Italian Trial Shows Benefit of Dose-Dense Adjuvant Therapy With Sequential Epirubicin-Cyclophosphamide-Paclitaxel in Early Node-Positive Breast Cancer
In an Italian 2×2 phase III trial reported in The Lancet, Del Mastro et al found that dose-dense adjuvant therapy with sequential epirubicin, cyclophosphamide, and paclitaxel (EC-P) with or without fluorouracil (5-FU) increased disease-free survival vs standard-interval therapy in early-stage node-positive breast cancer. No benefit of adding 5-FU to EC-P was observed.
Study Details
In this open-label trial, 2,091 patients from 81 Italian centers were randomly assigned 1:1:1:1 between April 2003 and July 2006 to receive adjuvant dose-dense chemotherapy every 2 weeks with pegfilgrastim (Neulasta) support with 5-FU plus EC-P (FEC-P, n = 500) or EC-P (n = 502) or standard-interval chemotherapy every 3 weeks with FEC-P (n = 544) or EC-P (n = 545). The primary endpoint was disease-free survival in the intention-to-treat population, with primary comparisons between every-2-week vs every-3-week schedules and FEC-P vs EC-P.
Overall, patients had a median age of 51 to 53 years, 47% to 55% were postmenopausal, 59% to 63% had lumpectomy, 48% to 52% had T1 tumors, 57% to 64% had one to three positive nodes, 43% to 49% had grade 3 tumors, 21% to 24% were HER2-positive, 77% to 81% were estrogen or progesterone receptor–positive, and 43% to 50% had ≥ 20% Ki67-positive cells.
Improved Survival With Dose-Dense Treatment
After a median follow-up of 7.0 years, a disease-free survival event had occurred in 26% of patients receiving EC-P every 3 weeks, 29% of the FEC-P every-3-week group, 22% of the EC-P every-2-week group, and 23% of the FEC-P every-2-week group. Disease-free survival at 5 years was 81% (95% confidence interval [CI] = 79%–84%) among patients treated every 2 weeks vs 76% (95% CI = 74%–79%) among those treated every 3 weeks (hazard ratio [HR] = 0.77, P = .004), and overall survival at 5 years was 94% (95% CI = 93%–96%) vs 89% (95% CI = 87%–91%; HR = 0.65, P = .001).
Disease-free survival at 5 years was 78% (95% CI = 75%–81%) in the FEC-P groups vs 79% (95% CI = 76%–82%) in the EC-P groups (HR = 1.06, P = .561), and overall survival at 5 years was 91% (95% CI = 89%–93%) vs 92% (95% CI = 90%–94%; HR = 1.16, P = .234).
High consistency in differences between 2-week and 3-week dosing was observed in subgroup analyses of disease-free survival, with no significant interaction being observed between type of regimen or any prognostic factors.
Toxicity
Dose-dense chemotherapy was associated with higher rates of grade 3 or 4 anemia (1.4% vs 0.2%), transaminitis (1.9% vs 0.4%), and myalgias (3.1% vs 1.6%) and a lower rate of grade 3 or 4 neutropenia (14.9% vs 44.0%). The addition of 5-FU was associated with increased incidence of grade 3 or 4 neutropenia (34.5% vs 24.2%), fever (0.9% vs 0.2%), nausea (4.6% vs 2.7%), and vomiting (3.1% vs 1.4%).
The investigators concluded: “In patients with node-positive early breast cancer, dose-dense adjuvant chemotherapy improved disease-free survival compared with standard interval chemotherapy. Addition of fluorouracil to a sequential EC-P regimen was not associated with an improved disease-free survival outcome.”
Lucia Del Mastro, MD, of Istituto Nazionale per la Ricerca sul Cancro, is the corresponding author for The Lancet article. Dr. Del Mastro and Sabino De Placido, MD, of Istituto Nazionale per la Ricerca sul Cancro, contributed equally to the work.
The study was funded by Bristol-Myers Squibb, Pharmacia, and Dompè Biotec. For full disclosures of the study authors, visit www.thelancet.com.
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