Skip to main content
SpringerLink
Log in

Dose-toxicity relationship of carboplatin in combination with cyclophosphamide in ovarian cancer patients

  • Original Articles
  • Carboplatin, Cyclophosphamide, Hematologic Toxicity, Pharmacokinetics
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Summary

A study was undertaken to examine the relationships between carboplatin's pharmacokinetic parameters and the myelotoxicity associated with its administration in combination with cyclophosphamide. An additional aim of the study was to test the applicability of the method proposed by Calvert et al. for calculation of the carboplatin dose to be used in the combination regimen. A total of 24 previously untreated ovarian cancer patients were given a combination of 250–500 mg/m2 carboplatin and 500 mg/m2 cyclophosphamide every 4 weeks for 4 months. The pharmacokinetics of carboplatin and the associated myelotoxicity were investigated in 64 courses. The results showed a significant correlation (r=0.89) between the AUC calculated for carboplatin and that predicted according to Calvert's formula [carboplatin dose in milligrams=AUC (glomerular filtration rate +25)]. We conclude that the model is a useful guide in the calculation of the carboplatin dose to be given in combination with cyclophosphamide, and it enables a more precise prediction of the carboplatin exposure than does the conventional calculation, which is based on milligrams of drug per square meter of body surface. The AUC for carboplatin was a reliable predictor of the myelotoxicity as measured by the relative decrease in thrombocyte count. However, the relationship between AUC and myelotoxicity changed during the treatment because of increasing bone marrow toxicity. Despite this finding, dose calculation based on carboplatin's AUC appears to provide an improvement in the clinical use of the drug, and the method also seems to be fully applicable in combination chemotherapy with cyclophosphamide.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Alberts D, Green S, Hannigan E, O'Toole R, Mason-Liddil N, Surwit E, Stock-Novack D, Goldberg R, Malviya V, Nahhas W (1989) Improved efficacy of carboplatin (CarboP)/cyclophosphamide (CPA) vs cisplatin (CisP)/CPA: preliminary report of a phase III, randomized trial in stages III–IV, suboptimal ovarian cancer (OV CA). Proc Am Soc Clin Oncol 8: 588

    Google Scholar 

  2. Belani CP, Egorin MJ (1990) Reply to letter. J Clin Oncol 8: 1284–1285

    Google Scholar 

  3. Belani CP, Egorin MJ, Abrams JS, Hiponia D, Eisenberger M, Aisner J, Van Echo DA (1989) A novel pharmacodynamically based approach to dose optimization of carboplatin when used in combination with etoposide. J Clin Oncol 7: 1896–1902

    Google Scholar 

  4. Brøchner-Mortensen J (1972) A simple method for determination of glomerular filtration rate. Scand J Clin Lab Invest 30: 271

    Google Scholar 

  5. Calvert AH, Harland SJ, Newell DR, Siddik ZH, Jones AC, McElwain TJ, Raju S, Wiltshaw E, Smith IE, Baker JM, Peckham MJ, Harrap KR (1982) Early clinical studies withcis-diammine-1,1-cyclobutane dicarboxylate platinum (II). Cancer Chemother Pharmacol 9: 140

    Google Scholar 

  6. Calvert AH, Newell DR, Gumbrell LA, O'Reilly S, Burnell M, Boxall FE, Siddik ZH, Judson IR, Gore ME, Wiltshaw E (1989) Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 7: 1748

    Google Scholar 

  7. Colvin M (1981) Cyclophosphamide and analogues. In: Crooke ST, Prestayko AW (eds) Cancer and chemotherapy, vol III. Academic Press, New York, p 25

    Google Scholar 

  8. Duncan GF, Faulkner HC, Farmen RH, Pittman KA (1988) Liquid chromatographic procedure for the quantitative analysis of carboplatin in Beagle dog plasma ultrafiltrate. J Pharm Sci 77: 273

    Google Scholar 

  9. Egorin MJ, Forrest A (1987) Reply to letter. Cancer Res 47: 3606

    Google Scholar 

  10. Egorin MJ, Van Echo DA, Tipping SJ, Olman EA, Whitacre MY, Thomson BW, Aisner J (1984) Pharmacokinetics and dosage reduction ofcis-diammine-(1,1-cyclobutanedicarboxylato) platinum in patients with impaired renal function. Cancer Res 44: 5432

