercise, a sensible daily intake of calcium (see below), and that every two years they have the bone density measured by their doctor. There is no need to take osteoporosis preventing medicines such as vitamin D and calcium supplements unless this is indicated by your doctor. For additional information on managing bone problems in the menopause CLICK HERE

Eye problems
In the early days of tamoxifen there were some reports of damage to the retina, and a slightly increased incidence of cataracts. However, in more recent large scale clinical trials there has been no significant increase in the incidence of eye disease. If you experience changes in vision while taking tamoxifen you should report these to your doctor. Keep in mind, though, that changes in visual acuity are very common in the Forties and Fifties when most people need to have their glasses adjusted quite frequently.
Ovarian cysts.
In younger women (especially those who are still having periods) it is quite common for tamoxifen to cause benign swellings in the ovary, known as ovarian cysts. These are often palpable by your doctor at the time when you have a pelvic examination each year for a Papsmear. Sometimes these cysts cause pelvic discomfort. It is extremely rare for them to become malignant.
Changes to menstrual periods
In some women who are still having menstrual periods when they start taking tamoxifen, there may be an alteration to the timing and nature of menstruation.
Rare side-effects
These include mood changes, headache, poor concentration, trouble sleeping (CLICK HERE)
, tiredeness (CLICK HERE) bald spots or thinning hair, and skin rashes.





Jill:
"I honestly wouldn't have known I was taking tamoxifen. If anything, I felt better on it than I did before I started it! My breast cancer is way behind me now. I know tamoxifen is just a little bit of extra insurance for me seeing these two grow up and for me to be a healthy grandmother to their children."



What tamoxifen does NOT do.

Although tamoxifen can sometimes cause fatty infiltration in the liver, there is no evidence that it causes liver cancer. Reports of this nature in the media and on the Internet, refer to early studies on rats. There is no evidence that tamoxifen increases the incidence of liver cancer in humans.
There is no clinical trials evidence that tamoxifen increases the incidence of weight gain. Weight gain is a common event at the time of the menopause due to changes in metabolic rate. It is critical that all women in mid-life, whether on tamoxifen or not, watch carefully their caloric intake, and engage in regular weight bearing exercise.




Advice to women taking tamoxifen

  • Have your doctor perform a pelvic examinations and Papsmear before you start tamoxifen and then each year while you are on it.
  • Take special precautions before long distance aeroplane travel (see above)
  • Tell your surgeon and anaesthetist you are on tamoxifen before elective surgery. It may be advised that you have Clexane injections post-operatively
  • Ask your doctor about monitoring bone density. In young women this should be performed every two years.
  • Engage in regular weight bearing exercise. This means, for example, walking four kilometres in under 40 minutes four times per week. Good alternatives include ballroom dancing and aerobics classes. For additional information CLICK HERE
  • Take calcium regularly in the diet. This means having at least one good serving daily of low-fat dairy product. One 200 g tub of low-fat yoghurt is ideal.
  • Report to your doctor your experience of any of the side-effects listed above, or any other symptoms that you attribute to the tamoxifen. Most importantly, you must report to your doctor any unusual vaginal bleeding.
  • Tamoxifen must not be taken if you are pregnant or could be pregnant. Tamoxifen is not a contraceptive.
  • Tamoxifen should not be taken with the blood-thinning drug warfarin, except under explicit medical advice and careful monitoring of blood coagulation parameters.
  • Seek prompt medical attention for new breast lumps, vaginal bleeding, gynaecologic symptoms (menstrual irregularities, changes in vaginal discharge, or pelvic pain or pressure),symptoms of leg swelling or tenderness, or unexplained shortness of breath.
  • Ensure that any of your medical attendants know that you are taking tamoxifen.





Do I really need to take tamoxifen for five years?

