INTRODUCTION — Several treatment options are available for women with advanced or metastatic breast cancer. These include chemotherapy, endocrine therapy, and targeted therapy with the monoclonal antibody trastuzumab (Herceptin®).
This topic review will discuss the options for endocrine therapy. General treatment and chemotherapy and trastuzumab for metastatic breast cancer are discussed elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer" and see "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Hormones and breast cancer growth — Some breast cancers require the hormone estrogen to grow and spread to other organs while other breast cancers are able to grow and spread without estrogen. Estrogen-dependent breast cancer cells produce a molecule called the estrogen receptor (ER). Approximately 30 to 50 percent of breast cancers in premenopausal women, and 70 to 80 percent of cancers in postmenopausal women make ERs. All women diagnosed with breast cancer should be tested to determine if their cancer expresses ER.
What is endocrine therapy? — Endocrine therapy removes the influence of estrogen on breast cancer cells, preventing the cancer cells from growing and spreading. All endocrine treatment is systemic or body-wide therapy, and is effective against cancer cells regardless of where they are located within the body (eg, the breast, bones, liver, etc). Because endocrine therapy usually has fewer side effects than chemotherapy, it is often recommended as the initial treatment for women with ER-positive metastatic breast cancer.
In general, endocrine therapy can be medical (through the use of drugs) or surgical (usually by removing the ovaries, the main source of estrogen production prior to menopause). In the United States, the majority of women receive medical rather than surgical endocrine therapy for metastatic breast cancer. The choice of therapy often depends upon a woman's menopausal status.
There are two ways of disrupting the effects of estrogen on breast cancer cells: by preventing estrogen production, and by interfering with the ability of estrogen to stimulate the breast cancer cells. Different estrogen deprivation therapies are usually recommended for premenopausal and postmenopausal women. (For more information on the use of endocrine therapy in early stage breast cancer, see "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in postmenopausal women" and see "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women").
Premenopausal endocrine therapy — In premenopausal women, most estrogen is produced by the ovaries. Therefore, removing the ovaries (ovariectomy) or preventing them from producing estrogen through medical therapy (usually requiring monthly injections) is an appropriate method for estrogen deprivation. A summary of endocrine therapies is available in figure 2 .
Postmenopausal endocrine therapy — In contrast, the ovaries of postmenopausal women no longer make estrogen. Two small glands above the kidneys, called the adrenal glands, make precursors for a variety of different hormones, including estrogen. These precursors are then converted to estrogen, mainly in the fat tissues within the body, by an enzyme called aromatase. Aromatase inhibitors are effective treatments for advanced breast cancer. They are most beneficial for postmenopausal women. (See "Selective aromatase inhibitors (SAIs)" below). A summary of endocrine therapies is available in figure 2 .
Importance of hormone receptor expression — Women with ER/PR-positive tumors respond better to endocrine therapy than women with ER/PR-negative tumors (>60 percent response versus 10 percent). However, a trial of endocrine therapy may be warranted in women with ER/PR negative disease because the benefits of endocrine therapy greatly outweigh the risks of chemotherapy. Thus, even if a woman has an ER/PR-negative cancer, she may be offered a trial of endocrine therapy as long as she has slow growing disease, metastasis limited to the bones and/or skin, and limited symptoms related to her cancer.
TAMOXIFEN — Tamoxifen is the first-line endocrine therapy in premenopausal women with advanced breast cancer. Tamoxifen is a standard option for postmenopausal women as well, although more recent data suggest that a different type of endocrine therapy, selective aromatase inhibitors, are better that tamoxifen, as long as a woman's tumor has not become resistant to these drugs. (See "Selective aromatase inhibitors (SAIs)" below).
Tamoxifen is a member of a class of drugs called the selective estrogen receptor modulators (SERMs). SERMs like tamoxifen are chemically similar to estrogen, but are in fact, very different. Tamoxifen prevents estrogen from binding to the ER, and also interacts with the ER. This interaction can stimulate the cells of different organs in one of two different ways: sometimes in ways that are similar to estrogen stimulation (estrogenic), and other times in a manner that is opposite to the effects of estrogen (that is, antiestrogenic). In the same person, SERMS can be antiestrogenic in some tissues, and estrogenic in others (show figure 1). The following illustrates these concepts: Tamoxifen has antiestrogenic actions on both normal and cancerous breast tissue. This is beneficial because taking tamoxifen decreases cancer growth in patients with established breast cancer. Furthermore, women at high risk of developing breast cancer may decrease their chance of getting breast cancer by taking tamoxifen. (See "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"). Tamoxifen also has antiestrogenic activity in the brain. This can lead to bothersome side effects such as hot flashes, sweating, insomnia that occur in 30 to 40 percent of women who take tamoxifen. Tamoxifen is estrogenic in bone. This can be beneficial because tamoxifen prevents progression of osteoporosis. Another SERM, raloxifene, is used for the prevention and treatment of osteoporosis. (See "Patient information: Osteoporosis prevention and treatment"). Tamoxifen is also estrogenic in the liver, leading to an increase in liver production of blood-clotting proteins. This results in a slight increase in the risk of strokes and heart attacks during the first 18 to 24 months of tamoxifen use, particularly in women who are at high risk for these events (ie, smokers, those with a past history of blood clots). Increased clotting proteins also increases the risk of deep vein thrombosis (blood clots in the major internal veins of the leg) and pulmonary embolus (movement of a blood clot to the lungs). Tamoxifen is estrogenic in the endometrium (the lining of the uterus). The risk of uterine cancers is increased by two- to threefold in women who take tamoxifen. However, the risk of a new uterine cancer is well below 1 percent.
This information must be placed in appropriate context for women who are considering tamoxifen. Women with advanced breast cancer are at high risk of dying of breast cancer in the short term, and the benefits of tamoxifen far outweigh the risks of uterine cancer, blood clots, or other long term effects.
Effectiveness — Between 50 and 60 percent of women whose breast cancers are ER-positive will respond to tamoxifen therapy. In contrast, fewer than 10 percent of women with metastatic ER-negative breast cancers respond to tamoxifen. Chemotherapy or trastuzumab (Herceptin®) therapy are recommended for women with ER-negative disease. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Tamoxifen is taken by mouth, at a dose of 20 mg daily. Most breast cancers become resistant to tamoxifen over time. The majority of breast cancers that initially respond remain sensitive to tamoxifen for 12 to 18 months, although some continue to respond for several years. An alternative hormone therapy should be considered if a woman becomes resistant to tamoxifen.
Resistance — The resistance of breast cancer cells to tamoxifen is the greatest limitation of this therapy. However, even among ER-positive breast cancers, some do not respond at all to tamoxifen (called primary resistance); secondary resistance occurs if the tumor initially responds but later become resistant.
Preliminary studies suggest that a protein that is expressed by breast cancer cells called HER2 may help to identify women who are less likely to benefit from tamoxifen therapy (ie, those with primary resistance). However, the results of studies to date have been conflicting, and most doctors offer initial tamoxifen therapy to all premenopausal women with ER-positive breast cancer, regardless of their HER2 status.
Resistance to tamoxifen does not necessarily imply resistance to other endocrine therapies. Treatment options for women who are resistant to tamoxifen include discontinuation of tamoxifen (see "Withdrawal response" below), an alternative endocrine therapy, or systemic chemotherapy.
Premenopausal women with metastatic breast cancer that is resistant to tamoxifen should be treated with surgical removal of the ovaries followed by an SAI (see "Ovariectomy" below).
Flare reaction — Between 3 and 13 percent of women with metastatic disease experience a flare of their breast cancer within two days to three weeks after starting tamoxifen. This "flare" reaction may be characterized by an increase in bone pain, a high blood calcium level, and in women who have tumor deposits within the skin, an increase in the size and/or number of these metastatic skin nodules, or skin redness.
Tumor flares usually subside within four to six weeks. In the meantime, the symptoms can be treated with measures that reduce pain and lower blood levels of calcium. In severe cases, a woman may have to temporarily stop taking tamoxifen until the flare subsides. Many doctors consider a flare reaction to be a sign that hormonal therapy is having a beneficial effect on the breast cancer.
Withdrawal response — Some women who stop tamoxifen when breast cancer begins to progress have an improvement, even if no other treatment is begun. This tamoxifen withdrawal response is most likely to occur in women whose breast cancers initially responded well to tamoxifen. Some women do not require further treatment for up to six months.
Summary — Many women with metastatic breast cancer benefit from tamoxifen, and it is often the first choice for endocrine therapy in premenopausal women. Alternate endocrine therapies may be recommended for women who have a history of blood clots, and for women with risk factors for blood clots.
SELECTIVE AROMATASE INHIBITORS (SAIs) — Aromatase is an enzyme that converts hormones to estrogen in the body's adrenal glands, and aromatase inhibitors are drugs that reduce estrogen levels by blocking the action of aromatase. Drugs in this class include anastrozole (Arimidex®), letrozole (Femara®) and exemestane (Aromasin®).
SAIs cause hot flashes and increase the risk of osteoporosis (thinning of the bones) and subsequent bone fractures. In contrast to tamoxifen, they do not appear to increase the risk of blood clots or endometrial cancer.
SAIs are recommended only for postmenopausal women (those without functioning ovaries). They should not be used in menstruating women for two reasons: They are not strong enough to block the higher estrogen levels that are produced in the ovaries Women with functioning ovaries who receive SAIs can have increased blood levels of male hormones, leading to side effects such as excessive hair growth and a deeper voice. They may also induce ovarian cysts.
As compared to tamoxifen, anastrozole, letrozole, and exemestane are associated with superior response rates, time to progression, and overall survival when they are used as a first line treatment in postmenopausal women with metastatic breast cancer [1]. As a result, these medications have become the treatment of choice for postmenopausal women with hormone-responsive breast cancer if there is a relapse while receiving adjuvant tamoxifen, if adjuvant endocrine treatments have not been used, or if there is a relapse more than one year after discontinuing adjuvant tamoxifen or an SAI. If a woman has relapsed during or within 12 months after receiving an SAI in the adjuvant setting, fulvestrant or a SERM, such as tamoxifen or toremifene, is an appropriate first-line treatment (see "Pure antiestrogens" below and see "Other SERMS" below).
Anastrozole — Anastrozole is taken by mouth, at a dose of 1 mg once daily. The possible side effects of anastrozole are mild, and include postmenopausal symptoms (since it reduces estrogen levels), and rarely gastrointestinal complaints.
Trials of first-line therapy in postmenopausal women with newly diagnosed metastatic breast cancer have shown that anastrozole is at least as active as tamoxifen, with fewer thromboembolic events and less vaginal bleeding.
Letrozole — Letrozole was directly compared to tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. Compared to tamoxifen, letrozole was associated with a significantly higher overall response rate, longer time to progression, and longer time until chemotherapy was required.
Exemestane — Like the others, exemestane is at least as good as tamoxifen for first-line therapy. Unlike the others, exemestane may also be effective in women who have never responded to tamoxifen and in women who have had a poor response to anastrozole and letrozole. In one study of women whose breast cancers had failed to respond to multiple endocrine therapies, exemestane led to a response in 13 percent of women, and the cancer was stabilized in an additional 17 percent of women [2].
PURE ANTIESTROGENS — Like tamoxifen, pure antiestrogens such as fulvestrant (Faslodex®) block the stimulatory influence of estrogen on breast cancer cells. However, unlike tamoxifen, they do not mimic the effects of estrogen in other tissues.
Fulvestrant is administered as a monthly intramuscular (IM) injection, and it is effective in women whose cancers have progressed on tamoxifen. Two separate studies have compared fulvestrant to the selective aromatase inhibitor anastrozole in postmenopausal women with tamoxifen-resistant advanced breast cancer. In both, fulvestrant was at least as good as anastrozole. One of the most important advantages of this drug is that it is given by injection rather than taken in pill form; this is important for patients whose insurance does not cover prescriptions but does cover office visits and hospital treatment.
OTHER SERMS — Newer SERMs such as toremifene (Fareston®) are currently being studied in women with metastatic breast cancer. As initial hormone therapy, toremifene has similar activity and side effects as tamoxifen, and is a reasonable alternative to tamoxifen for initial treatment of advanced breast cancer. However, toremifene is not effective for women who have failed tamoxifen and should not be used in this setting.
Raloxifene is not an acceptable alternative to tamoxifen because there are no data that it is is effective in metastatic breast cancer.
ESTROGEN DEPRIVATION THERAPY
Premenopausal women
Ovariectomy — Ovariectomy refers to surgical removal of the ovaries. Since the ovaries are not the main source of estrogen production in postmenopausal women, this therapy is only recommended for premenopausal women.
About one-third of women with metastatic breast cancer will have a response to ovariectomy. However, tamoxifen is as effective as ovariectomy, and is usually recommended first (see "Tamoxifen" above). If a breast cancer becomes resistant to tamoxifen, ovariectomy may then be considered.
Gonadotropin releasing hormone agonists — Gonadotropin releasing hormone agonists (GnRH) agonists prevent the ovaries from functioning. All of the GnRH agonists (eg, goserelin (Zoladex®) and leuprolide (Lupron®)) must be injected to be effective. As occurs with tamoxifen therapy, some women may experience a transient flare of breast cancer symptoms when they first begin taking GnRH agonists.
Therapy with GnRH agonists is as effective as ovariectomy for premenopausal women with metastatic breast cancer that is ER or PR positive. However, women treated with a GnRH agonist are more likely to have hot flashes and a flare of breast cancer symptoms.
GnRH agonists have also been combined with tamoxifen in premenopausal women. Combined therapy with tamoxifen and ovarian ablation/suppression is sometimes favored over either approach alone for premenopausal women because it results in higher response rates, a longer time to progression, and possibly has a small beneficial impact on overall survival.
Once a premenopausal woman has disease progression with tamoxifen and ovarian ablation/suppression, she has become postmenopausal and SAIs are an appropriate alternative.
Postmenopausal women — As noted above, estrogen deprivation therapies are usually recommended for women whose breast cancers have become resistant to tamoxifen, rather than as initial endocrine therapy. While premenopausal women may be offered ovariectomy or a GnRH agonist, the available options for postmenopausal women who have failed tamoxifen include SAIs, pure antiestrogens, and if endocrine therapy is still appropriate, sex steroid hormones such as progestins, androgens, and/or estrogen.
Progestins — Progestins can be fairly effective for the treatment of metastatic breast cancer, although it is not clear how they work. Drugs in this class include oral megestrol acetate (Megace®); medroxyprogesterone acetate (Depo-Provera®) is an injectable form of treatment given every 12 weeks, though it has no advantages over megestrol acetate. These are effective hormone therapies, and are typically used third line, after failure of estrogen deprivation therapy and tamoxifen.
Progestins like megestrol can be associated with significant side effects, including weight gain, fluid retention, and vaginal bleeding. Progestins also increase the risk of blood clots, and are not recommended for women who have previously had blood clots or women who have risk factors for blood clots (eg, smokers).
Estrogen — Before current endocrine therapies were available, advanced breast cancer in postmenopausal women was commonly treated with high dose estrogen; this approach is ineffective before the menopause. It is not known how high dose estrogen therapy works.
Patients with prior heavy exposure to endocrine therapy (tamoxifen, megestrol acetate, SAI) may still respond to high dose estrogens. It is usually given as 15 mg estradiol twice daily. Side effects including breast tenderness, vaginal discharge, nausea/vomiting, and more seriously, heart failure and blood clots. As with progestins, estrogens are not recommended for women with a blood clotting disorder or women who have risk factors for blood clots (eg, smokers).
Androgens — Androgens (eg, testosterone, fluoxymesterone [Halotestin®], and testolactone) are male hormones; some are useful in the treatment of advanced breast cancer. About 20 percent of such women will respond to androgens such as fluoxymesterone. These drugs are rarely used because of their associated side effects, which include deepening of the voice, growth of dark hair on the body, fluid retention, and jaundice (yellowing of the skin caused by altered liver function).
Danazol, a weaker androgen, has a response rate of 20 percent. The possible side effects of danazol include swelling and hot flashes. In general, androgen therapy is not as effective as progestin therapy or high-dose estrogen.
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
The Hormone Foundation
(www.hormone.org/public/other.cfm, available in English, Spanish, and Portuguese)
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Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Mauri, D, Pavlidis, N, Polyzos, NP, Ioannidis, JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. J Natl Cancer Inst 2006; 98:1285.
2. Jones, S, Vogel, C, Arkhipov, A, et al. Multicenter, phase II trial of exemestane as third-line hormonal therapy of postmenopausal women with metastatic breast cancer. Aromasin Study Group. J Clin Oncol 1999; 17:3418.
3. Bonneterre, J, Thurlimann, B, Robertson, JF, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the tamoxifen or arimidex randomized group efficacy and tolerability study. J Clin Oncol 2000; 18:3748.
4. Nabholtz, JM, Buzdar, A, Pollak, M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. J Clin Oncol 2000; 18:3758.
5. Mouridsen, H, Gershanovich, M, Sun, Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001; 19:2596.
6. Rose, C, Vtoraya, O, Pluzanska, A, et al. Letrozole vs anastrozole: second line treatment in postmenopausal women with advanced breast cancer (abstract). Proc Am Soc Clin Oncol 2002; 21:34a.
7. Noberasco, C, Bajetta, E, Zilembo, N, et al. Activity of formestane in de novo tamoxifen-resistant patients with metastatic breast cancer. Oncology 1995; 52:454.
8. Kaufmann, M, Bajetta, E, Dirix, LY, et al. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol 2000; 18:1399.
9. Taylor, CW, Green, S, Dalton, WS, et al. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study. J Clin Oncol 1998; 16:994.
10. Klijn, JG, Blamey, RW, Boccardo, F, et al. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 2001; 19:343.
Friday, October 12, 2007
Endocrine therapy for metastatic breast cancer
INTRODUCTION — Several treatment options are available for women with advanced or metastatic breast cancer. These include chemotherapy, endocrine therapy, and targeted therapy with the monoclonal antibody trastuzumab (Herceptin®).
This topic review will discuss the options for endocrine therapy. General treatment and chemotherapy and trastuzumab for metastatic breast cancer are discussed elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer" and see "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Hormones and breast cancer growth — Some breast cancers require the hormone estrogen to grow and spread to other organs while other breast cancers are able to grow and spread without estrogen. Estrogen-dependent breast cancer cells produce a molecule called the estrogen receptor (ER). Approximately 30 to 50 percent of breast cancers in premenopausal women, and 70 to 80 percent of cancers in postmenopausal women make ERs. All women diagnosed with breast cancer should be tested to determine if their cancer expresses ER.
