High-dose chemotherapy in breast cancer.

High-dose chemotherapy is based on the scientific hypothesis that escalating the dose of drug will overcome drug resistance and improve outcome. Autologous bone marrow transplantation and, more recently, peripheral stem cell transplantation used as a means to restore marrow, made this a viable treatment for patients with selected tumours such as haematological malignancies. The role in breast cancer is less certain. Given the known as well as the potential toxicities, the objective of high-dose chemotherapy should be cure as opposed to palliation. However, the natural history of breast cancer can be protracted, with relapses occurring 15-20 years after treatment or within months of curative surgery. In breast cancer there is a positive correlation between recurrence-free and long-term survival. Therefore, the recurrence-free survival can be considered a surrogate endpoint in clinical trials. In patients with metastatic disease where cure is rare, at best, duration of a disease-free state may be a surrogate for overall benefit. Alternatively, time to progression may be another endpoint in the evaluation of treatment for metastatic disease. This is based on the assumption that quality of life is enhanced without progression of disease. Toxicity is the significant issue in the use of high-dose chemotherapy. The most common toxicity is myeloablation, potentially requiring prolonged hospitalisation. The only justification for these toxicities would be evidence of significant and meaningful benefit. A clinically relevant benefit with high-dose chemotherapy has not been seen in major randomised clinical trials of breast cancer in both the adjuvant and metastatic setting. In patients with advanced breast cancer, a small percentage may achieve long-term, disease-free survival, although there is no improvement in overall survival. Nonetheless, some investigators believe that high-dose chemotherapy holds promise, although currently this treatment is not recommended outside of a well designed prospective trial. These studies have provided useful information regarding cancer treatment. However, ongoing study of drug administration intervals, that is, dose-dense therapies, may lead to an approach that allows superior and less toxic treatment for breast cancer.