David Cameron, MD
The phase III UK TACT2 trial has shown no efficacy benefit of accelerated vs standard epirubicin and a potential quality-of-life benefit of capecitabine vs CMF (cyclophosphamide, methotrexate, fluorouracil) as adjuvant therapy for breast cancer. The findings were reported in The Lancet Oncology by David Cameron, MD, of Cancer Research UK Edinburgh Centre, The University of Edinburgh, and colleagues.
In the 2 x 2 factorial open-label trial, 4,391 patients from 129 UK centers with node-positive or high-risk node-negative disease who had undergone complete excision were randomized between December 2005 and December 2008 to receive four cycles of 100 mg/m2 of epirubicin either every 3 weeks (standard; 1,116 with CMF, 1,105 with capecitabine) or every 2 weeks with 6 mg of pegfilgrastim (Neulasta) on day 2 of each cycle (accelerated; 1,086 with CMF, 1,084 with capecitabine) followed by four 4-week cycles of either CMF (600 mg/m2 of cyclophosphamide intravenously on days 1 and 8 or 100 mg/m2 orally on days 1–14; 40 mg/m2 of methotrexate on days 1 and 8; and 600 mg/m2 of fluorouracil on days 1 and 8 of each cycle) or four 3-week cycles of capecitabine at 1,250 mg/m2 twice daily on days 1 to 14 of each cycle. The primary endpoint was time to tumor recurrence (invasive relapse or breast cancer death) with intention-to-treat analysis of standard vs accelerated epirubicin and per-protocol analysis of CMF vs capecitabine.
Median follow-up was 85.6 months. No significant difference in the time to tumor recurrence was observed between the accelerated vs standard epirubicin groups (overall hazard ratio [HR] = 0.94, stratified P = .42; proportion free of events at 5 years = 87.1% vs 85.9%). Among 4,358 patients included in the per-protocol analysis for capecitabine vs CMF, the time to tumor recurrence events occurred in 16% of 2,180 capecitabine patients vs 17% of 2,178 CMF patients (overall HR = 0.98, P = .00092 for noninferiority, stratified P = .81 for superiority of capecitabine vs CMF). There was no difference in overall survival for accelerated vs standard epirubicin (HR = 1.04, stratified P = .68) or for capecitabine vs CMF (HR = 1.01, stratified P = .92).
Quality of Life and Adverse Events
Compared with baseline, clinically relevant worsening of quality life was more common in CMF patients vs capecitabine patients at the end of treatment (58% vs 50%, P = .011) and at 12 months (34% vs 22%, P < .001), with CMF patients having worse quality of life over time (P < .0001). The most common grade ≥ 3 adverse events in cycles 1 to 4 were neutropenia (16%) and fatigue (5%) in patients receiving standard epirubicin and fatigue (6%) and infection (3%) in those receiving accelerated epirubicin. In cycles 5 to 8, the most common grade ≥ 3 adverse events were neutropenia (31%) and fatigue (11%) in CMF patients and hand-foot syndrome (12%) and diarrhea (6%) in capecitabine patients.
The investigators concluded: “We found no benefit from increasing the dose density of the anthracycline component of chemotherapy. However, capecitabine could be used in place of CMF without significant loss of efficacy and with improved quality of life.” ■
The study was funded by Cancer Research UK, Amgen, Pfizer, and Roche.