title: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer.
abstract: 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.
authors.affiliation: Comprehensive Breast Center, Washington, DC 20015-2034, USA. swainsm@aol.com
authors.forename: S M
authors.initials: SM
authors.lastname: Swain
authors.forename: F S
authors.initials: FS
authors.lastname: Whaley
authors.forename: M C
authors.initials: MC
authors.lastname: Gerber
authors.forename: S
authors.initials: S
authors.lastname: Weisberg
authors.forename: M
authors.initials: M
authors.lastname: York
authors.forename: D
authors.initials: D
authors.lastname: Spicer
authors.forename: S E
authors.initials: SE
authors.lastname: Jones
authors.forename: S
authors.initials: S
authors.lastname: Wadler
authors.forename: A
authors.initials: A
authors.lastname: Desai
authors.forename: C
authors.initials: C
authors.lastname: Vogel
authors.forename: J
authors.initials: J
authors.lastname: Speyer
authors.forename: A
authors.initials: A
authors.lastname: Mittelman
authors.forename: S
authors.initials: S
authors.lastname: Reddy
authors.forename: K
authors.initials: K
authors.lastname: Pendergrass
authors.forename: E
authors.initials: E
authors.lastname: Velez-Garcia
authors.forename: M S
authors.initials: MS
authors.lastname: Ewer
authors.forename: J R
authors.initials: JR
authors.lastname: Bianchine
authors.forename: R A
authors.initials: RA
authors.lastname: Gams
mesh_terms: 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
chemical_list: D000903:Antibiotics, Antineoplastic; D002317:Cardiovascular Agents; D011929:Razoxane; D004317:Doxorubicin; D003520:Cyclophosphamide; D005472:Fluorouracil