A clinical and pharmacokinetic study of high-dose carboplatin, paclitaxel, granulocyte colony-stimulating factor, and peripheral blood stem cells in patients with unresectable or metastatic cancer.
We have developed a regimen incorporating multiple cycles of high-dose carboplatin and fixed-dose paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) with granulocyte colony-stimulating factor and peripheral blood stem cell support given every 21 days for up to four cycles. Our phase I study of this regimen has treated 26 patients with good performance status and histologically documented unresectable or metastatic carcinoma, sarcoma, or melanoma, 21 of whom received all planned courses every 21 days. Paclitaxel 250 mg/m2 was infused over 24 hours, followed by a 1-hour carboplatin infusion, with doses escalated between area under the concentration-time curve (AUC) targets of 8 and 20. Considering the carboplatin doses administered (two to three times those generally achieved with growth factor support), toxicity has been relatively modest. The median duration of grade 4 neutropenia and thrombocytopenia was not significantly different between the AUCs of 8 and 18, which proved to be the maximum tolerated carboplatin dose. Twelve courses were associated with hospitalization for neutropenic fever or catheter-related thrombophlebitis. One treatment-related death occurred, and severe toxicity caused withdrawal of two patients treated at the AUC of 20. Peripheral neuropathy was the most common serious nonhematologic complication. Pharmacokinetic analysis showed significantly lower measured versus predicted AUC values. Among 25 evaluable patients, preliminary results show one complete response (ovarian cancer) and 11 partial responses, including four in patients with non-small cell lung cancer. Additional issues to be addressed include the effect of a shorter (or longer) paclitaxel infusion on the carboplatin AUC (and the incidence of toxicity) and whether the discrepancy between actual and predicted AUCs (greater in our study than reported elsewhere) is due to the variability of creatinine clearance-determined glomerular filtration rate or to altered carboplatin pharmacokinetics when a short high-dose infusion follows paclitaxel. Additional patients are being accrued at the AUC of 18.
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics; D003131:Combined Modality Therapy; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006402:Hematologic Diseases / Q000139:chemically induced; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000628:therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced
D016179:Granulocyte Colony-Stimulating Factor; D016190:Carboplatin; D017239:Paclitaxel