Ann Arbor Hematology Oncology Associates PC

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TAMOXIFEN

What is Tamoxifen?

Estrogen and progesterone are hormones that play an important role in regulating reproductive function in women. Normal breast and uterine cells respond to estrogen and progesterone. Levels of estrogen and progesterone decrease but do not completely disappear as women go through menopause or if both of the ovaries are surgically removed. Estrogen can also stimulate the growth of breast cancer cells. Tamoxifen is a synthetic hormone that counteracts the effects of estrogen in some breast cancer cells. Tamoxifen was developed in the 1970's, and physicians have used it to treat patients with breast cancer since 1977. It is also used to treat certain other cancers. Physicians and researchers have carefully tested Tamoxifen in breast cancer patients in the United States and throughout the world, and the risks and benefits of the drug continue to be studied.

Who should take tamoxifen?

At the time of your biopsy or surgery, the surgeon will send a sample of the tumor to check for estrogen and progesterone receptors. Receptors can attach to estrogen and progesterone circulating in your body and stimulate cancer cells to grow. If your tumor contains either estrogen or progesterone receptors, your oncologist may recommend that you take Tamoxifen to block these receptors and slow down the growth of tumor cells.

Tamoxifen may be given as adjuvant therapy for breast cancer. Adjuvant therapy is given shortly after surgery or radiation therapy. Adjuvant therapy is recommended for many women, because breast cancer cells may show up later even when surgery appears to remove all of the tumor. The National Surgical Adjuvant Breast Program (NSABP) recently completed a large study which demonstrated that many women benefit from taking Tamoxifen for five years after surgery. There appears to be no added benefit in taking adjuvant Tamoxifen for more than five years.

Breast cancer is metastatic if it has spread outside the breast to the bones, lungs, skin, liver, or other parts of the body. Your oncologist may prescribe Tamoxifen to treat estrogen or progesterone sensitive metastatic breast cancer. In this case, you will take Tamoxifen as long as it continues to be effective.

A recent study conducted by the NSABP demonstrated that Tamoxifen may benefit some women with ductal carcinoma in situ (DCIS). DCIS is a form of breast cancer in which the malignant cells are found only inside the ducts. DCIS cannot metastasize to other parts of the body, but in some women it can develop into invasive tumors that do eventually metastasize. Women with DCIS are also at higher risk for developing invasive cancers in either breast. The NSABP studied women with DCIS over a 5-year period. All of the women underwent lumpectomies (excision of the DCIS) and radiation treatments. Half of the women received Tamoxifen, and half received placebo. At this time 13% of the women who received placebo have developed either additional DCIS or invasive breast cancer compared to only 8% of the women in the Tamoxifen-treated group. Based upon these findings the NSABP has recommended that all women with DCIS consider taking Tamoxifen for five years. The decision to take Tamoxifen in this setting must be made after discussing the risks and benefits with your physician.

What are the side effects of Tamoxifen?

Tamoxifen is usually very well tolerated, and most women will have no side effects. When women do have side effects, they are usually minor. Some of these, such as nausea and headache, may cause temporary discomfort and resolve after taking the drug for two-to-eight weeks. Others, such as hot flashes and vaginal dryness, may persist but can often be relieved by simple measures. In studies comparing Tamoxifen to placebo, many of these minor effects occurred with equal frequency in both groups. Rarely Tamoxifen may be associated with more severe problems that cannot always be predicted or prevented. Below is a list of the more common side effects of Tamoxifen.

Early Side Effects

Early side effects occur during the first few weeks of Tamoxifen therapy and usually resolve without discontinuing the drug or prescribing other treatments.

	*Nausea and vomiting* may occur during the first 1-2 weeks and usually resolve spontaneously. This is rarely an indication to discontinue the drug.
	*Bloating and weight gain* may occur during the first few weeks, but usually resolve without treatment.
	*Headache* may occur during the first two weeks of treatment and may be treated with Tylenol.
	*Rashes* are unusual side effects which may necessitate stopping the drug. Notify your physician immediately if you develop a rash while taking Tamoxifen.
	*Leg cramps* may occur for the first 2-4 weeks. These usually resolve over time and may be relieved with Tylenol or ibuprofen. Other remedies include magnesium tablets (500-1,000 mg/day) or over-the-counter preparations designed to treat leg cramps.

