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

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 >2 cm and M0; or node negative with tumors >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.

Bevacizumab Added to Neoadjuvant Chemotherapy for Breast Cancer

“…Thus, it appears unlikely that these drugs would add much benefit in the adjuvant setting. Indeed, our results confirm (and would have predicted) the largely negative results of several trials of adjuvant therapy with these drugs, [21][22][23] supporting our hypothesis that trials of neoadjuvant therapy serve as better predictors of adjuvant benefits than studies of metastatic disease. The addition of bevacizumab resulted in a modest but significant increase in the rate of pathological complete response in the breast, but the rate of pathological complete response in the breast and nodes was not significantly increased, which may indicate that this drug will have a lesser effect on patient outcomes.…”

Triple-negative breast cancer: are we making headway at least?

“…On the other hand, grade 3/4 infection and neutropenia were seen in the control arm, especially in relation to docetaxel since dose of docetaxel was higher in the control arm [Joensuu et al 2007]. In a similar study, O'Shaughnessy reported a trend for benefit with the addition of capecitabine to docetaxel after adjuvant AC in TNBC patients (HR = 0.64; 95% CI 0.44-0.95) [O'Shaughnessy et al 2010].…”

Aktuelle Veränderungen der S3-Leitlinie Mammakarzinom

“…OS erkennen. Diese Verbesserung war jedoch mit einer erhöhten Toxizität verbunden [14,22]. Nach fünf Jahren war die Verbesserung von DFS und OS nicht mehr im Gesamtkollektiv der FinXX-Studie signifikant, sondern nur …”