What is endocrine therapy? — Endocrine therapy removes the influence of estrogen on breast cancer cells, preventing the cancer cells from growing and spreading. All endocrine treatment is systemic or body-wide therapy, and is effective against cancer cells regardless of where they are located within the body (eg, the breast, bones, liver, etc). Because endocrine therapy usually has fewer side effects than chemotherapy, it is often recommended as the initial treatment for women with ER-positive metastatic breast cancer.
In general, endocrine therapy can be medical (through the use of drugs) or surgical (usually by removing the ovaries, the main source of estrogen production prior to menopause). In the United States, the majority of women receive medical rather than surgical endocrine therapy for metastatic breast cancer. The choice of therapy often depends upon a woman's menopausal status.
There are two ways of disrupting the effects of estrogen on breast cancer cells: by preventing estrogen production, and by interfering with the ability of estrogen to stimulate the breast cancer cells. Different estrogen deprivation therapies are usually recommended for premenopausal and postmenopausal women. (For more information on the use of endocrine therapy in early stage breast cancer, see "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in postmenopausal women" and see "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women").
Premenopausal endocrine therapy — In premenopausal women, most estrogen is produced by the ovaries. Therefore, removing the ovaries (ovariectomy) or preventing them from producing estrogen through medical therapy (usually requiring monthly injections) is an appropriate method for estrogen deprivation. A summary of endocrine therapies is available in figure 2 .
Postmenopausal endocrine therapy — In contrast, the ovaries of postmenopausal women no longer make estrogen. Two small glands above the kidneys, called the adrenal glands, make precursors for a variety of different hormones, including estrogen. These precursors are then converted to estrogen, mainly in the fat tissues within the body, by an enzyme called aromatase. Aromatase inhibitors are effective treatments for advanced breast cancer. They are most beneficial for postmenopausal women. (See "Selective aromatase inhibitors (SAIs)" below). A summary of endocrine therapies is available in figure 2 .
Importance of hormone receptor expression — Women with ER/PR-positive tumors respond better to endocrine therapy than women with ER/PR-negative tumors (>60 percent response versus 10 percent). However, a trial of endocrine therapy may be warranted in women with ER/PR negative disease because the benefits of endocrine therapy greatly outweigh the risks of chemotherapy. Thus, even if a woman has an ER/PR-negative cancer, she may be offered a trial of endocrine therapy as long as she has slow growing disease, metastasis limited to the bones and/or skin, and limited symptoms related to her cancer.
TAMOXIFEN — Tamoxifen is the first-line endocrine therapy in premenopausal women with advanced breast cancer. Tamoxifen is a standard option for postmenopausal women as well, although more recent data suggest that a different type of endocrine therapy, selective aromatase inhibitors, are better that tamoxifen, as long as a woman's tumor has not become resistant to these drugs. (See "Selective aromatase inhibitors (SAIs)" below).
Tamoxifen is a member of a class of drugs called the selective estrogen receptor modulators (SERMs). SERMs like tamoxifen are chemically similar to estrogen, but are in fact, very different. Tamoxifen prevents estrogen from binding to the ER, and also interacts with the ER. This interaction can stimulate the cells of different organs in one of two different ways: sometimes in ways that are similar to estrogen stimulation (estrogenic), and other times in a manner that is opposite to the effects of estrogen (that is, antiestrogenic). In the same person, SERMS can be antiestrogenic in some tissues, and estrogenic in others (show figure 1). The following illustrates these concepts: Tamoxifen has antiestrogenic actions on both normal and cancerous breast tissue. This is beneficial because taking tamoxifen decreases cancer growth in patients with established breast cancer. Furthermore, women at high risk of developing breast cancer may decrease their chance of getting breast cancer by taking tamoxifen. (See "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"). Tamoxifen also has antiestrogenic activity in the brain. This can lead to bothersome side effects such as hot flashes, sweating, insomnia that occur in 30 to 40 percent of women who take tamoxifen. Tamoxifen is estrogenic in bone. This can be beneficial because tamoxifen prevents progression of osteoporosis. Another SERM, raloxifene, is used for the prevention and treatment of osteoporosis. (See "Patient information: Osteoporosis prevention and treatment"). Tamoxifen is also estrogenic in the liver, leading to an increase in liver production of blood-clotting proteins. This results in a slight increase in the risk of strokes and heart attacks during the first 18 to 24 months of tamoxifen use, particularly in women who are at high risk for these events (ie, smokers, those with a past history of blood clots). Increased clotting proteins also increases the risk of deep vein thrombosis (blood clots in the major internal veins of the leg) and pulmonary embolus (movement of a blood clot to the lungs). Tamoxifen is estrogenic in the endometrium (the lining of the uterus). The risk of uterine cancers is increased by two- to threefold in women who take tamoxifen. However, the risk of a new uterine cancer is well below 1 percent.
This information must be placed in appropriate context for women who are considering tamoxifen. Women with advanced breast cancer are at high risk of dying of breast cancer in the short term, and the benefits of tamoxifen far outweigh the risks of uterine cancer, blood clots, or other long term effects.
Effectiveness — Between 50 and 60 percent of women whose breast cancers are ER-positive will respond to tamoxifen therapy. In contrast, fewer than 10 percent of women with metastatic ER-negative breast cancers respond to tamoxifen. Chemotherapy or trastuzumab (Herceptin®) therapy are recommended for women with ER-negative disease. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Tamoxifen is taken by mouth, at a dose of 20 mg daily. Most breast cancers become resistant to tamoxifen over time. The majority of breast cancers that initially respond remain sensitive to tamoxifen for 12 to 18 months, although some continue to respond for several years. An alternative hormone therapy should be considered if a woman becomes resistant to tamoxifen.
Resistance — The resistance of breast cancer cells to tamoxifen is the greatest limitation of this therapy. However, even among ER-positive breast cancers, some do not respond at all to tamoxifen (called primary resistance); secondary resistance occurs if the tumor initially responds but later become resistant.
Preliminary studies suggest that a protein that is expressed by breast cancer cells called HER2 may help to identify women who are less likely to benefit from tamoxifen therapy (ie, those with primary resistance). However, the results of studies to date have been conflicting, and most doctors offer initial tamoxifen therapy to all premenopausal women with ER-positive breast cancer, regardless of their HER2 status.
Resistance to tamoxifen does not necessarily imply resistance to other endocrine therapies. Treatment options for women who are resistant to tamoxifen include discontinuation of tamoxifen (see "Withdrawal response" below), an alternative endocrine therapy, or systemic chemotherapy.
Premenopausal women with metastatic breast cancer that is resistant to tamoxifen should be treated with surgical removal of the ovaries followed by an SAI (see "Ovariectomy" below).
Flare reaction — Between 3 and 13 percent of women with metastatic disease experience a flare of their breast cancer within two days to three weeks after starting tamoxifen. This "flare" reaction may be characterized by an increase in bone pain, a high blood calcium level, and in women who have tumor deposits within the skin, an increase in the size and/or number of these metastatic skin nodules, or skin redness.
Tumor flares usually subside within four to six weeks. In the meantime, the symptoms can be treated with measures that reduce pain and lower blood levels of calcium. In severe cases, a woman may have to temporarily stop taking tamoxifen until the flare subsides. Many doctors consider a flare reaction to be a sign that hormonal therapy is having a beneficial effect on the breast cancer.
Withdrawal response — Some women who stop tamoxifen when breast cancer begins to progress have an improvement, even if no other treatment is begun. This tamoxifen withdrawal response is most likely to occur in women whose breast cancers initially responded well to tamoxifen. Some women do not require further treatment for up to six months.
Summary — Many women with metastatic breast cancer benefit from tamoxifen, and it is often the first choice for endocrine therapy in premenopausal women. Alternate endocrine therapies may be recommended for women who have a history of blood clots, and for women with risk factors for blood clots.
SELECTIVE AROMATASE INHIBITORS (SAIs) — Aromatase is an enzyme that converts hormones to estrogen in the body's adrenal glands, and aromatase inhibitors are drugs that reduce estrogen levels by blocking the action of aromatase. Drugs in this class include anastrozole (Arimidex®), letrozole (Femara®) and exemestane (Aromasin®).
SAIs cause hot flashes and increase the risk of osteoporosis (thinning of the bones) and subsequent bone fractures. In contrast to tamoxifen, they do not appear to increase the risk of blood clots or endometrial cancer.
SAIs are recommended only for postmenopausal women (those without functioning ovaries). They should not be used in menstruating women for two reasons: They are not strong enough to block the higher estrogen levels that are produced in the ovaries Women with functioning ovaries who receive SAIs can have increased blood levels of male hormones, leading to side effects such as excessive hair growth and a deeper voice. They may also induce ovarian cysts.
As compared to tamoxifen, anastrozole, letrozole, and exemestane are associated with superior response rates, time to progression, and overall survival when they are used as a first line treatment in postmenopausal women with metastatic breast cancer [1]. As a result, these medications have become the treatment of choice for postmenopausal women with hormone-responsive breast cancer if there is a relapse while receiving adjuvant tamoxifen, if adjuvant endocrine treatments have not been used, or if there is a relapse more than one year after discontinuing adjuvant tamoxifen or an SAI. If a woman has relapsed during or within 12 months after receiving an SAI in the adjuvant setting, fulvestrant or a SERM, such as tamoxifen or toremifene, is an appropriate first-line treatment (see "Pure antiestrogens" below and see "Other SERMS" below).
Anastrozole — Anastrozole is taken by mouth, at a dose of 1 mg once daily. The possible side effects of anastrozole are mild, and include postmenopausal symptoms (since it reduces estrogen levels), and rarely gastrointestinal complaints.
Trials of first-line therapy in postmenopausal women with newly diagnosed metastatic breast cancer have shown that anastrozole is at least as active as tamoxifen, with fewer thromboembolic events and less vaginal bleeding.
Letrozole — Letrozole was directly compared to tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. Compared to tamoxifen, letrozole was associated with a significantly higher overall response rate, longer time to progression, and longer time until chemotherapy was required.
Exemestane — Like the others, exemestane is at least as good as tamoxifen for first-line therapy. Unlike the others, exemestane may also be effective in women who have never responded to tamoxifen and in women who have had a poor response to anastrozole and letrozole. In one study of women whose breast cancers had failed to respond to multiple endocrine therapies, exemestane led to a response in 13 percent of women, and the cancer was stabilized in an additional 17 percent of women [2].
PURE ANTIESTROGENS — Like tamoxifen, pure antiestrogens such as fulvestrant (Faslodex®) block the stimulatory influence of estrogen on breast cancer cells. However, unlike tamoxifen, they do not mimic the effects of estrogen in other tissues.
Fulvestrant is administered as a monthly intramuscular (IM) injection, and it is effective in women whose cancers have progressed on tamoxifen. Two separate studies have compared fulvestrant to the selective aromatase inhibitor anastrozole in postmenopausal women with tamoxifen-resistant advanced breast cancer. In both, fulvestrant was at least as good as anastrozole. One of the most important advantages of this drug is that it is given by injection rather than taken in pill form; this is important for patients whose insurance does not cover prescriptions but does cover office visits and hospital treatment.
OTHER SERMS — Newer SERMs such as toremifene (Fareston®) are currently being studied in women with metastatic breast cancer. As initial hormone therapy, toremifene has similar activity and side effects as tamoxifen, and is a reasonable alternative to tamoxifen for initial treatment of advanced breast cancer. However, toremifene is not effective for women who have failed tamoxifen and should not be used in this setting.
Raloxifene is not an acceptable alternative to tamoxifen because there are no data that it is is effective in metastatic breast cancer.
ESTROGEN DEPRIVATION THERAPY
Premenopausal women
Ovariectomy — Ovariectomy refers to surgical removal of the ovaries. Since the ovaries are not the main source of estrogen production in postmenopausal women, this therapy is only recommended for premenopausal women.
About one-third of women with metastatic breast cancer will have a response to ovariectomy. However, tamoxifen is as effective as ovariectomy, and is usually recommended first (see "Tamoxifen" above). If a breast cancer becomes resistant to tamoxifen, ovariectomy may then be considered.
Gonadotropin releasing hormone agonists — Gonadotropin releasing hormone agonists (GnRH) agonists prevent the ovaries from functioning. All of the GnRH agonists (eg, goserelin (Zoladex®) and leuprolide (Lupron®)) must be injected to be effective. As occurs with tamoxifen therapy, some women may experience a transient flare of breast cancer symptoms when they first begin taking GnRH agonists.
Therapy with GnRH agonists is as effective as ovariectomy for premenopausal women with metastatic breast cancer that is ER or PR positive. However, women treated with a GnRH agonist are more likely to have hot flashes and a flare of breast cancer symptoms.
GnRH agonists have also been combined with tamoxifen in premenopausal women. Combined therapy with tamoxifen and ovarian ablation/suppression is sometimes favored over either approach alone for premenopausal women because it results in higher response rates, a longer time to progression, and possibly has a small beneficial impact on overall survival.
Once a premenopausal woman has disease progression with tamoxifen and ovarian ablation/suppression, she has become postmenopausal and SAIs are an appropriate alternative.
Postmenopausal women — As noted above, estrogen deprivation therapies are usually recommended for women whose breast cancers have become resistant to tamoxifen, rather than as initial endocrine therapy. While premenopausal women may be offered ovariectomy or a GnRH agonist, the available options for postmenopausal women who have failed tamoxifen include SAIs, pure antiestrogens, and if endocrine therapy is still appropriate, sex steroid hormones such as progestins, androgens, and/or estrogen.
Progestins — Progestins can be fairly effective for the treatment of metastatic breast cancer, although it is not clear how they work. Drugs in this class include oral megestrol acetate (Megace®); medroxyprogesterone acetate (Depo-Provera®) is an injectable form of treatment given every 12 weeks, though it has no advantages over megestrol acetate. These are effective hormone therapies, and are typically used third line, after failure of estrogen deprivation therapy and tamoxifen.
Progestins like megestrol can be associated with significant side effects, including weight gain, fluid retention, and vaginal bleeding. Progestins also increase the risk of blood clots, and are not recommended for women who have previously had blood clots or women who have risk factors for blood clots (eg, smokers).
Estrogen — Before current endocrine therapies were available, advanced breast cancer in postmenopausal women was commonly treated with high dose estrogen; this approach is ineffective before the menopause. It is not known how high dose estrogen therapy works.
Patients with prior heavy exposure to endocrine therapy (tamoxifen, megestrol acetate, SAI) may still respond to high dose estrogens. It is usually given as 15 mg estradiol twice daily. Side effects including breast tenderness, vaginal discharge, nausea/vomiting, and more seriously, heart failure and blood clots. As with progestins, estrogens are not recommended for women with a blood clotting disorder or women who have risk factors for blood clots (eg, smokers).
Androgens — Androgens (eg, testosterone, fluoxymesterone [Halotestin®], and testolactone) are male hormones; some are useful in the treatment of advanced breast cancer. About 20 percent of such women will respond to androgens such as fluoxymesterone. These drugs are rarely used because of their associated side effects, which include deepening of the voice, growth of dark hair on the body, fluid retention, and jaundice (yellowing of the skin caused by altered liver function).
Danazol, a weaker androgen, has a response rate of 20 percent. The possible side effects of danazol include swelling and hot flashes. In general, androgen therapy is not as effective as progestin therapy or high-dose estrogen.
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
The Hormone Foundation
(www.hormone.org/public/other.cfm, available in English, Spanish, and Portuguese)
[1-10]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Mauri, D, Pavlidis, N, Polyzos, NP, Ioannidis, JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. J Natl Cancer Inst 2006; 98:1285.
2. Jones, S, Vogel, C, Arkhipov, A, et al. Multicenter, phase II trial of exemestane as third-line hormonal therapy of postmenopausal women with metastatic breast cancer. Aromasin Study Group. J Clin Oncol 1999; 17:3418.
3. Bonneterre, J, Thurlimann, B, Robertson, JF, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the tamoxifen or arimidex randomized group efficacy and tolerability study. J Clin Oncol 2000; 18:3748.
4. Nabholtz, JM, Buzdar, A, Pollak, M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. J Clin Oncol 2000; 18:3758.
5. Mouridsen, H, Gershanovich, M, Sun, Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001; 19:2596.
6. Rose, C, Vtoraya, O, Pluzanska, A, et al. Letrozole vs anastrozole: second line treatment in postmenopausal women with advanced breast cancer (abstract). Proc Am Soc Clin Oncol 2002; 21:34a.
7. Noberasco, C, Bajetta, E, Zilembo, N, et al. Activity of formestane in de novo tamoxifen-resistant patients with metastatic breast cancer. Oncology 1995; 52:454.
8. Kaufmann, M, Bajetta, E, Dirix, LY, et al. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol 2000; 18:1399.
9. Taylor, CW, Green, S, Dalton, WS, et al. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study. J Clin Oncol 1998; 16:994.
10. Klijn, JG, Blamey, RW, Boccardo, F, et al. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 2001; 19:343.
This topic review will discuss the options for endocrine therapy. General treatment and chemotherapy and trastuzumab for metastatic breast cancer are discussed elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer" and see "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Hormones and breast cancer growth — Some breast cancers require the hormone estrogen to grow and spread to other organs while other breast cancers are able to grow and spread without estrogen. Estrogen-dependent breast cancer cells produce a molecule called the estrogen receptor (ER). Approximately 30 to 50 percent of breast cancers in premenopausal women, and 70 to 80 percent of cancers in postmenopausal women make ERs. All women diagnosed with breast cancer should be tested to determine if their cancer expresses ER.
What is endocrine therapy? — Endocrine therapy removes the influence of estrogen on breast cancer cells, preventing the cancer cells from growing and spreading. All endocrine treatment is systemic or body-wide therapy, and is effective against cancer cells regardless of where they are located within the body (eg, the breast, bones, liver, etc). Because endocrine therapy usually has fewer side effects than chemotherapy, it is often recommended as the initial treatment for women with ER-positive metastatic breast cancer.
In general, endocrine therapy can be medical (through the use of drugs) or surgical (usually by removing the ovaries, the main source of estrogen production prior to menopause). In the United States, the majority of women receive medical rather than surgical endocrine therapy for metastatic breast cancer. The choice of therapy often depends upon a woman's menopausal status.
