Phase I Study of Nonpegylated Liposomal Doxorubicin plus Trastuzumab in Patients with HER2-Positive Breast Cancer (original) (raw)

Breast cancer is the most common malignancy among women, with about one million cases diagnosed each year worldwide. In the United States, breast cancer is the second leading cause of cancerrelated death in women after lung cancer and the leading cause of cancer-related death in women aged 45−55 years. The human epidermal growth factor receptor 2 (HER2) gene is amplified in 20%−25% of human breast cancers, and overexpression of HER2 is associated with shortened disease-free and overall survival. For 3 decades, doxorubicin has been the most active chemotherapeutic agent in the treatment of advanced breast cancer. Its clinical use is limited by cardiomyopathy and the risk of congestive heart failure (CHF) increasing sharply with lifetime cumulative doxorubicin doses above 450 mg/m 2 . Nonpegylated liposomal doxorubicin (NLD) was designed to reduce the cardiac toxicity of doxorubicin while preserving its antitumor efficacy. This nonpegylated, liposome-encapsulated formulation has a pharmacokinetic profile that is distinct from conventional doxorubicin, resulting in a higher area under the curve, smaller volume of distribution and pattern of biodistribution (substantially reduced uptake into the heart and gastroin-