Potential strategies for improving the results of high-dose chemotherapy in patients with metastatic breast cancer

High-dose chemotherapy (HDC) is the most effective approach for inducing complete remissions in patients with metastatic breast cancer, and although most patients will relapse, a small percentage (10%-15%) achieve durable remissions beyond five years. Additionally, HDC has produced five-year relapse-free survival rates in excess of 70% in patients with stage II breast cancer with >10 nodes. The use of HDC in breast cancer remains controversial and randomised trials are required to assess the survival impact of this approach. The introduction of haematopoietic growth factors (HGF) and peripheral blood progenitor cells (PBPC) has advanced the use of HDC by reducing treatment-related mortality (from 20% to 5%) and by allowing the development of multiple cycles of intensive therapy. Based on tumour kinetic models we have hypothesised that multiple, rapidly cycled courses of high-dose therapy may improve the rate of durable remission in metastatic breast cancer. The feasibility of this approach has been shown in a series of pilot studies in which one or more courses of high-dose cyclophosphamide and recombinant granulocyte colony-stimulating factor (G-CSF) (filgrastim) were given to obtain PBPC which were then used to support one or more courses of HDC. In successive studies the HDC component consisted of: a single course of carboplatin, etoposide and cyclophosphamide; four courses of carboplatin; tandem courses of thiotepa; or a sequence of melphalan and thiotepa. Promising response rates have been produced in advanced breast and ovarian cancer with the later generation of regimens. These results justify the conduct of prospective randomised trials.