Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer.
OBJECTIVE
Dexrazoxane was found effective in reducing doxorubicin cardiotoxicity when given at a dose ratio (dexrazoxane: doxorubicin) of 20:1. Preclinical studies indicated that dexrazoxane at a dose ratio of 10 to 15:1 also protected against epirubicin-induced cardiotoxicity. The main objective of this study was to investigate the efficacy of dexrazoxane, given at a dose ratio of 10:1 against epirubicin cardiotoxicity.


METHODS
One hundred sixty-two advanced breast cancer patients were randomized to receive epirubicin-based chemotherapy with or without dexrazoxane. Patients who had previously received adjuvant chemotherapy that contained anthracyclines were treated with cyclophosphamide 600 mg/m2 intravenously (IV), epirubicin 60 mg/m2 IV, and fluorouracil 600 mg/m2 IV, on day 1 every 3 weeks. The other patients were treated with epirubicin 120 mg/m2 IV on day 1 every 3 weeks. Cardiac toxicity was defined as clinical signs of congestive heart failure, a decrease in resting left ventricular ejection fraction (LVEF) to < or = 45%, or a decrease from baseline resting LVEF of > or = 20 EF units.


RESULTS
One hundred sixty patients were evaluated. Cardiotoxicity was recorded in 18 of 78 patients (23.1%) in the control arm and in six of 82 (7.3%) in the dexrazoxone arm. The cumulative probability of developing cardiotoxicity was significantly lower in dexrazoxane-treated patients than in control patients (P = .006; odds ratio, 0.29; 95% confidence limit [CL], 0.09 to 0.78). Noncardiac toxicity, objective response, progression-free survival, and overall survival were similar in both arms.


CONCLUSIONS
Dexrazoxane given at a dexrazoxane:epirubicin dose ratio of 10:1 protects against epirubicin-induced cardiotoxicity and does not affect the clinical activity and the noncardiac toxicity of epirubicin. The clinical use of dexrazoxane should be recommended in patients whose risk of developing cardiotoxicity could hamper the eventual use and possible benefit of epirubicin.
Venturini
M
M
Divisione di Oncologia Medica 1, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy. marco.venturini@schering-pl.it
Michelotti
A
A
Del Mastro
L
L
Gallo
L
L
Carnino
F
F
Garrone
O
O
Tibaldi
C
C
Molea
N
N
Bellina
R C
RC
Pronzato
P
P
Cyrus
P
P
Vinke
J
J
Testore
F
F
Guelfi
M
M
Lionetto
R
R
Bruzzi
P
P
Conte
P F
PF
Rosso
R
R
D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D006801:Humans; D008875:Middle Aged; D011929:Razoxane / Q000627:therapeutic use*
D000903:Antibiotics, Antineoplastic; D002317:Cardiovascular Agents; D015251:Epirubicin; D011929:Razoxane