Other Side Effects

Some of the side effects of Tamoxifen may occur several weeks after starting the drug and may persist for months or years. Most of these symptoms can be alleviated, although for some women they can be uncomfortable.

	*Hot flashes* are common during tamoxifen therapy. If the hot flashes are frequent or intense, your physician can prescribe non-hormonal medications (Bellergal-S or Clonidine patches) to help control them. Some women find that Vitamin E (400-800 IU/day) and Vitamin C (500 mg/day) decrease hot flashes. There is some evidence that phytoestrogens derived from soy products (soy milk, tofu, etc.) may also decrease hot flashes. Certain antidepressants including Effexor are also effective for some women.
	*Vaginal dryness* can be accompanied by itching or discharge. If vaginal dryness causes discomfort or problems with sexual intercourse, an over-the-counter, non-hormonal product is recommended (Replens or Gyne-Moistrin). To be effective, these products must be used regularly as prescribed in the package insert. Our office can provide you with a list of non-hormonal lubricants that may help painful intercourse. The product that most women find helpful is Astroglide.
	*Menstrual irregularities* may occur in pre-menopausal women on tamoxifen. These may include missed periods and long or short menstrual cycles. Menstrual periods may stop completely. These effects are usually reversible by discontinuing the tamoxifen, but permanent menopause may occur in some women, especially those over age 35.
	*Mood swings* may occur in some women. Tearfulness and depression may be transient or persistent. It is sometimes difficult to determine whether emotional changes are due to the drug or to the stress of dealing with the cancer and other life problems. Rarely it may be necessary to discontinue tamoxifen therapy temporarily or permanently if depression becomes severe.

Toxicities

Toxicities are more severe side effects that can be potentially life-threatening. Toxicities are rare and can often be minimized by careful monitoring and treatment.

	The risk of *blood clots* increases in women on many hormonal medications including birth control pills, estrogen supplements (Premarin or Estrace), and tamoxifen. For women under age 70, this risk is very low (<1%). The risk is higher in women who are over age 70, overweight, sedentary, or have diabetes, heart disease, atherosclerosis (hardening of the arteries), or a history of blood clots. Chemotherapy also increases the risk of blood clots. Blood clots may appear as superficial thrombophlebitis (clots in small veins in the legs), *deep venous thrombosis* (large clots, usually in the legs), *pulmonary embolism* (a blood clot that travels from the leg to the lung), heart attack, or stroke. It is very important that you report to your physician immediately any swelling in a leg, shortness of breath, or chest pain. Because tamoxifen can increase the risk of blood clots, your physician may recommend that you temporarily discontinue it if you are undergoing surgery or if you are at bedrest for any reason (e.g., hip or knee surgery).
	There is an increased incidence of *endometrial (uterine) cancer* in women with breast cancer. Endometrial cancer has been reported in some women taking tamoxifen for extended periods of time. Recent studies suggest that there may be a 3- to 7-fold increase in uterine cancer in women on tamoxifen (from 1 case per 1000 women to between 3 and 7 cases per 1000 women). We recommend that any woman on tamoxifen (unless she has had a hysterectomy) have *at least* an annual pelvic examination and pap smear. Screening ultrasounds and endometrial biopsies have not been shown to be of significant value. We strongly recommend that any woman on tamoxifen notify her gynecologist when she begins the medication and discuss with him or her the recommendations for follow-up. Any abnormal vaginal bleeding or discharge should be reported *immediately* to your gynecologist.
	Tamoxifen may also cause *uterine fibroids* to grow more rapidly. The Federal Drug Administration (FDA) recently released an alert that tamoxifen may be linked to aggressive uterine cancers known as *sarcomas*. The number of cases is small (about 160 reported cases world-wide). Uterine sarcomas may present with lower abdominal fullness, bloating, pain or abnormal vaginal bleeding. Any of these symptoms should be reported immediately to your oncologist and to your gynecologist.
	Tamoxifen may stimulate the growth of *ovarian cysts* in premenopausal women. To date there has been no reported link between tamoxifen and ovarian cancer.
	A Scandinavian study has suggested that women taking tamoxifen may have an increased risk of cancers of the colon and stomach. None of the randomized studies in the United States have confirmed this risk. We do know that women with breast cancer, regardless of treatment, have an increased risk of cancers of the colon and rectum. We recommend that *all* women undergo colonoscopy beginning at age 50 and then every 10 years, or more often if polyps are discovered. We strongly urge women on tamoxifen to comply with these recommendations.
	*Eye problems* have been reported in women taking tamoxifen. Tamoxifen may increase the risk of developing cataracts. Women with cataracts may have more rapid progression of visual loss. The magnitude of this risk is unknown. Changes in the retina have been reported in women on high doses of tamoxifen, but this risk appears to be minimal. At the present time we recommend that women have a baseline ophthalmologic exam prior to starting on tamoxifen and a follow-up examination every two years thereafter.
	There are no data on the safety of tamoxifen during *pregnancy. Tamoxifen may affect the development of the fetus. Tamoxifen may increase* fertility. Premenopausal women on tamoxifen should use effective birth control measures.