There are two ways of disrupting the effects of estrogen on breast cancer cells: by preventing estrogen production, and by interfering with the ability of estrogen to stimulate the breast cancer cells. Different estrogen deprivation therapies are usually recommended for premenopausal and postmenopausal women. (For more information on the use of endocrine therapy in early stage breast cancer, see "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in postmenopausal women" and see "Patient information: Adjuvant systemic therapy for hormone-responsive early stage breast cancer in premenopausal women").
Premenopausal endocrine therapy — In premenopausal women, most estrogen is produced by the ovaries. Therefore, removing the ovaries (ovariectomy) or preventing them from producing estrogen through medical therapy (usually requiring monthly injections) is an appropriate method for estrogen deprivation. A summary of endocrine therapies is available in figure 2 .
Postmenopausal endocrine therapy — In contrast, the ovaries of postmenopausal women no longer make estrogen. Two small glands above the kidneys, called the adrenal glands, make precursors for a variety of different hormones, including estrogen. These precursors are then converted to estrogen, mainly in the fat tissues within the body, by an enzyme called aromatase. Aromatase inhibitors are effective treatments for advanced breast cancer. They are most beneficial for postmenopausal women. (See "Selective aromatase inhibitors (SAIs)" below). A summary of endocrine therapies is available in figure 2 .
Importance of hormone receptor expression — Women with ER/PR-positive tumors respond better to endocrine therapy than women with ER/PR-negative tumors (>60 percent response versus 10 percent). However, a trial of endocrine therapy may be warranted in women with ER/PR negative disease because the benefits of endocrine therapy greatly outweigh the risks of chemotherapy. Thus, even if a woman has an ER/PR-negative cancer, she may be offered a trial of endocrine therapy as long as she has slow growing disease, metastasis limited to the bones and/or skin, and limited symptoms related to her cancer.
TAMOXIFEN — Tamoxifen is the first-line endocrine therapy in premenopausal women with advanced breast cancer. Tamoxifen is a standard option for postmenopausal women as well, although more recent data suggest that a different type of endocrine therapy, selective aromatase inhibitors, are better that tamoxifen, as long as a woman's tumor has not become resistant to these drugs. (See "Selective aromatase inhibitors (SAIs)" below).
Tamoxifen is a member of a class of drugs called the selective estrogen receptor modulators (SERMs). SERMs like tamoxifen are chemically similar to estrogen, but are in fact, very different. Tamoxifen prevents estrogen from binding to the ER, and also interacts with the ER. This interaction can stimulate the cells of different organs in one of two different ways: sometimes in ways that are similar to estrogen stimulation (estrogenic), and other times in a manner that is opposite to the effects of estrogen (that is, antiestrogenic). In the same person, SERMS can be antiestrogenic in some tissues, and estrogenic in others (show figure 1). The following illustrates these concepts: Tamoxifen has antiestrogenic actions on both normal and cancerous breast tissue. This is beneficial because taking tamoxifen decreases cancer growth in patients with established breast cancer. Furthermore, women at high risk of developing breast cancer may decrease their chance of getting breast cancer by taking tamoxifen. (See "Patient information: Tamoxifen and raloxifene for the prevention of breast cancer"). Tamoxifen also has antiestrogenic activity in the brain. This can lead to bothersome side effects such as hot flashes, sweating, insomnia that occur in 30 to 40 percent of women who take tamoxifen. Tamoxifen is estrogenic in bone. This can be beneficial because tamoxifen prevents progression of osteoporosis. Another SERM, raloxifene, is used for the prevention and treatment of osteoporosis. (See "Patient information: Osteoporosis prevention and treatment"). Tamoxifen is also estrogenic in the liver, leading to an increase in liver production of blood-clotting proteins. This results in a slight increase in the risk of strokes and heart attacks during the first 18 to 24 months of tamoxifen use, particularly in women who are at high risk for these events (ie, smokers, those with a past history of blood clots). Increased clotting proteins also increases the risk of deep vein thrombosis (blood clots in the major internal veins of the leg) and pulmonary embolus (movement of a blood clot to the lungs). Tamoxifen is estrogenic in the endometrium (the lining of the uterus). The risk of uterine cancers is increased by two- to threefold in women who take tamoxifen. However, the risk of a new uterine cancer is well below 1 percent.
This information must be placed in appropriate context for women who are considering tamoxifen. Women with advanced breast cancer are at high risk of dying of breast cancer in the short term, and the benefits of tamoxifen far outweigh the risks of uterine cancer, blood clots, or other long term effects.
Effectiveness — Between 50 and 60 percent of women whose breast cancers are ER-positive will respond to tamoxifen therapy. In contrast, fewer than 10 percent of women with metastatic ER-negative breast cancers respond to tamoxifen. Chemotherapy or trastuzumab (Herceptin®) therapy are recommended for women with ER-negative disease. (See "Patient information: Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer").
Tamoxifen is taken by mouth, at a dose of 20 mg daily. Most breast cancers become resistant to tamoxifen over time. The majority of breast cancers that initially respond remain sensitive to tamoxifen for 12 to 18 months, although some continue to respond for several years. An alternative hormone therapy should be considered if a woman becomes resistant to tamoxifen.
Resistance — The resistance of breast cancer cells to tamoxifen is the greatest limitation of this therapy. However, even among ER-positive breast cancers, some do not respond at all to tamoxifen (called primary resistance); secondary resistance occurs if the tumor initially responds but later become resistant.
Preliminary studies suggest that a protein that is expressed by breast cancer cells called HER2 may help to identify women who are less likely to benefit from tamoxifen therapy (ie, those with primary resistance). However, the results of studies to date have been conflicting, and most doctors offer initial tamoxifen therapy to all premenopausal women with ER-positive breast cancer, regardless of their HER2 status.
Resistance to tamoxifen does not necessarily imply resistance to other endocrine therapies. Treatment options for women who are resistant to tamoxifen include discontinuation of tamoxifen (see "Withdrawal response" below), an alternative endocrine therapy, or systemic chemotherapy.
Premenopausal women with metastatic breast cancer that is resistant to tamoxifen should be treated with surgical removal of the ovaries followed by an SAI (see "Ovariectomy" below).
Flare reaction — Between 3 and 13 percent of women with metastatic disease experience a flare of their breast cancer within two days to three weeks after starting tamoxifen. This "flare" reaction may be characterized by an increase in bone pain, a high blood calcium level, and in women who have tumor deposits within the skin, an increase in the size and/or number of these metastatic skin nodules, or skin redness.
Tumor flares usually subside within four to six weeks. In the meantime, the symptoms can be treated with measures that reduce pain and lower blood levels of calcium. In severe cases, a woman may have to temporarily stop taking tamoxifen until the flare subsides. Many doctors consider a flare reaction to be a sign that hormonal therapy is having a beneficial effect on the breast cancer.
Withdrawal response — Some women who stop tamoxifen when breast cancer begins to progress have an improvement, even if no other treatment is begun. This tamoxifen withdrawal response is most likely to occur in women whose breast cancers initially responded well to tamoxifen. Some women do not require further treatment for up to six months.
Summary — Many women with metastatic breast cancer benefit from tamoxifen, and it is often the first choice for endocrine therapy in premenopausal women. Alternate endocrine therapies may be recommended for women who have a history of blood clots, and for women with risk factors for blood clots.
SELECTIVE AROMATASE INHIBITORS (SAIs) — Aromatase is an enzyme that converts hormones to estrogen in the body's adrenal glands, and aromatase inhibitors are drugs that reduce estrogen levels by blocking the action of aromatase. Drugs in this class include anastrozole (Arimidex®), letrozole (Femara®) and exemestane (Aromasin®).
SAIs cause hot flashes and increase the risk of osteoporosis (thinning of the bones) and subsequent bone fractures. In contrast to tamoxifen, they do not appear to increase the risk of blood clots or endometrial cancer.
SAIs are recommended only for postmenopausal women (those without functioning ovaries). They should not be used in menstruating women for two reasons: They are not strong enough to block the higher estrogen levels that are produced in the ovaries Women with functioning ovaries who receive SAIs can have increased blood levels of male hormones, leading to side effects such as excessive hair growth and a deeper voice. They may also induce ovarian cysts.
As compared to tamoxifen, anastrozole, letrozole, and exemestane are associated with superior response rates, time to progression, and overall survival when they are used as a first line treatment in postmenopausal women with metastatic breast cancer [1]. As a result, these medications have become the treatment of choice for postmenopausal women with hormone-responsive breast cancer if there is a relapse while receiving adjuvant tamoxifen, if adjuvant endocrine treatments have not been used, or if there is a relapse more than one year after discontinuing adjuvant tamoxifen or an SAI. If a woman has relapsed during or within 12 months after receiving an SAI in the adjuvant setting, fulvestrant or a SERM, such as tamoxifen or toremifene, is an appropriate first-line treatment (see "Pure antiestrogens" below and see "Other SERMS" below).
Anastrozole — Anastrozole is taken by mouth, at a dose of 1 mg once daily. The possible side effects of anastrozole are mild, and include postmenopausal symptoms (since it reduces estrogen levels), and rarely gastrointestinal complaints.
Trials of first-line therapy in postmenopausal women with newly diagnosed metastatic breast cancer have shown that anastrozole is at least as active as tamoxifen, with fewer thromboembolic events and less vaginal bleeding.
Letrozole — Letrozole was directly compared to tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. Compared to tamoxifen, letrozole was associated with a significantly higher overall response rate, longer time to progression, and longer time until chemotherapy was required.
Exemestane — Like the others, exemestane is at least as good as tamoxifen for first-line therapy. Unlike the others, exemestane may also be effective in women who have never responded to tamoxifen and in women who have had a poor response to anastrozole and letrozole. In one study of women whose breast cancers had failed to respond to multiple endocrine therapies, exemestane led to a response in 13 percent of women, and the cancer was stabilized in an additional 17 percent of women [2].
PURE ANTIESTROGENS — Like tamoxifen, pure antiestrogens such as fulvestrant (Faslodex®) block the stimulatory influence of estrogen on breast cancer cells. However, unlike tamoxifen, they do not mimic the effects of estrogen in other tissues.
Fulvestrant is administered as a monthly intramuscular (IM) injection, and it is effective in women whose cancers have progressed on tamoxifen. Two separate studies have compared fulvestrant to the selective aromatase inhibitor anastrozole in postmenopausal women with tamoxifen-resistant advanced breast cancer. In both, fulvestrant was at least as good as anastrozole. One of the most important advantages of this drug is that it is given by injection rather than taken in pill form; this is important for patients whose insurance does not cover prescriptions but does cover office visits and hospital treatment.
OTHER SERMS — Newer SERMs such as toremifene (Fareston®) are currently being studied in women with metastatic breast cancer. As initial hormone therapy, toremifene has similar activity and side effects as tamoxifen, and is a reasonable alternative to tamoxifen for initial treatment of advanced breast cancer. However, toremifene is not effective for women who have failed tamoxifen and should not be used in this setting.
Raloxifene is not an acceptable alternative to tamoxifen because there are no data that it is is effective in metastatic breast cancer.
ESTROGEN DEPRIVATION THERAPY
Premenopausal women
Ovariectomy — Ovariectomy refers to surgical removal of the ovaries. Since the ovaries are not the main source of estrogen production in postmenopausal women, this therapy is only recommended for premenopausal women.
About one-third of women with metastatic breast cancer will have a response to ovariectomy. However, tamoxifen is as effective as ovariectomy, and is usually recommended first (see "Tamoxifen" above). If a breast cancer becomes resistant to tamoxifen, ovariectomy may then be considered.
Gonadotropin releasing hormone agonists — Gonadotropin releasing hormone agonists (GnRH) agonists prevent the ovaries from functioning. All of the GnRH agonists (eg, goserelin (Zoladex®) and leuprolide (Lupron®)) must be injected to be effective. As occurs with tamoxifen therapy, some women may experience a transient flare of breast cancer symptoms when they first begin taking GnRH agonists.
Therapy with GnRH agonists is as effective as ovariectomy for premenopausal women with metastatic breast cancer that is ER or PR positive. However, women treated with a GnRH agonist are more likely to have hot flashes and a flare of breast cancer symptoms.
GnRH agonists have also been combined with tamoxifen in premenopausal women. Combined therapy with tamoxifen and ovarian ablation/suppression is sometimes favored over either approach alone for premenopausal women because it results in higher response rates, a longer time to progression, and possibly has a small beneficial impact on overall survival.
Once a premenopausal woman has disease progression with tamoxifen and ovarian ablation/suppression, she has become postmenopausal and SAIs are an appropriate alternative.
Postmenopausal women — As noted above, estrogen deprivation therapies are usually recommended for women whose breast cancers have become resistant to tamoxifen, rather than as initial endocrine therapy. While premenopausal women may be offered ovariectomy or a GnRH agonist, the available options for postmenopausal women who have failed tamoxifen include SAIs, pure antiestrogens, and if endocrine therapy is still appropriate, sex steroid hormones such as progestins, androgens, and/or estrogen.
Progestins — Progestins can be fairly effective for the treatment of metastatic breast cancer, although it is not clear how they work. Drugs in this class include oral megestrol acetate (Megace®); medroxyprogesterone acetate (Depo-Provera®) is an injectable form of treatment given every 12 weeks, though it has no advantages over megestrol acetate. These are effective hormone therapies, and are typically used third line, after failure of estrogen deprivation therapy and tamoxifen.
Progestins like megestrol can be associated with significant side effects, including weight gain, fluid retention, and vaginal bleeding. Progestins also increase the risk of blood clots, and are not recommended for women who have previously had blood clots or women who have risk factors for blood clots (eg, smokers).
Estrogen — Before current endocrine therapies were available, advanced breast cancer in postmenopausal women was commonly treated with high dose estrogen; this approach is ineffective before the menopause. It is not known how high dose estrogen therapy works.
Patients with prior heavy exposure to endocrine therapy (tamoxifen, megestrol acetate, SAI) may still respond to high dose estrogens. It is usually given as 15 mg estradiol twice daily. Side effects including breast tenderness, vaginal discharge, nausea/vomiting, and more seriously, heart failure and blood clots. As with progestins, estrogens are not recommended for women with a blood clotting disorder or women who have risk factors for blood clots (eg, smokers).
Androgens — Androgens (eg, testosterone, fluoxymesterone [Halotestin®], and testolactone) are male hormones; some are useful in the treatment of advanced breast cancer. About 20 percent of such women will respond to androgens such as fluoxymesterone. These drugs are rarely used because of their associated side effects, which include deepening of the voice, growth of dark hair on the body, fluid retention, and jaundice (yellowing of the skin caused by altered liver function).
Danazol, a weaker androgen, has a response rate of 20 percent. The possible side effects of danazol include swelling and hot flashes. In general, androgen therapy is not as effective as progestin therapy or high-dose estrogen.
CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:
www.cancer.gov/clinical_trials/learning/
www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
The Hormone Foundation
(www.hormone.org/public/other.cfm, available in English, Spanish, and Portuguese)
[1-10]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Mauri, D, Pavlidis, N, Polyzos, NP, Ioannidis, JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. J Natl Cancer Inst 2006; 98:1285.
2. Jones, S, Vogel, C, Arkhipov, A, et al. Multicenter, phase II trial of exemestane as third-line hormonal therapy of postmenopausal women with metastatic breast cancer. Aromasin Study Group. J Clin Oncol 1999; 17:3418.
3. Bonneterre, J, Thurlimann, B, Robertson, JF, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the tamoxifen or arimidex randomized group efficacy and tolerability study. J Clin Oncol 2000; 18:3748.
4. Nabholtz, JM, Buzdar, A, Pollak, M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. J Clin Oncol 2000; 18:3758.
5. Mouridsen, H, Gershanovich, M, Sun, Y, et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001; 19:2596.
6. Rose, C, Vtoraya, O, Pluzanska, A, et al. Letrozole vs anastrozole: second line treatment in postmenopausal women with advanced breast cancer (abstract). Proc Am Soc Clin Oncol 2002; 21:34a.
7. Noberasco, C, Bajetta, E, Zilembo, N, et al. Activity of formestane in de novo tamoxifen-resistant patients with metastatic breast cancer. Oncology 1995; 52:454.
8. Kaufmann, M, Bajetta, E, Dirix, LY, et al. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol 2000; 18:1399.
9. Taylor, CW, Green, S, Dalton, WS, et al. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study. J Clin Oncol 1998; 16:994.
10. Klijn, JG, Blamey, RW, Boccardo, F, et al. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: a meta-analysis of four randomized trials. J Clin Oncol 2001; 19:343.
Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer
INTRODUCTION — Breast cancer is the most common female cancer in the United States, the second most common cause of cancer death in women (after lung cancer), and the main cause of death in women ages 45 to 55. Every year, approximately 205,000 American women are diagnosed with breast cancer and more than 40,000 die from this disease. Early detection and treatment can improve survival by removing the breast tumor before it has a chance to spread (metastasize).
Despite early diagnosis and treatment, breast cancer can reappear at a later time (a recurrence), even if the cancer was confined to the breast at the time of detection. A recurrence can be either local (confined to the breast area or nearby tissues) or at a distant site (beyond the breast and nearby tissues). Areas of distant tumor involvement are called metastases. Although the vast majority of women with metastatic breast cancer have a recurrent or relapsed tumor, 1 to 5 percent of women with breast cancer already have metastatic disease at the time their cancers are discovered.
Metastatic breast cancer is usually not a curable condition. However, systemic (bodywide) treatment can prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life (QOL). Options for systemic treatment in women with metastatic breast cancer include chemotherapy, hormone therapy, and targeted agents such as Herceptin (trastuzumab).
This topic review will discuss the use of chemotherapy and Herceptin in advanced and metastatic breast cancer. General principles that guide the treatment of metastatic breast cancer and the use of hormone therapy in this situation are presented elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer" and see "Patient information: Endocrine therapy for metastatic breast cancer").
General principles of treatment — As noted above, the goals of systemic treatment for metastatic breast cancer include symptom control, improved quality of life, and prolonged survival rather than cure. To quantify these benefits, oncologists use certain endpoints to measure a treatment's effectiveness. These include: Response rate — The proportion of persons who have a measurable (50 percent or more) decrease in the amount of cancer Clinical benefit rate — The proportion of patients who have measurable as well as partial or stable responses to treatment Disease progression time — The duration of time that a certain therapy is effective before an alternate treatment is required Survival — Despite the importance of response rate, clinical benefit, and disease progression, the gold standard for deciding whether one therapy is better than another is the impact the treatment has on survival. Even if one treatment has a higher response rate than another, it does not follow that survival is also better.
