Feasibility and pharmacokinetic study of infusional dexrazoxane and dose-intensive doxorubicin administered concurrently over 96 h for the treatment of advanced malignancies

Warren A. Chow, Timothy W. Synold, Merry L. Tetef, Jeffrey Longmate, Paul Frankel, Joyce Lawrence, Zaid Al-Khadimi, Lucille Leong, Dean Lim, Kim Margolin, Robert J. Morgan, James Raschko, Stephen Shibata, George Somlo, Przemyslaw Twardowski, Yun Yen, James H. Doroshow

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Purpose: Dexrazoxane administration prior to short infusion doxorubicin prevents anthracycline-related heart damage. Since delivery of doxorubicin by 96-h continuous intravenous infusion also reduces cardiac injury, we studied delivering dexrazoxane and doxorubicin concomitantly by prolonged intravenous infusion. Methods: Patients with advanced malignancies received tandem cycles of concurrent 96-h infusions of dexrazoxane 500 mg/m2 and doxorubicin 165 mg/m2, and 24 h after completion of chemotherapy, granulocyte-colony stimulating factor (5 μg/kg) and oral levofloxacin (500 mg) were administered daily until the white blood cell count reached 10,000 μl-1. Plasma samples were analyzed for dexrazoxane and doxorubicin concentrations. Results: Ten patients were enrolled; eight patients had measurable disease. Two partial responses were observed in patients with soft-tissue sarcoma. The median number of days of granulocytopenia (< 500 μl-1) was nine and of platelet count < 20,000 μl -1 was seven. Six patients received a single cycle because of progression (one), stable disease (four), or reversible, asymptomatic 10% decrease in cardiac ejection fraction (two). Principal grade 3/4 toxicities included hypotension (two), anorexia (four), stomatitis (four), typhlitis (two), and febrile neutropenia (seven), with documented infection (three). One death from neutropenic sepsis occurred. Dexrazoxane levels ranged from 1270 to 2800 nM, and doxorubicin levels ranged from 59.1 to 106.9 nM. Conclusions: These results suggest that tandem cycles of concurrent 96-h infusions of dexrazoxane and high-dose doxorubicin can be administered with minimal cardiac toxicity, and have activity in patients with recurrent sarcomas. However, significant non-cardiac toxicities indicate that the cardiac sparing potential of this approach would be maximized at lower dose levels of doxorubicin.

Original languageEnglish
Pages (from-to)241-248
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume54
Issue number3
DOIs
Publication statusPublished - Jan 1 2004
Externally publishedYes

Fingerprint

Dexrazoxane
Pharmacokinetics
Feasibility Studies
Doxorubicin
Neoplasms
Toxicity
Therapeutics
Intravenous Infusions
Sarcoma
Typhlitis
Febrile Neutropenia
Stomatitis
Levofloxacin
Agranulocytosis
Chemotherapy
Anthracyclines
Anorexia
Granulocyte Colony-Stimulating Factor
Platelets
Platelet Count

Keywords

  • Anthracycline
  • Cardiotoxicity
  • Dexrazoxane
  • Doxorubicin
  • Pharmacokinetcs

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Feasibility and pharmacokinetic study of infusional dexrazoxane and dose-intensive doxorubicin administered concurrently over 96 h for the treatment of advanced malignancies. / Chow, Warren A.; Synold, Timothy W.; Tetef, Merry L.; Longmate, Jeffrey; Frankel, Paul; Lawrence, Joyce; Al-Khadimi, Zaid; Leong, Lucille; Lim, Dean; Margolin, Kim; Morgan, Robert J.; Raschko, James; Shibata, Stephen; Somlo, George; Twardowski, Przemyslaw; Yen, Yun; Doroshow, James H.

In: Cancer Chemotherapy and Pharmacology, Vol. 54, No. 3, 01.01.2004, p. 241-248.

