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Chapter: Basic & Clinical Pharmacology : Cancer Chemotherapy

Breast Cancer

The management of primary breast cancer has undergone a remarkable evolution as a result of major efforts at early diagnosis .



The management of primary breast cancer has undergone a remarkable evolution as a result of major efforts at early diagnosis (through encouragement of self-examination as well as throughthe use of cancer detection centers) and the implementation of combined modality approaches incorporating systemic chemo-therapy as an adjuvant to surgery and radiation therapy. Women with stage I disease (small primary tumors and negative axillary lymph node dissections) are currently treated with surgery alone, and they have an 80% chance of cure.


Women with node-positive disease have a high risk of both local and systemic recurrence. Thus, lymph node status directly indicates the risk of occult distant micrometastasis. In this situation, postop-erative use of systemic adjuvant chemotherapy with six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF proto-col) or of fluorouracil, doxorubicin, and cyclophosphamide (FAC) has been shown to significantly reduce the relapse rate and prolong survival. Alternative regimens with equivalent clinical benefit include four cycles of doxorubicin and cyclophosphamide and six cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). Each of these chemotherapy regimens has benefited women with stage II breast cancer with one to three involved lymph nodes. Women with four or more involved nodes have had limited benefit thus far from adjuvant chemotherapy. Long-term analysis has clearly shown improved survival rates in node-positive premeno-pausal women who have been treated aggressively with multiagent combination chemotherapy. The results from three randomized clinical trials clearly show that the addition of trastuzumab, a monoclonal antibody directed against the HER-2/neu receptor, to anthracycline- and taxane-containing adjuvant chemotherapy ben-efits women with HER-2-overexpressing breast cancer with respect to disease-free and overall survival.

Breast cancer was the first neoplasm shown to be responsive to hormonal manipulation. Tamoxifen is beneficial in postmeno-pausal women when used alone or in combination with cytotoxic chemotherapy. The present recommendation is to administer tamoxifen for 5 years of continuous therapy after surgical resec-tion. Longer durations of tamoxifen therapy do not appear to add additional clinical benefit. Postmenopausal women who complete 5 years of tamoxifen therapy should be placed on an aromatase inhibitor such as anastrozole for at least 2.5 years, although the optimal duration is unknown. In women who have completed 2–3 years of tamoxifen therapy, treatment with an aromatase inhibitor for a total of 5 years of hormonal therapy is now recom-mended .

Results from several randomized trials for breast cancer have established that adjuvant chemotherapy for premenopausal women and adjuvant tamoxifen for postmenopausal women are of benefit to women with stage I (node-negative) breast cancer. While this group of patients has the lowest overall risk of recurrence after surgery alone (about 35–50% over 15 years), this risk can be fur-ther reduced with adjuvant therapy.


The approach to women with advanced breast cancer remains a major challenge, as current treatment options are only palliative. Combination chemotherapy, endocrine therapy, or a combination of both results in overall response rates of 40–50%, but only a 10–20% complete response rate. Breast cancers expressing estro-gen receptors (ER) or progesterone receptors (PR), retain the intrinsic hormonal sensitivities of the normal breast—including the growth-stimulatory response to ovarian, adrenal, and pituitary hormones. Patients who show improvement with hormonal abla-tive procedures also respond to the addition of tamoxifen. The aromatase inhibitors anastrozole and letrozole are now approved as first-line therapy in women with advanced breast cancer whose tumors are hormone-receptor positive. In addition, these agents and exemestane are approved as second-line therapy following treatment with tamoxifen.

Patients with significant involvement of the lung, liver, or brain and those with rapidly progressive disease rarely benefit from hor-monal maneuvers, and initial systemic chemotherapy is indicated in such cases. For the 25–30% of breast cancer patients whose tumors express the HER-2/neu cell surface receptor, the human-ized monoclonal anti-HER-2/neu antibody, trastuzumab, is avail-able for therapeutic use alone or in combination with cytotoxic chemotherapy.

About 50–60% of patients with metastatic disease respond to initial chemotherapy. A broad range of anticancer agents have activity in this disease, including the anthracyclines (doxorubicin, mitoxantrone, and epirubicin), the taxanes (docetaxel, paclitaxel, and albumin-bound paclitaxel) along with the microtubule inhib-itor ixabepilone, navelbine, capecitabine, gemcitabine, cyclophos-phamide, methotrexate, and cisplatin. The anthracyclines and the taxanes are two of the most active classes of cytotoxic drugs. Combination chemotherapy has been found to induce higher and more durable remissions in up to 50–80% of patients, and anthra-cycline-containing regimens are now considered the standard of care in first-line therapy. With most combination regimens, partial remissions have a median duration of about 10 months and com-plete remissions have a duration of about 15 months. Unfortunately, only 10–20% of patients achieve complete remissions with any of these regimens, and as noted, complete remissions are usually not long-lasting.


Prostate cancer was the second cancer shown to be responsive to hormonal manipulation. The treatment of choice for patients with advanced prostate cancer is elimination of testosterone production by the testes through either surgical or chemical castration. Bilateral orchiectomy or estrogen therapy in the form of diethylstilbestrol was previously used as first-line therapy. Presently, the use of luteinizing hormone-releasing hormone (LHRH) agonists— including leuprolide and goserelin agonists, alone or in combina-tion with an antiandrogen (eg, flutamide, bicalutamide, or nilutamide)—is the preferred approach. There appears to be no survival advantage of total androgen blockade using a combination of LHRH agonist and antiandrogen agent compared with single-agent therapy. Hormonal treatment reduces symptoms—especially bone pain—in 70–80% of patients and may cause a significant reduction in the prostate-specific antigen (PSA) level, which is now widely accepted as a surrogate marker for response to treatment in prostate cancer. Although initial hormonal manipulation is able to control symptoms for up to 2 years, patients usually develop pro-gressive disease. Second-line hormonal therapies include aminoglu-tethimide plus hydrocortisone, the antifungal agent ketoconazole plus hydrocortisone, or hydrocortisone alone.

Unfortunately, nearly all patients with advanced prostate cancer eventually become refractory to hormone therapy. A regimen of mitoxantrone and prednisone is approved in patients with hor-mone-refractory prostate cancer because it provides effective pallia-tion in those who experience significant bone pain. Estramustine is an antimicrotubule agent that produces an almost 20% response rate as a single agent. However, when used in combination with either etoposide or a taxane such as docetaxel or paclitaxel, response rates are more than doubled to 40–50%. The combination of doc-etaxel and prednisone was recently shown to confer survival advan-tage when compared with the mitoxantrone-prednisone regimen, and this combination has now become the standard of care for hormone-refractory prostate cancer.

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