Fluorouracil, Epirubicin, and Cyclophosphamide Alone or Followed by Paclitaxel for Early Breast Cancer

The efficacy of adjuvant chemotherapy is limited in patients with a high risk of recurrence. Also, for axillary positive node patients, optimum chemotherapy regimens are still under discussion. Some previous studies suggest that, in the subset of node-positive patients, treatments based on sequential administration of anthracyclines and taxanes are more efficient. Paclitaxel dose-dense (weekly) administration renders an improved therapeutic index (activity/toxicity). The study is designed to compare 6 courses of FEC scheme (600/90/600), a combination of proven efficacy in node positive breast cancer patients, versus 4 FEC courses followed by 8 weekly paclitaxel administrations (100mg/m2). The study hypothesis is that 5-year disease-free survival in the control arm will be 60%. The investigators expect to increase this by 8% with the experimental treatment. With an alpha error of 0.05, 80% power, and a post-randomization estimated drop-out rate of 10%, 1250 patients are needed, 625 per arm.

Sex

Female

Minimum age

18 Years

Maximum age

70 Years

Inclusion Criteria:

* Written informed consent.
* Histological diagnosis of breast cancer.
* Node positive operable breast cancer (stages II-III).
* Breast cancer surgery, consisting of radical mastectomy or conservative surgery, plus lymphadenectomy with at least 6 extirpated nodes. Surgery must have happened in the 8 weeks prior to randomisation.
* Age \>=18 and \<= 70 years old.
* Negative pregnancy test. Adequate contraceptive method during the study participation.
* Performance status of 90-100 (Karnofsky index) or ECOG \<=1.
* Haemoglobin \>= 10 g/dl; neutrophils \> 1,500/cc; platelets \> 100,000/cc.
* Adequate hepatic function with bilirubin, SGOT and SGPT \< 1.5 x upper normal limit (UNL).
* Adequate cardiac function documented by left ventricular ejection fraction (LVEF).
* Adequate renal function with creatinine \< 1.5 mg/dl.

Exclusion Criteria:

* Previous chemotherapy, hormone therapy and/or radiotherapy for breast cancer.
* Bilateral breast cancer. Lobular in situ carcinoma.
* Previous or current malignancies, except for basal skin carcinoma, cervical in situ carcinoma or superficial bladder carcinoma, adequately treated.
* History of arrhythmias and/or congestive heart failure or cardiac blocking grade 2-3; history of myocardial infarction in 6 months before recruitment.
* Inability for treatment and study compliance.
* Pregnant or lactating women.
* Active infection.
* History of hypersensitivity to cremophor or cyclosporine.
* Pre-existing grade 2 motor or sensorial neurotoxicity (National Cancer Institute Common Toxicity Criteria \[NCI CTC\]).
* Hormonal receptor status not determined.
* Any other criteria which, in investigator's opinion, may jeopardize patient's security or compliance.
* Administration of other investigational product in the 30 days prior to randomisation; current participation in another clinical trial.

• RESULTMartin M, Rodriguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Santaballa A, Rodriguez CA, Crespo C, Abad M, Dominguez S, Florian J, Llorca C, Mendez M, Godes M, Cubedo R, Murias A, Batista N, Garcia MJ, Caballero R, de Alava E. Molecular predictors of efficacy of adjuvant weekly paclitaxel in early breast cancer. Breast Cancer Res Treat. 2010 Aug;123(1):149-57. doi: 10.1007/s10549-009-0663-z. PMID 20037779
• RESULTEbbert MT, Bastien RR, Boucher KM, Martin M, Carrasco E, Caballero R, Stijleman IJ, Bernard PS, Facelli JC. Characterization of uncertainty in the classification of multivariate assays: application to PAM50 centroid-based genomic predictors for breast cancer treatment plans. J Clin Bioinforma. 2011 Dec 23;1:37. doi: 10.1186/2043-9113-1-37. PMID 22196354
• RESULTde la Haba-Rodriguez J, Rodriguez-Lescure A, Ruiz A, Alba E, Calvo L, Carrasco E, Escudero MJ, Martin M. Regional and seasonal influence in patient's toxicity to adjuvant chemotherapy for early breast cancer. Breast Cancer Res Treat. 2011 Jan;125(1):273-8. doi: 10.1007/s10549-010-1136-0. Epub 2010 Aug 28. PMID 20803065
• RESULTBastien RR, Rodriguez-Lescure A, Ebbert MT, Prat A, Munarriz B, Rowe L, Miller P, Ruiz-Borrego M, Anderson D, Lyons B, Alvarez I, Dowell T, Wall D, Segui MA, Barley L, Boucher KM, Alba E, Pappas L, Davis CA, Aranda I, Fauron C, Stijleman IJ, Palacios J, Anton A, Carrasco E, Caballero R, Ellis MJ, Nielsen TO, Perou CM, Astill M, Bernard PS, Martin M. PAM50 breast cancer subtyping by RT-qPCR and concordance with standard clinical molecular markers. BMC Med Genomics. 2012 Oct 4;5:44. doi: 10.1186/1755-8794-5-44. PMID 23035882
• RESULTPajares B, Pollan M, Martin M, Mackey JR, Lluch A, Gavila J, Vogel C, Ruiz-Borrego M, Calvo L, Pienkowski T, Rodriguez-Lescure A, Segui MA, Tredan O, Anton A, Ramos M, Camara Mdel C, Rodriguez-Martin C, Carrasco E, Alba E. Obesity and survival in operable breast cancer patients treated with adjuvant anthracyclines and taxanes according to pathological subtypes: a pooled analysis. Breast Cancer Res. 2013 Nov 6;15(6):R105. doi: 10.1186/bcr3572.