Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer.
OBJECTIVE
To determine the cardioprotective effect of dexrazoxane (DZR) used in a doxorubicin-based combination therapy in advanced breast cancer.


METHODS
Between November 1988 and January 1991, 534 patients with advanced breast cancer were randomized to two multicenter, double-blind studies (088001 and 088006). Patients received fluorouracil, doxorubicin, and cyclophosphamide (FAC) with either DZR (DZR-to-doxorubicin ratio, 10:1) or placebo (PLA) every 3 weeks and were monitored with serial multiplegated acquisition (MUGA) scans.


RESULTS
The hazards ratio (HR) of PLA to DZR for a cardiac event, which was predefined ejection fraction changes or congestive heart failure (CHF), was 2.63 (95% confidence interval [CI], 1.61 to 4.27; P < .001) for 088001 and 2.00 (95% CI, 1.01 to 3.96; P = .038) for 088006. The objective response rates for 088001 were 46.8% for DZR and 60.5% for PLA, a difference of 14% (95% CI, -25% to -2%; P = .019), and for 088006 were 53.7% for DZR and 49.3% for PLA, a difference of 4% (95% CI, -13% to 22%; P = .63). Time to progression and survival were not significantly different between treatment arms in either study. Toxicities on the DZR arms included lower granulocyte and platelet counts at nadir (P = .009 and P = .004, respectively) and more pain on injection (P = .001), with no difference in the rates of fever, infection, or hemorrhage.


CONCLUSIONS
DZR had a significant cardioprotective effect as measured by noninvasive testing and clinical CHF. One of the two studies (088001) showed a lower response rate with DZR, but time to progression and survival were not significantly different. DZR is the first agent shown to reduce cardiotoxicity from doxorubicin.
Swain
S M
SM
Comprehensive Breast Center, Washington, DC 20015-2034, USA. swainsm@aol.com
Whaley
F S
FS
Gerber
M C
MC
Weisberg
S
S
York
M
M
Spicer
D
D
Jones
S E
SE
Wadler
S
S
Desai
A
A
Vogel
C
C
Speyer
J
J
Mittelman
A
A
Reddy
S
S
Pendergrass
K
K
Velez-Garcia
E
E
Ewer
M S
MS
Bianchine
J R
JR
Gams
R A
RA
D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006333:Heart Failure / Q000139:chemically induced / Q000517:prevention & control*; D006801:Humans; D011446:Prospective Studies; D011929:Razoxane / Q000627:therapeutic use*; D012307:Risk Factors; D016019:Survival Analysis; D016896:Treatment Outcome
D000903:Antibiotics, Antineoplastic; D002317:Cardiovascular Agents; D011929:Razoxane; D004317:Doxorubicin; D003520:Cyclophosphamide; D005472:Fluorouracil