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Systemic treatments are drugs and agents that are administered through the bloodstream and can affect all parts of the body. In breast cancer, the three primary types of systemic therapies are hormone therapy, chemotherapy and biologic therapies. Hormone Therapy Hormone treatments for breast cancer should not be confused with menopausal hormone therapy or hormone replacement therapy. Menopausal hormone therapy is typically used by postmenopausal women to treat symptoms, such as hot flashes, that are associated with menopause. Hormone therapy for breast cancer blocks hormones from being used by cancer cells to stimulate their growth. The hormones estrogen and progesterone circulate in the bloodstream. They can attach to breast cancer cells and stimulate tumor growth. Estrogen is the major promoter of cell growth in hormone dependent breast cancer. The goal of hormone therapy is to deprive the cancer tissue of estrogen, resulting in halting or slowing of cancer cell growth. Unlike chemotherapy, hormone therapy, also called endocrine (EN doe krin) therapy, does not kill the cancer cell. Hormone therapy acts by either blocking estrogen from reaching cancer cells (receptor blocker) or reducing the production of estrogen. The specific hormone treatment chosen depends on many factors including whether the tumor has the protein features, called receptors, needed to use these hormones to spur growth. Tumors that have these receptors are called receptor positive; those that do not have the receptors are receptor negative. All breast cancers are now routinely tested at the time of diagnosis to determine whether the tumor is receptor positive or negative for estrogen and or progesterone receptors (ER/PR receptor status). The test is done on the breast cancer biopsy or tumor specimen. If a breast cancer has measurable receptor sites present, then it is called estrogen- and or progesterone-positive, or simply hormone receptor-positive. If the breast cancer does not contain measurable receptor sites, then it is called estrogen/progesterone or hormone receptor-negative. Breast cancers that have not been tested for hormone receptors are referred to as unknown receptor status. Hormone therapy has proven effective only in hormone receptor-positive or unknown status breast cancers. Hormone therapy is not used with ER/PR negative breast cancers, as they are unlikely to respond to hormone therapy. Categories of Hormone treatments include:
Now that estrogen-blocking drugs are available, surgically removing the ovaries (called an oophorectomy [oo fore ECK to me]) is done infrequently but remains a very effective option for women with breast cancer who are premenopausal. The ovaries are the two small reproductive organs on either side of the uterus that produce estrogen and the eggs that are released each month during menstrual cycles. Oophorectomy is not done for postmenopausal women because their ovaries are no longer functioning as the main source of estrogen. Inhibiting the effect of estrogen, either by oophorectomy or by hormonal drug therapy, is called ovarian ablation or ovarian suppression. Hormone therapy drugs that cause ovarian ablation are called "luteinizing hormone-releasing hormone (LHRH)" analogues, meaning these drugs are similar to natural chemicals that the body normally produces. These include goserelin (Zoladex®) and a similar drug called leuprolide acetate (Lupron®), but these are rarely used anymore. Most patients achieve the same estrogen reduction through surgical removal of the ovaries. Removing or ablating the ovaries causes early menopause. Young women who undergo ovarian ablation will experience menopause immediately, and the side effects of early menopause (such as hot flashes) may be more bothersome than natural menopause. Drug characteristics and side effects SERMs The oldest and most commonly used antiestrogen drug is tamoxifen (also known as Nolvadex®), which usually is prescribed after chemotherapy is complete. It is an effective treatment for both early and advanced stage breast cancer. It prevents breast cancer cells from growing by latching onto the cancer cells' estrogen receptors and preventing the estrogen hormone from reaching the receptor. Tamoxifen does not stop estrogen from being made in the body but blocks the cancer cell's use of estrogen. It decreases local recurrences, delays and possibly prevents secondary breast cancers from forming, and is effective in treating advanced, metastatic breast cancer. Tamoxifen recently was approved by the Food and Drug Administration (FDA) for use by high-risk healthy women to reduce their chances of developing breast cancer. While tamoxifen has side effects, the serious ones are rare. Among the most serious is an increased risk of cancer of the uterine lining, known as endometrial cancer. This does not apply to women who have undergone surgical removal of the uterus (hysterectomy). Endometrial