The objective of adjuvant chemotherapy and hormonal therapy (systemic therapy following surgery) in the treatment of breast cancer is the elimination of micrometastases that are believed to be present at the time of original diagnosis.

Overview of Adjuvant Chemotherapy

In 1998 the Early Breast Cancer Trialists’ Collaborative Group published an overview of randomized adjuvant trials for the treatment of early breast cancer.⁴Their analysis involved approximately 30,000 patients in 69 clinical trials. These included 47 trials of prolonged combination chemotherapy versus no chemotherapy, 11 trials of short versus prolonged use of combination chemotherapy, and 11 trials of anthracycline-containing regimens versus CMF (cyclophosphamide, methotrexate, and fluorouracil).

The overview analysis revealed that combination chemotherapy produced substantial and highly significant reductions in recurrence, both in women under 50 years of age (35% reduction) and in women ages 50 to 69 (20% reduction); few women ³70 years of age had been studied. Significant reductions in mortality were also observed for these age groups, 27% and 11%, respectively. After standardization for age and time since randomization, the proportional reductions in risk were similar for those patients with node-negative and node-positive disease. The age-specific benefits of therapy also appeared to be irrespective of menopausal status at presentation, estrogen-receptor status of the primary tumor, and of whether adjuvant hormonal therapy had been administered.

The collaborative group also found that there appeared to be no survival advantage associated with the use of combination chemotherapy for more than 3 to 6 months. Regarding specific chemotherapy regimens, available data from randomized studies suggested that anthracycline-based regimens produced somewhat greater effects on both delaying recurrence and survival than did CMF; however, the investigators stated that it could not be determined based on available evidence whether these differences were meaningful.

Six cycles of FAC (fluorouracil, doxorubicin, and cyclophosphamide; duration 18-24 weeks) or FEC (fluorouracil, epirubicin, and cyclophosphamide; duration 18-24 weeks), six cycles of CMF (duration 18-24 weeks), or four cycles of AC (doxorubicin and cyclophosphamide, duration 12 to 16 weeks) are currently considered standard chemotherapy. However, new strategies are being investigated, with the goal of optimizing the effects of chemotherapeutic agents.
 

Recent Advances in Adjuvant Chemotherapy

Administering chemotherapy in a dose-dense manner is a new strategy whose usefulness has been borne out in a clinical trial. Dose density (amount of therapy over a given period of time) may be increased by one of two methods: increasing the dose of the agent, or decreasing the time between cycles of administration.

While dose escalation typically results in a better response rate, cures are still uncommon. This observation is consistent with the Gompertzian model of tumor growth. According to this model, the proportion of cells killed by chemotherapy increases as the overall number of tumor cells decreases; however, cell regrowth becomes more rapid as the number of tumor cells decreases. Therefore, while small tumors are more susceptible to chemotherapy than larger tumors, they also regrow at a faster rate. The development of growth factors has more recently allowed investigators to experiment with decreasing the time between treatment cycles, in hopes of limiting tumor regrowth between cycles.

When administering more than one chemotherapeutic agent, dose density is maximized by sequential—not alternating—therapy. With alternating therapy, if a subpopulation of cells exists that is resistant to one component of therapy, but not the other, the subpopulation has a chance to regrow while the second agent is being administered. Sequential therapy permits administration of several short cycles of one component, followed by several short cycles of the second component.

A recent phase III Intergroup study (CALGB 9344) investigated how the active adjuvant regimen doxorubicin plus cyclophosphamide could be modified to improve results. Patients with node-positive primary disease were randomized using a 3 x 2 factorial trial design   to determine whether dose escalation of doxorubicin, or the sequential addition of paclitaxel to the regimen, could increase response rate or survival.
 

At the first preplanned interim analysis (450 events), there were no differences in disease-free or overall survival related to increasing the dose of doxorubicin; however, the sequential addition of paclitaxel reduced the recurrence rate by 22% and the death rate by 26% by multivariate analysis as compared with doxorubicin/cyclophosphamide alone. To date, no unexpected toxicities have been observed and there does not appear to be any increase in the expected cardiotoxicity. The investigators have concluded that the sequential addition of paclitaxel to doxorubicin/cyclophosphamide as postoperative adjuvant therapy of node-positive primary breast cancer is well tolerated and significantly improves disease-free and overall survival (Table).

Estimates of Disease-Free and Overall Survival at 18 Months

 AC                                              AC  --> T                                P =