Many of my patients are often ask me whether or not they can stop tamoxifen early. There are already a number of clinical trials which clearly indicate that the optimum duration of tamoxifen is five years. An update of a large Swedish study was presented at ASCO this year which further emphasises this clinical advice.
During the period from 1983 through 1992, a total of 4610 patients were entered in the trial; 4175 women remained alive and recurrence free at 2 years and could thus contribute meaningful information to the 2-year versus 5-year comparison. Patients assigned to 5 years of tamoxifen experienced significantly longer breast cancer event-free survival and overall. In the 5-year group, the incidence of cancer in the contra-lateral breast was significantly reduced while the incidence of endometrial cancer was very slightly increased. There was no significant increase in the incidence of any other type of cancer. The mortality from coronary heart disease was significantly reduced in patients randomized to 5 years of tamoxifen treatment compared with those in the 2-year group. The mortality from deep venous thrombisis and pulmonary embolism not increased.




Are there alternatives to tamoxifen?
The main agents that are in clinical trial to possibly replace tamoxifen in post-menopausal women are the oestrogen-lowering drugs known as “aromatase inhibitors”. There are three of them currently in use in the treatment of advanced breast cancer, letrazole ("Femara"), anastrozole ("Arimidex"), and exemestane (“Aromasin”).
The main trial in early breast cancer is the ATAC (‘Arimidex’, Tamoxifen, Alone or in Combination) Trial. The early results of this trial have received considerable publicity in the Australian press, and indeed the results are promising. In this trial, over 9000 women were randomised in a double-blind fashion (neither the women nor the investigators knew who was getting what, to avoid any sort of bias). They received either tamoxifen, anastrazole or both drugs together. At 4 years of follow up the study shows that in the anastrazole-only arm there were statistically significant data to support:

Fewer recurrences of breast cancer
Improved disease-free survival
Fewer hot flashes
Less vaginal bleeding
Less endometrial cancer
Less thromobotic events
More arthritis
More bone fractures from osteoporosis

However, these data are considered by most experts to be too early to recommend an overall change from tamoxifen to anastrazole in the adjuvant treatment of early breast cancer. Remember that the trial was confined to post-menopausal women with an average age of 65. Also, remember that tamoxifen has a 30-year track-record of safety.
The end-point of most relevance in these studies of adjuvant treatment in early breast cancer is overall survival. This will probably not be known for another 4-5 years. However, if the differences in disease-free survival are maintained, it may be that anastrazole comes on to the Australian Pharmaceutical Benefits Scheme (PBS) for use in early breast cancer some time in the next few years. Currently it is only available for the treatment of advanced breast cancer in post-menopausal women.
For more information on the aromatase inhibitors, including how they work, CLICK HERE
.





Can tamoxifen make some breast cancers worse?

A Swedish group have reported in th journal “Cancer Research” (September 2005) that a particular subset of women may not benefit from tamoxifen, even if their tumours are estrogen-sensitive (that is, positive for the estrogen receptor). These particular women had breast cancers that were strongly expressing another protein that regulates cell division, called Cyclin D1. There was a suggestion in this study that tamoxifen may act as a stimulatory hormone in this subset of tumours, rather than as an inhibitory drug.
This study is small, on just 500 women, whereas the data showing benefits of tamoxifen have been generated from over 30,000 women.
Cyclin D1 is not routinely measured in pathology laboratories, and this study is not a reason to start doing it. Rather, it is a juatification to see if other groups and laboratories can replicate the findings. At present, the report must be regarded as preliminary.
Further information may be found at:
http://www.bci.org.au/public/news/media/0905_1media.htm or HERE







Contraception and tamoxifen

In women who are still having regular menstrual periods it is possible to fall pregnant while taking tamoxifen. As tamoxifen may potential harm the development of a tiny embryo we would recommend a termination if pregnancy did occur while tamoxifen was being taken. Obviously it is better to avoid this possibility. Probably the best contraceptive in this setting, for women who have had children, is an intra-uterine device like "Mirena" which produces a local progesterone hormone. This is a highly specialised subject and one on which you should seek specialist advice. You should not take the oral contraceptive pill while taking tamoxifen.




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