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Multiple Courses of Cyclophosphamide, Thiotepa,
and Carboplatin: Managing Toxicity
by Dose Reduction and Pharmacokinetic Monitoring
Sjoerd Rodenhuis, Alwin D.R. Huitema, Joke W. Baars,
Anneke Westermann, Marjo M.J. Holtkamp,
Jan H. Schornagel, Jos H. Beijnen
Division of Medical Oncology, The Netherlands Cancer Institute
(S.R., J.W.B., A.W., M.M.J.H., J.H.S.), and Department of Pharmacy and
Pharmacology (A.D.R.H., J.H.B.), The Netherlands Cancer Institute and
Slotervaart Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
ABSTRACT
Multiple courses of high-dose alkylating chemotherapy have been made
possible by the technique of peripheral blood progenitor cell transplantation, but
end-organ toxicities such as hemorrhagic cystitis, veno-occlusive disease of the
liver, or hemolytic uremic syndrome are now dose-limiting. Because of this, three
subsequent administrations of CTC—cyclophosphamide (6 g/m 2
), thiotepa (480
mg/m 2
), and carboplatin (1600 mg/m 2
)—have been shown to be not feasible. To
overcome these problems, we have developed a regimen called "tiny CTC" (tCTC)
that contains two-thirds of the CTC dose combination. Three subsequent courses
of tCTC, administered every 4-5 weeks, are well tolerated and, in contrast to CTC,
allow discharge of the patients after stem cell transplantation. Similar end-organ
toxicities as after the full-dose CTC regimen were observed in the first 20 patients
to undergo three subsequent courses, but were not life-threatening and were readily
reversible. To identify patients at risk for developing severe organ toxicity, we have
developed and validated methods for determining plasma concentration vs. time
curves of cyclophosphamide, 2-dechloroethyl cyclophosphamide, thiotepa, and
carboplatin after tCTC. The pharmacokinetic/pharmacodynamic studies are in
progress. These data should serve to individualize doses of alkylating agents so as
to improve both the safety and the efficacy of this regimen.
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