Breast Cancer-6

ADJUVANT TREATMENT


1)Chemotherapy
2)Hormone Therapy
3)Natural Therapy

The goal of an adjuvant treatment is to systemically eliminate any cancer cells or micrometastases that may have spread from the breast tumor to other parts of the body as well as to eliminate any microscopic cancer cells that may remain in the local breast/lymph node area. These therapies are referred to as adjuvant, meaning "in addition to," because they are used with surgery and radiation. It is called adjuvant systemic therapy because the entire system of the body is treated. Several types of adjuvant systemic treatments are used for early-stage breast cancer: chemotherapy and hormone therapy are well established conventional adjuvant therapies; nutritional supplementation and diet modification may be incorporated in any conventional adjuvant treatment plan.

Except for some women with very small tumors (less than 1 cm) and with lymph nodes that do not have cancer, adjuvant therapy is usually recommended for women with early-stage breast cancer. Which therapies, and in what combination, depends on many things, such as the woman's age, whether the tumor has estrogen receptors, and the number of positive lymph nodes.

Chemotherapy
Chemotherapy uses drugs that can be taken in oral form or injected intravenously to kill cancer cells; sometimes, a combination is used. However, intravenous drugs are usually given in a hospital or doctor's office. Depending on the drugs used, chemotherapy is administered once or twice a month for 3-6 months. Sometimes the range might be extended to 7 or 8 months. Chemotherapy usually begins 4-6 weeks after the final surgery and is administered in a combination of 2-3 drugs that have been found to be the most effective. Unfortunately, chemotherapy drugs have many side effects that can damage or destroy normal healthy tissues throughout the body.

Although the exact schedule depends on the specific drugs used, drugs may be given on day 1 of a 3-week cycle or there may be a period of a week or two on the drugs, followed by a period of about 2 weeks off the drugs. This cycling allows the body a chance to rest and recover between treatments; however, it also gives the cancer cells an opportunity to rest, recover, and possibly mutate into a type of cancer that is chemotherapy-resistant. An entire course of chemotherapy lasts about 4-6 months, depending on the drugs used. Recent studies indicate that a more efficacious approach would be to lower the dose of conventional chemotherapy agents, reschedule their application, and combine them with agents designed to interfere with cancer's ability to produce new blood vessels (anti-angiogenic agents) (Holland et al. 2000).

This lower-dose approach, known as "metronomic dosing," uses a dosing schedule as often as every day. An amount as low as 25% of the maximum tolerated dose (MTD) in combination with anti-angiogenesis agents targets the tumor endothelial cells making up the blood vessels and microvessels feeding the tumor. Tumor endothelial cells can be killed with much less chemotherapy than tumor cells, and the side effects to healthy tissue and the patient in general are dramatically reduced (Hanahan et al. 2000).

While chemotherapy is an effective treatment for many women, it is associated with a number of well-known and traumatic side effects, such as hair loss, and exhausting bouts of nausea and vomiting, which many patients find difficult to tolerate. (For more information on chemotherapy, please refer to the Cancer Chemotherapy protocol.)


Hormone Therapy
1)Tamoxifen
2)Raloxifene
3)Toremifene
4)Anastrozole, Femara, Aromasin
5)Megestrol Acetate
6)Trastuzumab
7)Paclitaxel
8)Oophorectomy

Breast tumors often require hormones for growth, which poses a unique problem because the hormones involved in tumor growth are either estrogen, progesterone, or both. Estrogen and progesterone are naturally occurring and necessary hormones, produced mainly in the ovaries and adrenal glands in varying amounts throughout a woman's lifetime. These hormones are essential for many physiological functions, such as bone integrity, which will be discussed later in this protocol.

Hormone receptor-positive tumors can consist of cancer cells with receptor sites for estrogen, progesterone, or both. The hormones attach to receptor sites and promote cell proliferation. Hormone therapy blocks the hormones from attaching to the tumor receptor sites and may slow or stop the cancer's growth. The drug most often used in this type of endocrine therapy is tamoxifen, with a response rate from 30-60%. Other therapies are sometimes used, such as aromatase inhibitors (that inhibit the conversion of precursors to estrogens) or oophorectomy (the removal of the ovaries).

The effective role of some newer hormonal therapies in the treatment of both pre- and post-menopausal women with early breast cancer has been studied. Hormonal therapy with goserelin, either with or without tamoxifen, has been endorsed as an alternative to chemotherapy for young women with hormone-sensitive disease since it is equally effective and better tolerated. Twenty-five percent of all women diagnosed with breast cancer are premenopausal; of these women approximately 60% have hormone-sensitive tumors.

While chemotherapy kills cancer cells by destroying all rapidly dividing cells in the body, goserelin suppresses the supply of estrogen from the ovaries, which stimulates the cancer cells to grow. This is achieved by inhibiting production of another hormone called luteinizing hormone (LH), which stimulates the ovaries to make estrogen. Since many breast cancers grow more rapidly in the presence of estrogen, this can help to reduce tumor growth.

