Breast Cancer

Description

Alternative Names

Chemotherapy

Chemotherapy regimens are designed to kill cancer cells throughout the body. It has advantages for nearly every breast cancer patient regardless of whether the cancer is hormone receptor-positive or negative.

Adjuvant and Neoadjuvant Regimens

Adjuvant chemotherapy is used with surgery, radiation or both. Its goal is to eradicate microscopic disease in other parts of the body. Neoadjuvant chemotherapy, which is given before other treatments, is also proving to be useful for women with locally advanced breast cancer (Stage III). In such cases, it may reduce the tumor size so that it is operable.

Candidates for Adjuvant Chemotherapy. Adjuvant chemotherapy is an appropriate consideration for most women with invasive breast cancer, regardless of menopausal status. Studies are also reporting the adjuvant therapy may be beneficial for women with early stage cancers. Chemotherapy can reduce risk of relapse and prolong survival whether the tumor is node-negative or positive, or whether it is hormone-receptor positive or negative.

Chemotherapy Regimens and Drug Combinations. Adjuvant chemotherapy is usually administered after initial surgery in combination regimens in four to six courses of treatment over three to six months and usually before follow-up radiation therapy to the breast.

The following are some important agents used in combination treatments:

• Anthracyclines. Anthracyclines include doxorubicin (Adriamycin) or epirubicin (Ellence). To date, combinations using these agents have the best survival benefits. Patients who overexpress the HER-2/neu gene and have hormone receptor-negative tumors may particularly benefit from anthracyclines. The drug may have toxic effects on the heart, however.
• Cyclophosphamide, 5-fluorouracil (5-FU), and methotrexate (CMF). This was the standard regimen for years, but its use has declined with the introduction of anthracyclines. A variation in which mitoxantrone (Novantrone) replaced methotrexate may offer better survival rates than CMF.
• Taxanes include paclitaxel (Taxol) and docetaxel (Taxotere). Two studies published in 2003 suggest that women should strongly consider taxane-based therapy for node-positive breast cancer. The first study compared the standard regimen of 5-fluorouracil, doxorubicin, and cyclophosphomide (FAC) to the combination of docetaxel (Taxotere), doxorubicin (Adriamycin), and cyclophosphomide (Cytoxan) (TAC). After 55 months of follow-up, TAC-treated patients had a 28% lower risk of relapse and and 30% lower mortality rate than FAC-treated patients. In the second study, TAC therapy given on a dose-dense schedule (every two weeks) was shown to be superior to a standard schedule (every three weeks).
• A new form of paclitaxel (ABI-007, or Abraxane) uses a novel technology to deliver chemotherapy to the tumor site. In a 2003 study, ABI-007 increased the efficacy of paclitaxel by doubling the response rate (33% vs. 19%) and significantly prolonging the time to tumor progression. ABI-007 is associated with fewer side effects than paclitaxel, and does not require pretreatment with a steroid. The makers of ABI-007 submitted an application for FDA approval in March, 2004.

Hormonal Agents.After the completion of all treatments, including adjuvant chemotherapy, women with hormone-receptor-positive cancers generally take tamoxifen, which has reduced their risk of recurrence by approximately 30%. Two trials recently confirmed the benefits of undergoing estrogen-reducing therapy with a class of agents called aromatase inhibitors (AIs) after completing standard tamoxifen therapy. A 2003 study showed that five years of AI treatment with letrozole, taken after five years of tamoxifen therapy, improved disease-free survival by 6%. A 2004 study showed that switching to AI therapy with exemestane after two to three years of tamoxifen therapy was more effective than continuing tamoxifen therapy for the remainder of the five years of treatment. Studies are also suggesting the ovarian ablation (drugs that suppress estrogen) can be very helpful.

Chemotherapy and Other Agents Used in Metastatic Cancer

Patients who develop metastatic disease (i.e., who relapse at distant sites) are generally not curable. Combination therapies, however, are often effective at shrinking tumors and improving quality of life and may even be improving survival rates.

Agents Used to Treat Metastatic Cancer. Combination agents that are most effective are the following:

• Docetaxel (Taxotere) and taxanes, paclitaxel (Taxol).
• Anthracyclines, doxorubicin (Adriamycin) or epirubicin (Ellence).

Combinations that include both anthracyclines and taxanes are showing high response rates although it is not clear whether such combinations improve overall survival compared to these drugs used as single agents.

Other promising combinations or agents used alone or in combinations are the following:

• Cyclophosphamide, 5-fluorouracil (5-FU), and methotrexate (CMF) with a corticosteroid (e.g., prednisone).
• Capecitabine (Xeloda). This is a unique oral agent that may be a good substitute for 5-FU and when used alone may an effective alternative to CMF in older patients. Studies have reported response rates of up to 26% in patients previously treated with chemotherapy and of 30% when used as the first treatment for metastatic breast cancer. A combination of capecitabine and docetaxel may prove to be particularly important.
• Trastuzumab (Herceptin). Trastuzumab (Herceptin) is a monoclonal antibody, a genetically designed agent that binds only to cells that have a specific marker on the cell surface. Trastuzumab destroys cells carrying the HER-2 protein, and is being used in women who tests positive for the gene that regulates this protein. HER-2 plays a role in cancer cell growth in about 30% of breast cancer patients. This agent is producing longer survival rates in metastatic breast cancer patients when it is used in combination with paclitaxel. (This agent is useful only in women who test positive for HER-2 gene overexpression.) Of concern are reports of toxic effects on the heart with this combination. Other agents are also showing promise in combination with Herceptin.