This is a particularly important concept when considering the sequential use of single drugs versus combination chemotherapy regimens for treatment of metastatic breast cancer. Combinations of drugs typically have a higher response rate than a drug given individually, but also have more side effects; survival benefits are modest, at best. It is possible that similar outcomes may be obtained by giving the individual drugs of the combination regimen one at a time (sequentially), rather than all at the same time (concurrently). This is a controversial area in the treatment of metastatic breast cancer, and is discussed in more detail below.
More detailed explanation about the issues surrounding assessment of treatment benefit is provided elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer").
CHEMOTHERAPY — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. These cytotoxic (toxic to cells) drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are not affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues give rise to side effects during treatment.
Most chemotherapy drugs are given into the vein (IV) rather than by mouth; one exception is the drug Xeloda (capecitabine), which is given by mouth. Chemotherapy is usually not administered daily but periodically, in cycles. A cycle of chemotherapy refers to the time it takes to give the treatment and then allow the body to recover from the side effects of the medicines.
Many different cytotoxic drugs are effective in the treatment of metastatic breast cancer. The most commonly used include: cyclophosphamide (C), methotrexate (M), doxorubicin (often abbreviated A for its brand name Adriamycin®), epirubicin (Ellence®), 5-fluorouracil (abbreviated 5-FU, or F), capecitabine (Xeloda®), paclitaxel (Taxol®), docetaxel (Taxotere®), vinorelbine (Navelbine®), and gemcitabine (Gemzar®).
Combination versus sequential single agent therapy — Specific combinations of these individual drugs (called regimens) have been developed to improve the likelihood of successfully shrinking tumors. As noted above, one of the most pressing and unanswered questions in chemotherapy treatment of metastatic breast cancer is whether similar outcomes can be achieved, with less toxicity, by the sequential use of active single agents, rather than combination regimens. (See "Selecting optimal therapy" below).
Many oncologists consider single-drug chemotherapy a reasonable treatment option, especially for women who have received several different types of chemotherapy for breast cancer. On the other hand, because combination therapy is often associated with a higher response rate, it may be chosen over single agent therapy if the breast cancer is growing rapidly, causing severe symptoms, or if vital organs (eg, liver, lungs) are involved in the tumor.
In the following sections, we will review the most active agents and drug combinations.
Anthracyclines and related drugs — The anthracyclines and related drugs include doxorubicin (Adriamycin®), epirubicin (Ellence®), and mitoxantrone (Novantrone®). When used alone, these drugs have a response rate of 35 to 40 percent. Doxil® is a special form of doxorubicin in which the drug is contained or encapsulated within a fat-containing substance called liposomes. This allows the drug to remain in the body for a longer period of time and may reduce the likelihood of side effects involving the heart.
Anthracyclines are often used in combination with other drugs. Common combinations include AC (doxorubicin plus cyclophosphamide), FAC or CAF (cyclophosphamide plus doxorubicin and 5-FU) and CEF (cyclophosphamide plus epirubicin and 5-FU). A good response to these combinations occurs in 20 to 60 percent of women with metastatic breast cancer who have not been previously treated for advanced disease. Side effects — The possible side effects of anthracyclines include nausea, vomiting, hair loss, and temporary loss of bone marrow function. Bone marrow suppression can lead to infections (which can occur with a low white blood cell count), anemia (which can cause fatigue and low energy) and bleeding (which can occur if the platelet count is very low).
The anthracyclines and related drugs can also damage the heart muscle and cause heart failure. Several measures can reduce the likelihood of this side effect, including limiting the total or cumulative dose of these drugs, administering them gradually (over 6 to 96 hours) or in more frequent smaller doses, simultaneously administering drugs that protect the heart muscle, or by using the liposome-encapsulated form of doxorubicin, Doxil®.
Taxanes — As a group, the taxanes (paclitaxel [Taxol®] and docetaxel [Taxotere®]) are some of the most active drugs available for the treatment of advanced breast cancer. Drugs of this class are often the first drugs chosen to treat breast cancers that do not respond to hormone therapy and those that have responded poorly to other chemotherapy drugs such as anthracyclines.
Paclitaxel (and less commonly docetaxel) can cause serious hypersensitivity (allergic) reactions in some women. Because of this, premedication with steroids and antihistamines is generally recommended prior to each treatment. A newer formulation of paclitaxel is available (Abraxane®) which is associated with significantly fewer allergic reactions. Pretreatment is not necessary, but the drug is quite a bit more expensive than conventional paclitaxel.
More frequent administration of these drugs (ie, weekly rather than every three week treatment) allows a higher total dose of chemotherapy drugs to be given, and also appears to lower the likelihood of some side effects, such as bone marrow suppression, or muscle and joint aches, but not others.
Paclitaxel — Paclitaxel may be given once every three weeks or in lower doses once per week. It produces a response in 35 to 55 percent of women with metastatic breast cancer who have not been previously treated with doxorubicin, and in about 20 percent of women whose breast cancers are resistant to doxorubicin. Side effects — Hair loss is a common side effect of paclitaxel; nausea and vomiting are less common. About 5 to 15 percent of women experience muscle and joint pain after paclitaxel treatment; the symptoms typically begin 24 to 72 hours after treatment and last two to four days. This side effect can be minimized with steroid premedication, and seems to be less common when paclitaxel is administered weekly.
Paclitaxel can also suppress the bone marrow function, temporarily lowering the blood counts. It may be possible to reduce the effects of paclitaxel on the bone marrow and nerves by using more frequent, smaller doses.
It can cause a type of nerve damage that affects the fingers and toes. This is called peripheral neuropathy, and is severe in only 10 to 15 percent of women. However, the effects are cumulative (ie, it is more common and more severe as more drug is given). Paclitaxel may be inappropriate for some women with poor liver function.
Abraxane — Abraxane® is a unique formulation of paclitaxel whose main benefit is that it causes significantly fewer allergic reactions. In addition, at least one study suggests that Abraxane may be associated with a moderately higher response rate and duration of benefit compared to paclitaxel, but it may also cause more neurologic toxicity, and is also significantly more expensive than paclitaxel. As a result, there is controversy as to whether Abraxane® should replace standard paclitaxel for the treatment of metastatic breast cancer.
Docetaxel — Like paclitaxel, docetaxel may be given once every three weeks or in lower doses once per week. Docetaxel has a response rate of 35 to 60 percent in women with metastatic breast cancer, including women with advanced disease who have been previously treated with many other types of chemotherapy. In addition, up to 25 percent of breast cancers that are resistant to paclitaxel respond to docetaxel. Side effects — Docetaxel occasionally causes nausea and vomiting and often causes hair loss. Like paclitaxel, docetaxel can also temporarily suppress bone marrow function and may cause peripheral neuropathy, which may or may not be reversible. Docetaxel may cause fluid retention, which can be prevented if steroids are given prior to docetaxel.
It is possible to reduce the side effects of docetaxel by using more frequent, smaller doses (ie, weekly therapy). However, weekly therapy is more often associated with excess tear production in the eyes and nail changes.
Taxane combinations — Paclitaxel or docetaxel may be used in combination with other chemotherapy drugs. Adding a taxane to other chemotherapy drugs increases the likelihood of response, but also increases the chance of serious side effects. Furthermore, as noted above, the increase in response rate with combination therapy has translated into only minor improvements in survival compared to sequential administration of active single agents [1-3]. As an example, in a single study, women receiving both gemcitabine plus paclitaxel had a higher response rate (41 versus 22 percent) and a slightly longer (two month) survival compared to those receiving paclitaxel alone [1]. Although the side effects were more pronounced in women receiving both gemcitabine and paclitaxel, they were not particularly severe in either group.
Although combinations of paclitaxel and doxorubicin have been associated with very high response rates, they also cause higher than expected rates of heart damage in many but not all [3] studies. While combination of docetaxel and doxorubicin do not appear to increase the risk for heart problems, they have been associated with life-threatening bone marrow suppression and associated infection.
It is not clear that the added toxicities of anthracycline/taxane combinations are justified by a greater therapeutic benefit, or that anthracycline/taxane combinations provide clear benefit over sequential administration of each agent alone [3]. A pooled analysis of seven trials comparing anthracycline/taxane regimens versus other combinations of an anthracycline/cyclophosphamide with or without 5-FU for first-line therapy came to the following conclusions [4]: Use of a taxane/anthracycline combination significantly increased the response rate, and doubled the chance of a complete response Taxane-based regimens were associated with a borderline improvement in time to tumor progression, but survival was not improved Patients treated with a taxane/anthracycline regimen were nearly three times more likely to require hospitalization for fever in the setting of low blood counts
Alkylating drugs — Cyclophosphamide is the alkylating drug most commonly used to treat metastatic breast cancer, usually in combination regimens, as described above. Side effects — Treatment with alkylating drugs carries a slight risk of bladder inflammation and blood in the urine, but this risk can be minimized by drinking plenty of fluids and urinating frequently during treatment. Cyclophosphamide is also associated with an approximately three-fold increased risk of leukemia at a later time, and a loss of fertility, particularly in women over the age of 30 at the time of treatment.
Antimetabolites — The antimetabolites methotrexate and 5-FU are generally used in combination regimens such as CMF (cyclophosphamide, methotrexate, and 5-FU). 5-FU may also be combined with the drug leucovorin. Both of these drugs may be used together in the triple combination NFL (mitoxantrone, 5-FU, and leucovorin).
An oral (tablet form) derivative of 5-FU with activity against breast cancer is available (Xeloda® [capecitabine]). When used alone for the treatment of patients with breast cancer that has progressed in spite of multiple prior therapies, about 20 percent of women have a response, including those whose breast cancers have responded poorly to intravenous 5-FU. Side effects — 5-FU and related drugs are less likely than many other chemotherapy drugs to cause hair loss or suppress bone marrow function. Furthermore, fewer than 10 percent of women experience nausea and vomiting when treated with these drugs. However, 5-FU and related drugs can cause other gastrointestinal symptoms, including diarrhea and inflammation of the mouth (mucositis). The dose of Xeloda may be reduced if a temporary side effect called hand-foot syndrome develops. This causes the skin of the palms and soles of the feet become red and sore, sometimes with peeling.
Gemcitabine — Gemcitabine (Gemzar®) has a low frequency of side effects such as nausea, vomiting, hair loss, and temporary suppression of bone marrow function. It is more often used,in combination with paclitaxel (see above), for treatment of metastatic breast cancer in patients whose disease has progressed while receiving anthracycline-containing regimens.
Vinca drugs — Vinorelbine (Navelbine®) is the most widely used vinca-type drug for advanced breast cancer. Weekly administration results in a response in over 50 percent of women. Side effects — All of these agents can cause damage to the nervous system, which may cause a feeling of numbness and tingling in the fingers and toes (called peripheral neuropathy). This typically develops after several courses of therapy, and is usually reversible when treatment is stopped. Vinorelbine is less likely than vincristine to cause peripheral neuropathy, and the likelihood of bone marrow suppression is low. Occasionally, vinca alkaloids can cause sudden, severe pain around the tumor that begins during or immediately after the drug is administered, and lasts several minutes to hours.
Summary — Among the many chemotherapy drugs available for treatment of metastatic breast cancer, the most active are the anthracyclines and taxanes. Taxanes are often used first in women with metastatic breast cancer whose cancers are unlikely to respond to hormone therapy, and for breast cancers that have recurred after other types of chemotherapy. An anthracycline combination may be used for women who have not previously received anthracycline or those who have had a recurrence more than 12 months since anthracyclines were used. Xeloda, Navelbine, and Gemzar are good second or third-line options, or they may be used as a first line treatment in combination with a taxane.
Due to the small survival difference and more favorable side effect profile, therapy with serial single agents is a reasonable alternative to combination regimens, especially in the second, third, or fourth-line treatment setting (show figure 1). On the other hand, for symptomatic patients or those with rapidly progressive vital organ metastases, combination therapy may be a more appropriate first-line choice because of the greater likelihood of an objective response.
HERCEPTIN — Herceptin (trastuzumab) is an antibody (a type of protein) that specifically targets HER2/neu, a protein present on the cells of some breast cancers. About 30 percent of breast cancers express very high levels of HER2/neu, and Herceptin appears to be effective only in this group of women. The level of HER2/neu within a tumor is determined using a special stain on a microscopic slide containing a sample of the tumor.
Herceptin inhibits the growth of breast cancer cells when given alone or in combination with other chemotherapy drugs. For women with metastatic breast cancer whose breast cancers have not responded to conventional cytotoxic chemotherapy drugs, Herceptin used alone has a response rate of 15 percent.
Herceptin plus other chemotherapy drugs — Adding Herceptin to treatment with other chemotherapy drugs may improve the effectiveness of treatment [5]. Herceptin plus anthracyclines — The use of Herceptin plus an anthracycline-containing drug has been found to cause serious side effects affecting the heart. Thus, despite their high level of activity, combinations of Herceptin and doxorubicin are avoided. Herceptin plus taxanes — The combination of Herceptin plus a taxane may be associated with less toxicity than Herceptin plus an anthracycline, and a better outcome when compared to paclitaxel alone. In one research study, women with breast cancers that produced high levels of the HER2/neu marker and that were resistant to doxorubicin were treated with either paclitaxel alone or paclitaxel plus Herceptin [6]. The women treated with combination therapy had a higher response rate (57 versus 25 percent), a longer time until the cancer progressed, and they also survived for four months longer. Herceptin plus other drugs — High response rates have been reported with combinations of Herceptin plus other cytotoxic drugs such as cisplatin, and vinorelbine, even in women who have used several prior therapies [7]. These combinations may be considered in women with HER2/neu-producing metastatic breast cancer who have failed Herceptin alone or in combination with a taxane.
Side effects — Herceptin occasionally causes a hypersensitivity or allergic reaction, which can be severe. Rarely, severe lung damage can occur. Heart damage develops in about 3 to 5 percent of women treated with Herceptin alone or with paclitaxel; the risk is higher in women who receive Herceptin with an anthracycline drug. Because of this, Herceptin is NOT given with an anthracycline-type drug. When given alone, Herceptin does not cause bone marrow suppression, nausea, vomiting, or hair loss.
Summary — Herceptin alone is a reasonable treatment option for women whose metastatic breast cancers make have high levels of HER2/neu, and that have become resistant to standard hormone therapy and chemotherapy drugs. The combination of Herceptin with paclitaxel is also a reasonable choice.
Herceptin resistance — Lapatinib is an oral medication that targets HER2 in a different way than Herceptin. It can be effective for women whose disease is resistant to Herceptin. Lapatinib is approved, in combination with capecitabine, for women with advanced or metastatic breast cancer who have high levels of HER2 and who have failed tretment with an anthracycline, a taxane, and Herceptin. It is not yet approved as an initial treatment for women with HER2-positive advanced breast cancer.
AVASTIN (BEVACIZUMAB) — Avastin® (bevacizumab) is an antibody that targets a protein called vascular endothelial growth factor (VEGF). VEGF is involved in the process by which a growing cancer develops its own blood supply, which is essential in order for the tumor to grow and spread. Bevacizumab disrupts the process of new blood vessel formation, thereby depriving the tumor of its supply of nutrients.
Early data suggest that selected patients with metastatic breast cancer may benefit from the use of bevacizumab. In one study, bevacizumab was combined with paclitaxel and compared to paclitaxel alone as initial chemotherapy for metastatic breast cancer [8]. Combined therapy was associated with a higher response rate (28 versus 14 percent), and a longer time to progression of the breast cancer; however, the study has not yet determined the impact on survival [8]. Potentially serious side effects with bevacizumab included high blood pressure, bleeding, and loss of protein in the urine.
At present, bevacizumab is not approved for treatment of metastatic breast cancer in the United States; it is only approved for patients with advanced colorectal cancer. Nevertheless, using bevacizumab plus paclitaxel could be considered for a woman who had not received chemotherapy for metastatic breast cancer, and who does not have clotting or bleeding problems, kidney problems, recent surgery, or spread of cancer to the brain (brain metastases). It is not yet known whether the modestly better outcomes from this approach justify the more serious side effect profile and greater expense.
CONTINUOUS VERSUS INTERMITTENT THERAPY — The optimal duration of chemotherapy for women with metastatic breast cancer is unknown. Several studies have compared the effectiveness of continuous chemotherapy until it becomes ineffective versus intermittent chemotherapy (approximately six cycles or courses of chemotherapy followed by a discontinuation of chemotherapy until progression of the cancer). In general, overall survival is the same in women treated with continuous or intermittent chemotherapy, although tumor progression may be delayed a little while longer in women treated with continuous therapy.
Because of the periods of time where chemotherapy is not being given, intermittent chemotherapy may also be associated with a better quality of life. Intermittent chemotherapy may therefore be a reasonable option for women whose cancer-related symptoms are relieved with this therapy.
BONE MARROW TRANSPLANTATION — The improved outcomes with higher as compared to lower doses of chemotherapy drugs raise the possibility that outcomes can be further improved by administering very high doses of chemotherapy. Such doses not only kill more cancer cells, but also destroy young blood cells (stem cells) in the circulating blood and bone marrow. This requires that new stem cells be provided or transplanted into the patient in order to restore the production of blood cells. This entire procedure is referred to as high dose chemotherapy with stem cell transplantation (commonly called a bone marrow transplant). (See "Patient information: Overview of bone marrow transplantation").
Although some women with metastatic breast cancer and few sites of tumor involvement have been offered a bone marrow transplant in the past, this approach has fallen out of favor since studies suggest that it does not provide any benefit over the currently recommended standard dose treatment regimens that do not require stem cell support [1,9]. Because of this, and the substantially greater toxicity of high-dose chemotherapy, this approach should not be considered standard for any women with metastatic breast cancer.
SELECTING OPTIMAL THERAPY
Hormone receptor status — Because hormone therapy generally causes fewer side effects than chemotherapy or biologic therapy, it is usually chosen as initial treatment for women with hormone receptor-positive metastatic breast cancer.
