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Nonpegylated Liposomal Doxorubicin (TLC-D99), Paclitaxel, and Trastuzumab in HER-2-Overexpressing Breast Cancer: A Multicenter Phase I/II Study

Authors' Affiliations: ¹ Vall d'Hebron University Hospital; ² Hospital Clínic i Provincial de Barcelona; ³ Institut Català d' Oncologia, Hospitalet de Llobregat; ⁴ Hospital Santa Creu i Sant Pau; ⁵ Spanish Breast Cancer Cooperative Group Operations Office, SOLTI, Barcelona, Spain; ⁶ Instituto Valenciano de Oncología; ⁷ Hospital Clínico Universitario, Valencia, Spain; ⁸ Hospital Universitario 12 de Octubre; ⁹ Roche Farma, S.A.; ¹⁰ SGS Life science Services, Madrid, Spain; ¹¹ Hospital Clínico Universitario de Zaragoza, Zaragoza, Spain; ¹² Hospital Carlos Haya, Málaga, Spain; ¹³ Hospital Mútua de Terrasa, Terrasa, Spain; and ¹⁴ Hospital Clínico de Salamanca, Salamanca, Spain

Requests for reprints: José Baselga, Medical Oncology Department, Vall d'Hebron University Hospital, Pg. Vall d'Hebron, 119-129, 08035 Barcelona, Spain. Phone: 34-93-274-6077; Fax: 34-93-274-6059; E-mail: jbaselga{at}vhebron.net.

Purpose: To determine the recommended dose, cardiac safety, and antitumor activity of nonpegylated liposomal doxorubicin (TLC-D99), paclitaxel, and the anti-HER-2 monoclonal antibody trastuzumab in patients with HER-2-overexpressing locally advanced nonoperable breast cancer (LABC) and metastatic breast cancer (MBC).

Experimental Design: Women with measurable, previously untreated, HER-2-overexpressing LABC and MBC with a baseline left ventricular ejection fraction (LVEF) >50% received weekly trastuzumab in combination with escalating doses of weekly paclitaxel and TLC-D99 every 3 weeks for 6 cycles. LVEF monitoring was done every 3 weeks for the first 18 weeks and every 8 weeks thereafter.

Results: Sixty-nine patients participated, 15 in the dose escalating part and 54 at the recommended phase II dose (28 patients with LABC and 26 patients with MBC). The recommended doses of TLC-D99 and paclitaxel were 50 mg/m² every 3 weeks and 80 mg/m²/wk, respectively. Twelve (17%) patients developed asymptomatic declines in LVEF. In 8 of these patients, LVEF recovered to 50% after a median time of 9 weeks (range, 3-38 weeks). In the rest of patients, LVEF ranged from 44% to 49%. No patients developed symptomatic cardiac heart failure. The overall response rate was 98.1% (95% confidence interval, 90.1-99.9) with a median time to progression not reached in LABC and of 22.1 months (95% confidence interval, 16.4-46.3) in MBC patients.

Conclusions: Nonpegylated doxorubicin, paclitaxel, and trastuzumab combination is safe, does not result in clinically manifest cardiac toxicity, and has a high rate of durable responses in HER-2-overexpressing breast cancer patients. Further exploration of this combination is warranted.