    Google Scholar 

  11. Egorin MJ, Van Echo DA, Olman EA, Whitacre MY, Forrest A, Aisner J (1985) Prospective validation of a pharmacologically based dosing scheme for thecis-diamminedichloroplatinum(II) analogue diamminecyclobutanedicarboxylato-platinum. Cancer Res 45: 6502

    Google Scholar 

  12. Egorin MJ, Sigman LM, Van Echo DA, Forrest A, Whitacre MY, Aisner J (1987) Phase I clinical and pharmacokinetic study of hexamethylene bisacetamide (NSC 95 580) administered as a five-day continuous infusion. Cancer Res 47: 617

    Google Scholar 

  13. Elferink F, Vijgh WJF van der, Klein I, Vermorken JB, Gall HE, Pinedo HM (1987) Pharmacokinetics of carboplatin after i. v. administration. Cancer Treat Rep 71: 1231

    Google Scholar 

  14. Fish RG, Shelley MD, Griffiths H, Adams M (1987). Letter to the editor. Cancer Res 47: 3606

    Google Scholar 

  15. Freedman LS, Workman P (1988) When can the infusion period be safely ignored in the estimation of pharmacokinetic parameters of drugs in humans? Cancer Chemother Pharmacol 22: 95

    Google Scholar 

  16. Gaver RC, Colombo N, Green MD, George AM, Deeb G, Morris AD, Canetta RM, Speyer JL, Farmen RH, Muggia FM (1988) The disposition of carboplatin in ovarian cancer patients. Cancer Chemother Pharmacol 22: 263

    Google Scholar 

  17. Harland SJ, Newell DR, Siddik ZH, Chadwick R, Calvert AH, Harrap KR (1984) Pharmacokinetics ofcis-diammine-1,1-cyclobutane dicarboxylate platinum(II) in patients with normal and impaired renal function. Cancer Res 44: 1693

    Google Scholar 

  18. Muggia FM (1989) Overview of carboplatin: replacing, complementing, and extending the therapeutic horizons of cisplatin. Semin Oncol 16: 7

    Google Scholar 

  19. Pater J (1990) Cyclophosphamide (C)/cisplatin (CDDP) versus cyclophosphamide/carboplatin (CBDCA) in macroscopic residual ovarian cancer. Initial results of a National Cancer Institute of Canada (NCIC) Clinical Trials Group trial. Proc Am Soc Clin Oncol 9: 602

    Google Scholar 

  20. Pinkerton CR, Hardy JR (1990) Correspondence: carboplatin dose optimization. J Clin Oncol 8: 1283–1284

    Google Scholar 

  21. Taguchi J, Saijo N, Miura K, Shinkai T, Eguchi K, Sasaki Y, Tamura T, Sakurai M, Minato K, Fujiwara Y, Nakano H, Nakagawa K, Hong W-S (1987) Prediction of hematologic toxicity of carboplatin by creatinine clearance rate. Jpn J Cancer Res 78: 977

    Google Scholar 

  22. Teeling M, Carney DN (1987) Carboplatin and cyclophosphamide combination chemotherapy in advanced ovarian cancer. Proc Am Soc Clin Oncol 6: 458

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Pharmacology, University of Aarhus, Denmark

    Preben Jakobsen

  2. The Danish Cancer Society, Section of Clinical Research, Department of Oncology, Aarhus University Hospital, Nørrebrogade 44, DK-8000, Aarhus C, Denmark

    Bente T. Sørensen, Annette Strömgren & Anders Jakobsen

Authors
  1. Bente T. Sørensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Annette Strömgren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Preben Jakobsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anders Jakobsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Supported by grants from the Lundbeck Foundation and the Danish Cancer Society

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sørensen, B.T., Strömgren, A., Jakobsen, P. et al. Dose-toxicity relationship of carboplatin in combination with cyclophosphamide in ovarian cancer patients. Cancer Chemother. Pharmacol. 28, 397–401 (1991). https://doi.org/10.1007/BF00685696

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00685696

Keywords

Search

Navigation