Chemotherapy is initially recommended if the cancer is ER-negative, and in some circumstances for ER-positive tumors. Women with ER-positive breast cancer are most likely to be treated with chemotherapy initially if: The breast cancer is progressing rapidly Metastases are present in vital organs There are many cancer-related symptoms
Chemotherapy is also an appropriate option for treatment of ER-positive breast cancers when hormone therapy is no longer effective.
HER2/neu-negative — Options for initial chemotherapy depend on whether a woman's breast cancer makes the protein HER2/neu. Several options are available for initial treatment in women with HER2/neu-negative metastatic breast cancer: Combination therapy with an anthracycline-containing regimen such as AC (doxorubicin plus cyclophosphamide), FAC (5-FU plus doxorubicin and cyclophosphamide), or FEC (5-FU plus epirubicin and cyclophosphamide) Single agent treatment with an anthracycline or a taxane The combination of a taxane plus either capecitabine or gemcitabine The combination of paclitaxel plus bevacizumab
All of these options have a 30 to 60 percent likelihood of response and relief of cancer-related symptoms. However, questions remain as to whether any of these regimens have a significant survival benefit over another. If there is a survival benefit from combination therapy, it is probably modest (between two and five months); this has been seen with the combinations of paclitaxel plus either gemcitabine or bevacizumab (compared to paclitaxel alone), and docetaxel plus capecitabine (compared to docetaxel alone) [2,3,5].
The decision regarding which regimen to choose, and whether to choose single agent or combination chemotherapy is complex, and depends upon a number of different factors, including what treatments have been used and the length of time since the last treatment. For women considering paclitaxel plus bevacizumab, a history of bleeding problems, blood clots, kidney problems, recent surgery, or poorly controlled high blood pressure are important considerations.
HER2/neu-positive — For women whose breast cancers contain high levels of the HER2/neu protein, Herceptin alone or in combination with a taxane are reasonable choices for initial treatment. Lapatinib is approved, in combination with capecitabine, for women with advanced or metastatic breast cancer who have high levels of HER2 and who have failed tretment with an anthracycline, a taxane, and Herceptin.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
[1-3,5-9]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Albain, KS, Nag, S, Calderillo-Ruiz, G, et al. Global phase III study of gemcitabine plus paclitaxel versus paclitaxel as frontline therapy for metastatic breast cancer: first report of overall survival (abstract). Proc Am Soc Clin Oncol 2004; 22:5a.
2. O'Shaughnessy, J, Miles, D, Vukelja, S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002; 20:2812.
3. Sledge, GW, Neuberg, D, Bernardo, P, et al. Phase III Trial of Doxorubicin, Paclitaxel, and the Combination of Doxorubicin and Paclitaxel as Front-Line Chemotherapy for Metastatic Breast Cancer: An Intergroup Trial (E1193). J Clin Oncol 2003; 21:588.
4. Bria, E, Giannarelli, D, Felici, A, et al. Taxanes with anthracyclines as first-line chemotherapy for metastatic breast carcinoma. Cancer 2005; 103:672.
5. Pegram, MD, Konecny, GE, O'Callaghan, C, et al. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 2004; 96:739.
6. Slamon, DJ, Leyland-Jones, B, Shak, S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783.
7. Pegram, M, Lipton, A, Hayes, DF, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998; 16:2659.
8. Miller, KD. E2100: a randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. Data presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 16, 2005. (Available at www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD (Accessed May 26, 2006).
9. Giordano, SH, Buzdar, AU, Smith, TL, et al. Is breast cancer survival improving?. Cancer 2004; 100:44.
Despite early diagnosis and treatment, breast cancer can reappear at a later time (a recurrence), even if the cancer was confined to the breast at the time of detection. A recurrence can be either local (confined to the breast area or nearby tissues) or at a distant site (beyond the breast and nearby tissues). Areas of distant tumor involvement are called metastases. Although the vast majority of women with metastatic breast cancer have a recurrent or relapsed tumor, 1 to 5 percent of women with breast cancer already have metastatic disease at the time their cancers are discovered.
Metastatic breast cancer is usually not a curable condition. However, systemic (bodywide) treatment can prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life (QOL). Options for systemic treatment in women with metastatic breast cancer include chemotherapy, hormone therapy, and targeted agents such as Herceptin (trastuzumab).
This topic review will discuss the use of chemotherapy and Herceptin in advanced and metastatic breast cancer. General principles that guide the treatment of metastatic breast cancer and the use of hormone therapy in this situation are presented elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer" and see "Patient information: Endocrine therapy for metastatic breast cancer").
General principles of treatment — As noted above, the goals of systemic treatment for metastatic breast cancer include symptom control, improved quality of life, and prolonged survival rather than cure. To quantify these benefits, oncologists use certain endpoints to measure a treatment's effectiveness. These include: Response rate — The proportion of persons who have a measurable (50 percent or more) decrease in the amount of cancer Clinical benefit rate — The proportion of patients who have measurable as well as partial or stable responses to treatment Disease progression time — The duration of time that a certain therapy is effective before an alternate treatment is required Survival — Despite the importance of response rate, clinical benefit, and disease progression, the gold standard for deciding whether one therapy is better than another is the impact the treatment has on survival. Even if one treatment has a higher response rate than another, it does not follow that survival is also better.
This is a particularly important concept when considering the sequential use of single drugs versus combination chemotherapy regimens for treatment of metastatic breast cancer. Combinations of drugs typically have a higher response rate than a drug given individually, but also have more side effects; survival benefits are modest, at best. It is possible that similar outcomes may be obtained by giving the individual drugs of the combination regimen one at a time (sequentially), rather than all at the same time (concurrently). This is a controversial area in the treatment of metastatic breast cancer, and is discussed in more detail below.
More detailed explanation about the issues surrounding assessment of treatment benefit is provided elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer").
CHEMOTHERAPY — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. These cytotoxic (toxic to cells) drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are not affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues give rise to side effects during treatment.
Most chemotherapy drugs are given into the vein (IV) rather than by mouth; one exception is the drug Xeloda (capecitabine), which is given by mouth. Chemotherapy is usually not administered daily but periodically, in cycles. A cycle of chemotherapy refers to the time it takes to give the treatment and then allow the body to recover from the side effects of the medicines.
Many different cytotoxic drugs are effective in the treatment of metastatic breast cancer. The most commonly used include: cyclophosphamide (C), methotrexate (M), doxorubicin (often abbreviated A for its brand name Adriamycin®), epirubicin (Ellence®), 5-fluorouracil (abbreviated 5-FU, or F), capecitabine (Xeloda®), paclitaxel (Taxol®), docetaxel (Taxotere®), vinorelbine (Navelbine®), and gemcitabine (Gemzar®).
Combination versus sequential single agent therapy — Specific combinations of these individual drugs (called regimens) have been developed to improve the likelihood of successfully shrinking tumors. As noted above, one of the most pressing and unanswered questions in chemotherapy treatment of metastatic breast cancer is whether similar outcomes can be achieved, with less toxicity, by the sequential use of active single agents, rather than combination regimens. (See "Selecting optimal therapy" below).
Many oncologists consider single-drug chemotherapy a reasonable treatment option, especially for women who have received several different types of chemotherapy for breast cancer. On the other hand, because combination therapy is often associated with a higher response rate, it may be chosen over single agent therapy if the breast cancer is growing rapidly, causing severe symptoms, or if vital organs (eg, liver, lungs) are involved in the tumor.
In the following sections, we will review the most active agents and drug combinations.
Anthracyclines and related drugs — The anthracyclines and related drugs include doxorubicin (Adriamycin®), epirubicin (Ellence®), and mitoxantrone (Novantrone®). When used alone, these drugs have a response rate of 35 to 40 percent. Doxil® is a special form of doxorubicin in which the drug is contained or encapsulated within a fat-containing substance called liposomes. This allows the drug to remain in the body for a longer period of time and may reduce the likelihood of side effects involving the heart.
Anthracyclines are often used in combination with other drugs. Common combinations include AC (doxorubicin plus cyclophosphamide), FAC or CAF (cyclophosphamide plus doxorubicin and 5-FU) and CEF (cyclophosphamide plus epirubicin and 5-FU). A good response to these combinations occurs in 20 to 60 percent of women with metastatic breast cancer who have not been previously treated for advanced disease. Side effects — The possible side effects of anthracyclines include nausea, vomiting, hair loss, and temporary loss of bone marrow function. Bone marrow suppression can lead to infections (which can occur with a low white blood cell count), anemia (which can cause fatigue and low energy) and bleeding (which can occur if the platelet count is very low).
The anthracyclines and related drugs can also damage the heart muscle and cause heart failure. Several measures can reduce the likelihood of this side effect, including limiting the total or cumulative dose of these drugs, administering them gradually (over 6 to 96 hours) or in more frequent smaller doses, simultaneously administering drugs that protect the heart muscle, or by using the liposome-encapsulated form of doxorubicin, Doxil®.
Taxanes — As a group, the taxanes (paclitaxel [Taxol®] and docetaxel [Taxotere®]) are some of the most active drugs available for the treatment of advanced breast cancer. Drugs of this class are often the first drugs chosen to treat breast cancers that do not respond to hormone therapy and those that have responded poorly to other chemotherapy drugs such as anthracyclines.
Paclitaxel (and less commonly docetaxel) can cause serious hypersensitivity (allergic) reactions in some women. Because of this, premedication with steroids and antihistamines is generally recommended prior to each treatment. A newer formulation of paclitaxel is available (Abraxane®) which is associated with significantly fewer allergic reactions. Pretreatment is not necessary, but the drug is quite a bit more expensive than conventional paclitaxel.
More frequent administration of these drugs (ie, weekly rather than every three week treatment) allows a higher total dose of chemotherapy drugs to be given, and also appears to lower the likelihood of some side effects, such as bone marrow suppression, or muscle and joint aches, but not others.
Paclitaxel — Paclitaxel may be given once every three weeks or in lower doses once per week. It produces a response in 35 to 55 percent of women with metastatic breast cancer who have not been previously treated with doxorubicin, and in about 20 percent of women whose breast cancers are resistant to doxorubicin. Side effects — Hair loss is a common side effect of paclitaxel; nausea and vomiting are less common. About 5 to 15 percent of women experience muscle and joint pain after paclitaxel treatment; the symptoms typically begin 24 to 72 hours after treatment and last two to four days. This side effect can be minimized with steroid premedication, and seems to be less common when paclitaxel is administered weekly.
Paclitaxel can also suppress the bone marrow function, temporarily lowering the blood counts. It may be possible to reduce the effects of paclitaxel on the bone marrow and nerves by using more frequent, smaller doses.
It can cause a type of nerve damage that affects the fingers and toes. This is called peripheral neuropathy, and is severe in only 10 to 15 percent of women. However, the effects are cumulative (ie, it is more common and more severe as more drug is given). Paclitaxel may be inappropriate for some women with poor liver function.
Abraxane — Abraxane® is a unique formulation of paclitaxel whose main benefit is that it causes significantly fewer allergic reactions. In addition, at least one study suggests that Abraxane may be associated with a moderately higher response rate and duration of benefit compared to paclitaxel, but it may also cause more neurologic toxicity, and is also significantly more expensive than paclitaxel. As a result, there is controversy as to whether Abraxane® should replace standard paclitaxel for the treatment of metastatic breast cancer.
Docetaxel — Like paclitaxel, docetaxel may be given once every three weeks or in lower doses once per week. Docetaxel has a response rate of 35 to 60 percent in women with metastatic breast cancer, including women with advanced disease who have been previously treated with many other types of chemotherapy. In addition, up to 25 percent of breast cancers that are resistant to paclitaxel respond to docetaxel. Side effects — Docetaxel occasionally causes nausea and vomiting and often causes hair loss. Like paclitaxel, docetaxel can also temporarily suppress bone marrow function and may cause peripheral neuropathy, which may or may not be reversible. Docetaxel may cause fluid retention, which can be prevented if steroids are given prior to docetaxel.
It is possible to reduce the side effects of docetaxel by using more frequent, smaller doses (ie, weekly therapy). However, weekly therapy is more often associated with excess tear production in the eyes and nail changes.
Taxane combinations — Paclitaxel or docetaxel may be used in combination with other chemotherapy drugs. Adding a taxane to other chemotherapy drugs increases the likelihood of response, but also increases the chance of serious side effects. Furthermore, as noted above, the increase in response rate with combination therapy has translated into only minor improvements in survival compared to sequential administration of active single agents [1-3]. As an example, in a single study, women receiving both gemcitabine plus paclitaxel had a higher response rate (41 versus 22 percent) and a slightly longer (two month) survival compared to those receiving paclitaxel alone [1]. Although the side effects were more pronounced in women receiving both gemcitabine and paclitaxel, they were not particularly severe in either group.
Although combinations of paclitaxel and doxorubicin have been associated with very high response rates, they also cause higher than expected rates of heart damage in many but not all [3] studies. While combination of docetaxel and doxorubicin do not appear to increase the risk for heart problems, they have been associated with life-threatening bone marrow suppression and associated infection.
It is not clear that the added toxicities of anthracycline/taxane combinations are justified by a greater therapeutic benefit, or that anthracycline/taxane combinations provide clear benefit over sequential administration of each agent alone [3]. A pooled analysis of seven trials comparing anthracycline/taxane regimens versus other combinations of an anthracycline/cyclophosphamide with or without 5-FU for first-line therapy came to the following conclusions [4]: Use of a taxane/anthracycline combination significantly increased the response rate, and doubled the chance of a complete response Taxane-based regimens were associated with a borderline improvement in time to tumor progression, but survival was not improved Patients treated with a taxane/anthracycline regimen were nearly three times more likely to require hospitalization for fever in the setting of low blood counts
Alkylating drugs — Cyclophosphamide is the alkylating drug most commonly used to treat metastatic breast cancer, usually in combination regimens, as described above. Side effects — Treatment with alkylating drugs carries a slight risk of bladder inflammation and blood in the urine, but this risk can be minimized by drinking plenty of fluids and urinating frequently during treatment. Cyclophosphamide is also associated with an approximately three-fold increased risk of leukemia at a later time, and a loss of fertility, particularly in women over the age of 30 at the time of treatment.
Antimetabolites — The antimetabolites methotrexate and 5-FU are generally used in combination regimens such as CMF (cyclophosphamide, methotrexate, and 5-FU). 5-FU may also be combined with the drug leucovorin. Both of these drugs may be used together in the triple combination NFL (mitoxantrone, 5-FU, and leucovorin).
An oral (tablet form) derivative of 5-FU with activity against breast cancer is available (Xeloda® [capecitabine]). When used alone for the treatment of patients with breast cancer that has progressed in spite of multiple prior therapies, about 20 percent of women have a response, including those whose breast cancers have responded poorly to intravenous 5-FU. Side effects — 5-FU and related drugs are less likely than many other chemotherapy drugs to cause hair loss or suppress bone marrow function. Furthermore, fewer than 10 percent of women experience nausea and vomiting when treated with these drugs. However, 5-FU and related drugs can cause other gastrointestinal symptoms, including diarrhea and inflammation of the mouth (mucositis). The dose of Xeloda may be reduced if a temporary side effect called hand-foot syndrome develops. This causes the skin of the palms and soles of the feet become red and sore, sometimes with peeling.
Gemcitabine — Gemcitabine (Gemzar®) has a low frequency of side effects such as nausea, vomiting, hair loss, and temporary suppression of bone marrow function. It is more often used,in combination with paclitaxel (see above), for treatment of metastatic breast cancer in patients whose disease has progressed while receiving anthracycline-containing regimens.
Vinca drugs — Vinorelbine (Navelbine®) is the most widely used vinca-type drug for advanced breast cancer. Weekly administration results in a response in over 50 percent of women. Side effects — All of these agents can cause damage to the nervous system, which may cause a feeling of numbness and tingling in the fingers and toes (called peripheral neuropathy). This typically develops after several courses of therapy, and is usually reversible when treatment is stopped. Vinorelbine is less likely than vincristine to cause peripheral neuropathy, and the likelihood of bone marrow suppression is low. Occasionally, vinca alkaloids can cause sudden, severe pain around the tumor that begins during or immediately after the drug is administered, and lasts several minutes to hours.
Summary — Among the many chemotherapy drugs available for treatment of metastatic breast cancer, the most active are the anthracyclines and taxanes. Taxanes are often used first in women with metastatic breast cancer whose cancers are unlikely to respond to hormone therapy, and for breast cancers that have recurred after other types of chemotherapy. An anthracycline combination may be used for women who have not previously received anthracycline or those who have had a recurrence more than 12 months since anthracyclines were used. Xeloda, Navelbine, and Gemzar are good second or third-line options, or they may be used as a first line treatment in combination with a taxane.
Due to the small survival difference and more favorable side effect profile, therapy with serial single agents is a reasonable alternative to combination regimens, especially in the second, third, or fourth-line treatment setting (show figure 1). On the other hand, for symptomatic patients or those with rapidly progressive vital organ metastases, combination therapy may be a more appropriate first-line choice because of the greater likelihood of an objective response.
HERCEPTIN — Herceptin (trastuzumab) is an antibody (a type of protein) that specifically targets HER2/neu, a protein present on the cells of some breast cancers. About 30 percent of breast cancers express very high levels of HER2/neu, and Herceptin appears to be effective only in this group of women. The level of HER2/neu within a tumor is determined using a special stain on a microscopic slide containing a sample of the tumor.
Herceptin inhibits the growth of breast cancer cells when given alone or in combination with other chemotherapy drugs. For women with metastatic breast cancer whose breast cancers have not responded to conventional cytotoxic chemotherapy drugs, Herceptin used alone has a response rate of 15 percent.
Herceptin plus other chemotherapy drugs — Adding Herceptin to treatment with other chemotherapy drugs may improve the effectiveness of treatment [5]. Herceptin plus anthracyclines — The use of Herceptin plus an anthracycline-containing drug has been found to cause serious side effects affecting the heart. Thus, despite their high level of activity, combinations of Herceptin and doxorubicin are avoided. Herceptin plus taxanes — The combination of Herceptin plus a taxane may be associated with less toxicity than Herceptin plus an anthracycline, and a better outcome when compared to paclitaxel alone. In one research study, women with breast cancers that produced high levels of the HER2/neu marker and that were resistant to doxorubicin were treated with either paclitaxel alone or paclitaxel plus Herceptin [6]. The women treated with combination therapy had a higher response rate (57 versus 25 percent), a longer time until the cancer progressed, and they also survived for four months longer. Herceptin plus other drugs — High response rates have been reported with combinations of Herceptin plus other cytotoxic drugs such as cisplatin, and vinorelbine, even in women who have used several prior therapies [7]. These combinations may be considered in women with HER2/neu-producing metastatic breast cancer who have failed Herceptin alone or in combination with a taxane.