"Flare" Reactions

Flare reactions may occur in women with metastatic breast cancer. Flare reactions do not occur in women taking adjuvant Tamoxifen. Flare reactions occur during the first 2 months of treatment. They are due to death of breast cancer cells and healing of normal tissue. Flare reactions include:

	*Pain* in bones where breast cancer has spread.
	*Elevated calcium levels* in the blood. This may present with increased thirst, increased urination, nausea, dizziness, or mental status changes such as drowsiness or slurred speech.
	*Redness, swelling, or warmth* in areas where breast cancer has spread to the skin.

The flare reaction is temporary. Symptoms should be reported to your physician.

What are the benefits of Tamoxifen?

It is not possible to predict accurately which women will be cured by surgery and radiation therapy and which women will relapse (have a recurrence of their cancer). When used as adjuvant therapy for women with breast cancer after mastectomy or lumpectomy and radiation therapy, Tamoxifen has been shown to increase the survival. This means that if a woman is not cured by the surgery and radiation, Tamoxifen may increase the length of time it takes the cancer to reappear. When used to treat known metastatic breast cancer, Tamoxifen may suppress the growth of the cancer cells for months or years. Tamoxifen also appears to reduce the risk of developing new breast cancers.

Although Tamoxifen has an "anti-estrogen" effect on breast cancer cells, it may have a "pro-estrogen" effect on some other cells. There are preliminary reports that suggest that Tamoxifen, like estrogen, helps prevent osteoporosis and heart disease. Since women with hormone-sensitive breast cancer are advised not to take estrogen supplements, we recommend that all post-menopausal women with breast cancer and all pre-menopausal women on Tamoxifen make an effort to reduce the risk of osteoporosis and heart disease by:

Regular exercise
Calcium supplements (800-1200 mg/day
Vitamin D supplements (400 IU/day)
A well-balanced diet low in saturated fats and cholesterol
Avoiding alcohol and tobacco

Should I take Tamoxifen?

Every woman is different, and each must be evaluated on an individual basis. You and your physician should discuss the risks and benefits of Tamoxifen in your case. For some women, the benefits clearly outweigh the risks (e.g., women with estrogen receptor positive metastatic breast cancer or positive lymph nodes). For other women, the benefits are smaller and the risks may be high (e.g., women over age 70 with very small cancers and other serious medical problems).

