title: Feasibility and pharmacokinetic study of infusional dexrazoxane and dose-intensive doxorubicin administered concurrently over 96 h for the treatment of advanced malignancies.
abstract: OBJECTIVE
  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 microg/kg) and oral levofloxacin (500 mg) were administered daily until the white blood cell count reached 10,000 microl(-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 microl(-1)) was nine and of platelet count <20,000 microl(-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.
authors.affiliation: Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, 1500 E. Duarte Rd., Duarte, CA 91010, USA. wchow@coh.org
authors.forename: Warren A
authors.initials: WA
authors.lastname: Chow
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Synold
authors.forename: Merry L
authors.initials: ML
authors.lastname: Tetef
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Longmate
authors.forename: Paul
authors.initials: P
authors.lastname: Frankel
authors.forename: Joyce
authors.initials: J
authors.lastname: Lawrence
authors.forename: Zaid
authors.initials: Z
authors.lastname: Al-Khadimi
authors.forename: Lucille
authors.initials: L
authors.lastname: Leong
authors.forename: Dean
authors.initials: D
authors.lastname: Lim
authors.forename: Kim
authors.initials: K
authors.lastname: Margolin
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Morgan
authors.forename: James
authors.initials: J
authors.lastname: Raschko
authors.forename: Stephen
authors.initials: S
authors.lastname: Shibata
authors.forename: George
authors.initials: G
authors.lastname: Somlo
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Twardowski
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
mesh_terms: D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects*; D002317:Cardiovascular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006333:Heart Failure / Q000139:chemically induced* / Q000517:prevention & control*; D006801:Humans; D007262:Infusions, Intravenous; D064704:Levofloxacin; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D009503:Neutropenia / Q000139:chemically induced; D015242:Ofloxacin / Q000008:administration & dosage; D011929:Razoxane / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012509:Sarcoma / Q000188:drug therapy; D018805:Sepsis; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D002317:Cardiovascular Agents; D016179:Granulocyte Colony-Stimulating Factor; D011929:Razoxane; D064704:Levofloxacin; D004317:Doxorubicin; D015242:Ofloxacin