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, methotrexate, and 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
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 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
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
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 (Adriamycin) or epirubicin (Ellence)
in combination with other agents provided greater benefit than combinations
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).
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