cancer caused by tamoxifen usually occurs in women over 50 years old and tends to be an early stage cancer that is easily treated and has a good prognosis. Women taking the drug must be vigilant and promptly report to their doctor any unusual symptoms such as vaginal bleeding or a new, unusual discharge. Vaginal discharge or bleeding occurs in approximately one-third of the women taking the drug, but it doesn't necessarily mean there is another malignancy. Nevertheless, if suspicious symptoms appear, women taking this drug must be evaluated and annual pelvic exams must be done, sometimes with a uterine biopsy (a sample of tissue from within the womb is examined under the microscope) or ultrasound procedure (called a transvaginal uterine ultrasound). In a small percentage of women, tamoxifen also may cause blood clots in the veins (usually within the legs or lungs). There have been a few reports of liver toxicity, and blood tests to monitor liver function may be given from time to time. Some eye problems have been reported, and women taking tamoxifen are at a slightly increased risk of a stroke or developing cataracts, a clouding of the lens of the eye. Although these side effects are serious, in most cases they are outweighed by the drug's breast-cancer control benefits. It is estimated, for example, that the reduction of occurrence of a new cancer in the opposite breast is twice as great as the increase in incidence of endometrial cancer. And there are other benefits not related to breast cancer. In some tissues, tamoxifen has estrogen-like action, such as lowering blood cholesterol and slowing bone loss that may lead to osteoporosis. In premenopausal women however, tamoxifen may increase bone loss. Less serious but uncomfortable side effects that trouble some women include hot flashes, irregular menstrual periods, vaginal discharge, and irritation of the skin around the vagina. Less than 10% of women experience nausea, vomiting, fatigue, or depression. Despite these potential problems, tamoxifen is so effective in preventing breast cancer recurrence that women with estrogen-positive breast cancer may be advised to take it for five years after surgery. Studies have shown that when it is taken for this time period, there is a significant reduction in the risk of cancer recurrence. To help make decisions about preventing recurrence, a new diagnostic test for women with estrogen receptor-positive, early stage, lymph node-negative breast cancer has been developed to estimate the likelihood of recurrence within 10 years. This test, called Oncotype DX™, involves a specialized assay of 21 genes within a breast tumor sample and is currently being used in research studies and clinical practice. Randomized trials have failed to demonstrate an advantage for taking tamoxifen for more than 5 years, so the current practice is to take the drug for 5 years only, but the beneficial effect will continue for many years after the person stops taking the drug. Tamoxifen has been FDA-approved for women of all ages. Today, tamoxifen is the most frequently prescribed cancer drug worldwide, and the only antiestrogen approved to lower the risk of breast cancer in high-risk women, making it the first FDA-approved chemoprevention drug. A second anti-estrogen drug called raloxifene (Evista®) is now available. The Study of Tamoxifen and Raloxifene (STAR) clinical trial results show that raloxifene is as effective for prevention of invasive breast cancer as tamoxifen. When side effects are compared between the two drugs, raloxifene had slightly fewer blood clotting events (thromboembolisms) and fewer incidences of cataracts and cataract surgeries. Tamoxifen had a slightly higher incidence of uterine cancer but this was not statistically significant. Raloxifene (Evista®) now provides an additional antiestrogen choice. Aromatase inhibitors Anastrozole (Arimidex®), letrozole (Femara®), and exemestane (Aromasin®) are now used as first line therapy in early stage breast cancer as well as advanced or metastatic breast cancer. Patients with metastatic breast cancer who respond to one type of hormone therapy have a good chance of responding to another when the first one is no longer effective. Sometimes metastatic breast cancer can be controlled for as much as 5 to 10 years with hormone therapy, and some patients have responded to multiple forms of endocrine treatment by using one, then a second, and then a third drug some months or years later and so on. The aromatase inhibitors can be used in any order, and the widespread use of tamoxifen first is probably as much due to the fact that tamoxifen was the first of these newer drugs to be shown to be effective. Hormone modulators Megestrol acetate (Megace®--a progestin), an older hormone-altering drug remains a third-line therapy, if needed. Its' use has decreased with the availability of the aromatase inhibitors. Still other hormone therapies that may be considered for third