You may find it useful to consult the excellent patient information "Guide for NOLVADEX (tamoxifen citrate) Tablets" that can found in the PDR. The following is a supplement to that information. 

 

Tamoxifen given as part of an adjuvant therapy program is usually taken as a pill (or pills) once a day every day for 5 years. 

 

Tamoxifen is generally considered one of the very best anti-cancer medicines.  This is because:

 

1) It is effective in reducing the risk of recurrence and death in women who have had breast cancer.  It is also effective in reducing the risk of getting a second breast cancer. 

 

2) There are tests available that can help identify which women are most likely to benefit from taking tamoxifen. 

 

3) For most women the side-effects of taking tamoxifen are very mild. 

 

Although taking tamoxifen can cause great benefit by decreasing the risk of recurrence and death due to breast cancer, many women who take tamoxifen have some mild side-effects, a few women may have severe side effects, and a very few women may die as a result of taking tamoxifen.  

 

The benefits of taking tamoxifen for a woman after breast cancer surgery include:

 

Reduced risk of developing recurrent metastatic disease. 

Reduced risk of developing local recurrence. 

Reduced risk of a second new breast cancer in the opposite breast. 

Reduced risk of osteoporosis related bone fractures. 

 

The side effects of tamoxifen that you should be aware of and discuss with your doctor include:

 

Increase in hot flashes 

Increase in vaginal dryness

Increased risk of endometrial cancer and endometrial changes

Increased risk of blood clots in the legs, lung, or brain

Increased risk of cataracts

 

For the average woman the risk of dying due to taking tamoxifen is about 0.2 % (one in five hundred), but for you (depending on your age and health) the risk may be smaller or larger. 

 

Brief summary about tamoxifen:

   

Tamoxifen is not really a form of chemotherapy. It is actually a man made hormone. In some tissues it acts as an anti-hormone.  It acts as an anti-hormone in breast tissue.  Many breast cancers need the female hormone estrogen to grow, and tamoxifen can block the action of estrogen in these cancers. 

 

Which tumors are most likely to need estrogen to grow can be predicted by testing the tumors for a protein called the estrogen receptor.  The estrogen receptor is usually tested for in hospital laboratories on cancer tissue removed at the time of biopsy or surgery.  There is a companion receptor to the estrogen receptor, called the progesterone receptor, which is also often tested for.  If a breast cancer has high levels of either the estrogen or the progesterone receptors, tamoxifen is often recommended. 

 

In the United States the dose of tamoxifen is usually 20 milligrams (either one 20 milligram tablet or two 10 milligram tablets) taken by month once a day.  Tamoxifen is usually taken for 5 years. 

 

Risks of taking tamoxifen. 

 

A great deal is known about the side-effects of tamoxifen. Two studies are particularly valuable sources of information.  In one of these studies of tamoxifen 2,800 women with breast cancers that were at low risk for recurrence were randomly assigned to receive either tamoxifen or placebo (a sugar pill).  This study was called NSABP B14.  (Reference 1)

 

A second study tested whether tamoxifen might be used to prevent breast cancer in women who had never had breast cancer. In this study 13,000 women with high risk for getting  breast cancer (but who had never had breast cancer) were randomized to either get tamoxifen or a sugar pill. This study which showed that tamoxifen may be used to reduce the risk of getting breast cancer was called NSABP P1. (Reference 2) 

 

Tamoxifen has been used for the treatment of breast cancer for over 30 years.  A great deal is known about its side effects.  In fact the side effects of tamoxifen are usually so mild that it has been approved by the FDA (Food and Drug Administration) to be taken by healthy women who have a high risk of developing breast cancer, as an agent to reduce the risk of getting breast cancer. 

 

The balance of risk versus benefit for a woman is a very individual thing. The benefit of taking tamoxifen is that it can reduce the risk of breast cancer recurrence and breast cancer related death.  It can also reduce the risk of developing a second breast cancer.  

 

Any woman with early breast cancer should talk with a health professional about the balance of risks and benefits for her as an individual.  The discussion given on these sheets is for average women, but for each individual woman the risks may be different. Women who should be particularly cautious about taking tamoxifen are those who:  1) require anticoagulant (anti-blood clotting) therapy for serious medical conditions, 2) who have had blood clots in their legs or lungs, 3) have a history of uterine polyps or abnormalities, and 4) may be pregnant or become pregnant while taking tamoxifen. 

