In theory, maximizing tumor exposure to chemotherapy should more effectively eliminate clonogenic malignant cells and prolong disease control (1). Given the preclinical evidence that demonstrates that the steepest dose response curves occur during the period of logarithmic growth, increased chemotherapy exposure should be most effective in the setting of micrometastatic disease. This principle should translate into higher survival rates when patients are treated in a minimal disease state, as in the case of adjuvant chemotherapy for early-stage breast cancer (1-3). One measure of chemotherapy exposure is dose-intensity, which is defined as the amount of a specific agent given over a fixed interval of time. Under this definition, dose-intensity can be increased by increasing the dose size (escalation), decreasing the inter-treatment interval (density), or both. Dose-escalation is supported by both retrospective analyses and prospective studies that demonstrate a clinically relevant dose-response effect in treating breast cancer patients with some agents, in some dose-ranges (3).
One pivotal, prospective, randomized clinical trial (CALGB 8541) demonstrated that the dose and dose-intensity of doxorubicin (Adriamycin, A) and cyclophosphamide (Cytoxan, C) administered with 5-fluorouracil (Adrucil, F) impact significantly on the clinical outcomes of women receiving adjuvant chemotherapy for resected node-positive breast cancer (4;5). However, treatment in this clinical trial was limited to conventional doses and schedules of chemotherapy because of the lack of supportive care technology during the period of patient accrual (1985-1991). It was not until the development of hematopoietic supportive care (e.g., autologous bone marrow transplantation and myeloid growth factor support) and improved antiemetics (e.g., serotonin antagonists) in the 1990’s that oncologists could prescribe higher doses and/or more intensive schedules of chemotherapy with an acceptable level of patient tolerability. Such dose and schedule modifications could fall into one of several approaches: (i) the one-time administration of very high dose chemotherapy (e.g., with bone marrow or peripheral blood stem cell support); (ii) the repetitive administration of standard dose chemotherapy with shortened inter-treatment intervals (e.g., dose-dense treatment); and (iii) the repetitive administration of higher dose chemotherapy with standard inter-treatment variables, as studied in the protocol described herein.
In addition to dose escalation and dose intensification, novel therapeutics (including the taxanes paclitaxel and docetaxel) became available in the 1980’s and 1990’s. These chemotherapeutic agents demonstrated impressive non-cross-resistance to the other available therapies, as clinical responses were observed in metastatic breast cancer patients who had progressed on prior anthracyclines or alkylating agents (6-9). The demonstration of benefit in advanced disease generated interest in incorporating these agents into adjuvant treatment regimens, and trials evaluating the benefit of the taxanes following standard combination chemotherapy with AC were initiated.
Two promising strategies were therefore presented to breast cancer clinical researchers in the early 1990’s: (i) the dose-intensification of conventional agents, and (ii) the incorporation of novel agents into the adjuvant therapy of early stage breast cancer. The Cancer and Leukemia Group B (CALGB) elected to test both strategies in adequately powered, multicenter clinical trials for patients with early stage breast cancer. Thus, CALGB 9141 was designed as a pilot study with the primary goal of assessing tolerance to paclitaxel following repetitive, nonmyeloablative cycles of maximally dose-intensified doxorubicin and cyclophosphamide (AC) with G-CSF for hematopoietic growth factor support. A secondary objective was to determine if there were additional benefits with higher than conventional doses of G-CSF (10 vs. 5 mcg/kg/day). This manuscript provides the results of this multicenter pilot study.