Journal of the National Cancer Institute Advance Access originally published online on May 27, 2008
JNCI Journal of the National Cancer Institute 2008 100(11):805-814; doi:10.1093/jnci/djn151
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ARTICLES |
Randomized Phase 3 Trial of Fluorouracil, Epirubicin, and Cyclophosphamide Alone or Followed by Paclitaxel for Early Breast Cancer
On behalf of the GEICAM 9906 Study Investigators
Affiliations of authors: Departments of Medical Oncology (MM) and Pathology (JALGA), Hospital Universitario San Carlos, Madrid, Spain; Department of Medical Oncology, Hospital Universitario de Elche, Elche, Spain (ARL); Departments of Medical Oncology (AR) and Pathology (S. Almenar), Instituto Valenciano de Oncologia, Valencia, Spain; Department of Medical Oncology, Hospital Virgen de la Victoria, Málaga, Spain (E. Alba); Departments of Medical Oncology (LC) and Pathology (MDG), Complejo Hospitalario Juan Canalejo, La Coruña, Spain; Departments of Medical Oncology (MR) and Pathology (JP), Hospital Vírgen del Rocío, Sevilla, Spain; Departments of Medical Oncology (BM) and Pathology (FV), Hospital La Fe, Valencia, Spain; Department of Medical Oncology, Hospital Universitario de Salamanca, Salamanca, Spain (CAR); Departments of Medical Oncology (CC) and Pathology (JFGP), Hospital Ramón y Cajal, Madrid, Spain; Department of Pathology, Centro de Investigación del Cáncer, Salamanca, Spain (E. de Alava); Department of Medical Oncology, Centro Oncológico de Galicia, La Coruña, Spain (MR); Department of Medical Oncology, Hospital de Cabueñes, Gijón, Spain (JMGM); Department of Medical Oncology, Hospital Clínico Universitario de Valencia, Valencia, Spain (AL); Department of Medical Oncology, Hospital de Donostia, San Sebastián, Spain (IA); Department of Medical Oncology, Hospital Parc Taulí, Sabadell, Spain (MAS); Department of Medical Oncology, Hospital Clínico Lozano Blesa, Zaragoza, Spain (JIM); Department of Medical Oncology, Hospital Miguel Servet, Zaragoza, Spain (AA); Department of Medical Oncology, Complejo Hospitalario Puerta del Mar, Cádiz, Spain (JMB); Department of Medical Oncology, Instituto Oncológico de Guipúzcoa, San Sebastián, Spain (A. Plazaola); Department of Medical Oncology, Clínica Corachan, Barcelona, Spain (AM); Department of Medical Oncology, Hospital Universitario San Joan de Reus, Tarragona, Spain (A. Pelegri); Department of Medical Oncology, Complejo Hospitalario Xeral Calde, Lugo, Spain (JMM); Department of Medical Oncology, Hospital Provincial de Córdoba, Córdoba, Spain (E. Aranda); Department of Medical Oncology, Hospital General de Alicante, Alicante, Spain (E. Adrover); Hospital Provincial de Zamora, Zamora, Spain (JVA); Department of Medical Oncology, Hospital San Cecilio de Granada, Granada, Spain (JLGP); Department of Medical Oncology, Hospital Ciudad de Jaén, Jaén, Spain (PSR); Department of Medical Oncology, Mutua de Terrasa, Terrasa, Spain (SG); Department of Medical Oncology, Hospital Universitario Marqués de Valdecilla, Santander, Spain (JMLV)
Correspondence to: Miguel Martín, MD, Servicio de Oncologia Medica, Hospital Universitario San Carlos, Ciudad Universitaria s/n, 28040 Madrid, Spain (e-mail: mmartin{at}geicam.org).
Background: Taxanes are among the most active drugs for the treatment of metastatic breast cancer, and, as a consequence, they have also been studied in the adjuvant setting.
Methods: After breast cancer surgery, women with lymph node–positive disease were randomly assigned to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study—5-year disease-free survival (DFS)—was assessed by Kaplan–Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular (hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization) markers. Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests were two-sided.
Results: Among the 1246 eligible patients, estimated rates of DFS at 5 years were 78.5% in the FEC-P arm and 72.1% in the FEC arm (difference = 6.4%, 95% confidence interval [CI] = 1.6% to 11.2%; P = .006). FEC-P treatment was associated with a 23% reduction in the risk of relapse compared with FEC treatment (146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm, hazard ratio [HR] = 0.77, 95% CI = 0.62 to 0.95; P = .022) and a 22% reduction in the risk of death (73 and 95 deaths, respectively, HR = 0.78, 95% CI = 0.57 to 1.06; P = .110). Among the 928 patients for whom tumor samples were centrally analyzed, type of chemotherapy (FEC vs FEC-P) (P = .017), number of involved axillary lymph nodes (P < .001), tumor size (P = .020), hormone receptor status (P = .004), and HER2 status (P = .006) were all associated with DFS. We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment.
Conclusions: Among patients with operable breast cancer, FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy.
| CONTEXT AND CAVEATS Prior knowledge Taxanes are among the most active drugs for the treatment of metastatic breast cancer. Study design Phase 3 randomized trial among women with lymph node–positive disease evaluating treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) with FEC followed by weekly paclitaxel (FEC-P). Contribution FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy. FEC-P treatment was associated with a statistically significant 23% reduction in the risk of relapse compared with FEC treatment and a non–statistically significant 22% reduction in the risk of death. Implications In the adjuvant setting, addition of taxanes to FEC chemotherapy reduces the risk of relapse for patients with lymph node–positive breast cancer. Limitations The number of patients evaluated in this trial was small.
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Manuscript received December 26, 2007; revised March 25, 2008; accepted April 10, 2008.
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J Natl Cancer Inst 2008 100: 761-763.
J Natl Cancer Inst 2008 100: 755.
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