The last three decades have yielded marked progress in the diagnosis and management of breast cancer. Not only is the disease being detected at a much earlier stage through screening mammography and heightened patient awareness, but the addition of systemic therapy has also improved survival. The efforts of hundreds of trials, thousands of investigators, and tens of thousands of women with breast cancer, have helped establish adjuvant treatment of breast cancer as effective in prolonging both disease-free and overall survival.
Adjuvant therapy is the only treatment for breast cancer that currently offers the prospect of cure by eliminating micrometastases, even with regimens that are noncurative in metastatic disease. Adjuvant therapy was initially directed at patients with node-positive disease; however, with the maturation of clinical trial data, it became apparent that all patient groups would benefit significantly from the incorporation of this modality into overall treatment. Unfortunately, large numbers of patients still succumb to their disease, mandating ongoing research to improve existing treatments and incorporate new agents and novel therapies into adjuvant regimens.
The following article provides an overview of data from adjuvant trials evaluating chemotherapy in all groups of women with breast cancer. Key findings from the Early Breast Cancer Trialists Collaborative Group are discussed. Because the margins in terms of survival benefit can be small, toxicity issues and the need for predictive markers are considered. The use of adjuvant endocrine therapy was reviewed by Pritchard in the April 2000 issue of Oncology.
The 1995 overview analysis of polychemotherapy by the Early Breast Cancer Trialists Collaborative Group summarized the results of any randomized trial that began before 1990 and involved treatment groups that differed only with respect to the adjuvant chemotherapy regimens that were being compared. The analysis involved 18,000 women in 47 trials of prolonged vs no polychemotherapy, 6,000 women in 11 trials of longer vs shorter chemotherapy, and 6,000 women in 11 trials of anthracycline-containing chemotherapy vs CMF (cyclophosphamide [Cytoxan, Neosar], methotrexate(Drug information on methotrexate), fluorouracil(Drug information on fluorouracil)).
Polychemotherapy consisting of regimens in which two or more agents were administered over several months produced proportional reductions in recurrence and mortality in all groups analyzed. In women younger than 50 years old at the time of randomization, polychemotherapy decreased the annual risk of relapse by 35% and mortality by 27%. In women older than age 50 at the time of randomization, the benefits were more modest, with an annual risk reduction of 20% for recurrence and 11% for mortality (Table 1).
When nodal involvement was considered, the absolute reductions in recurrence and mortality with polychemotherapy were similar in both node-negative and node-positive disease (Table 2). For all women under age 50 at randomization, polychemotherapy improved 10-year survival from 71% to 78% for those with node-negative disease and from 42% to 53% for those with node-positive disease. This represents an absolute survival benefit of 7% and 11% in node-negative and node-positive patients, respectively. For women aged 50 to 69 years, polychemotherapy improved 10-year survival from 67% to 69% for node-negative disease and from 46% to 49% for node-positive disease, conveying an absolute benefit of 2% and 3%, respectively.
Estrogen-receptor (ER) status had little impact on the overall benefit of polychemotherapy in women less than 50 years. In women aged 50 to 69 years, chemotherapy also significantly reduced recurrence and mortality in both ER-positive and ER-negative patients, with the reduction in recurrence being almost twice as large for ER-negative patients as for ER-positive patients (Table 1).
The analysis of the addition of chemotherapy to tamoxifen(Drug information on tamoxifen) (Nolvadex) in women less than 50 years old did not demonstrate a significant reduction in recurrence or mortality compared to tamoxifen alone, which may reflect the relatively small number of younger women in trials of combined chemoendocrine therapy. In women aged 50 to 69 years, the proportional reductions in recurrence and mortality gained with polychemotherapy were significant, with or without tamoxifen. Thus, chemotherapy and hormonal therapy should be considered complementary in the adjuvant setting (Table 3).
There was no survival advantage associated with the use of polychemotherapy for more than 3 to 6 months. A trend toward fewer recurrences was demonstrated with prolonged treatment (about 6 to 24 months), but this difference was not significant.
The overview analysis indirectly compared chemotherapy regimens containing CMF, CMF with additional cytotoxic drugs, and other cytotoxic drug regimens. No significant advantage was apparent among the many variants of CMF.
The overview also compared anthracycline-containing regimens vs CMF in approximately 6,000 women in 11 trials, where 70% of the women evaluated were less than 50 years old. The results showed a statistically significant 12% (standard deviation [SD], 4%) reduction in recurrence and an 11% (SD, 5%) reduction in mortality for the anthracycline-containing regimens. This translated into an absolute risk reduction of 3.2% and 2.7% for recurrence and mortality, respectively, above the advantages seen with CMF. However, confidence intervals were relatively wide.
