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.1 New administration strategies based on more refined models of tumor growth are currently being evaluated. In addition, new active agents are being incorporated into adjuvant regimens. It is hoped that investigation of new agents and strategies will result in greater reduction of occult metastatic disease.1-3
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.4 Their 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 ³ 70 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.4
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.4
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.5 However, new strategies are being investigated, with the goal of optimizing the effects of chemotherapeutic agents.
U.S. & World
Recent Advances in Adjuvant Chemotherapy6,7
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 (see Figure 1).
Figure 1. Mathematical models of tumor cytoreduction and regrowth following alternating and sequential dose-dense cytotoxic treatment regimens. Broken lines indicate cells sensitive to treatment A; solid lines indicate cells sensitive to treatment B.6
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 (see Figure 2) to determine whether dose escalation of doxorubicin, or the sequential addition of paclitaxel to the regimen, could increase response rate or survival. 7
Figure 2. CALGB 9344 study design.7
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.7,8 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).
Table. Kaplan-Meier Estimates of Disease-Free and Overall Survival at 18 Months7
AC AC --> T P =
| DFS 86% ± 1.2% | 90% ± 1.0% | .0077 |
| OS 95% ± 0.7% | 97% ± 0.6% | .0390 |
DFS = disease-free survival; OS = overall survival.
- Sledge GW Jr. Adjuvant therapy for early stage breast cancer. Semin Oncol. 1996;23(suppl 2):51-54.
- Hudis CA, Norton L. Adjuvant drug therapy for operable breast cancer. Semin Oncol. 1996;23:475-493.
- Norton L. Conceptual basis for advances in the systemic drug therapy of breast cancer. Semin Oncol. 1997b;24(suppl 11):S11-2-S11-12.
- Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet. 1998;352:930-942.
- Hortobagyi GN. Treatment of breast cancer. N Engl J Med. 1998;339:974-984.
- Norton L. Evolving concepts in the systemic drug therapy of breast cancer. Semin Oncol. 1997a;24(suppl 10):S10-3-S10-10.
- Henderson IC, Berry D, Demetri G, et al. Improved disease-free (DFS) and overall survival (OS) from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients (PTS) with node-positive primary breast cancer (BC). Proc Am Soc Clin Oncol. 1998;17:101a. Abstract 390A.
- Hudis C, Riccio L, Seidman A, et al. Lack of increased cardiac toxicity with sequential doxorubicin and paclitaxel. Cancer Invest. 1998;16:67-71.
