Dose intensification and breast cancer: current results and future perspectives.

Although the existence of a dose-response relationship in anti-cancer chemotherapy of solid tumours has long been suggested on the basis of experimental and preclinical models [1], the clinical validation of these theoretical concepts still requires clinical validation. As long ago as 1981, Bonadonna and several others studied retrospective surveys in breast cancer and suggested the importance of dose and dose-intensity (dose per unit of time) in both adjuvant therapy and metastatic disease [2,3]. While it is true that the statistical and methodological bias inherent in several of these surveys had to be considered with caution, they nevertheless had the merit of inciting the design of controlled, prospective studies. The most recent results obtained have made it possible to show the importance of the threshold dose concept [4-6], although they have yet to demonstrate a true dose-response relationship. The first prospective studies to assess the notion of dose and/or dose-intensity in metastatic breast cancer date from the 1980s and, in most cases, did not demonstrate a significant advantage in terms of disease-free survival or overall survival, despite an increase in response rates [7]. It should, however, be emphasized that the dose increase in these studies ranged from 1.25 to 2.0, that most of them did not involve haematopoietic support, and that the only two studies which were positive in terms of survival included small patient populations and control groups which could be considered as receiving an insufficient dose [5,6]. The CALGB (Cancer and Leukemia Group B) recently published Tesults of a randomized trial in the adjuvant setting comparing three schedules of (FAC) 5-FU, adriamycin, cyclophosphamide [4]. Dose levels and dose-intensity were similar to the studies mentioned above, and no haematopoietic support was given. With a current follow-up of five years, this trial has confirmed the concept of a threshold-effect, a significant advantage being observed in terms of disease-free survival and overall survival in the two 'intensified' groups when compared with the moderate dosage group. However, the latter group could be considered as under-dosed (5-FU: 300 mg/m, d l -d8; adriamycin: 30 mg/m, dl ; cyclophosphamide: 300 mg/m, dl; 4 cycles repeated every 28 days). The most striking results, suggesting the existence of a true dose-response effect in breast cancer, have in fact been obtained in intensification studies involving haematopoietic support (autologous bone marrow transplantation with or without haematopoietic growth factors, or, peripheral blood stem cell transplantation) with the dose increase ranging from 5 to 10. Most of these studies were conducted between 1985 and 1990 in patients with advanced metastatic disease and/or refractory to conventional chemotherapy; high response rates of about 60% were obtained, with complete response rates of 15% to 20%. However, the median duration of response was short and no significant improvement could be seen in terms of survival [8, 9]. Nonetheless, insofar as these trials suggested the possibility of overcoming acquired or intrinsic resistance by dose intensification, they validated the concept of a dose-response effect in breast cancer, at least in terms of the clinical response rate endpoint. Spectacular advances have also been achieved in recent years in the use of haematopoietic support, particularly with the development of growth factors and peripheral blood stem cell transplantation. While a significant reduction in the morbidity and the mortality linked to chemotherapy-induced haematological toxicity is still awaited, these trials have encouraged numerous teams to study dose intensification in the setting of greatest potential interest, in other words, first line chemotherapy in metastatic breast cancer, high risk breast cancer including cases with massive axillary node involvement (>6-10), locally advanced breast cancer and inflammatory breast cancer [10].