Feasibility and pharmacokinetic study of infusional dexrazoxane and dose-intensive doxorubicin administered concurrently over 96 h for the treatment of advanced malignancies.
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.
Chow
Warren A
WA
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, 1500 E. Duarte Rd., Duarte, CA 91010, USA. wchow@coh.org
Synold
Timothy W
TW
Tetef
Merry L
ML
Longmate
Jeffrey
J
Frankel
Paul
P
Lawrence
Joyce
J
Al-Khadimi
Zaid
Z
Leong
Lucille
L
Lim
Dean
D
Margolin
Kim
K
Morgan
Robert J
RJ
Raschko
James
J
Shibata
Stephen
S
Somlo
George
G
Twardowski
Przemyslaw
P
Yen
Yun
Y
Doroshow
James H
JH
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
D000903:Antibiotics, Antineoplastic; D002317:Cardiovascular Agents; D016179:Granulocyte Colony-Stimulating Factor; D011929:Razoxane; D064704:Levofloxacin; D004317:Doxorubicin; D015242:Ofloxacin