Other drugs showing some promise in chemotherapeutic regimens for metastatic cancer include vinorelbine (Navelbine), gemcitabine (Gemzar) and, platinum-based agents (cisplatin, carboplatin, oxaplatin), edatrexate, and losoxantrone.

Bisphosphonates: Supportive Agents. Bisphosphonates (Zometa, Aredia) are supportive important agents for preventing fractures and reducing pain in people whose cancer has spread to the bones. Clodronate and pamidronate are the agents currently used and newer bisphosphonates (ibandronate and zoledronate) are being studied. To date, evidence strongly supports their use for reducing pain and improving quality of life. Bisphosphonates are also being investigated in early stage breast cancer, with some studies suggesting that they may help prevent metastasis in the bone and improve survival rates.

Side Effects of Chemotherapy

Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment.

Common side effects include the following:

• Nausea and vomiting. Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve these side effects in nearly all patients given moderate drugs and most patients who take more powerful drugs. In one study, a combination of dexamethasone (a corticosteroid) with ondansetron taken within 24 hours of chemotherapy achieved either a major or complete reduction in nausea and vomiting.
• Diarrhea.
• Temporary hair loss.
• Weight loss.
• Fatigue.
• Depression.

Serious short- and long-term complications can also occur and may vary depending on the specific agents used. They include the following:

• Anemia. The erythropoetins epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp) stimulate red blood cell production age and can help reduce or prevent anemia, resulting in significant improvement in quality of life. Aranesp persists longer in the blood than epoetin alfa and may therefore require fewer injections.
• Increased chance for infection from severe reduction in white blood cells (neutropenia). The addition of a drug called granulocyte colony-stimulating factor (filgrastim and lenograstim) is very helpful in reducing the risk for severe infection.
• Liver and kidney damage.
• Abnormal blood clotting (thrombocytopenia).
• Allergic reaction, particularly to platinum-based agents.
• Menstrual abnormalities and infertility. Premature menopause occurs in about 30% of women, particularly in those over 40. A natural hormone medication called a gonadotropin-releasing hormone analogue that puts women in a temporary pre-pubescent state during chemotherapy may preserve fertility in some women.
• Sexual dysfunction.
• Rarely, secondary cancers such as leukemia.
• Between a quarter and a third of women report problems in concentration, motor function, and memory, which can be long-term. In one study, women were experiencing such symptoms two years after treatment, although by four years they had resolved.
• Cumulative doses of anthracyclines can damage heart muscles over time and increase the risk for heart failure. An encapsulated form doxorubicin (Myocet, Doxil) may reduce the risk for toxic effects on the heart, but has not been approved for breast cancer use as of the date of this report.
• Taxanes can cause a drop in white blood cells and possible problems in the heart and central nervous system. Allergic reactions can occur, more often in Taxol than Taxotere. Taking a steroid before taxane administration can help prevent such reactions. Taxane therapy may also cause severe joint and muscle pain in some patients, relievable with corticosteroids.

Investigative Agents

Biologic Agents. A number of drugs are continually being tested that use the patient's own immune system to prevent or fight off cancer. No significant benefits have been achieved as yet, however.

Pemetrexed. Pemetrexed, known as an antifolate, inhibits three enzymes involved in the cancer process. It is being investigated for enhancing the effects of many chemotherapies used for breast cancer.

High-Dose Chemotherapy with Bone Marrow or Peripheral-Blood Stem-Cell Transplantation

High-dose chemotherapy along with peripheral-blood stem-cell rescue or bone marrow transplantation procedures have been used for cancer that has metastasized and, in some cases, for earlier stages of breast cancer in high-risk patients. The objective of this treatment is to be able to give patients very high toxic doses of cell-killing drugs. Transplantation procedures are based on stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments can harm these growing cells as well as cancer cells. Transplantation procedures, then, first removes these stem cells either directly (peripheral blood stem cell transplantation) or from bone marrow (bone marrow transplantation).

Despite the initial enthusiasm over the use of high dose therapy for treatment of high risk breast cancer, this approach can no longer be generally recommended and should not be used outside of a clinical trial setting. The results of three randomized studies failed to show a convincing advantage for the use of high dose therapy. (A fourth study that was originally thought to show an advantage was subsequently found to be flawed.) Nevertheless, some experts believe this approach can still be useful in selected patients and studies continue. In general, however, transplantation has a limited role in breast cancer management, and its use should be restricted to clinical trials.