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Association of high-dose cyclophosphamide, cisplatin, and carmustine pharmacokinetics with survival, toxicity, and dosing weight in patients with primary breast cancer.

Publication ,  Journal Article
Petros, WP; Broadwater, G; Berry, D; Jones, RB; Vredenburgh, JJ; Gilbert, CJ; Gibbs, JP; Colvin, OM; Peters, WP
Published in: Clin Cancer Res
March 2002

This report investigates relationships between the pharmacokinetics and pharmacodynamics of high-dose alkylators used for the treatment of primary breast cancer. Eighty-five women with primary breast cancer involving >or=10 lymph nodes received four cycles of standard-dose chemotherapy followed by a high-dose regimen consisting of: cyclophosphamide (1875 mg/m(2) once daily x 3), cisplatin (165 mg/m(2) given over 72 h), carmustine (600 mg/m(2)), and stem cell transplantation. Dosages were attenuated in patients whose body weight exceeded their calculated ideal weight by >20%. Pharmacokinetics of the high-dose chemotherapeutic agents were evaluated in each patient by collection and analysis of serial blood samples. Area under the concentration time curve (AUC) for cyclophosphamide and carmustine was highly variable (>10-fold inter-patient range) with coefficients of variation > 50%, in contrast to cisplatin exposures (2-fold range; coefficient of variation 12%). The dosing method for overweight patients resulted in significantly lower systemic exposure to cisplatin (P = 0.035). The parent cyclophosphamide clearance on the 1st day of administration was significantly higher in patients who experienced acute cardiac toxicity (n = 5; P = 0.011), whereas carmustine disposition was not found to be different in those developing pulmonary toxicity (n = 25; P = 0.96). Kaplan-Meier analysis (median follow-up of 5.9 years) demonstrated that patients with lower cyclophosphamide AUC (faster parent drug clearance to potentially cytotoxic compounds) survived longer (P = 0.031). Inter-individual differences in the pharmacokinetic disposition of high-dose chemotherapy may explain variability in both response and toxicity. Prospective strategies, which attempt to individualize AUC, should be evaluated in this setting.

Duke Scholars

Published In

Clin Cancer Res

ISSN

1078-0432

Publication Date

March 2002

Volume

8

Issue

3

Start / End Page

698 / 705

Location

United States

Related Subject Headings

  • Time Factors
  • Survival Rate
  • Oncology & Carcinogenesis
  • Lymphatic Metastasis
  • Humans
  • Female
  • Drug Administration Schedule
  • Dose-Response Relationship, Drug
  • Disease-Free Survival
  • Cyclophosphamide
 

Citation

APA
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MLA
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Petros, W. P., Broadwater, G., Berry, D., Jones, R. B., Vredenburgh, J. J., Gilbert, C. J., … Peters, W. P. (2002). Association of high-dose cyclophosphamide, cisplatin, and carmustine pharmacokinetics with survival, toxicity, and dosing weight in patients with primary breast cancer. Clin Cancer Res, 8(3), 698–705.
Petros, William P., Gloria Broadwater, Donald Berry, Roy B. Jones, James J. Vredenburgh, Colleen J. Gilbert, John P. Gibbs, O Michael Colvin, and William P. Peters. “Association of high-dose cyclophosphamide, cisplatin, and carmustine pharmacokinetics with survival, toxicity, and dosing weight in patients with primary breast cancer.Clin Cancer Res 8, no. 3 (March 2002): 698–705.
Petros WP, Broadwater G, Berry D, Jones RB, Vredenburgh JJ, Gilbert CJ, et al. Association of high-dose cyclophosphamide, cisplatin, and carmustine pharmacokinetics with survival, toxicity, and dosing weight in patients with primary breast cancer. Clin Cancer Res. 2002 Mar;8(3):698–705.
Petros WP, Broadwater G, Berry D, Jones RB, Vredenburgh JJ, Gilbert CJ, Gibbs JP, Colvin OM, Peters WP. Association of high-dose cyclophosphamide, cisplatin, and carmustine pharmacokinetics with survival, toxicity, and dosing weight in patients with primary breast cancer. Clin Cancer Res. 2002 Mar;8(3):698–705.

Published In

Clin Cancer Res

ISSN

1078-0432

Publication Date

March 2002

Volume

8

Issue

3

Start / End Page

698 / 705

Location

United States

Related Subject Headings

  • Time Factors
  • Survival Rate
  • Oncology & Carcinogenesis
  • Lymphatic Metastasis
  • Humans
  • Female
  • Drug Administration Schedule
  • Dose-Response Relationship, Drug
  • Disease-Free Survival
  • Cyclophosphamide