Originally published as JCO Early Release 10.1200/JCO.2008.19.2567 on March 30 2009

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Phase III Trial Evaluating the Addition of Paclitaxel to Doxorubicin Followed by Cyclophosphamide, Methotrexate, and Fluorouracil, As Adjuvant or Primary Systemic Therapy: European Cooperative Trial in Operable Breast Cancer

Luca Gianni, José Baselga, Wolfgang Eiermann, Vincente Guillem Porta, Vladimir Semiglazov, Aa Lluch, Milvia Zambetti, Dolores Sabadell, Günther Raab, Antonio Llombart Cussac, Alla Bozhok, Angel Martinez-Agulló, Marco Greco, Mikhail Byakhov, Juan Josè Lopez Lopez, Mauro Mansutti, Pinuccia Valagussa, Gianni Bonadonna

From the Fondazione IRCCS Istituto Nazionale Tumori, Milan; Ospedale Universitario Santa Maria della Misericordia, Udine, Italy; Hospital Vall d'Hebron and Hospital de San Pau, Barcelona; Istituto Valenciano de Oncologia and Hospital Clinico Universitario de Valencia, Valencia, Spain; Frauenklinik vom Roten Kreuz, Munich, Germany; N.N. Petrov Research Institute of Oncology, St Petersburg; and the N.A. Semashko Central Clinical Hospital, Moscow, Russia.

Corresponding author: Luca Gianni, MD, Fondazione IRCCS "Istituto Nazionale dei Tumori", Via Venezian, 1, 20133 Milan, Italy; e-mail: luca.gianni{at}istitutotumori.mi.it.

Purpose To evaluate the addition of paclitaxel to an anthracycline-based adjuvant regimen and to compare this combination with the same regimen given as primary systemic (neoadjuvant) therapy.

Patients and Methods A total of 1,355 women with operable breast cancer were randomly assigned to one of three treatments: surgery followed by adjuvant doxorubicin (75 mg/m²) followed by cyclophosphamide, methotrexate, and fluorouracil (CMF; arm A); surgery followed by adjuvant paclitaxel (200 mg/m²) plus doxorubicin (60 mg/m²), followed by CMF (arm B); or paclitaxel (200 mg/m²) plus doxorubicin (60 mg/m²) followed by CMF followed by surgery (arm C). The two coprimary objectives were to assess the effects on relapse-free survival (RFS) of the addition of paclitaxel to postoperative chemotherapy (arm B v arm A) and primary chemotherapy versus adjuvant chemotherapy (arm B v arm C).

Results Doxorubicin plus paclitaxel followed by CMF was well-tolerated as adjuvant or as primary chemotherapy. The addition of paclitaxel to adjuvant doxorubicin followed by CMF significantly improved RFS compared with adjuvant doxorubicin alone followed by CMF (hazard ratio [HR], 0.73; P = .03). Distant RFS was similarly improved (HR, 0.70; P = .027). There was no significant difference in RFS when the paclitaxel/doxorubicin/CMF chemotherapy was given before surgery compared with the same regimen given after surgery (HR, 1.21; P = .18). However, the rate of breast-conserving surgery was significantly higher with preoperative chemotherapy (63% v 34%; P < .001).

Conclusion Incorporating paclitaxel into anthracycline-based adjuvant therapy resulted in a significant improvement in RFS and distant RFS. When given as primary systemic therapy, the paclitaxel-containing regimen allowed breast-sparing surgery in a significant percentage of patients.

Supported by an unrestricted grant from Bristol Myers Squibb which had no role in the design of the study, the collection, analysis, and interpretation of the data, nor on the decision to submit the manuscript or the writing of the manuscript itself.

Presented in part at the Annual Meeting of the American Society of Clinical Oncology, 2005.

Written on behalf of the European Cooperative Trial in Operable Breast Cancer Study Group.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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