Phase II Trial of Neoadjuvant Pegylated Liposomal Doxorubicin with Paclitaxel and Trastuzumab in Patients with Operable Her2-Positive Breast Cancer.

Abstract

Abstract Background: Doxorubicin, paclitaxel and trastuzumab are among the most active agents used in the treatment of Her2-positive invasive breast cancer. However, trastuzumab is associated with cardiotoxicity that is significantly amplified in the presence of doxorubicin. Pegylated liposomal doxorubicin (PLD) has been reported to have greatly reduced cardiotoxicity when compared to native doxorubicin. This pilot study was designed to assess safety and efficacy of concurrent PLD, paclitaxel (TAX), and trastuzumab in the preoperative setting.Methods: Eligible patients included women with T1c-T4, N0-1, M0, Her2-positive invasive breast cancer who had received no prior treatment. The treatment regimen consisted of concomitant PLD 24 mg/m2 or 20 mg/m2 (14pts/10pts) q 3 weeks, TAX 80 mg/m2 weekly, and trastuzumab 2mg/m2 weekly after an initial 4 mg/m2 loading dose, for a total of 18 weeks. MUGA scans were obtained at baseline, after 9 weeks, and after 18 weeks prior to surgery. The primary endpoint was pathologic complete response (pCR).Results: Twenty-four patients were entered on study. The median age was 55 (range 30-72). One subject had AJCC Stage I disease, 14 subjects had Stage II disease, 9 subjects had Stage III disease, and the median pre-treatment tumor size was 4.5 cm (1.2 cm-10.0 cm). Twelve subjects required dose reductions of PLD, 9 required dose reduction of TAX, and 5 discontinued therapy early. One subject withdrew during the 1st cycle, and 1 patient died due to an event unrelated to the investigational treatment. Thirteen of the 22 evaluable subjects had pCR (59%), 9 subjects had PR (41%). The principal treatment-related toxicity was Grade II or III skin toxicity in 18 of 24 subjects (75%). No overt cardiotoxicity was noted, with the mean change between pre-treatment and pre-surgical MUGA of -.25% (range -12-7%).Discussion: The combination of PLD, TAX, and trastuzumab given every 3 weeks, appears to be a highly effective regimen, without evidence of increased cardiotoxicity. However skin toxicity is prominent and may be exacerbated by a previously reported effect of TAX on PLD pharmacokinetics. Further investigation of this highly effective regimen should focus on reducing skin toxicity, while maintaining efficacy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1098.