This protocol amendment included the following changes: To allow the inclusion of patients treated with previous neoadjuvant chemotherapy. On that date, the clinical trials published did not show inferior results with neoadjuvant treatment compared to the adjuvant one. In addition, a meta-analysis showed that the comparison of both therapies did not have differences in terms of DFS and OS. In regards to it, to consider the absence of a biological reason justifying different efficacy results of the same regimen administered before or after the breast surgery was thought to be critical. All these considerations were taken into account to allow the inclusion of this subgroup of patients on the study. To allow the administration of 4 cycles of adriamycin and cyclophosphamide (AC) as chemotherapy for patients without axillary lymph node involvement. At that moment of time, in some countries of Latin America participating on the study, the treatment of this type of patients (considered to have an intermediate risk) included 6 cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) regimen or 4 cycles of AC regimen as per local clinical guidelines. With this consideration, patients without axillary lymph node involvement were allowed to be enrolled on the study. Grammatical mistakes were corrected, some administrative data were updated and there was an increase in the number of study sites with 2 new sites (Hospital General Yagüe in Burgos and Hospital Infanta Luisa in Seville, both in Spain).

This protocol amendment was made to re-calculate the sample size of the study based on the results of the FinXX trial presented by Joensuu H. et al, at San Antonio Breast Cancer Symposium in 2008. The Finnish group showed the initial results from a clinical trial in adjuvant setting that evaluated the addition of capecitabine to the combination chemotherapy with epirubicin, cyclophosphamide and docetaxel. These results showed a statistically significant difference in terms of DFS and distant DFS in favor of the addition of capecitabine. The Hazard Ratio was of 0.66 showing an advantage of 34%. Patient population on this study included patients with positive or negative regional lymph node involvement, and tumor size > 2 cm. An estimated comparative analysis of the risk of recurrence indicated that patients on CIBOMA study had a higher risk of recurrence. Additionally, an exploratory subgroup analysis already presented at San Antonio Breast Cancer Symposium in 2008, showed that patients with HER2-negative tumors (not all of them triple negative), had a relevant benefit with the addition of capecitabine. We thought that at least a good proportion of patients on CIBOMA study could have better outcomes with the addition of adjuvant capecitabine. Our initial proposal estimated a benefit of 25% with the addition of capecitabine compared to observation; this required the inclusion of approximately 1,324 patients. When adjusting the potential benefit expected to 30% with a drop-out rate of 5%, the number of patients necessary to reach a possible positive result of the study was of 876. These data were obtained from the database of the “El Alamo” project (Project “The Alamo III”. ISBN: 84-938762-5-9. Legal deposit: M-36626-2013). One thousand six hundred and twenty-seven (1,627) in total were considered during the years from 1990 to 1997. The population was formed of patients with operable breast cancer, with surgery, positive nodes, and negative hormone receptors, or ne