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 Citations (Scopus)

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

Fingerprint

Thiotepa
Autologous Transplantation
Bone Marrow Transplantation
Alkylating Agents
Neoplasms
Central Nervous System
Mechlorethamine
Stomatitis
Maximum Tolerated Dose
Dermatitis
Hematopoietic Stem Cells
Combination Drug Therapy
Lymphoma
Stem Cells
Clinical Trials
Pediatrics

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Wolff, S. N., Herzig, R. H., Fay, J. W., LeMaistre, C. F., Brown, R. A., Frei-Lahr, D., ... 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.

High-dose N,N′,N″-triethylenethiophosphoramide (thiotepa) with autologous bone marrow transplantation : Phase I studies. / Wolff, Steven N.; Herzig, Roger H.; Fay, Joseph W.; LeMaistre, C. Fred; Brown, Randy A.; Frei-Lahr, Debra; Stranjord, Sarah; Giannone, Leonard; Coccia, Peter; Weick, James L.; Rothman, Susan A.; Krupp, Kenneth R.; Lowder, James; Bolwell, Brian; Herzig, Geoffrey P.

In: Seminars in Oncology, Vol. 17, No. 1 SUPPL. 3, 02.1990, p. 2-6.

Research output: Contribution to journalArticle

Wolff, SN, Herzig, RH, Fay, JW, LeMaistre, CF, Brown, RA, Frei-Lahr, D, Stranjord, S, Giannone, L, Coccia, P, Weick, JL, Rothman, SA, Krupp, KR, Lowder, J, Bolwell, B & Herzig, GP 1990, 'High-dose N,N′,N″-triethylenethiophosphoramide (thiotepa) with autologous bone marrow transplantation: Phase I studies', Seminars in Oncology, vol. 17, no. 1 SUPPL. 3, pp. 2-6.
Wolff SN, Herzig RH, Fay JW, LeMaistre CF, Brown RA, Frei-Lahr D et al. High-dose N,N′,N″-triethylenethiophosphoramide (thiotepa) with autologous bone marrow transplantation: Phase I studies. Seminars in Oncology. 1990 Feb;17(1 SUPPL. 3):2-6.
Wolff, Steven N. ; Herzig, Roger H. ; Fay, Joseph W. ; LeMaistre, C. Fred ; Brown, Randy A. ; Frei-Lahr, Debra ; Stranjord, Sarah ; Giannone, Leonard ; Coccia, Peter ; Weick, James L. ; Rothman, Susan A. ; Krupp, Kenneth R. ; Lowder, James ; Bolwell, Brian ; Herzig, Geoffrey P. / High-dose N,N′,N″-triethylenethiophosphoramide (thiotepa) with autologous bone marrow transplantation : Phase I studies. In: Seminars in Oncology. 1990 ; Vol. 17, No. 1 SUPPL. 3. pp. 2-6.
@article{4efc9bed51304b2eb5a7301a4a9f0882,
title = "High-dose N,N′,N″-triethylenethiophosphoramide (thiotepa) with autologous bone marrow transplantation: Phase I studies",
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.",
author = "Wolff, {Steven N.} and Herzig, {Roger H.} and Fay, {Joseph W.} and LeMaistre, {C. Fred} and Brown, {Randy A.} and Debra Frei-Lahr and Sarah Stranjord and Leonard Giannone and Peter Coccia and Weick, {James L.} and Rothman, {Susan A.} and Krupp, {Kenneth R.} and James Lowder and Brian Bolwell and Herzig, {Geoffrey P.}",
year = "1990",
month = "2",
language = "English (US)",
volume = "17",
pages = "2--6",
journal = "Seminars in Oncology",
issn = "0093-7754",
publisher = "W.B. Saunders Ltd",
number = "1 SUPPL. 3",

}

TY - JOUR

T1 - High-dose N,N′,N″-triethylenethiophosphoramide (thiotepa) with autologous bone marrow transplantation

T2 - Phase I studies

AU - Wolff, Steven N.

AU - Herzig, Roger H.

AU - Fay, Joseph W.

AU - LeMaistre, C. Fred

AU - Brown, Randy A.

AU - Frei-Lahr, Debra

AU - Stranjord, Sarah

AU - Giannone, Leonard

AU - Coccia, Peter

AU - Weick, James L.

AU - Rothman, Susan A.

AU - Krupp, Kenneth R.

AU - Lowder, James

AU - Bolwell, Brian

AU - Herzig, Geoffrey P.

PY - 1990/2

Y1 - 1990/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0025017117&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0025017117&partnerID=8YFLogxK

M3 - Article

C2 - 2106165

AN - SCOPUS:0025017117

VL - 17

SP - 2

EP - 6

JO - Seminars in Oncology

JF - Seminars in Oncology

SN - 0093-7754

IS - 1 SUPPL. 3

ER -