Research output: Contribution to journalArticle

Chow, WA, Synold, TW, Tetef, ML, Longmate, J, Frankel, P, Lawrence, J, Al-Khadimi, Z, Leong, L, Lim, D, Margolin, K, Morgan, RJ, Raschko, J, Shibata, S, Somlo, G, Twardowski, P, Yen, Y & Doroshow, JH 2004, 'Feasibility and pharmacokinetic study of infusional dexrazoxane and dose-intensive doxorubicin administered concurrently over 96 h for the treatment of advanced malignancies', Cancer Chemotherapy and Pharmacology, vol. 54, no. 3, pp. 241-248. https://doi.org/10.1007/s00280-004-0803-4
Chow, Warren A. ; Synold, Timothy W. ; Tetef, Merry L. ; Longmate, Jeffrey ; Frankel, Paul ; Lawrence, Joyce ; Al-Khadimi, Zaid ; Leong, Lucille ; Lim, Dean ; Margolin, Kim ; Morgan, Robert J. ; Raschko, James ; Shibata, Stephen ; Somlo, George ; Twardowski, Przemyslaw ; Yen, Yun ; Doroshow, James H. / Feasibility and pharmacokinetic study of infusional dexrazoxane and dose-intensive doxorubicin administered concurrently over 96 h for the treatment of advanced malignancies. In: Cancer Chemotherapy and Pharmacology. 2004 ; Vol. 54, No. 3. pp. 241-248.
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T1 - Feasibility and pharmacokinetic study of infusional dexrazoxane and dose-intensive doxorubicin administered concurrently over 96 h for the treatment of advanced malignancies

AU - Chow, Warren A.

AU - Synold, Timothy W.

AU - Tetef, Merry L.

AU - Longmate, Jeffrey

AU - Frankel, Paul

AU - Lawrence, Joyce

AU - Al-Khadimi, Zaid

AU - Leong, Lucille

AU - Lim, Dean

AU - Margolin, Kim

AU - Morgan, Robert J.

AU - Raschko, James

AU - Shibata, Stephen

AU - Somlo, George

AU - Twardowski, Przemyslaw

AU - Yen, Yun

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N2 - Purpose: Dexrazoxane administration prior to short infusion doxorubicin prevents anthracycline-related heart damage. Since delivery of doxorubicin by 96-h continuous intravenous infusion also reduces cardiac injury, we studied delivering dexrazoxane and doxorubicin concomitantly by prolonged intravenous infusion. Methods: Patients with advanced malignancies received tandem cycles of concurrent 96-h infusions of dexrazoxane 500 mg/m2 and doxorubicin 165 mg/m2, and 24 h after completion of chemotherapy, granulocyte-colony stimulating factor (5 μg/kg) and oral levofloxacin (500 mg) were administered daily until the white blood cell count reached 10,000 μl-1. Plasma samples were analyzed for dexrazoxane and doxorubicin concentrations. Results: Ten patients were enrolled; eight patients had measurable disease. Two partial responses were observed in patients with soft-tissue sarcoma. The median number of days of granulocytopenia (< 500 μl-1) was nine and of platelet count < 20,000 μl -1 was seven. Six patients received a single cycle because of progression (one), stable disease (four), or reversible, asymptomatic 10% decrease in cardiac ejection fraction (two). Principal grade 3/4 toxicities included hypotension (two), anorexia (four), stomatitis (four), typhlitis (two), and febrile neutropenia (seven), with documented infection (three). One death from neutropenic sepsis occurred. Dexrazoxane levels ranged from 1270 to 2800 nM, and doxorubicin levels ranged from 59.1 to 106.9 nM. Conclusions: These results suggest that tandem cycles of concurrent 96-h infusions of dexrazoxane and high-dose doxorubicin can be administered with minimal cardiac toxicity, and have activity in patients with recurrent sarcomas. However, significant non-cardiac toxicities indicate that the cardiac sparing potential of this approach would be maximized at lower dose levels of doxorubicin.

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