Cytotoxic drugs should be considered for the treatment of metastatic breast cancer (1) if visceral metastases are present (especially brain or lymphangitic pulmonary), (2) if hormonal treatment is unsuccessful or the disease has progressed after an initial response to hormonal manipulation, or (3) if the tumor is ER negative. The most useful single chemotherapeutic agent to date is doxorubicin (Adriamycin), with a response rate of 40-50%. Single agents are rarely used but rather are given in combination with other cytotoxic drugs.

Combination chemotherapy using multiple agents has proved to be more effective, with objectively observed favorable responses achieved in 60-80% of patients with stage IV disease. Various combinations of drugs have been used, and clinical trials are continuing in an effort to improve results and reduce undesirable side effects. Nausea and vomiting are well controlled with drugs that directly affect the central nervous system, such as ondansetron and granisetron.

These drugs are selective antagonists of serotonin receptors in the central nervous system and block nausea caused by cytotoxic chemotherapy. Doxorubicin (40 mg/m2 intravenously on day 1) and cyclophosphamide (200 mg/m2 orally on days 3-6) produce an objective response in about 85% of patients so treated. Other chemotherapeutic regimens have consisted of various combinations of drugs, including cyclophosphamide, vincristine, methotrexate, fluorouracil, and taxanes, with response rates ranging up to 60-70%. Prior adjuvant chemotherapy does not seem to alter response rates in patients who relapse. Growth factors such as erythropoietin (epoetin alfa), which stimulates red blood cell production and mimics the effect of erythropoietin, and filgrastim (granulocyte colony-stimulating factor; G-CSF), which stimulates proliferation and differentiation of hematopoietic cells, prevent life-threatening anemia and neutropenia seen commonly with high doses of chemotherapy. These agents greatly diminish the incidence of infections that may complicate the use of myelosuppressive chemotherapy.

The taxanes (paclitaxel and docetaxel) have been shown to be very effective for patients with metastatic breast cancer. They have usually been given after failure of combination chemotherapy for metastatic disease or relapse shortly after completion of adjuvant chemotherapy. However, they are becoming more important in both the management of metastatic disease and even adjuvant therapy. These drugs have response rates of 30-40% in patients with metastatic disease. They may be especially valuable in treating anthracycline-resistant tumors. Both agents are currently being used after treatment with anthracyclines in patients with advanced disease as well as in adjuvant and neoadjuvant settings. High-dose chemotherapy and autologous bone marrow or stem cell transplantation aroused widespread interest for the treatment of metastatic breast cancer. With this technique, the patient receives high doses of cytotoxic agents, eradicating the marrow, for which the patient subsequently undergoes autologous bone marrow or stem cell transplantation. Complete response rates are as high as 30-35% - considerably better than what can be achieved with conventional chemotherapy. Most randomized trials, however, comparing high-dose chemotherapy with stem cell support show no improvement in survival over conventional chemotherapy. A study purporting to show a survival advantage to high-dose chemotherapy in South Africa was found to be falsified and discredited. Enthusiasm for high-dose chemotherapy with stem cell support has waned, but additional studies continue and recently showed a beneficial effect in some high-risk women. The technique is extremely costly, and the treatment itself is associated with a mortality rate of about 3-7%.

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