In 1976 Bonadonna and colleagues (1) revolutionized the treatment of breast cancer when they reported the positive effect of adjuvant cytototoxic chemotherapy in women with node-positive breast cancer. Women with node-positive breast malignancies who had undergone mastectomy with axillary dissection were randomized to observation or 12 cycles of chemotherapy with cyclophosphamide (C), methotrexate (M) and 5-fluo-rouracil (F). The initial analysis indicated that 24% of the patients in the observation cohort experienced treatment failure, whereas only 5.3% of the patients in the chemotherapy cohort developed disease recurrence. Besides hair loss and amenorrhea, the most common toxicities were thrombocytopenia (platelet count < 130 x 109/L) in 71% and leukopenia (white blood cell count < 4 x 109/L) in 71%. Patients in the treat-

From: Cancer Drug Discovery and Development Hematopoietic Growth Factors in Oncology: Basic Science and Clinical Therapeutics Edited by: G. Morstyn, M. A. Foote, and G. J. Lieschke © Humana Press Inc., Totowa, NJ

Table 1

Relation of Dose Level of Adjuvant Chemotherapy to 5-Year Relapse-Free Survival (RFS)

Dose level Total group

Total with adjuvant therapy 449 (61)

Controls (no chemotherapy) 179 (45)

ment group had no increased rate of infection. The authors concluded that cytotoxic chemotherapy could be delivered safely with manageable toxicity and that it appeared to have an early impact on disease recurrence (1).

In a retrospective review of this same group of patients 5 yr later, the investigators made a startling discovery: the amount of chemotherapy that a patient received had an effect on outcome, a dose-response effect. Patients who received >85% of the planned dose of chemotherapy had a 5-yr relapse-free survival of 77% vs 45% for patients who received no adjuvant therapy (Table 1). Interestingly, patients who received <65% of the planned dose had relapse-free and overall survival rates similar to the patients who received no adjuvant therapy (2). After 20 yr of follow-up, the improvement in disease-free and overall survival for women treated with adjuvant CMF chemotherapy has persisted (3). From these data, the concept of dose intensity was born: to have the optimal effect, cytotoxic chemotherapy needs to be given at the right dose over the right time period.

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