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Feasibility and Tolerability of Sequential Doxorubicin/Paclitaxel Followed by Cyclophosphamide, Methotrexate, and Fluorouracil and Its Effects on Tumor Response as Preoperative Therapy

Authors' Affiliations: ¹ Istituto Nazionale Tumori, Milan, Italy; ² Hospital Vall d'Hebron and ³ Hospital de San Pau, Barcelona, Spain; ⁴ Frauenklinik vom Roten Kreuz, Munich, Germany; ⁵ Istituto Valenciano de Oncologia and ⁶ Hospital Clinico Universitario de Valencia, Valencia, Spain; ⁷ N.N. Petrov Research Institute of Oncology, St. Petersburg, Russia; ⁸ Central Clinical Hospital named after N.A. Semashko, Moscow, Russia; and ⁹ Azienda Ospedaliera Santa Maria della Misericordia, Udine, Italy

Requests for reprints: Luca Gianni, CTO Coordinating Center, Istituto Nazionale Tumori, Via Venezian, 1, 20133 Milan, Italy. Phone: 39-02-2390-2789; Fax: 39-02-2390-2678; E-mail: gianni{at}istitutotumori.mi.it.

Purpose: The European Cooperative Trial in Operable breast cancer (ECTO) randomly tested whether efficacy of adjuvant doxorubicin followed by i.v. cyclophosphamide, methotrexate, and fluorouracil (CMF; doxorubicin CMF, arm A) could be improved by adding paclitaxel (doxorubicin/paclitaxel CMF) as adjuvant (arm B) or primary systemic therapy (PST, arm C). We report here feasibility, tolerability, locoregional antitumor activity, and breast conservation rate.

Methods: A total of 1,355 women entered the study. Feasibility and safety were compared in arm A versus arms B plus C. Surgical findings were compared in arms A plus B versus arm C.

Results: Grade 3 or 4 National Cancer Institute toxicities were low (<5%) in all arms. Neuropathy was more frequent in the paclitaxel-containing arms (grade 2, 20.5% versus 5.0%; grade 3, 1.3% versus 0.2%). At 31 months of follow-up, asymptomatic drop of left ventricular ejection fraction was similar in all arms, whereas symptomatic cardiotoxicity was recorded in three patients (0.5%) in A and in three patients (0.3%) in B plus C. PST induced clinical complete plus partial remission in 78%, with an in-breast pathologic complete response rate of 23% and an in-breast plus axilla pathologic complete response rate of 20%. In the multivariate analysis, only estrogen receptor (ER) status was significantly associated with pathologic complete response (odds ratio for ER negative, 5.77; 95% confidence interval, 3.49-9.52; P < 0.0001). PTS induced a significant axillary downstaging (P < 0.001), and breast sparing surgery was feasible in 65% versus 34% (P < 0.001).

Conclusions: Doxorubicin/paclitaxel CMF is feasible, safe, and well tolerated. Given as PST, it is markedly active, allowing for breast-sparing surgery in a large fraction of patients.

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