High-dose N,N′,N″-triethylenethiophosphoramide (thiotepa) with autologous bone marrow transplantation: Phase I studies

Steven N. Wolff, Roger H. Herzig, Joseph W. Fay, C. Fred LeMaistre, Randy A. Brown, Debra Frei-Lahr, Sarah Stranjord, Leonard Giannone, Peter Coccia, James L. Weick, Susan A. Rothman, Kenneth R. Krupp, James Lowder, Brian Bolwell, Geoffrey P. Herzig

Research output: Contribution to journalArticle

88 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2-6
Number of pages5
JournalSeminars in Oncology
Volume17
Issue number1 SUPPL. 3
StatePublished - Feb 1990
Externally publishedYes

ASJC Scopus subject areas

  • Hematology
  • Oncology

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    Wolff, S. N., Herzig, R. H., Fay, J. W., LeMaistre, C. F., Brown, R. A., Frei-Lahr, D., Stranjord, S., Giannone, L., Coccia, P., Weick, J. L., Rothman, S. A., Krupp, K. R., Lowder, J., Bolwell, B., & Herzig, G. P. (1990). High-dose N,N′,N″-triethylenethiophosphoramide (thiotepa) with autologous bone marrow transplantation: Phase I studies. Seminars in Oncology, 17(1 SUPPL. 3), 2-6.