 

Quality of Life Issues

 

Part of the breast cancer prevention trial (NSABP P1) was a set of questionnaires to allow an assessment of "Quality of Life".  This was a study of healthy women at increased risk to develop breast cancer, but who had never developed breast cancer themselves. This study was particularly valuable because it was large (with 11,064 women) and because it was double blind and placebo controlled. 

 

Double blind and placebo controlled means that the women were assigned to get either tamoxifen or placebo and neither the woman herself or her doctor knew which pills she was getting. Thus there could be no bias by preconceptions about the effects of tamoxifen by either the woman or her doctor. 

 

This Quality of Life study showed no major or statistically significant differences in the "Physical Component Scores" or the "Mental Component Scores" between the women who got tamoxifen and those who got placebo. This is reassuring and is consistent with most of the experience with tamoxifen. It showed that women taking tamoxifen could expect to maintain a good "Quality of Life", for the most part the same as women taking a placebo (sugar pill). 

 

There were important sub-studies of problems that tamoxifen was known to or suspected of causing.  

 

 

Hot flashes:

 

Taking tamoxifen increases the chance that a woman will experience hot flashes.  The evidence from NSABP P1 again shows this.  The following table shows the number of women who after 36 months of taking the study medication (either tamoxifen or placebo) reported hot flashes.  In the NSABP P1 study 184 women taking tamoxifen stopped therapy because of hot-flashes (about 3 out of 100 women), while only 67 women taking placebo stopped because of hot flashes (about 1 out of 100). Thus overall slightly more really severe hot flashes did occur in women taking tamoxifen, but this problem was still relatively uncommon. 

 

 

 

Weight Gain:

 

Some women report weight gain after starting tamoxifen. It is not clear however that this is due to tamoxifen rather than other effects, such as going through menopausal after getting chemotherapy. For the women in the P-1 breast cancer prevention trial in which they were randomized to tamoxifen or placebo, in the tamoxifen group compared to the placebo group weight gain "did not increase in frequency in this large placebo controlled trial". In fact there was a slight increase in the number of women who reported a period of weight loss (45% vs 41%).  (see reference 3)

 

 

Depression:

 

It has long been thought that tamoxifen causes depression in some women, but the evidence from NSABP P1 does not show this.  The following table shows the number of women who after 36 months of taking the study medication (either tamoxifen or placebo) scored as depressed on the study questionnaire.  If anything there was a slight trend for the women taking tamoxifen to be less depressed. 

 

 

 

Sex

 

In the study of NSABP P1 no major effects were reported on the frequency and satisfaction with sexual activity. Overall the number of women who were sexually active after taking the study medication (either tamoxifen or placebo) at 36 months was nearly identical. Overall there was a small but consistently higher number of women who reported a problem with sex in the tamoxifen group, but there were not major differences between the groups. 

 

 

Vaginal problems:

 

Taking tamoxifen increases the chance that a woman will experience vaginal changes, that while usually mild (and are common in women even if they are not taking tamoxifen), are generally felt to be unfavorable.  These include vaginal dryness and itching. There was also an increased number of women who experience a watery vaginal discharge. Here are results of NSABP P1.

 

 

 

Increased risk of cancer of the uterus (endometrial cancer).

 

Taking tamoxifen increases the risk of getting cancer of the uterus (also called endometrial cancer).  In one of the early large American studies of women with early breast cancer (NSABP B14) taking tamoxifen as adjuvant therapy about 1400 women took tamoxifen and 1400 women took placebo for 5 years. These women were carefully followed for 7 years. During this time 15 women taking tamoxifen and 2 women taking placebo developed endometrial cancer. This represents about a 1% increased risk caused by tamoxifen for women taking tamoxifen.

