Efforts to combine endocrine and chemotherapy in the management of breast cancer: do two and two equal three?

Standard approaches to the systemic management of breast cancer have probably reached a plateau. Endocrine therapy leads to responses in only 1/3 of patients, probably even less if no clinical preselection is applied, and the median benefit probably does not exceed one year. Although three-drug chemotherapeutic combinations yield responses in 55-65% of patients, the median duration of response is at best only 10 months, and addition of more drugs does not seem to offer much additional benefit. Although combining these approaches seems attractive initially, the theoretical improvement would be modest even if the effects were additive, and in fact the endocrine component may well perturb the cell cycle kinetics to reduce sensitivity to the cytotoxic component so that results would be less than additive. Clinical trials of combined chemo-endocrine regimens have tended to evaluate only the initial response rate, whereas a valid comparison must consider the total response duration and survival given either combined or the usual sequential approaches. Combining endocrine and cytotoxic chemotherapies may have a greater effect when a more rational means for their amalgamation is employed. Early trials using endocrine manipulation to synchronize cell sensitivity to cytotoxic treatment have been promising. Increasing attention needs to be directed towards more innovative trial design which is respectful of the biological realities of cancer.