Best use of adjuvant systemic therapies II, chemotherapy aspects: dose of chemotherapy—cytotoxicity, duration and responsiveness

Abstract

The overall survival improvement by adjuvant chemotherapy is partly related to patient age, stage and chemotherapy regimens used. Too low dose dose-intensities or total doses will result in inferior outcomes. Conventional dose escalations above standard doses will not be beneficial for doxorubicin or cyclophosphamide, while an epirubicin dose of 90–100 mg/m 2 given every third week in polychemotherapy regimens results in overall survival gains. The issue is more complex, while retrospective analysis of adjuvant regimens have revealed inferior outcomes for patients receiving standard chemotherapy doses and regimens without toxicity. Most cytostatics demonstrate a marked inter-individual variation in different pharmacokinectic parameters, not compensated for by dosage based on body surface area. These facts have partly been the basis for the randomised Scandinavian Breast Group (SBG) studies SBG 9401 and 2000–1, respectively, using tailored dosage strategies aiming at interpatient equivalent dosage. Randomised studies using marrow supported-high dose strategies have so far not been demonstrated to result in overall survival improvements. G-CSF (granulocyte-colony stimulating factor) and dose-dense paclitaxel containing regimens have resulted in a small but significant survival gain compared with conventional three weekly regimens, challenging the present dogma of conventional three–four weekly scheduling, based on normal tissue side-effects rather than tumour biological considerations. The recent microarray based studies demonstrated marked inter-patient variability in gene expression and underline the potential for better patient selection and more tailored therapy strategies.