Tamoxifen prevents estrogen from stimulating cancer cell growth by blocking the estrogen receptors in the cancer cells. Cutting off the cancer's supply of estrogen provides an effective alternative method of combating the disease and avoids the distressing side effects of chemotherapy. Based upon evidence from adjuvant studies, hormonal therapy with goserelin is better-tolerated and equally effective as an alternative to chemotherapy. This gives physicians and patients a real choice in treatment following initial surgery (Goldhirsch et al. 2003).


Tamoxifen (Nolvadex)
Tamoxifen is an anti-estrogenic drug used to treat women whose tumors are estrogen or progesterone receptor-positive. This endocrine therapy blocks the female hormone estrogen from binding to the tumor cells. Tamoxifen has been the gold standard hormonal agent used for the treatment of breast cancer for more than 8 years. It is a prototype for a class of compounds called selective estrogen receptor-modulators (SERMs) of breast cancer but is also an effective primary treatment for advanced disease. Women with early-stage breast cancer who take tamoxifen have, on average, a 25% proportional increase in their chances of surviving 5 years after diagnosis.

Tamoxifen does not work equally well in all women. As the name implies, estrogen receptor-negative tumors do not have estrogen receptors, and therefore do not respond to tamoxifen. A Phase III study of 2691 high-risk cancer patients tested the effectiveness of tamoxifen with both pre- and postmenopausal subsets of receptor-negative and receptor-positive tumors. Both the 5-year disease-free and overall survival in patients with receptor-positive tumors treated with the addition of tamoxifen to chemotherapy was significantly higher than with chemotherapy alone, while no such advantage in disease-free or overall survival was found in receptor-negative patients. Further, in the receptor-positive postmenopausal group, the addition of tamoxifen showed a significant improvement in both disease-free and overall survival. However, in the premenopausal receptor-negative patients, tamoxifen led to a worse outcome, as indicated by the significantly reduced survival rate (ONI 2000). Women with estrogen receptor-negative tumors may receive chemotherapy instead of tamoxifen.

Therefore, for the patient whose breast cancer's growth is estrogen-dependent, tamoxifen can keep estrogen from these cells, slowing or stopping their growth. Tamoxifen is a pill taken daily for 5 years. To date, studies do not show any benefit to taking tamoxifen for longer than 5 years (NCI 1998). Studies show that the use of tamoxifen as a post-surgical adjuvant therapy can reduce the chances of the cancer reoccurring.

Tamoxifen has a host of side effects, including hot flashes, weight gain, mood swings, abnormal secretions from the vagina, fatigue, nausea, depression, loss of libido, headache, swelling of the limbs, decreased number of platelets, vaginal bleeding, blood clots in the large veins (deep venous thrombosis), blood clots in the lungs (pulmonary emboli), cataracts (Fisher et al. 1998), and--the side effect of the greatest concern--endometrial cancer (Harris et al. 1997).

Studies have shown an increase of early-stage endometrial cancer (cancer of the lining of the uterus) among women taking tamoxifen, and the risk increases if the drug is taken for more than 5 years. Endometrial cancer is usually diagnosed at a very early stage and is usually curable by surgery. The studies have also shown an increased risk of uterine sarcoma (a rare cancer of the connective tissues of the uterus) among women taking tamoxifen. Unusual vaginal bleeding is a common symptom of both of these cancers. The treating physician should be notified immediately if vaginal bleeding occurs.


Raloxifene
Raloxifene is a drug similar to tamoxifen. It is a selective estrogen receptor-modulator (SERM) that blocks the effect of estrogen on breast tissue and breast cancer. It is currently in the testing phase to assess its effectiveness in reducing the risk of developing breast cancer. Pending testing completion, this drug is not recommended as hormonal therapy for women who have been diagnosed with breast cancer.


Toremifene (Fareston)
Toremifene (Fareston) is an anti-estrogen drug closely related to tamoxifen that may be an option for postmenopausal women with breast cancer that has metastasized. Fareston is a type of anti-estrogen medication that is used in tumors that are estrogen-receptor-positive or estrogen receptor-unknown.

Some patients treated with anti-estrogens who have bone metastasis may experience a tumor flare with pain and inflammation in the muscles and bones that will usually subside quickly. Blood calcium level should be monitored because tumor flare can cause a raised level of calcium in the blood (hypercalcemia) with symptoms of nausea, vomiting, and thirst. Often a short stay in the hospital is necessary until the calcium levels have been reduced or treatment may need to be stopped. Fareston is being studied in clinical trials for use in earlier stages of breast cancer.


