High-dose N,N',N"-triethylenethiophosphoramide (thiotepa) with autologous bone marrow transplantation: phase I studies.
N,N',N''-triethylenethiophosphoramide (thiotepa) is a polyfunctional alkylating agent similar in structure to nitrogen mustard. Thiotepa (synthesized by American Cyanamid Company, Wayne, NJ) underwent clinical trials in the 1960s that showed that it was active against a wide variety of tumors. At a standard dose level (10 to 30 mg/m2), the dose-limiting toxicity is myelosuppression; other toxicities are infrequent. Therefore, high-dose phase I evaluation was encouraged by these observations. Approximately 217 patients have been treated with single-agent high-dose thiotepa administered intravenously daily over 2 hours for 3 days followed by hematopoietic stem cell rescue to prevent prolonged myelotoxicity. The total doses administered ranged from 135 to 1,575 mg/m2. As anticipated, myelotoxicity was substantial, with 180 mg/m2 being the highest dose not requiring stem cell rescue to ensure hematopoietic recovery. Extramedullary toxicities consisted of stomatitis, dermatitis, hepatoxicity, and central nervous system (CNS) toxicity. CNS toxicity was dose-limiting; other toxicities were problematic, ie, dose-dependent but not truly dose-limiting. The maximal tolerated dose of thiotepa is 900 to 1,125 mg/m2, with the lower dose being the maximal dose for evaluation in combination chemotherapy. In high-dose phase I evaluation, the overall response rate was approximately 50% with responses seen in a wide variety of solid tumors, lymphomas, and pediatric tumors. High-dose thiotepa appears to be an alkylating agent with broad-spectrum antitumor efficacy, which should add to the cytoreductive regimens for both solid and hematopoietic tumors.
Wolff
S N
SN
Department of Medicine, Vanderbilt University, Nashville, TN 37232-2535.
Herzig
R H
RH
Fay
J W
JW
LeMaistre
C F
CF
Brown
R A
RA
Frei-Lahr
D
D
Stranjord
S
S
Giannone
L
L
Coccia
P
P
Weick
J L
JL
D016026:Bone Marrow Transplantation; D003131:Combined Modality Therapy; D004341:Drug Evaluation; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D013852:Thiotepa / Q000008:administration & dosage* / Q000009:adverse effects
D013852:Thiotepa