Side effects — Herceptin occasionally causes a hypersensitivity or allergic reaction, which can be severe. Rarely, severe lung damage can occur. Heart damage develops in about 3 to 5 percent of women treated with Herceptin alone or with paclitaxel; the risk is higher in women who receive Herceptin with an anthracycline drug. Because of this, Herceptin is NOT given with an anthracycline-type drug. When given alone, Herceptin does not cause bone marrow suppression, nausea, vomiting, or hair loss.
Summary — Herceptin alone is a reasonable treatment option for women whose metastatic breast cancers make have high levels of HER2/neu, and that have become resistant to standard hormone therapy and chemotherapy drugs. The combination of Herceptin with paclitaxel is also a reasonable choice.
Herceptin resistance — Lapatinib is an oral medication that targets HER2 in a different way than Herceptin. It can be effective for women whose disease is resistant to Herceptin. Lapatinib is approved, in combination with capecitabine, for women with advanced or metastatic breast cancer who have high levels of HER2 and who have failed tretment with an anthracycline, a taxane, and Herceptin. It is not yet approved as an initial treatment for women with HER2-positive advanced breast cancer.
AVASTIN (BEVACIZUMAB) — Avastin® (bevacizumab) is an antibody that targets a protein called vascular endothelial growth factor (VEGF). VEGF is involved in the process by which a growing cancer develops its own blood supply, which is essential in order for the tumor to grow and spread. Bevacizumab disrupts the process of new blood vessel formation, thereby depriving the tumor of its supply of nutrients.
Early data suggest that selected patients with metastatic breast cancer may benefit from the use of bevacizumab. In one study, bevacizumab was combined with paclitaxel and compared to paclitaxel alone as initial chemotherapy for metastatic breast cancer [8]. Combined therapy was associated with a higher response rate (28 versus 14 percent), and a longer time to progression of the breast cancer; however, the study has not yet determined the impact on survival [8]. Potentially serious side effects with bevacizumab included high blood pressure, bleeding, and loss of protein in the urine.
At present, bevacizumab is not approved for treatment of metastatic breast cancer in the United States; it is only approved for patients with advanced colorectal cancer. Nevertheless, using bevacizumab plus paclitaxel could be considered for a woman who had not received chemotherapy for metastatic breast cancer, and who does not have clotting or bleeding problems, kidney problems, recent surgery, or spread of cancer to the brain (brain metastases). It is not yet known whether the modestly better outcomes from this approach justify the more serious side effect profile and greater expense.
CONTINUOUS VERSUS INTERMITTENT THERAPY — The optimal duration of chemotherapy for women with metastatic breast cancer is unknown. Several studies have compared the effectiveness of continuous chemotherapy until it becomes ineffective versus intermittent chemotherapy (approximately six cycles or courses of chemotherapy followed by a discontinuation of chemotherapy until progression of the cancer). In general, overall survival is the same in women treated with continuous or intermittent chemotherapy, although tumor progression may be delayed a little while longer in women treated with continuous therapy.
Because of the periods of time where chemotherapy is not being given, intermittent chemotherapy may also be associated with a better quality of life. Intermittent chemotherapy may therefore be a reasonable option for women whose cancer-related symptoms are relieved with this therapy.
BONE MARROW TRANSPLANTATION — The improved outcomes with higher as compared to lower doses of chemotherapy drugs raise the possibility that outcomes can be further improved by administering very high doses of chemotherapy. Such doses not only kill more cancer cells, but also destroy young blood cells (stem cells) in the circulating blood and bone marrow. This requires that new stem cells be provided or transplanted into the patient in order to restore the production of blood cells. This entire procedure is referred to as high dose chemotherapy with stem cell transplantation (commonly called a bone marrow transplant). (See "Patient information: Overview of bone marrow transplantation").
Although some women with metastatic breast cancer and few sites of tumor involvement have been offered a bone marrow transplant in the past, this approach has fallen out of favor since studies suggest that it does not provide any benefit over the currently recommended standard dose treatment regimens that do not require stem cell support [1,9]. Because of this, and the substantially greater toxicity of high-dose chemotherapy, this approach should not be considered standard for any women with metastatic breast cancer.
SELECTING OPTIMAL THERAPY
Hormone receptor status — Because hormone therapy generally causes fewer side effects than chemotherapy or biologic therapy, it is usually chosen as initial treatment for women with hormone receptor-positive metastatic breast cancer.
Chemotherapy is initially recommended if the cancer is ER-negative, and in some circumstances for ER-positive tumors. Women with ER-positive breast cancer are most likely to be treated with chemotherapy initially if: The breast cancer is progressing rapidly Metastases are present in vital organs There are many cancer-related symptoms
Chemotherapy is also an appropriate option for treatment of ER-positive breast cancers when hormone therapy is no longer effective.
HER2/neu-negative — Options for initial chemotherapy depend on whether a woman's breast cancer makes the protein HER2/neu. Several options are available for initial treatment in women with HER2/neu-negative metastatic breast cancer: Combination therapy with an anthracycline-containing regimen such as AC (doxorubicin plus cyclophosphamide), FAC (5-FU plus doxorubicin and cyclophosphamide), or FEC (5-FU plus epirubicin and cyclophosphamide) Single agent treatment with an anthracycline or a taxane The combination of a taxane plus either capecitabine or gemcitabine The combination of paclitaxel plus bevacizumab
All of these options have a 30 to 60 percent likelihood of response and relief of cancer-related symptoms. However, questions remain as to whether any of these regimens have a significant survival benefit over another. If there is a survival benefit from combination therapy, it is probably modest (between two and five months); this has been seen with the combinations of paclitaxel plus either gemcitabine or bevacizumab (compared to paclitaxel alone), and docetaxel plus capecitabine (compared to docetaxel alone) [2,3,5].
The decision regarding which regimen to choose, and whether to choose single agent or combination chemotherapy is complex, and depends upon a number of different factors, including what treatments have been used and the length of time since the last treatment. For women considering paclitaxel plus bevacizumab, a history of bleeding problems, blood clots, kidney problems, recent surgery, or poorly controlled high blood pressure are important considerations.
HER2/neu-positive — For women whose breast cancers contain high levels of the HER2/neu protein, Herceptin alone or in combination with a taxane are reasonable choices for initial treatment. Lapatinib is approved, in combination with capecitabine, for women with advanced or metastatic breast cancer who have high levels of HER2 and who have failed tretment with an anthracycline, a taxane, and Herceptin.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
[1-3,5-9]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Albain, KS, Nag, S, Calderillo-Ruiz, G, et al. Global phase III study of gemcitabine plus paclitaxel versus paclitaxel as frontline therapy for metastatic breast cancer: first report of overall survival (abstract). Proc Am Soc Clin Oncol 2004; 22:5a.
2. O'Shaughnessy, J, Miles, D, Vukelja, S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002; 20:2812.
3. Sledge, GW, Neuberg, D, Bernardo, P, et al. Phase III Trial of Doxorubicin, Paclitaxel, and the Combination of Doxorubicin and Paclitaxel as Front-Line Chemotherapy for Metastatic Breast Cancer: An Intergroup Trial (E1193). J Clin Oncol 2003; 21:588.
4. Bria, E, Giannarelli, D, Felici, A, et al. Taxanes with anthracyclines as first-line chemotherapy for metastatic breast carcinoma. Cancer 2005; 103:672.
5. Pegram, MD, Konecny, GE, O'Callaghan, C, et al. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 2004; 96:739.
6. Slamon, DJ, Leyland-Jones, B, Shak, S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783.
7. Pegram, M, Lipton, A, Hayes, DF, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998; 16:2659.
8. Miller, KD. E2100: a randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. Data presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 16, 2005. (Available at www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD (Accessed May 26, 2006).
9. Giordano, SH, Buzdar, AU, Smith, TL, et al. Is breast cancer survival improving?. Cancer 2004; 100:44.
Chemotherapy and Herceptin (trastuzumab) for metastatic breast cancer
INTRODUCTION — Breast cancer is the most common female cancer in the United States, the second most common cause of cancer death in women (after lung cancer), and the main cause of death in women ages 45 to 55. Every year, approximately 205,000 American women are diagnosed with breast cancer and more than 40,000 die from this disease. Early detection and treatment can improve survival by removing the breast tumor before it has a chance to spread (metastasize).
Despite early diagnosis and treatment, breast cancer can reappear at a later time (a recurrence), even if the cancer was confined to the breast at the time of detection. A recurrence can be either local (confined to the breast area or nearby tissues) or at a distant site (beyond the breast and nearby tissues). Areas of distant tumor involvement are called metastases. Although the vast majority of women with metastatic breast cancer have a recurrent or relapsed tumor, 1 to 5 percent of women with breast cancer already have metastatic disease at the time their cancers are discovered.
Metastatic breast cancer is usually not a curable condition. However, systemic (bodywide) treatment can prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life (QOL). Options for systemic treatment in women with metastatic breast cancer include chemotherapy, hormone therapy, and targeted agents such as Herceptin (trastuzumab).
This topic review will discuss the use of chemotherapy and Herceptin in advanced and metastatic breast cancer. General principles that guide the treatment of metastatic breast cancer and the use of hormone therapy in this situation are presented elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer" and see "Patient information: Endocrine therapy for metastatic breast cancer").
General principles of treatment — As noted above, the goals of systemic treatment for metastatic breast cancer include symptom control, improved quality of life, and prolonged survival rather than cure. To quantify these benefits, oncologists use certain endpoints to measure a treatment's effectiveness. These include: Response rate — The proportion of persons who have a measurable (50 percent or more) decrease in the amount of cancer Clinical benefit rate — The proportion of patients who have measurable as well as partial or stable responses to treatment Disease progression time — The duration of time that a certain therapy is effective before an alternate treatment is required Survival — Despite the importance of response rate, clinical benefit, and disease progression, the gold standard for deciding whether one therapy is better than another is the impact the treatment has on survival. Even if one treatment has a higher response rate than another, it does not follow that survival is also better.
This is a particularly important concept when considering the sequential use of single drugs versus combination chemotherapy regimens for treatment of metastatic breast cancer. Combinations of drugs typically have a higher response rate than a drug given individually, but also have more side effects; survival benefits are modest, at best. It is possible that similar outcomes may be obtained by giving the individual drugs of the combination regimen one at a time (sequentially), rather than all at the same time (concurrently). This is a controversial area in the treatment of metastatic breast cancer, and is discussed in more detail below.
More detailed explanation about the issues surrounding assessment of treatment benefit is provided elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer").
CHEMOTHERAPY — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. These cytotoxic (toxic to cells) drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are not affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues give rise to side effects during treatment.
Most chemotherapy drugs are given into the vein (IV) rather than by mouth; one exception is the drug Xeloda (capecitabine), which is given by mouth. Chemotherapy is usually not administered daily but periodically, in cycles. A cycle of chemotherapy refers to the time it takes to give the treatment and then allow the body to recover from the side effects of the medicines.
Many different cytotoxic drugs are effective in the treatment of metastatic breast cancer. The most commonly used include: cyclophosphamide (C), methotrexate (M), doxorubicin (often abbreviated A for its brand name Adriamycin®), epirubicin (Ellence®), 5-fluorouracil (abbreviated 5-FU, or F), capecitabine (Xeloda®), paclitaxel (Taxol®), docetaxel (Taxotere®), vinorelbine (Navelbine®), and gemcitabine (Gemzar®).
Combination versus sequential single agent therapy — Specific combinations of these individual drugs (called regimens) have been developed to improve the likelihood of successfully shrinking tumors. As noted above, one of the most pressing and unanswered questions in chemotherapy treatment of metastatic breast cancer is whether similar outcomes can be achieved, with less toxicity, by the sequential use of active single agents, rather than combination regimens. (See "Selecting optimal therapy" below).
Many oncologists consider single-drug chemotherapy a reasonable treatment option, especially for women who have received several different types of chemotherapy for breast cancer. On the other hand, because combination therapy is often associated with a higher response rate, it may be chosen over single agent therapy if the breast cancer is growing rapidly, causing severe symptoms, or if vital organs (eg, liver, lungs) are involved in the tumor.
In the following sections, we will review the most active agents and drug combinations.
Anthracyclines and related drugs — The anthracyclines and related drugs include doxorubicin (Adriamycin®), epirubicin (Ellence®), and mitoxantrone (Novantrone®). When used alone, these drugs have a response rate of 35 to 40 percent. Doxil® is a special form of doxorubicin in which the drug is contained or encapsulated within a fat-containing substance called liposomes. This allows the drug to remain in the body for a longer period of time and may reduce the likelihood of side effects involving the heart.
Anthracyclines are often used in combination with other drugs. Common combinations include AC (doxorubicin plus cyclophosphamide), FAC or CAF (cyclophosphamide plus doxorubicin and 5-FU) and CEF (cyclophosphamide plus epirubicin and 5-FU). A good response to these combinations occurs in 20 to 60 percent of women with metastatic breast cancer who have not been previously treated for advanced disease. Side effects — The possible side effects of anthracyclines include nausea, vomiting, hair loss, and temporary loss of bone marrow function. Bone marrow suppression can lead to infections (which can occur with a low white blood cell count), anemia (which can cause fatigue and low energy) and bleeding (which can occur if the platelet count is very low).
The anthracyclines and related drugs can also damage the heart muscle and cause heart failure. Several measures can reduce the likelihood of this side effect, including limiting the total or cumulative dose of these drugs, administering them gradually (over 6 to 96 hours) or in more frequent smaller doses, simultaneously administering drugs that protect the heart muscle, or by using the liposome-encapsulated form of doxorubicin, Doxil®.
Taxanes — As a group, the taxanes (paclitaxel [Taxol®] and docetaxel [Taxotere®]) are some of the most active drugs available for the treatment of advanced breast cancer. Drugs of this class are often the first drugs chosen to treat breast cancers that do not respond to hormone therapy and those that have responded poorly to other chemotherapy drugs such as anthracyclines.
Paclitaxel (and less commonly docetaxel) can cause serious hypersensitivity (allergic) reactions in some women. Because of this, premedication with steroids and antihistamines is generally recommended prior to each treatment. A newer formulation of paclitaxel is available (Abraxane®) which is associated with significantly fewer allergic reactions. Pretreatment is not necessary, but the drug is quite a bit more expensive than conventional paclitaxel.
More frequent administration of these drugs (ie, weekly rather than every three week treatment) allows a higher total dose of chemotherapy drugs to be given, and also appears to lower the likelihood of some side effects, such as bone marrow suppression, or muscle and joint aches, but not others.
Paclitaxel — Paclitaxel may be given once every three weeks or in lower doses once per week. It produces a response in 35 to 55 percent of women with metastatic breast cancer who have not been previously treated with doxorubicin, and in about 20 percent of women whose breast cancers are resistant to doxorubicin. Side effects — Hair loss is a common side effect of paclitaxel; nausea and vomiting are less common. About 5 to 15 percent of women experience muscle and joint pain after paclitaxel treatment; the symptoms typically begin 24 to 72 hours after treatment and last two to four days. This side effect can be minimized with steroid premedication, and seems to be less common when paclitaxel is administered weekly.
Paclitaxel can also suppress the bone marrow function, temporarily lowering the blood counts. It may be possible to reduce the effects of paclitaxel on the bone marrow and nerves by using more frequent, smaller doses.
It can cause a type of nerve damage that affects the fingers and toes. This is called peripheral neuropathy, and is severe in only 10 to 15 percent of women. However, the effects are cumulative (ie, it is more common and more severe as more drug is given). Paclitaxel may be inappropriate for some women with poor liver function.
Abraxane — Abraxane® is a unique formulation of paclitaxel whose main benefit is that it causes significantly fewer allergic reactions. In addition, at least one study suggests that Abraxane may be associated with a moderately higher response rate and duration of benefit compared to paclitaxel, but it may also cause more neurologic toxicity, and is also significantly more expensive than paclitaxel. As a result, there is controversy as to whether Abraxane® should replace standard paclitaxel for the treatment of metastatic breast cancer.
Docetaxel — Like paclitaxel, docetaxel may be given once every three weeks or in lower doses once per week. Docetaxel has a response rate of 35 to 60 percent in women with metastatic breast cancer, including women with advanced disease who have been previously treated with many other types of chemotherapy. In addition, up to 25 percent of breast cancers that are resistant to paclitaxel respond to docetaxel. Side effects — Docetaxel occasionally causes nausea and vomiting and often causes hair loss. Like paclitaxel, docetaxel can also temporarily suppress bone marrow function and may cause peripheral neuropathy, which may or may not be reversible. Docetaxel may cause fluid retention, which can be prevented if steroids are given prior to docetaxel.
It is possible to reduce the side effects of docetaxel by using more frequent, smaller doses (ie, weekly therapy). However, weekly therapy is more often associated with excess tear production in the eyes and nail changes.
Taxane combinations — Paclitaxel or docetaxel may be used in combination with other chemotherapy drugs. Adding a taxane to other chemotherapy drugs increases the likelihood of response, but also increases the chance of serious side effects. Furthermore, as noted above, the increase in response rate with combination therapy has translated into only minor improvements in survival compared to sequential administration of active single agents [1-3]. As an example, in a single study, women receiving both gemcitabine plus paclitaxel had a higher response rate (41 versus 22 percent) and a slightly longer (two month) survival compared to those receiving paclitaxel alone [1]. Although the side effects were more pronounced in women receiving both gemcitabine and paclitaxel, they were not particularly severe in either group.
Although combinations of paclitaxel and doxorubicin have been associated with very high response rates, they also cause higher than expected rates of heart damage in many but not all [3] studies. While combination of docetaxel and doxorubicin do not appear to increase the risk for heart problems, they have been associated with life-threatening bone marrow suppression and associated infection.