The NSABP has recently released findings from a national study that looked at the role of Tamoxifen in preventing breast cancer in women who do not have the disease but are at high risk. The study included women with a strong family history of breast cancer; women with a history of breast biopsies, especially those that showed lobular carcinoma in situ; women over age 60 and women with certain other risk factors. Tamoxifen may be useful in preventing or delaying breast cancer in these women, but individual risks and benefits vary greatly. The NSABP is conducting a new study (the STAR study) looking at the roles of Tamoxifen and a newer estrogen receptor modulator, raloxifene (Evista) in preventing breast cancer in high-risk women. This trial has closed and is not enrolling new patients, and the information from this trial will not be available for several years.

Are there alternative drugs that I should consider taking in place of tamoxifen?

Hormonal treatment of breast cancer is a rapidly developing area of study. There are several newer hormonal treatments that have been approved for certain types of breast cancer. These include the aromatase inhibitors (anastrozole/Arimidex and letrozole/Femara), an aromatase inactivator (exemestane/Aromasin) and an estrogen receptor suppressor (fulvestrant/Faslodex). The aromatase inhibitors work only in postmenopausal women (women whose ovaries have been surgically removed or stopped functioning). All of these drugs have been approved for metastatic breast cancer. If you have metastatic cancer, your oncologist may discuss the risks and benefits of these drugs compared with tamoxifen.

Anastrozole has been studied as adjuvant therapy for early-stage breast cancer. At the present time it appears that anastrozole is at least as effective if not slightly better than tamoxifen as adjuvant therapy for postmenopausal women. However, the side effects of anastrozole are different and may include a greater risk of osteoporosis and bone fractures as well as more joint and muscle pain. Anastrozole does not appear to increase the risk of blood clots or uterine cancer.

Another recent study indicates that some postmenopausal women may benefit by taking adjuvant tamoxifen for five years followed by five years of adjuvant letrozole. Your physician may discuss this with you when you complete five years of tamoxifen.

The aromatase inhibitors are not approved for use in women with ductal carcinoma in situ. There is currently a clinical trial for postmenopausal women with DCIS that compares tamoxifen and anastrozole. If you are interested in this trial, please talk with your physician. Women on this trial must meet eligibility requirements and must sign up prior to beginning radiation treatments.

Aromatase inhibitors are not approved to reduce the risk of breast cancer in women who do not have a personal history of breast cancer.

How should I take tamoxifen?

The standard dose of tamoxifen is 20 mg per day. It may be taken at any time of the day, but you should take it at approximately the same time every day. If you miss a day, you should simply skip the dose. Do not “double up” or take extra doses.

Tamoxifen may interact with several medications. Be sure your physician knows all the medications that you are taking, and be sure to update us when you start or stop a medication. The most important interactions include:

	*Warfarin* (Coumadin). Tamoxifen may increase the INR and increase the risk of bleeding. Coumadin doses should be carefully monitored. Be sure to inform the physician monitoring your coumadin that you have started taking tamoxifen.
	*Erythromycin, cyclosporine, nifedipine* (Adalat, Procardia), *diltiazem* (Cardizem)*, carbamazepine* (Tegretol), *barbituates, phenytoin* (Dilantin), and *benzodiazepines* (diazepam/Valium and lorazepam/Ativan) may inhibit tamoxifen and decrease its benefit.
	Tamoxifen can effect how *chemotherapy* works. Tamoxifen is usually started after completion of chemotherapy.
	There is no information on the how *phytoestrogens* (black cohash, soy isoflavones, etc.) interact with tamoxifen.
	There are no known interactions between tamoxifen and any types of food.

How much does ta moxifen cost?

Tamoxifen costs between $90.00 and $120.00/month. The cost varies widely among pharmacies. Tamoxifen is covered by all health care plans that include prescription coverage. If you do not have coverage, please let us know. Astra-Zeneca, the company that produces tamoxifen, has an assistance program for patients with limited income. Other options may be available for patients without prescription coverage.

Updated April 11, 2005

Ann Arbor Hematology Oncology Associates, P.C.
734-712-1000
Saint Joseph Mercy Cancer Center
Ypsilanti, Michigan

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