Historically, adjuvant chemotherapy has been tested in combination regimens, in which one multiagent regimen is cycled over time to allow recovery of normal tissues (in particular, hematologic recovery). The doses of each agent in the combination must be reduced from full single-agent doses to permit for acceptable toxicity. Recently, the use of full-dose single agents administered in a sequential fashion (e.g., doxorubicin for 4 cycles, followed by paclitaxel for 4 cycles, followed by cyclophosphamide for 4 cycles) to increase the dose intensity of the regimen has been explored.
In addition, the concept of dose density has also been investigated, in which similar doses of drugs are administered over shorter intervals of time (every 2 weeks as compared with every 3 weeks), with the use of colony-stimulating factors (G-CSF) to promote faster hematologic recovery between cycles. The concepts of dose intensity and dose density are being investigated in ongoing cooperative group trials, and answers to these questions should be available in the next few years.
A new approach to therapy that has been investigated in patients with metastatic disease is the use of trastuzumab (Herceptin®), a monoclonal antibody that is directed against the HER-2/neu receptor. When added to chemotherapy, trastuzumab has been shown to increase the efficacy of single-agent paclitaxel and doxorubicin in the metastatic setting in women with tumors that overexpress the HER-2/neu gene.
Presently, trials are underway to evaluate trastuzumab in the adjuvant setting, both in combination with chemotherapy and as single-agent maintenance therapy. Since this drug was found to increase doxorubicin-associated cardiotoxicity, careful cardiac monitoring will be an important component of these trials.
The EBCTCG will continue to perform overview analyses every 5 years, with the next planned analysis in the year 2000. At that time, there will be additional follow-up of trials addressing the duration of tamoxifen (10 vs. 5 years) and the addition of doxorubicin and paclitaxel to adjuvant regimens.
Although adjuvant therapy has contributed to the declining mortality of our patients, new strategies for the treatment and prevention of breast cancer are needed if mortality is to continue to be significantly reduced in the future.
Maura N. Dickler
American Cancer Society Guidelines for the Early Detection of Breast Cancer: Update 2003. CA Cancer J Clin 2003
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