It is not clear that the added toxicities of anthracycline/taxane combinations are justified by a greater therapeutic benefit, or that anthracycline/taxane combinations provide clear benefit over sequential administration of each agent alone [3]. A pooled analysis of seven trials comparing anthracycline/taxane regimens versus other combinations of an anthracycline/cyclophosphamide with or without 5-FU for first-line therapy came to the following conclusions [4]: Use of a taxane/anthracycline combination significantly increased the response rate, and doubled the chance of a complete response Taxane-based regimens were associated with a borderline improvement in time to tumor progression, but survival was not improved Patients treated with a taxane/anthracycline regimen were nearly three times more likely to require hospitalization for fever in the setting of low blood counts
Alkylating drugs — Cyclophosphamide is the alkylating drug most commonly used to treat metastatic breast cancer, usually in combination regimens, as described above. Side effects — Treatment with alkylating drugs carries a slight risk of bladder inflammation and blood in the urine, but this risk can be minimized by drinking plenty of fluids and urinating frequently during treatment. Cyclophosphamide is also associated with an approximately three-fold increased risk of leukemia at a later time, and a loss of fertility, particularly in women over the age of 30 at the time of treatment.
Antimetabolites — The antimetabolites methotrexate and 5-FU are generally used in combination regimens such as CMF (cyclophosphamide, methotrexate, and 5-FU). 5-FU may also be combined with the drug leucovorin. Both of these drugs may be used together in the triple combination NFL (mitoxantrone, 5-FU, and leucovorin).
An oral (tablet form) derivative of 5-FU with activity against breast cancer is available (Xeloda® [capecitabine]). When used alone for the treatment of patients with breast cancer that has progressed in spite of multiple prior therapies, about 20 percent of women have a response, including those whose breast cancers have responded poorly to intravenous 5-FU. Side effects — 5-FU and related drugs are less likely than many other chemotherapy drugs to cause hair loss or suppress bone marrow function. Furthermore, fewer than 10 percent of women experience nausea and vomiting when treated with these drugs. However, 5-FU and related drugs can cause other gastrointestinal symptoms, including diarrhea and inflammation of the mouth (mucositis). The dose of Xeloda may be reduced if a temporary side effect called hand-foot syndrome develops. This causes the skin of the palms and soles of the feet become red and sore, sometimes with peeling.
Gemcitabine — Gemcitabine (Gemzar®) has a low frequency of side effects such as nausea, vomiting, hair loss, and temporary suppression of bone marrow function. It is more often used,in combination with paclitaxel (see above), for treatment of metastatic breast cancer in patients whose disease has progressed while receiving anthracycline-containing regimens.
Vinca drugs — Vinorelbine (Navelbine®) is the most widely used vinca-type drug for advanced breast cancer. Weekly administration results in a response in over 50 percent of women. Side effects — All of these agents can cause damage to the nervous system, which may cause a feeling of numbness and tingling in the fingers and toes (called peripheral neuropathy). This typically develops after several courses of therapy, and is usually reversible when treatment is stopped. Vinorelbine is less likely than vincristine to cause peripheral neuropathy, and the likelihood of bone marrow suppression is low. Occasionally, vinca alkaloids can cause sudden, severe pain around the tumor that begins during or immediately after the drug is administered, and lasts several minutes to hours.
Summary — Among the many chemotherapy drugs available for treatment of metastatic breast cancer, the most active are the anthracyclines and taxanes. Taxanes are often used first in women with metastatic breast cancer whose cancers are unlikely to respond to hormone therapy, and for breast cancers that have recurred after other types of chemotherapy. An anthracycline combination may be used for women who have not previously received anthracycline or those who have had a recurrence more than 12 months since anthracyclines were used. Xeloda, Navelbine, and Gemzar are good second or third-line options, or they may be used as a first line treatment in combination with a taxane.
Due to the small survival difference and more favorable side effect profile, therapy with serial single agents is a reasonable alternative to combination regimens, especially in the second, third, or fourth-line treatment setting (show figure 1). On the other hand, for symptomatic patients or those with rapidly progressive vital organ metastases, combination therapy may be a more appropriate first-line choice because of the greater likelihood of an objective response.
HERCEPTIN — Herceptin (trastuzumab) is an antibody (a type of protein) that specifically targets HER2/neu, a protein present on the cells of some breast cancers. About 30 percent of breast cancers express very high levels of HER2/neu, and Herceptin appears to be effective only in this group of women. The level of HER2/neu within a tumor is determined using a special stain on a microscopic slide containing a sample of the tumor.
Herceptin inhibits the growth of breast cancer cells when given alone or in combination with other chemotherapy drugs. For women with metastatic breast cancer whose breast cancers have not responded to conventional cytotoxic chemotherapy drugs, Herceptin used alone has a response rate of 15 percent.
Herceptin plus other chemotherapy drugs — Adding Herceptin to treatment with other chemotherapy drugs may improve the effectiveness of treatment [5]. Herceptin plus anthracyclines — The use of Herceptin plus an anthracycline-containing drug has been found to cause serious side effects affecting the heart. Thus, despite their high level of activity, combinations of Herceptin and doxorubicin are avoided. Herceptin plus taxanes — The combination of Herceptin plus a taxane may be associated with less toxicity than Herceptin plus an anthracycline, and a better outcome when compared to paclitaxel alone. In one research study, women with breast cancers that produced high levels of the HER2/neu marker and that were resistant to doxorubicin were treated with either paclitaxel alone or paclitaxel plus Herceptin [6]. The women treated with combination therapy had a higher response rate (57 versus 25 percent), a longer time until the cancer progressed, and they also survived for four months longer. Herceptin plus other drugs — High response rates have been reported with combinations of Herceptin plus other cytotoxic drugs such as cisplatin, and vinorelbine, even in women who have used several prior therapies [7]. These combinations may be considered in women with HER2/neu-producing metastatic breast cancer who have failed Herceptin alone or in combination with a taxane.
Side effects — Herceptin occasionally causes a hypersensitivity or allergic reaction, which can be severe. Rarely, severe lung damage can occur. Heart damage develops in about 3 to 5 percent of women treated with Herceptin alone or with paclitaxel; the risk is higher in women who receive Herceptin with an anthracycline drug. Because of this, Herceptin is NOT given with an anthracycline-type drug. When given alone, Herceptin does not cause bone marrow suppression, nausea, vomiting, or hair loss.
Summary — Herceptin alone is a reasonable treatment option for women whose metastatic breast cancers make have high levels of HER2/neu, and that have become resistant to standard hormone therapy and chemotherapy drugs. The combination of Herceptin with paclitaxel is also a reasonable choice.
Herceptin resistance — Lapatinib is an oral medication that targets HER2 in a different way than Herceptin. It can be effective for women whose disease is resistant to Herceptin. Lapatinib is approved, in combination with capecitabine, for women with advanced or metastatic breast cancer who have high levels of HER2 and who have failed tretment with an anthracycline, a taxane, and Herceptin. It is not yet approved as an initial treatment for women with HER2-positive advanced breast cancer.
AVASTIN (BEVACIZUMAB) — Avastin® (bevacizumab) is an antibody that targets a protein called vascular endothelial growth factor (VEGF). VEGF is involved in the process by which a growing cancer develops its own blood supply, which is essential in order for the tumor to grow and spread. Bevacizumab disrupts the process of new blood vessel formation, thereby depriving the tumor of its supply of nutrients.
Early data suggest that selected patients with metastatic breast cancer may benefit from the use of bevacizumab. In one study, bevacizumab was combined with paclitaxel and compared to paclitaxel alone as initial chemotherapy for metastatic breast cancer [8]. Combined therapy was associated with a higher response rate (28 versus 14 percent), and a longer time to progression of the breast cancer; however, the study has not yet determined the impact on survival [8]. Potentially serious side effects with bevacizumab included high blood pressure, bleeding, and loss of protein in the urine.
At present, bevacizumab is not approved for treatment of metastatic breast cancer in the United States; it is only approved for patients with advanced colorectal cancer. Nevertheless, using bevacizumab plus paclitaxel could be considered for a woman who had not received chemotherapy for metastatic breast cancer, and who does not have clotting or bleeding problems, kidney problems, recent surgery, or spread of cancer to the brain (brain metastases). It is not yet known whether the modestly better outcomes from this approach justify the more serious side effect profile and greater expense.
CONTINUOUS VERSUS INTERMITTENT THERAPY — The optimal duration of chemotherapy for women with metastatic breast cancer is unknown. Several studies have compared the effectiveness of continuous chemotherapy until it becomes ineffective versus intermittent chemotherapy (approximately six cycles or courses of chemotherapy followed by a discontinuation of chemotherapy until progression of the cancer). In general, overall survival is the same in women treated with continuous or intermittent chemotherapy, although tumor progression may be delayed a little while longer in women treated with continuous therapy.
Because of the periods of time where chemotherapy is not being given, intermittent chemotherapy may also be associated with a better quality of life. Intermittent chemotherapy may therefore be a reasonable option for women whose cancer-related symptoms are relieved with this therapy.
BONE MARROW TRANSPLANTATION — The improved outcomes with higher as compared to lower doses of chemotherapy drugs raise the possibility that outcomes can be further improved by administering very high doses of chemotherapy. Such doses not only kill more cancer cells, but also destroy young blood cells (stem cells) in the circulating blood and bone marrow. This requires that new stem cells be provided or transplanted into the patient in order to restore the production of blood cells. This entire procedure is referred to as high dose chemotherapy with stem cell transplantation (commonly called a bone marrow transplant). (See "Patient information: Overview of bone marrow transplantation").
Although some women with metastatic breast cancer and few sites of tumor involvement have been offered a bone marrow transplant in the past, this approach has fallen out of favor since studies suggest that it does not provide any benefit over the currently recommended standard dose treatment regimens that do not require stem cell support [1,9]. Because of this, and the substantially greater toxicity of high-dose chemotherapy, this approach should not be considered standard for any women with metastatic breast cancer.
SELECTING OPTIMAL THERAPY
Hormone receptor status — Because hormone therapy generally causes fewer side effects than chemotherapy or biologic therapy, it is usually chosen as initial treatment for women with hormone receptor-positive metastatic breast cancer.
Chemotherapy is initially recommended if the cancer is ER-negative, and in some circumstances for ER-positive tumors. Women with ER-positive breast cancer are most likely to be treated with chemotherapy initially if: The breast cancer is progressing rapidly Metastases are present in vital organs There are many cancer-related symptoms
Chemotherapy is also an appropriate option for treatment of ER-positive breast cancers when hormone therapy is no longer effective.
HER2/neu-negative — Options for initial chemotherapy depend on whether a woman's breast cancer makes the protein HER2/neu. Several options are available for initial treatment in women with HER2/neu-negative metastatic breast cancer: Combination therapy with an anthracycline-containing regimen such as AC (doxorubicin plus cyclophosphamide), FAC (5-FU plus doxorubicin and cyclophosphamide), or FEC (5-FU plus epirubicin and cyclophosphamide) Single agent treatment with an anthracycline or a taxane The combination of a taxane plus either capecitabine or gemcitabine The combination of paclitaxel plus bevacizumab
All of these options have a 30 to 60 percent likelihood of response and relief of cancer-related symptoms. However, questions remain as to whether any of these regimens have a significant survival benefit over another. If there is a survival benefit from combination therapy, it is probably modest (between two and five months); this has been seen with the combinations of paclitaxel plus either gemcitabine or bevacizumab (compared to paclitaxel alone), and docetaxel plus capecitabine (compared to docetaxel alone) [2,3,5].
The decision regarding which regimen to choose, and whether to choose single agent or combination chemotherapy is complex, and depends upon a number of different factors, including what treatments have been used and the length of time since the last treatment. For women considering paclitaxel plus bevacizumab, a history of bleeding problems, blood clots, kidney problems, recent surgery, or poorly controlled high blood pressure are important considerations.
HER2/neu-positive — For women whose breast cancers contain high levels of the HER2/neu protein, Herceptin alone or in combination with a taxane are reasonable choices for initial treatment. Lapatinib is approved, in combination with capecitabine, for women with advanced or metastatic breast cancer who have high levels of HER2 and who have failed tretment with an anthracycline, a taxane, and Herceptin.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
[1-3,5-9]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Albain, KS, Nag, S, Calderillo-Ruiz, G, et al. Global phase III study of gemcitabine plus paclitaxel versus paclitaxel as frontline therapy for metastatic breast cancer: first report of overall survival (abstract). Proc Am Soc Clin Oncol 2004; 22:5a.
2. O'Shaughnessy, J, Miles, D, Vukelja, S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002; 20:2812.
3. Sledge, GW, Neuberg, D, Bernardo, P, et al. Phase III Trial of Doxorubicin, Paclitaxel, and the Combination of Doxorubicin and Paclitaxel as Front-Line Chemotherapy for Metastatic Breast Cancer: An Intergroup Trial (E1193). J Clin Oncol 2003; 21:588.
4. Bria, E, Giannarelli, D, Felici, A, et al. Taxanes with anthracyclines as first-line chemotherapy for metastatic breast carcinoma. Cancer 2005; 103:672.
5. Pegram, MD, Konecny, GE, O'Callaghan, C, et al. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 2004; 96:739.
6. Slamon, DJ, Leyland-Jones, B, Shak, S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783.
7. Pegram, M, Lipton, A, Hayes, DF, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998; 16:2659.
8. Miller, KD. E2100: a randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. Data presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 16, 2005. (Available at www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD (Accessed May 26, 2006).
9. Giordano, SH, Buzdar, AU, Smith, TL, et al. Is breast cancer survival improving?. Cancer 2004; 100:44.
Despite early diagnosis and treatment, breast cancer can reappear at a later time (a recurrence), even if the cancer was confined to the breast at the time of detection. A recurrence can be either local (confined to the breast area or nearby tissues) or at a distant site (beyond the breast and nearby tissues). Areas of distant tumor involvement are called metastases. Although the vast majority of women with metastatic breast cancer have a recurrent or relapsed tumor, 1 to 5 percent of women with breast cancer already have metastatic disease at the time their cancers are discovered.
Metastatic breast cancer is usually not a curable condition. However, systemic (bodywide) treatment can prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life (QOL). Options for systemic treatment in women with metastatic breast cancer include chemotherapy, hormone therapy, and targeted agents such as Herceptin (trastuzumab).
This topic review will discuss the use of chemotherapy and Herceptin in advanced and metastatic breast cancer. General principles that guide the treatment of metastatic breast cancer and the use of hormone therapy in this situation are presented elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer" and see "Patient information: Endocrine therapy for metastatic breast cancer").
General principles of treatment — As noted above, the goals of systemic treatment for metastatic breast cancer include symptom control, improved quality of life, and prolonged survival rather than cure. To quantify these benefits, oncologists use certain endpoints to measure a treatment's effectiveness. These include: Response rate — The proportion of persons who have a measurable (50 percent or more) decrease in the amount of cancer Clinical benefit rate — The proportion of patients who have measurable as well as partial or stable responses to treatment Disease progression time — The duration of time that a certain therapy is effective before an alternate treatment is required Survival — Despite the importance of response rate, clinical benefit, and disease progression, the gold standard for deciding whether one therapy is better than another is the impact the treatment has on survival. Even if one treatment has a higher response rate than another, it does not follow that survival is also better.
This is a particularly important concept when considering the sequential use of single drugs versus combination chemotherapy regimens for treatment of metastatic breast cancer. Combinations of drugs typically have a higher response rate than a drug given individually, but also have more side effects; survival benefits are modest, at best. It is possible that similar outcomes may be obtained by giving the individual drugs of the combination regimen one at a time (sequentially), rather than all at the same time (concurrently). This is a controversial area in the treatment of metastatic breast cancer, and is discussed in more detail below.
More detailed explanation about the issues surrounding assessment of treatment benefit is provided elsewhere. (See "Patient information: General principles of treatment for metastatic breast cancer").
CHEMOTHERAPY — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. These cytotoxic (toxic to cells) drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not actively growing, they are not affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues give rise to side effects during treatment.
Most chemotherapy drugs are given into the vein (IV) rather than by mouth; one exception is the drug Xeloda (capecitabine), which is given by mouth. Chemotherapy is usually not administered daily but periodically, in cycles. A cycle of chemotherapy refers to the time it takes to give the treatment and then allow the body to recover from the side effects of the medicines.
Many different cytotoxic drugs are effective in the treatment of metastatic breast cancer. The most commonly used include: cyclophosphamide (C), methotrexate (M), doxorubicin (often abbreviated A for its brand name Adriamycin®), epirubicin (Ellence®), 5-fluorouracil (abbreviated 5-FU, or F), capecitabine (Xeloda®), paclitaxel (Taxol®), docetaxel (Taxotere®), vinorelbine (Navelbine®), and gemcitabine (Gemzar®).
Combination versus sequential single agent therapy — Specific combinations of these individual drugs (called regimens) have been developed to improve the likelihood of successfully shrinking tumors. As noted above, one of the most pressing and unanswered questions in chemotherapy treatment of metastatic breast cancer is whether similar outcomes can be achieved, with less toxicity, by the sequential use of active single agents, rather than combination regimens. (See "Selecting optimal therapy" below).
Many oncologists consider single-drug chemotherapy a reasonable treatment option, especially for women who have received several different types of chemotherapy for breast cancer. On the other hand, because combination therapy is often associated with a higher response rate, it may be chosen over single agent therapy if the breast cancer is growing rapidly, causing severe symptoms, or if vital organs (eg, liver, lungs) are involved in the tumor.
In the following sections, we will review the most active agents and drug combinations.
Anthracyclines and related drugs — The anthracyclines and related drugs include doxorubicin (Adriamycin®), epirubicin (Ellence®), and mitoxantrone (Novantrone®). When used alone, these drugs have a response rate of 35 to 40 percent. Doxil® is a special form of doxorubicin in which the drug is contained or encapsulated within a fat-containing substance called liposomes. This allows the drug to remain in the body for a longer period of time and may reduce the likelihood of side effects involving the heart.
Anthracyclines are often used in combination with other drugs. Common combinations include AC (doxorubicin plus cyclophosphamide), FAC or CAF (cyclophosphamide plus doxorubicin and 5-FU) and CEF (cyclophosphamide plus epirubicin and 5-FU). A good response to these combinations occurs in 20 to 60 percent of women with metastatic breast cancer who have not been previously treated for advanced disease. Side effects — The possible side effects of anthracyclines include nausea, vomiting, hair loss, and temporary loss of bone marrow function. Bone marrow suppression can lead to infections (which can occur with a low white blood cell count), anemia (which can cause fatigue and low energy) and bleeding (which can occur if the platelet count is very low).