 

A similar increase in endometrial cancer risk was seen in the NSABP P1 breast cancer prevention trial.  Among women who took tamoxifen there were 33 cases of endometrial cancer compared to 14 cases among participants randomized to placebo.  In women older than 50 there was about 4 times the risk of developing endometrial cancer. In the women who were less than 50 years old there was no clear increase in risk, although data from other studies suggests that there is a doubling of risk in the younger women.  The total risk in younger women is small (less than 1%) while the increased risk for older women is 1-2%.  Because of the increased risk of endometrial cancer it is recommended that women taking tamoxifen should have an annual gynecologic exam. 

 

The estimates for increased risk of endometrial cancer caused by tamoxifen are similar for the NSABP B-14 study and the NSABP P-1 study.  Your risk may be somewhat different depending on whether you have some of the other risk factors for endometrial cancer such as diabetes, obesity, and family history of endometrial cancer. If you have had a complete hysterectomy (removal of the uterus) you do not have any risk of endometrial cancer.

 

For the average woman taking tamoxifen for 5 years, the extra risk of developing endometrial cancer is about 1 in 100 (1%). Because uterine cancer is usually cured by surgery (a hysterectomy) the risk of dying of endometrial cancer is increased by only about one tenth of  that or, 1 in 1,000 (0.1%). 

The following table gives estimates of endometrial cancer occurrence in different age groups (derived from the P-1 tamoxifen breast cancer prevention study).  The increase is the estimated extra risk for a woman taking tamoxifen for 5 years.

 

 

Non-Cancer Effects on the Uterus:  

 

An increased incidence of endometrial changes including hyperplasia (thickening of the lining of the uterus) and polyps (non-cancerous growth in the uterus) have been reported in association with tamoxifen treatment.  There have been a few reports of endometriosis and uterine fibroids in women receiving tamoxifen. Ovarian cysts have also been observed in a small number of premenopausal patients with advanced breast cancer who have been treated with tamoxifen.

 

 

Risk of problems related to blood clots:

 

There is data showing that tamoxifen may slightly increase how easily blood can clot. This effect is potentially bad, because it might lead to a higher risk of blood clots in the brain (stroke), legs, or lungs (pulmonary embolism).  These are uncommon but can possibly lead to severe symptoms, need for hospitalization, and even death.

 

 

This means that for someone taking tamoxifen for 5 years the risk of getting a serious blood clot is about 1% more than women not getting tamoxifen (2% rather than 1%) and the chance of dying of a blood clot is 0.1% higher (1 chance in 1,000). Taking tamoxifen seems to approximately increase by one and one half times the risk of serious blood clotting problems. 

 

There is some evidence that taking tamoxifen at the same time as chemotherapy may particularly increase the risk of blood clotting problems. For this reason some doctors wait until after completing adjuvant chemotherapy to start giving the tamoxifen.

 

The risk of blood clotting problems may be higher in women with some health problems such as a history of prior blood clots, immobility (not moving), and other factors. Age is an important risk factor with older women having a higher risk of blood clots. 

 

The following discussion shows how age affects of the risk of some of these problems. 

 

The following table gives estimates of stroke occurrence in different age groups (derived from the P-1 tamoxifen breast cancer prevention study).  The "Increase" is the estimated increase in risk for a woman taking tamoxifen for 5 years.  

 

 

Strokes

 

For the average woman of 60 69 years of age not taking tamoxifen the risk of having a stroke during a 5 year period is 1.6 in 100 (1.6 %).  This risk is increased to 2.5 in 100 (2.5%) in women taking tamoxifen. This is about a 1% increase.  

 

 

 

Blood Clot in the Legs     (Deep Venous Thrombosis)

 

For the average woman of 60 69 years of age the risk of having a serious blood clot in the legs (deep venous thrombosis) during a 5 year period is 0.5 in 100 (0.5 %).  If this woman took tamoxifen this risk is increased to 0.8 in 100 (0.8%). This is about a 0.3 % increase.  

 

 

 

Pulmonary Embolism 

 

For the average woman of 60 69 years of age the risk of having a serious blood clot in the lungs (pulmonary embolism) during a 5 year period is 0.4 in 100 (0.4 %).  If this woman took tamoxifen this risk is tripled to 1.3 in 100. This is about a 1 % increase.  

