Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer.
OBJECTIVE
To determine whether Myocet (liposome-encapsulated doxorubicin; The Liposome Company, Elan Corporation, Princeton, NJ) in combination with cyclophosphamide significantly reduces doxorubicin cardiotoxicity while providing comparable antitumor efficacy in first-line treatment of metastatic breast cancer (MBC).


METHODS
Two hundred ninety-seven patients with MBC and no prior chemotherapy for metastatic disease were randomized to receive either 60 mg/m(2) of Myocet (M) or conventional doxorubicin (A), in combination with 600 mg/m(2) of cyclophosphamide (C), every 3 weeks until disease progression or unacceptable toxicity. Cardiotoxicity was defined by reductions in left-ventricular ejection fraction, assessed by serial multigated radionuclide angiography scans, or congestive heart failure (CHF). Antitumor efficacy was assessed by objective tumor response rates (World Health Organization criteria), time to progression, and survival.


RESULTS
Six percent of MC patients versus 21% (including five cases of CHF) of AC patients developed cardiotoxicity (P =.0002). Median cumulative doxorubicin dose at onset was more than 2,220 mg/m(2) for MC versus 480 mg/m(2) for AC (P =.0001, hazard ratio, 5.04). MC patients also experienced less grade 4 neutropenia. Antitumor efficacy of MC versus AC was comparable: objective response rates, 43% versus 43%; median time to progression, 5.1% versus 5.5 months; median time to treatment failure, 4.6 versus 4.4 months; and median survival, 19 versus 16 months.


CONCLUSIONS
Myocet improves the therapeutic index of doxorubicin by significantly reducing cardiotoxicity and grade 4 neutropenia and provides comparable antitumor efficacy, when used in combination with cyclophosphamide as first-line therapy for MBC.
Jewish General Hospital, McGill University, Montreal, Quebec, Canada. gbatist@onc.jgh.mcgill.ca
G
G
Batist
G
G
Ramakrishnan
C S
CS
Rao
A
A
Chandrasekharan
J
J
Gutheil
T
T
Guthrie
P
P
Shah
A
A
Khojasteh
M K
MK
Nair
K
K
Hoelzer
K
K
Tkaczuk
Y C
YC
Park
L W
LW
Lee
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D006333:Heart Failure / Q000139:chemically induced / Q000517:prevention & control*; D006801:Humans; D008081:Liposomes; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control; D016019:Survival Analysis; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000517:prevention & control*
D008081:Liposomes; D004317:Doxorubicin; D003520:Cyclophosphamide