Summary

Abstract

Despite several decades of clinical research, a variety of questions about how to administer optimal adjuvant chemotherapy remain. One lingering question is the importance of dose as a determinant of outcome in both early and advanced stage breast cancer. The possibility that the dose of chemotherapy actually received by the patient might influence clinical outcome was first raised by Bonadonna and colleagues in their retrospective analysis of the seminal trial of cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy versus observation for treatment of women with node-positive breast cancer. The concepts of dose intensity, dose density, total dose, dose size, etc., have gradually evolved from this initial work. Technological developments such as the advent of colony-stimulating factors and the ability to harvest autologous bone marrow or peripheral blood progenitor cells have permitted substantial dose escalation of cytotoxics like the alkylating agents whose primary toxicity is myelosuppression. In addition, the administration of cytotoxics more frequently or at high doses repetitively has become feasible. However, few trials that explicitly test the value of these approaches have been reported as yet. In addition, those trials reported have not been uniformly positive. For example, two sequential trials of dose escalation of cyclophosphamide with a fixed dose of doxorubicin for women with node-positive breast cancer have thus far failed to show a major advantage of a fourfold escalation in cyclophosphamide dose from 600 mg/m² to 2400 mg/m² per cycle. Early follow-up of a trial of dose escalation of doxorubicin from 60 mg/m² to 90 mg/m² per cycle with a fixed dose of cyclophosphamide in the same group of women also shows no benefit. Thus, though supported by preclinical models, regimens with greatly increased dose, dose intensity, or dose density cannot be regarded as standard at present in the absence of clear proof of superiority. However, the area remains an active area of clinical investigation, as exemplified by two presentations during the session on cytotoxics and their dose.