Cardiac safety of adjuvant pegylated liposomal doxorubicin with concurrent trastuzumab: a randomized phase II trial

The cardiac safety of trastuzumab concurrent with pegylated liposomal doxorubicin (PLD) in an adjuvant breast cancer treatment regimen is unknown. Women with resected node-positive or intermediate-risk node-negative HER2 overexpressing breast cancer and baseline left ventricular ejection fraction (LVEF) >= 55% were randomized (1 : 2) to doxorubicin 60 mg/m(2) (A) + cyclophosphamide 600 mg/m(2) (C) every 21 days (q21d) for four cycles or PLD 35 mg/m(2) + C q21d + trastuzumab 2 mg/kg weekly (H) for 12 weeks. Both groups then received paclitaxel (Taxol, T) 80 mg/m(2) with H for 12 weeks followed by H to complete 1 year. The primary end point was cardiac event rate or inability to administer 1 year of trastuzumab. Of 181 randomized patients, 179 underwent cardiac analysis. The incidence of cardiac toxicity or inability to administer trastuzumab due to cardiotoxicity was 18.6% [n = 11; 95% confidence interval (CI) 9.7% to 30.9%] with A + C -> T + H and 4.2% (n = 5; 95% CI 1.4% to 9.5%) with PLD + C + H -> T + H (P = 0.0036). All events, except one, were asymptomatic systolic dysfunction or mildly symptomatic heart failure. Mean absolute LVEF reduction at cycle 8 was greater with doxorubicin (5.6% versus 2.1%; P = 0.0014). PLD + C + H -> T + H is feasible and results in lower early cardiotoxicity rates compared with A + C -> T + H.