Abstract S4-2: First Efficacy Results of a Randomized, Open-Label, Phase III Study of Adjuvant Doxorubicin Plus Cyclophosphamide, Followed by Docetaxel with or without Capecitabine, in High-Risk Early Breast Cancer
Authors: O'Shaughnessy J , Paul D , Stokoe C , Pippen Jr J , Blum JL , Krekow L , Holmes FA , Vukelja S , Lindquist D , Sedlacek S , Rivera R , Brooks R , McIntyre K , Pluenneke R , Schwartz J , Jones S , Brownstein C , Gilberg F. 
Published: April 2011

Abstract
Background: Combination regimens incorporating anthracyclines and taxanes are among the most effective for EBC and are particularly suitable for pts with high-risk disease. Significant efficacy benefit has been shown in phase III trials integrating capecitabine (X) into anthracycline/taxane-containing (neo)adjuvant regimens (Joensuu H, et al. Lancet Oncol 2009; Steger G, et al. ASCO 2010). We present first efficacy results of a large, randomized, multicenter phase III study comparing adjuvant doxorubicin plus cyclophosphamide (AC) followed by docetaxel (T) with or without X in high-risk early stage BC.
Methods: Pts aged 18-70 years, with high-risk, histologically-confirmed BC were eligible. High risk was defined as ≥1 positive lymph node, T1-3, and M0; or node negative with tumors &gt;2 cm and M0; or node negative with tumors &gt;1 cm, both ER and PgR negative, and M0. Treatment comprised four 3-weekly cycles of AC (A: 60mg/m2, C: 600mg/m2, both day 1) followed by four 3-weekly cycles of T (100mg/m2 day 1) or XT (X: 825mg/m2 b.i.d., days 1-14; T: 75mg/m2 day 1). Pts with hormone receptor-positive disease received tamoxifen or aromatase inhibitor for 5 years, and after 2005, pts with HER2-positive disease were offered 1-yr of concurrent or post-study trastuzumab. Primary endpoint: DFS (518 events were expected at 5 years); secondary endpoints: OS; safety; delivered dose intensity.
Results: Between Aug 2002 and Feb 2006, 2,611 pts were randomized to AC→T (n=1,304) or AC→XT (n=1,307). The treatment arms were well balanced at baseline: median age was 51 yrs (range 26–72) and most pts had ECOG PS 0 (91%). The study failed to meet its primary endpoint of DFS (HR 0.84, 95% CI: 0.67-1.05; p=0.125) after a median follow-up of 5 years, with 304 events. However, a statistically significant improvement in OS was seen in pts receiving AC→XT vs AC→T (HR 0.68, 95% CI: 0.51-0.92; p=0.011), with 183 events. Subgroup analyses of DFS and OS appeared to favor the AC→XT arm over the AC→T arm, with few exceptions. The frequency of AEs was similar in both arms: 99.8% AC→T (n=1,305) vs 100% AC→XT (n=1,283), as was the incidence of serious AEs: 20.2% vs 15.6%, respectively. Differences were noted between the AC→T and AC→XT arms, respectively, in terms of the incidence of grade 3 hand-foot syndrome (3.8% vs 18.1%), and grade 3/4 stomatitis (4.5% vs 9.1%), diarrhea (2.9% vs 5.1%) and febrile neutropenia (13.1% vs 9.4%). Median dose intensity of T was 0.97 (range: 0.08-1.41) in the AC→T arm and 0.96 (range: 0.03-1.45) in the AC→XT arm; the corresponding value for X was 0.67 (range: 0.00-1.20), which is lower than reported with XT in MBC.
Conclusions: Although this pivotal study failed to meet its primary endpoint of DFS, improvements in OS were seen with the addition of X to a standard anthracycline/taxane-containing adjuvant regimen. These results must be interpreted with caution due to the lower than expected event rate at 5 years. No new safety signals were detected, but the incidence of grade 3/4 stomatitis in the AC→XT arm was higher than previously reported with XT in the metastatic setting.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S4-2.