IMPACT OF CYCLOPHOSPHAMIDE ON RELATIONSHIPS BETWEEN CARBOPLATIN EXPOSURE AND RESPONSE OR TOXICITY WHEN USED IN THE TREATMENT OF ADVANCED OVARIAN-CANCER

Purpose: To determine (1) the impact of cyclophosphamide 600 mg/m2 on previously defined relationships between carboplatin area under the plasma concentration versus time curve (AUC) and indices of toxicity and response in women with advanced ovarian cancer; and (2) the relationships between indices of cumulative drug exposure and clinical outcomes. Methods: Carboplatin AUC = dose/(creatinine clearance [CCr] + 25) and was calculated in 224 women who received carboplatin 300 mg/m2 and cyclophosphamide 600 mg/m2. The likelihood of grade 3 or greater myelotoxicity at any carboplatin AUC was compared with the likelihood of myelotoxicity at the same single-agent carboplatin AUC. The nadir count predicted using the University of Maryland single-agent carboplatin dosing formula was compared with the nadir count observed. Received and relative-received dose-intensity were calculated. Carboplatin exposure-intensity was defined by substituting cumulative carboplatin exposure for total dose. Relationships were sought between these indices and therapeutic outcomes. Results: The incidence of leukopenia and thrombocytopenia at any carboplatin AUC was greater for the two-drug combination than for single-agent carboplatin. The platelet nadir in 83% of patients was less than or equal to the nadir predicted for the same single- agent carboplatin AUC. Despite a narrow range of received dose-intensities, carboplatin exposure-intensity was distributed over a twofold range. There were no relationships between received and relative-received dose-intensity or carboplatin exposure-intensity and time to progression or survival. Conclusion: Any carboplatin AUC when administered with cyclophosphamide 600 mg/m2 produces greater myelotoxicity than the same AUC of single-agent carboplatin. Received carboplatin dose-intensity underestimates the range of plasma drug exposure resulting from a fixed carboplatin dosing regimen. Whether higher carboplatin exposures can improve outcome requires prospective validation.