or fourth-line therapies include androgens (male hormones) and high-dose estrogen. Megestrol acetate (Megace®) and medroxyprogesterone acetate (Provera®) are synthetic hormone forms of progesterone. We don't know how they work, but they are very effective and relatively non-toxic. The most frustrating side effect from these drugs is weight gain. Due to the improved side effect profile and equal effectiveness, aromatase inhibitors have nearly replaced Megace® as second-line hormone therapy. Chemotherapy Chemotherapy is the use of medicines to destroy cancer cells throughout the body, and is considered a "systemic therapy" as it enters the bloodstream and travels throughout the body. Chemotherapy used following primary surgery is called adjuvant chemotherapy. When there is a high risk of disease recurrence, adjuvant chemotherapy is used with the goal of delaying or preventing the cancer returning in the same breast or elsewhere in the body. People with advanced stages of breast cancer also may be treated with chemotherapy to help control the disease, prolong survival, relieve symptoms, and improve quality of life. When chemotherapy is used to shrink a tumor before surgery or radiation therapy, it is called neoadjuvant chemotherapy. Adjuvant chemotherapy is routinely recommended for patients whose cancer has spread to lymph nodes, this is called node positive cancer. Lymph node positive cancer is considered a high risk feature for cancer recurrence. Adjuvant chemotherapy may be considered for some node negative patients. Currently, there is no consensus among breast cancer experts as to whether or not people with node-negative breast cancer should undergo chemotherapy. About two-thirds of those with node-negative breast cancer will not have a recurrence and so would not benefit from these strong, toxic drugs. Other tests used to predict your outcome, called prognostic tests, are considered, and if they indicate the cancer is aggressive, chemotherapy may be advised regardless of the lymph node status. Doctors also consider patient age, menopausal status, general health, activity level, and previously existing medical problems when making recommendations about chemotherapy. Getting a second opinion from another medical oncologist may be extremely helpful when thinking about chemotherapy. Chemotherapy uses drugs that are usually injected into a vein (IV, intravenous) or taken by mouth. In either case, the drug enters the bloodstream and is distributed throughout the body (except to the brain) so it can damage or destroy cancer cells. The physician administering the chemotherapy is called a medical oncologist. He or she attempts to determine the dose that will most effectively target the cancer cells, while causing the least possible damage to normal cells. Chemotherapy usually is given in an outpatient hospital clinic or doctor's office in cycles of three to four weeks, with time off between cycles to give the body time to recover. The entire treatment period typically is three to six months. Chemotherapy usually starts a few days to a few weeks after surgery and before radiation therapy if the physician has chosen to combine these treatments (combination modality therapy). Chemotherapy destroys fast-growing cells and does not distinguish between cancer cells and normal, healthy ones. When normal cells are killed, side effects from the drugs occur. Because cells of the blood, skin, nails, and hair divide quickly, chemotherapy can cause loss of red, white and platelet blood cells, dry skin, weak nails, and hair thinning or loss of hair over the entire body. When normal cells of the digestive tract are affected, diarrhea, mouth sores, nausea, or vomiting occur. Weight gain is a common side effect, but it is not clear why it occurs. On the other hand, some patients may lose weight from loss of appetite due to chemotherapy. These well-known, temporary side effects of chemotherapy are usually managed with appropriate medicines and self-care measures, such as maintaining a well-balanced diet. Because the chemotherapy drugs interfere with blood cell production, blood tests (red blood cell count, white blood cell count, and platelet count) are performed frequently to measure the effects of chemotherapy on the blood cells. Treatment is suspended if any blood cells reach a level so low as to be unhealthy. When the number of oxygen-carrying red blood cells is low, severe fatigue is a common problem. Likewise when the number of infection-fighting white blood cells is low, the person is more susceptible to infection; and when the number of blood-clotting platelets is low, bleeding or bruising may occur. As soon as the white blood cell and platelet production recovers to acceptable levels during a rest period, treatment can resume. If blood cells diminish seriously or persist at low levels, drugs called growth factors may be given to stimulate blood cell production. Specific growth factor drugs are now available