 

 

 

Decreased risk of bone fracture:

 

There is data showing that in women after menopause tamoxifen can actually stabilize and sometimes even increase the amount of calcium in bone.  This effect seems to help prevent bone fractures.  For the average woman who participated in the breast cancer prevention trial the risk of facture was reduced by taking tamoxifen.

 

 

 

The following table gives estimates of bone fracture occurrence in different age groups (derived from the P-1 tamoxifen breast cancer prevention study).  The reduction is the estimated reduction in risk for a woman taking tamoxifen for 5 years.  

 

For the average woman of 60 69 years of age taking tamoxifen for 5 years, the risk of having a hip fracture during that 5 year period is about 1.2 in 100 (1.2 %).  This risk is reduced by about one half (50%) to 0.6%.  A woman's risk may be somewhat different than average depending on her risk factors for osteoporosis and her starting bone mineral density (how strong her bones are). 

 

 

 

As can be seen in the table below the risk of fractures of other bones is reduced as well. For example the risk of the common compression fracture of spine vertebra (causing pain, and shortening and curving of the spine) is reduced by about one quarter (25%) for the average woman. 

 

 

 

No effect on risk of heart disease:

 

There is data that shows that tamoxifen may lower cholesterol in some women by about 20%.  It was hoped that this would lead to a great decrease in ischemic heart disease (problems caused by clogged arteries not bringing enough blood to the heart muscle). 

 

For women who participated in the breast cancer prevention trial, tamoxifen did not increase or decrease risk of heart attacks or other types of ischemic heart disease (hardening and clogging of the arteries of the heart).  (Reference 4)

 

 

 

Risk of cataracts

 

In the NSABP P1 trial there was a slight increase in the risk of developing cataracts among those women without cataracts when the study started.  For women taking tamoxifen for 5 years the risk of developing cataracts was 13%, and for women in the placebo group the risk of developing cataracts was 11%.   Therefore about 2% more of the women taking tamoxifen developed cataracts.  The risk of developing cataracts is strongly age dependent. About 1 in 5 women developing some signs of cataracts while taking tamoxifen had surgery for them within a few years. 

 

 

 

Summary: 

 

When tamoxifen is recommended it is because the average benefit is expected to be greater than the average risk of negative side-effects.  This is often true for women with estrogen receptor positive breast cancers. 

 

 

The benefits of taking tamoxifen for a woman after breast cancer surgery often are:

 

Reduced risk of developing recurrent metastatic disease. 

Reduced risk of developing local recurrence. 

Reduced risk of a second new breast cancer in the opposite breast. 

Reduced risk of fractures due to osteoporosis. 

 

 

The negative effects of tamoxifen sometimes are:

 

Hot flashes

Vaginal changes

Endometrial cancer

Blood clots 

Cataracts 

 

 

 

 

 

 

References:

 

1) Gail MH, Costantino JP, Bryant J, et al. Weighing the risks and benefits of tamoxifen for preventing breast cancer. Journal of the National Cancer Institute. Volume 91: pages 1829-1846, 1999. 

 

2) Fisher B, Costantino JP, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node negative breast cancer with estrogen receptor positive tumors. New England Journal of Medicine. Volume 320, pages 479-484, 1989. 

 

3) Day R,  Ganz P, Costantino JP, Cronin W,  Wickerham L, and Fisher B. Health related quality of life and tamoxifen in breast cancer prevention: A report from the National Surgical Adjuvant Breast and Bowel Project P-1 study. Journal of Clinical Oncology Volume 17: pages 2659 to 2669, 1999.

 

4) Reis SE, Costantino JP, Wickerham DL, et al. Cardiovascular effects of tamoxifen in women with and without heart disease: Breast Cancer Prevention Trial.  Journal of the National Cancer Institute. Volume 93: pages 16-21, 2001. 

 

Additional information may be available from:

ASTRAZENECA

Wilmington, DE 19850-5437 USA

General Number: (302) 886-3000

 FOR MEDICAL INFORMATION CONTACT:

 (302) 886-8000

  Internet: www.astrazeneca-us.com

     www.astrazeneca-us.com/pi/NL1273.pdf

 

Some of the information for this review came from the:

Physicians' Desk Reference

800-232-7379.  

PDR@MEDEC.COM