Concepts and clinical trials of dose-dense chemotherapy for breast cancer

This article will review the strategy of dose-dense administration of chemotherapy for breast cancer. Increased dose density is achieved by reducing the interval between each dose of chemotherapy. The cumulative drug dose remains constant, but the same amount of drug is administered over a shorter period. Mathematical models of tumor growth have provided the basis for the clinical application of dose-dense chemotherapy. The Norton-Simon model suggests that increasing the dose density of chemotherapy will increase efficacy by minimizing the opportunity for regrowth of tumor cells between cycles of chemotherapy. Intergroup trial 9741, coordinated by the Cancer and Leukemia Group B (CALGB), tested the 2 hypotheses that dose-dense and sequential administration of chemotherapy regimens incorporating doxorubicin, cyclophosphamide, and paclitaxel would improve disease-free survival and overall survival. A statistically significant 4-year disease-free survival advantage was detected for the 2 dose-dense regimens compared with the regimens administered every 3 weeks. The mathematical concepts and previous clinical trials of dose density that contributed to the design of CALGB 9741 will be reviewed. The strengths and limitations of CALGB 9741 will then be discussed before the presentation of future directions of research and recommendations for clinical practice today.