Summary
Combinations of alkylating agents in intensive doses with autologous hematopoietic cell support (AHCS) are commonly used to treat advanced, solid tumors. Relatively little is known about the pharmacokinetic or pharmacodynamic aspects of their use. The cyclophosphamide, cisplatin, and BCNU (CPA/cDDP/BCNU) regimen is often used in patients with breast cancer. In these individuals, the blood levels of BCNU vary by more than tenfold. In rats given BCNU, the blood level variability is associated with cisplatin pretreatment, and mean levels are much higher than those that occur when cisplatin pretreatment is omitted. These observations suggest that a major elimination pathway for BCNU is metabolic and is subject to cisplatin disruption. Between 30–50% of patients receiving the CPA/cDDP/BCNU regimen experience a steroid-responsive pulmonary injury that can be fatal if untreated. Blood levels of BCNU are positively correlated with the risk of pulmonary injury in these patients. Others have demonstrated that blood levels of CPA can be inversely correlated with the likelihood of cardiac toxicity and 2-year, relapse-free survival in patients with breast cancer. Emerging data suggest that circulating drug levels, rather than the calculated dose, best explain the variability of outcome in patients treated with combination alkylating agents and AHCS.
Similar content being viewed by others
References
Peters WP, Eder JP, Henner WD, Bast RC Jr, Schnipper L, Frei E III: Novel toxicities associated with high-dose combination alkylating agents and autologous bone marrow support.In: Dicke C, Spitzer G, Zander A (eds) Autologous Bone Marrow Transplantation: Proceedings of the First International Symposium. Houston, University of Texas MD Anderson Hospital and Tumor Institute, 1985, pp 231-236
Jones RB, Matthes S: Pharmacokinetics.In: Armitage JO, Antman KH (eds) High-Dose Cancer Therapy: Pharmacology, Hematopoietins, and Stem Cells. Williams and Wilkins, Baltimore, 1992, pp 43–60
Jones RB, Shpall EJ, Ross M, Coniglio D, Affronti ML, Peters WP: High-dose carboplatin, cyclophosphamide, and BCNU with autologous bone marrow support: excessive hepatic toxicity. Cancer Chemother Pharmacol 26:155–156, 1990
Ayash LS, Wright JE, Tretyakov O, Gonin R, Elisa A, Wheeler C, Eder JP, Rowosky A, Antman K, Frei E: Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and antitumor response. J Clin Oncol 10:995–1000, 1992
Jones RB, Matthes SM, Shpall EJ, Stemmer S, Bearman SI: Acute lung injury following high-dose cyclophosphamide, cisplatin, and BCNU: pharmacodynamic evaluation of BCNU. J Natl Cancer Inst (in press)
Grochow LB, Jones RJ, Brundrett RB, Braine WG, Chen T-L, Saral R, Santos GW, Colvin DM: Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation. Cancer Chemother Pharmacol 25:55–61, 1989
Grochow LB, Piantidosi S, Santos G, Jones R: Busulfan dose adjustment decreases the risk of hepatic veno-occlusive disease in patients undergoing bone marrow transplantation [Abstract]. Proc Am Assoc Cancer Res 33:200, 1992
Peters WP, Ross M, Vredenburgh J, Meisenberg B, Rosner G, Marks L, Mathias B, Henderson C, Hurd D, Budman D, Norton L, Weiss RB: High-dose alkylating agents and autologous bone marrow support (ABMS) for stage II/III breast cancer involving 10 or more axillary lymph nodes (Duke and CALGB 8782) [Abstract]. Proc Am Soc Clin Oncol 11:58, 1992
Aronin PA, Mahaley MS, Rudnick SA, Dudkal L, Donohue JF, Selker RG, Moore P: Prediction of BCNU pulmonary toxicity in patients with malignant gliomas: an assessment of risk factors. N Engl J Med 303:183–188, 1980
Author information
Authors and Affiliations
Additional information
Held in conjunction with the 15th Annual San Antonio Breast Cancer Symposium, December 1992, and supported by an educational grant from Lederle Oncology; editing by The Medicine Group USA, Inc.
Rights and permissions
About this article
Cite this article
Jones, R.B., Matthes, S., Dufton, C. et al. Pharmacokinetic/pharmacodynamic interactions of intensive cyclophosphamide, cisplatin, and BCNU in patients with breast cancer. Breast Cancer Res Tr 26, S11–S17 (1993). https://doi.org/10.1007/BF00668355
Issue Date:
DOI: https://doi.org/10.1007/BF00668355