The anthracyclines and related drugs can also damage the heart muscle and cause heart failure. Several measures can reduce the likelihood of this side effect, including limiting the total or cumulative dose of these drugs, administering them gradually (over 6 to 96 hours) or in more frequent smaller doses, simultaneously administering drugs that protect the heart muscle, or by using the liposome-encapsulated form of doxorubicin, Doxil®.
Taxanes — As a group, the taxanes (paclitaxel [Taxol®] and docetaxel [Taxotere®]) are some of the most active drugs available for the treatment of advanced breast cancer. Drugs of this class are often the first drugs chosen to treat breast cancers that do not respond to hormone therapy and those that have responded poorly to other chemotherapy drugs such as anthracyclines.
Paclitaxel (and less commonly docetaxel) can cause serious hypersensitivity (allergic) reactions in some women. Because of this, premedication with steroids and antihistamines is generally recommended prior to each treatment. A newer formulation of paclitaxel is available (Abraxane®) which is associated with significantly fewer allergic reactions. Pretreatment is not necessary, but the drug is quite a bit more expensive than conventional paclitaxel.
More frequent administration of these drugs (ie, weekly rather than every three week treatment) allows a higher total dose of chemotherapy drugs to be given, and also appears to lower the likelihood of some side effects, such as bone marrow suppression, or muscle and joint aches, but not others.
Paclitaxel — Paclitaxel may be given once every three weeks or in lower doses once per week. It produces a response in 35 to 55 percent of women with metastatic breast cancer who have not been previously treated with doxorubicin, and in about 20 percent of women whose breast cancers are resistant to doxorubicin. Side effects — Hair loss is a common side effect of paclitaxel; nausea and vomiting are less common. About 5 to 15 percent of women experience muscle and joint pain after paclitaxel treatment; the symptoms typically begin 24 to 72 hours after treatment and last two to four days. This side effect can be minimized with steroid premedication, and seems to be less common when paclitaxel is administered weekly.
Paclitaxel can also suppress the bone marrow function, temporarily lowering the blood counts. It may be possible to reduce the effects of paclitaxel on the bone marrow and nerves by using more frequent, smaller doses.
It can cause a type of nerve damage that affects the fingers and toes. This is called peripheral neuropathy, and is severe in only 10 to 15 percent of women. However, the effects are cumulative (ie, it is more common and more severe as more drug is given). Paclitaxel may be inappropriate for some women with poor liver function.
Abraxane — Abraxane® is a unique formulation of paclitaxel whose main benefit is that it causes significantly fewer allergic reactions. In addition, at least one study suggests that Abraxane may be associated with a moderately higher response rate and duration of benefit compared to paclitaxel, but it may also cause more neurologic toxicity, and is also significantly more expensive than paclitaxel. As a result, there is controversy as to whether Abraxane® should replace standard paclitaxel for the treatment of metastatic breast cancer.
Docetaxel — Like paclitaxel, docetaxel may be given once every three weeks or in lower doses once per week. Docetaxel has a response rate of 35 to 60 percent in women with metastatic breast cancer, including women with advanced disease who have been previously treated with many other types of chemotherapy. In addition, up to 25 percent of breast cancers that are resistant to paclitaxel respond to docetaxel. Side effects — Docetaxel occasionally causes nausea and vomiting and often causes hair loss. Like paclitaxel, docetaxel can also temporarily suppress bone marrow function and may cause peripheral neuropathy, which may or may not be reversible. Docetaxel may cause fluid retention, which can be prevented if steroids are given prior to docetaxel.
It is possible to reduce the side effects of docetaxel by using more frequent, smaller doses (ie, weekly therapy). However, weekly therapy is more often associated with excess tear production in the eyes and nail changes.
Taxane combinations — Paclitaxel or docetaxel may be used in combination with other chemotherapy drugs. Adding a taxane to other chemotherapy drugs increases the likelihood of response, but also increases the chance of serious side effects. Furthermore, as noted above, the increase in response rate with combination therapy has translated into only minor improvements in survival compared to sequential administration of active single agents [1-3]. As an example, in a single study, women receiving both gemcitabine plus paclitaxel had a higher response rate (41 versus 22 percent) and a slightly longer (two month) survival compared to those receiving paclitaxel alone [1]. Although the side effects were more pronounced in women receiving both gemcitabine and paclitaxel, they were not particularly severe in either group.
Although combinations of paclitaxel and doxorubicin have been associated with very high response rates, they also cause higher than expected rates of heart damage in many but not all [3] studies. While combination of docetaxel and doxorubicin do not appear to increase the risk for heart problems, they have been associated with life-threatening bone marrow suppression and associated infection.
It is not clear that the added toxicities of anthracycline/taxane combinations are justified by a greater therapeutic benefit, or that anthracycline/taxane combinations provide clear benefit over sequential administration of each agent alone [3]. A pooled analysis of seven trials comparing anthracycline/taxane regimens versus other combinations of an anthracycline/cyclophosphamide with or without 5-FU for first-line therapy came to the following conclusions [4]: Use of a taxane/anthracycline combination significantly increased the response rate, and doubled the chance of a complete response Taxane-based regimens were associated with a borderline improvement in time to tumor progression, but survival was not improved Patients treated with a taxane/anthracycline regimen were nearly three times more likely to require hospitalization for fever in the setting of low blood counts
Alkylating drugs — Cyclophosphamide is the alkylating drug most commonly used to treat metastatic breast cancer, usually in combination regimens, as described above. Side effects — Treatment with alkylating drugs carries a slight risk of bladder inflammation and blood in the urine, but this risk can be minimized by drinking plenty of fluids and urinating frequently during treatment. Cyclophosphamide is also associated with an approximately three-fold increased risk of leukemia at a later time, and a loss of fertility, particularly in women over the age of 30 at the time of treatment.
Antimetabolites — The antimetabolites methotrexate and 5-FU are generally used in combination regimens such as CMF (cyclophosphamide, methotrexate, and 5-FU). 5-FU may also be combined with the drug leucovorin. Both of these drugs may be used together in the triple combination NFL (mitoxantrone, 5-FU, and leucovorin).
An oral (tablet form) derivative of 5-FU with activity against breast cancer is available (Xeloda® [capecitabine]). When used alone for the treatment of patients with breast cancer that has progressed in spite of multiple prior therapies, about 20 percent of women have a response, including those whose breast cancers have responded poorly to intravenous 5-FU. Side effects — 5-FU and related drugs are less likely than many other chemotherapy drugs to cause hair loss or suppress bone marrow function. Furthermore, fewer than 10 percent of women experience nausea and vomiting when treated with these drugs. However, 5-FU and related drugs can cause other gastrointestinal symptoms, including diarrhea and inflammation of the mouth (mucositis). The dose of Xeloda may be reduced if a temporary side effect called hand-foot syndrome develops. This causes the skin of the palms and soles of the feet become red and sore, sometimes with peeling.
Gemcitabine — Gemcitabine (Gemzar®) has a low frequency of side effects such as nausea, vomiting, hair loss, and temporary suppression of bone marrow function. It is more often used,in combination with paclitaxel (see above), for treatment of metastatic breast cancer in patients whose disease has progressed while receiving anthracycline-containing regimens.
Vinca drugs — Vinorelbine (Navelbine®) is the most widely used vinca-type drug for advanced breast cancer. Weekly administration results in a response in over 50 percent of women. Side effects — All of these agents can cause damage to the nervous system, which may cause a feeling of numbness and tingling in the fingers and toes (called peripheral neuropathy). This typically develops after several courses of therapy, and is usually reversible when treatment is stopped. Vinorelbine is less likely than vincristine to cause peripheral neuropathy, and the likelihood of bone marrow suppression is low. Occasionally, vinca alkaloids can cause sudden, severe pain around the tumor that begins during or immediately after the drug is administered, and lasts several minutes to hours.
Summary — Among the many chemotherapy drugs available for treatment of metastatic breast cancer, the most active are the anthracyclines and taxanes. Taxanes are often used first in women with metastatic breast cancer whose cancers are unlikely to respond to hormone therapy, and for breast cancers that have recurred after other types of chemotherapy. An anthracycline combination may be used for women who have not previously received anthracycline or those who have had a recurrence more than 12 months since anthracyclines were used. Xeloda, Navelbine, and Gemzar are good second or third-line options, or they may be used as a first line treatment in combination with a taxane.
Due to the small survival difference and more favorable side effect profile, therapy with serial single agents is a reasonable alternative to combination regimens, especially in the second, third, or fourth-line treatment setting (show figure 1). On the other hand, for symptomatic patients or those with rapidly progressive vital organ metastases, combination therapy may be a more appropriate first-line choice because of the greater likelihood of an objective response.
HERCEPTIN — Herceptin (trastuzumab) is an antibody (a type of protein) that specifically targets HER2/neu, a protein present on the cells of some breast cancers. About 30 percent of breast cancers express very high levels of HER2/neu, and Herceptin appears to be effective only in this group of women. The level of HER2/neu within a tumor is determined using a special stain on a microscopic slide containing a sample of the tumor.
Herceptin inhibits the growth of breast cancer cells when given alone or in combination with other chemotherapy drugs. For women with metastatic breast cancer whose breast cancers have not responded to conventional cytotoxic chemotherapy drugs, Herceptin used alone has a response rate of 15 percent.
Herceptin plus other chemotherapy drugs — Adding Herceptin to treatment with other chemotherapy drugs may improve the effectiveness of treatment [5]. Herceptin plus anthracyclines — The use of Herceptin plus an anthracycline-containing drug has been found to cause serious side effects affecting the heart. Thus, despite their high level of activity, combinations of Herceptin and doxorubicin are avoided. Herceptin plus taxanes — The combination of Herceptin plus a taxane may be associated with less toxicity than Herceptin plus an anthracycline, and a better outcome when compared to paclitaxel alone. In one research study, women with breast cancers that produced high levels of the HER2/neu marker and that were resistant to doxorubicin were treated with either paclitaxel alone or paclitaxel plus Herceptin [6]. The women treated with combination therapy had a higher response rate (57 versus 25 percent), a longer time until the cancer progressed, and they also survived for four months longer. Herceptin plus other drugs — High response rates have been reported with combinations of Herceptin plus other cytotoxic drugs such as cisplatin, and vinorelbine, even in women who have used several prior therapies [7]. These combinations may be considered in women with HER2/neu-producing metastatic breast cancer who have failed Herceptin alone or in combination with a taxane.
Side effects — Herceptin occasionally causes a hypersensitivity or allergic reaction, which can be severe. Rarely, severe lung damage can occur. Heart damage develops in about 3 to 5 percent of women treated with Herceptin alone or with paclitaxel; the risk is higher in women who receive Herceptin with an anthracycline drug. Because of this, Herceptin is NOT given with an anthracycline-type drug. When given alone, Herceptin does not cause bone marrow suppression, nausea, vomiting, or hair loss.
Summary — Herceptin alone is a reasonable treatment option for women whose metastatic breast cancers make have high levels of HER2/neu, and that have become resistant to standard hormone therapy and chemotherapy drugs. The combination of Herceptin with paclitaxel is also a reasonable choice.
Herceptin resistance — Lapatinib is an oral medication that targets HER2 in a different way than Herceptin. It can be effective for women whose disease is resistant to Herceptin. Lapatinib is approved, in combination with capecitabine, for women with advanced or metastatic breast cancer who have high levels of HER2 and who have failed tretment with an anthracycline, a taxane, and Herceptin. It is not yet approved as an initial treatment for women with HER2-positive advanced breast cancer.
AVASTIN (BEVACIZUMAB) — Avastin® (bevacizumab) is an antibody that targets a protein called vascular endothelial growth factor (VEGF). VEGF is involved in the process by which a growing cancer develops its own blood supply, which is essential in order for the tumor to grow and spread. Bevacizumab disrupts the process of new blood vessel formation, thereby depriving the tumor of its supply of nutrients.
Early data suggest that selected patients with metastatic breast cancer may benefit from the use of bevacizumab. In one study, bevacizumab was combined with paclitaxel and compared to paclitaxel alone as initial chemotherapy for metastatic breast cancer [8]. Combined therapy was associated with a higher response rate (28 versus 14 percent), and a longer time to progression of the breast cancer; however, the study has not yet determined the impact on survival [8]. Potentially serious side effects with bevacizumab included high blood pressure, bleeding, and loss of protein in the urine.
At present, bevacizumab is not approved for treatment of metastatic breast cancer in the United States; it is only approved for patients with advanced colorectal cancer. Nevertheless, using bevacizumab plus paclitaxel could be considered for a woman who had not received chemotherapy for metastatic breast cancer, and who does not have clotting or bleeding problems, kidney problems, recent surgery, or spread of cancer to the brain (brain metastases). It is not yet known whether the modestly better outcomes from this approach justify the more serious side effect profile and greater expense.
CONTINUOUS VERSUS INTERMITTENT THERAPY — The optimal duration of chemotherapy for women with metastatic breast cancer is unknown. Several studies have compared the effectiveness of continuous chemotherapy until it becomes ineffective versus intermittent chemotherapy (approximately six cycles or courses of chemotherapy followed by a discontinuation of chemotherapy until progression of the cancer). In general, overall survival is the same in women treated with continuous or intermittent chemotherapy, although tumor progression may be delayed a little while longer in women treated with continuous therapy.
Because of the periods of time where chemotherapy is not being given, intermittent chemotherapy may also be associated with a better quality of life. Intermittent chemotherapy may therefore be a reasonable option for women whose cancer-related symptoms are relieved with this therapy.
BONE MARROW TRANSPLANTATION — The improved outcomes with higher as compared to lower doses of chemotherapy drugs raise the possibility that outcomes can be further improved by administering very high doses of chemotherapy. Such doses not only kill more cancer cells, but also destroy young blood cells (stem cells) in the circulating blood and bone marrow. This requires that new stem cells be provided or transplanted into the patient in order to restore the production of blood cells. This entire procedure is referred to as high dose chemotherapy with stem cell transplantation (commonly called a bone marrow transplant). (See "Patient information: Overview of bone marrow transplantation").
Although some women with metastatic breast cancer and few sites of tumor involvement have been offered a bone marrow transplant in the past, this approach has fallen out of favor since studies suggest that it does not provide any benefit over the currently recommended standard dose treatment regimens that do not require stem cell support [1,9]. Because of this, and the substantially greater toxicity of high-dose chemotherapy, this approach should not be considered standard for any women with metastatic breast cancer.
SELECTING OPTIMAL THERAPY
Hormone receptor status — Because hormone therapy generally causes fewer side effects than chemotherapy or biologic therapy, it is usually chosen as initial treatment for women with hormone receptor-positive metastatic breast cancer.
Chemotherapy is initially recommended if the cancer is ER-negative, and in some circumstances for ER-positive tumors. Women with ER-positive breast cancer are most likely to be treated with chemotherapy initially if: The breast cancer is progressing rapidly Metastases are present in vital organs There are many cancer-related symptoms
Chemotherapy is also an appropriate option for treatment of ER-positive breast cancers when hormone therapy is no longer effective.
HER2/neu-negative — Options for initial chemotherapy depend on whether a woman's breast cancer makes the protein HER2/neu. Several options are available for initial treatment in women with HER2/neu-negative metastatic breast cancer: Combination therapy with an anthracycline-containing regimen such as AC (doxorubicin plus cyclophosphamide), FAC (5-FU plus doxorubicin and cyclophosphamide), or FEC (5-FU plus epirubicin and cyclophosphamide) Single agent treatment with an anthracycline or a taxane The combination of a taxane plus either capecitabine or gemcitabine The combination of paclitaxel plus bevacizumab
All of these options have a 30 to 60 percent likelihood of response and relief of cancer-related symptoms. However, questions remain as to whether any of these regimens have a significant survival benefit over another. If there is a survival benefit from combination therapy, it is probably modest (between two and five months); this has been seen with the combinations of paclitaxel plus either gemcitabine or bevacizumab (compared to paclitaxel alone), and docetaxel plus capecitabine (compared to docetaxel alone) [2,3,5].
The decision regarding which regimen to choose, and whether to choose single agent or combination chemotherapy is complex, and depends upon a number of different factors, including what treatments have been used and the length of time since the last treatment. For women considering paclitaxel plus bevacizumab, a history of bleeding problems, blood clots, kidney problems, recent surgery, or poorly controlled high blood pressure are important considerations.
HER2/neu-positive — For women whose breast cancers contain high levels of the HER2/neu protein, Herceptin alone or in combination with a taxane are reasonable choices for initial treatment. Lapatinib is approved, in combination with capecitabine, for women with advanced or metastatic breast cancer who have high levels of HER2 and who have failed tretment with an anthracycline, a taxane, and Herceptin.
WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.
This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.
A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information
website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network
(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute
1-800-4-CANCER
(www.nci.nih.gov)
American Cancer Society
1-800-ACS-2345
(www.cancer.org)
National Library of Medicine
(www.nlm.nih.gov/medlineplus/healthtopics.html)
Susan G. Komen Breast Cancer Foundation
(www.komen.org)
[1-3,5-9]
Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Albain, KS, Nag, S, Calderillo-Ruiz, G, et al. Global phase III study of gemcitabine plus paclitaxel versus paclitaxel as frontline therapy for metastatic breast cancer: first report of overall survival (abstract). Proc Am Soc Clin Oncol 2004; 22:5a.
2. O'Shaughnessy, J, Miles, D, Vukelja, S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002; 20:2812.
3. Sledge, GW, Neuberg, D, Bernardo, P, et al. Phase III Trial of Doxorubicin, Paclitaxel, and the Combination of Doxorubicin and Paclitaxel as Front-Line Chemotherapy for Metastatic Breast Cancer: An Intergroup Trial (E1193). J Clin Oncol 2003; 21:588.
4. Bria, E, Giannarelli, D, Felici, A, et al. Taxanes with anthracyclines as first-line chemotherapy for metastatic breast carcinoma. Cancer 2005; 103:672.
5. Pegram, MD, Konecny, GE, O'Callaghan, C, et al. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst 2004; 96:739.
6. Slamon, DJ, Leyland-Jones, B, Shak, S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783.
7. Pegram, M, Lipton, A, Hayes, DF, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 1998; 16:2659.
8. Miller, KD. E2100: a randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. Data presented at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 16, 2005. (Available at www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD (Accessed May 26, 2006).
9. Giordano, SH, Buzdar, AU, Smith, TL, et al. Is breast cancer survival improving?. Cancer 2004; 100:44.
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