for red and white blood cells, and platelets. Occasionally, a blood or platelet transfusion is necessary. Chemotherapy drugs may induce early or premature menopause, particularly in women who are already nearing menopause. During treatment, menstrual periods may stop, and typical menopausal symptoms such as hot flashes, burning sensation, or vaginal dryness may occur. Often, permanent infertility may also result. Some drugs, such as doxorubicin (Adriamycin®, Rubex®, Doxil®) or epirubilin (Ellence) can cause permanent damage to the heart, and therefore great care is taken to limit the amount of drug that is used and to monitor heart function periodically during therapy. More rarely, certain drugs may cause another cancer to develop as a result of the chemotherapy itself, such as leukemia. These chemotherapy-induced or treatment-related cancers usually occur two to six years after therapy is completed, but may take as long as 10 to 15 years or longer to appear. Because these drugs can cause both short- and long-term side effects or complications, the medical oncologist will consult with the patient to carefully weigh the potential benefits and risks of the chemotherapy and the impact on quality of life. Research has proven that combinations of chemotherapy drugs work best, and the medical oncologist can balance the drugs' actions and side effects. Because cancer cells can be radically altered giving them different qualities that can affect the response to different chemotherapy drugs, combination chemotherapy drugs that offer varying ways of destroying cells are most effective and reduce the chance of the cancer becoming resistant to one drug. Common chemotherapy combinations for breast cancer are listed in this chart:
Other chemotherapy drugs that may be included in combination with one or more of the above drugs include docetaxel (Taxotere®), mitomycin (Mutamycin®), vinorelbine (Navelbine®), and vinblastine (Velban®). Capecitabine (Xeloda®) and gemcitabine (Gemzar®). These are newer drugs for breast cancer and may be used alone in patients with advanced or metastatic disease or in combination with other chemotherapy drugs. Biological Therapy Biological therapies aim to enhance the body's own defense system, enabling it to destroy cancer cells. Biological therapy is also known as immunotherapy, biotherapy, or biological response modifier (BMR) therapy. Other immunotherapy approaches such as anti-tumor vaccines are under investigation, but thus far none have been shown to work for breast cancer. Trastuzumab (Herceptin®) is a monoclonal antibody that bonds specifically with a protein, called human epidermal growth factor receptor 2 or HER-2/neu. These cell surface receptors are often overproduced in some breast cancers making the cancer cells highly responsive to growth promoting proteins called growth factors. Such cancer cells are able to divide rapidly. HER2 positive tumors are known to be more aggressive, which is associated with shorter disease-free interval, early recurrence, and overall poorer outcome in breast cancer. Herceptin® binds to the HER-2/neu receptor, preventing the growth promoting protein from binding to the cell surface thus slowing tumor growth. Herceptin® has been found to be safe and active when used as a single drug or in combination with other chemotherapy drugs. Thus far, benefits from Herceptin® treatment have only been shown in patients whose tumors over produce HER2/neu. It works alone and has very little toxicity. When used with other chemotherapy drugs (such as paclitaxel (Taxol®, Onxol®), doxorubicin (Adriamycin®, Rubex® , Doxil®), and cyclophosphamide Cytoxan® ,Neosar®) it increases the potential of these drugs so that they will be effective in tumors that wouldn't respond if treated with just the one drug alone. Herceptin® alone is for patients whose tumors have progressed in spite of standard chemotherapy regimens, especially those who want to avoid toxicity. However, if a patient has a HER2-positive tumor that has just recurred, a combination of Taxol® and Herceptin® is often used immediately because it has been shown in randomized trials that these patients will live longer than those treated with Taxol® alone. Herceptin® is given as an IV injection once weekly. Some patients have received it on this schedule for years. Herceptin® is remarkably well tolerated, but it can cause mild nausea (very rarely vomiting), chills and fever (primarily on the first course), diarrhea, cough, or headache. A serious side effect is heart toxicity, which is more common among those who take Herceptin® in combination with anthracyclines (doxorubicin, epirubicin) or among those who have previously received an anthracycline. Heart function will be measured before and periodically throughout treatment and, if problems occur, it may be necessary to discontinue Herceptin®.  This content is reviewed regularly. Last Updated 6/6/2007
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