The introduction of adjuvant chemotherapy into treatment was based on improved understanding of the natural history and clinical course of breast cancer managed surgically during the first half of the 20th century. This experience led to the increased realization that micrometastases were in existence in most patients at the time of initial diagnosis.[1,2] The initial reports were based on single-agent alkylating therapy,[2,3] followed shortly by clinical trials that used the CMF combination regimen of cyclophosphamide(Drug information on cyclophosphamide), methotrexate(Drug information on methotrexate), and fluorouracil(Drug information on fluorouracil) (5-FU) as an adjuvant therapy to surgical resection. By 1980, most North American oncologists accepted adjuvant chemotherapy as a clinically beneficial intervention for premenopausal patients with axillary lymph node-positive breast cancer.
The Early Breast Cancer Trialists’ Collaborative Group established a database of all randomized clinical trials (whether published or not) of primary breast cancer. Meta-analyses of all available data explored the effect of systemic and locoregional therapies on odds of recurrence and mortality.[5-10] These meta-analyses, conducted at 5-year intervals starting in 1985, contributed substantially to the general acceptance of adjuvant systemic therapy as standard treatment.[7-9,11-12] By 1985, the clinical value of adjuvant tamoxifen(Drug information on tamoxifen) was demonstrated, and by 1990, there was evidence that extended the indications of adjuvant chemotherapy and hormonal therapy to lymph node-negative breast cancer. A recent National Institutes of Health (NIH)-organized Consensus Development Conference on Adjuvant Therapy of Breast Cancer issued a comprehensive, evidence-based report on the status of adjuvant chemotherapy (available at http://odp.od.nih.gov/consensus/cons/114/114_intro.htm).
Individual studies, and especially the overview of randomized trials, demonstrated the value of ovarian ablation (whether surgical, chemical, or radiation-induced) in reducing risk of recurrence or death for premenopausal patients.[5,11] The benefits from ovarian ablation appear similar to those of adjuvant chemotherapy and persist for at least 15 years after diagnosis. As is the case for all hormonal therapy, the benefits of ovarian ablation are limited to women with estrogen receptor-positive breast cancer. Mature evidence from individual trials and the overview not only confirmed the value of tamoxifen in reducing risk of recurrence and death, but also demonstrated that the effects of this intervention persist 10, and probably 15, years beyond diagnosis.[5,12] The optimal duration of tamoxifen therapy appears to be 5 years.[13-15] For patients of any age with estrogen receptor-positive breast cancer, the combination of tamoxifen and chemotherapy provides greater benefits than either treatment alone.[5,12]
Review of randomized clinical trials of cytotoxic therapy prompts several conclusions. First, combination chemotherapy is clearly more effective than single-agent treatment.[5,7-9,16-19] The question of whether the most effective drugs should be combined simultaneously, or in sequence, is currently under evaluation. Second, chemotherapy appears more effective for women under the age of 50 years than for those older than age 50.[7,9] Chemotherapy has both a cytotoxic and an endocrine effect in premenopausal patients, whereas the endocrine effect would be absent in postmenopausal women.[21-24] Lower than standard doses have been associated with inferior results.[25-27] The effect of adjuvant chemotherapy in women older than age 70 years has not been adequately tested.
The estrogen receptor status of the tumor is another factor that modifies the effect of adjuvant chemotherapy. There is a trend towards greater reductions in odds of recurrence and death for estrogen receptor-poor primary tumors than for estrogen receptor-rich tumors.[7-9] These differences are observed in both younger and older patient groups.
While several drugs and drug combinations have been used for adjuvant chemotherapy, most first-generation clinical trials utilized a combination of cyclophosphamide, methotrexate, and 5-FU (CMF). Evidence from second-generation trials supported the use of anthracycline-based therapy as the treatment of choice for most patients. The use of doxorubicin(Drug information on doxorubicin) (Adriamycin) or epirubicin(Drug information on epirubicin) (Ellence) in combination with other agents provided greater benefit than combinations without anthracyclines.
The AC regimen (doxorubicin [Adriamycin]/cyclophosphamide [Cytoxan, Neosar]) has been readily adopted in North America because of its ease of administration. There is no evidence, however, that this regimen is any better than CMF or that it is equivalent to more widely tested combinations, such as FAC (fluorouracil [5-FU]/doxorubicin [Adriamycin]/cyclophosphamide [Cytoxan]) or FEC (5-FU/epirubicin/cyclophosphamide), each of which has been shown to be superior to the classic CMF regimen (http://odp.od.nih.gov/consensus/cons/114/114_intro.htm).