Anastrozole (Arimidex), Femara (Letrozole), and Aromasin (Exemestane)
Anastrozole (Arimidex), Femara (Letrozole), and Aromasin (Exemestane) are three hormonal therapy drugs referred to as aromatase inhibitors. Aromatase is the enzyme that converts male hormones (testosterone) into female hormones (estrogens) in postmenopausal women. Premenopausal women get most of their estrogen from the ovaries. But postmenopausal women still have estrogen in their bodies, and it is this conversion to estrogen of androgens coming from adrenal glands in the body that needs to be interrupted so the breast cancer cells no longer have estrogen to stimulate their growth. Unlike tamoxifen, which slows the growth of breast cancer by preventing estrogen from activating its receptor, anastrozole blocks an enzyme needed for the production of estrogen, inhibiting the conversion of precursors to estrogens, and is effective in hormone receptor-positive breast cancers. Anastrozole is currently an option for women whose advanced breast cancer continues to grow during or after tamoxifen treatment.

Studies are ongoing to compare tamoxifen and anastrozole as adjuvant hormonal therapies. Anastrozole (Arimidex) was better than tamoxifen at preventing the recurrence of breast cancer in a study conducted in 381 centers in 21 countries, involving 9366 patients, and examining three treatment arms: tamoxifen alone, tamoxifen in combination with other therapy, and anastrozole alone. The trial results showed that women taking anastrozole experienced fewer side effects than women taking tamoxifen. However, women taking tamoxifen experienced fewer musculoskeletal disorders. The study was only conducted for a relatively short period of time, 2 years, and the long-term effects (5 years and beyond) are not yet known. Longer-term studies are needed to assess both the benefits and risks of this therapy. However, most recent studies have showed anastrozole to be slightly superior to tamoxifen (Susman 2001).

In a primary trial of 33 months, anastrozole was superior to tamoxifen in terms of disease-free survival (DFS), time to recurrence (TTR), and incidence of contra-lateral breast cancer (CLBC) in adjuvant endocrine therapy for postmenopausal patients with early-stage breast cancer. After an additional follow-up period of 47 months, anastrozole continued to show superior efficacy.

When compared with tamoxifen, anastrozole has numerous advantages in terms of tolerability. Endometrial cancer, vaginal bleeding and discharge, cerebrovascular events, venous thromboembolic events, and hot flashes all occurred less frequently in the anastrozole group. However, musculoskeletal disorders and fractures continued to occur less frequently in the tamoxifen group. The study concluded that the benefits of anastrozole are likely to be maintained in the long term and provide further support for the status of anastrozole as a valid treatment option for postmenopausal women with hormone-sensitive early-stage breast cancer (Baum 2003).

The biological basis for the superior efficacy of neoadjuvant letrozole versus tamoxifen for postmenopausal women with estrogen receptor (ER)-positive locally advanced breast cancer was investigated. Letrozole inhibited tumor proliferation more than tamoxifen. While the molecular basis for this advantage was complex, it appeared to include a possible tamoxifen agonist effect on the cell cycle in both HER1/2+ and HER1/2- tumors. Letrozole seems to inhibit tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status (Ellis et al. 2003).

Letrozole (2.5 mg per day) and anastrozole (1 mg per day) were compared as endocrine therapy in postmenopausal women with advanced breast cancer previously treated with an anti-estrogen. Letrozole was significantly superior to anastrozole in the overall response rate (ORR) and both agents were well tolerated. Advanced breast cancer is more responsive to letrozole than anastrozole as a second-line endocrine therapy, as letrozole has the greater aromatase-inhibiting activity (Rose et al. 2003). These results support previous studies which showed that letrozole (Femara) was significantly more potent than anastrozole (Arimidex) in inhibiting aromatase activity in vitro and in inhibiting total body aromatization in patients with breast cancer.

A once a day oral dose of Femara lowered the risk of breast cancer recurrence by 43% in 5000 older women who had already completed 5 years of treatment with tamoxifen. After just over 2 years, 207 women had a recurrence of cancer - 75 in the Femara group and 132 in the placebo group. There were 31 deaths in women receiving Femara and 42 deaths in women receiving placebo. Compared with placebo, Femara therapy after the completion of standard tamoxifen treatment significantly improved disease-free survival. This is a significant finding because in more than 50% of women treated for breast cancer, the cancer recurs 5 or more years after the original diagnosis (Goss et al. 2003).

Possible side effects of aromatase-inhibitor drugs include those associated with menopausal-like estrogen deficiency, such as hot flashes, night sweats, menstrual irregularity, depression, bone or tumor pain, pulmonary embolism (a blood clot in the lung), musculoskeletal disorders, and generalized weakness.


Megestrol Acetate
Megestrol acetate (Megace) is another drug used for hormonal treatment of advanced breast cancer, usually for women whose cancers do not respond to tamoxifen or have stopped responding to tamoxifen. Megestrol acetate is a man-made substance called progestin that is similar to the female hormone progesterone.

As with other therapies, there are reported side effects, including an increase in appetite causing weight gain, fluid retention causing ankle swelling, and nausea at the onset of therapy, which usually subsides. In rare cases, allergic reactions, jaundice, and raised blood pressure have been reported.