Trials evaluating newer anthracycline-based regimens, including the Intergroup node-negative trial (INT 0102), and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-23 trial, were not incorporated in this analysis, and thus, may overrepresent the use of CMF-type combinations (Table 4).
The Intergroup INT 0102 trial compared CMF with CAF (cyclophosphamide, Adriamycin [doxorubicin], fluorouracil) in high-risk node-negative patients, who were also treated with or without tamoxifen. Over 4,400 patients were enrolled in this trial and stratified into three groups according to risk.
The high-risk group included patients with tumors measuring 2 cm or greater and those who were hormone-receptor negative. The low-risk group included patients with tumors too small for biochemical hormone-receptor assay. The uncertain risk group included patients with tumors less than 2 cm and hormone-receptorpositive disease; these patients were further divided into low or high risk as determined by S-phase fraction of their tumor.
All patients in the high-risk group were randomized to receive either CAF or CMF, with or without tamoxifen, for 5 years. Low-risk patients were followed without receiving any adjuvant therapy. Both disease-free and overall survival were marginally better with CAF (P = .03), although at the cost of increased toxicity including granulocytopenias, gastrointestinal symptoms, and alopecia. The recurrence rate was 15% in the CAF group and 18% in the CMF group, and the mortality rate was 8% and 10%, respectively. In low-risk patients, the relapse rate was 11% and mortality, 4%. Tamoxifen provided additional benefit only in ER-positive patients.
The NCIC trial compared a moderately intensive regimen of CEF (cyclophosphamide, epirubicin [Ellence], fluorouracil) with CMF. Premenopausal women with node-positive breast cancer were randomly allocated to receive either standard CMF or cyclophosphamide(Drug information on cyclophosphamide) (75 mg/m² orally on days 1 through 14), epirubicin(Drug information on epirubicin) (60 mg/m² on days 1 and 8), and fluorouracil (500 mg/m² IV on days 1 and 8), with each cycle administered monthly for 6 months. At a median follow-up of 59 months, both relapse-free and overall survival improved in women who received CEF compared with those who received CMF, with a 29% relative risk reduction in recurrent breast cancer and a 19% relative reduction in mortality.
The 5-year relapse-free survival rate was 53% for patients who received CMF and 63% for patients who received CEF (P = .009), and the 5-year actuarial survival rates were 70% and 77%, respectively (P = .03). This benefit was seen in patients with one to three positive nodes and in those with more than three positive nodes. No patient in the CEF arm developed congestive cardiac failure; however, five patients developed acute leukemia including four cases of acute myelogenous leukemia.
The recently presented NSABP B-23 trial, compared four 3-week cycles of AC (Adriamycin [doxorubicin], cyclophosphamide) with six 4-week cycles of CMF, with or without tamoxifen, in approximately 2,000 women with ER-negative, node-negative disease. No difference in disease-free or overall survival was seen between those who received AC or CMF or those who received tamoxifen or placebo with either regimen.
Thus, the literature offers a number of large, well-designed, prospective randomized trials that show conflicting results. The debate continues as to whether the small difference in survival demonstrated for an anthracycline-based adjuvant regimen in the overview analysis by the Early Breast Cancer Trialists Collaborative Group translates into a clinically meaningful benefit in all patient groups. It may be that if four cycles of AC is equivalent to six cycles of CMF, then perhaps six cycles of an anthracycline-based regimen would show a benefit, as alluded to in the Intergroup and NCIC studies.
A retrospective analysis of existing adjuvant trials suggested a relationship between the dose-intensity (dose per unit time) of adjuvant chemotherapy and clinical outcome.[1,6] Preclinical studies have supported the concept of a steep dose-response curve for alkylating agents in the breast cancer cell lines studied. The expectation has been that for some drugsespecially alkylating agents and to a lesser extent anthracyclinesdoses above certain levels will successfully overcome drug resistance.
The Cancer and Leukemia Group B (CALGB) trial 8541 compared three dose intensities of CAF in 1,550 patients with node-positive breast cancer.[7,8] Patients received CAF, 300/30/300 mg/m² every 4 weeks for 4 cycles (low-dose arm); CAF, 400/40/400 mg/m² every 4 weeks for 6 cycles (moderate-dose arm); or CAF, 600/60/600 mg/m² every 4 weeks for 4 cycles (high-dose arm). The high-dose arm received twice the drug dose given the low-dose arm at twice the dose intensity. The moderate-dose arm received the same total drug dose as the high-dose arm but at only two-thirds the dose intensity.
Disease-free and overall survival rates for patients in the moderate- and high-dose arms were superior to those of the low-dose arm with no significant difference between these measures in the high- and intermediate-dose arms. The higher dose levels used in this study are now considered standard therapy, so it is probable that this trial supports the value of dose intensity or rather, supports the concept of a threshold total cumulative dose below which treatment becomes ineffective.