Dose-dense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial.

Background. To determine whether a dose-dense regimen improves outcome in early breast cancer patients, we compared outcomes with the same fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapeutic regimen administered every 3 weeks (FEC21) or administered every 2 weeks (FEC14 including support with filgrastim, a granulocyte colony-stimulating factor) in a multicenter phase III randomized trial. Methods: A total of 1214 patients with early-stage breast cancer were randomly assigned to receive six cycles of FEC14 (604 patients) or of FEC21 (610 patients). Study endpoints were overall survival and event-free survival. Associations were assessed by multivariable analysis with adjustment for age; tumor size; grade; proliferative rate; and menopausal, lymph node, estrogen receptor, and progesterone receptor status. All statistical tests were two-sided. Results: Patients in the FEC14 arm had fewer dose reductions or treatment delays or discontinuation (26%) than those in the FEC21 arm (33%) (difference = 7%, 95% confidence interval [CI] = 2% to 12%; P =.008). FEC14 therapy, compared with FEC21 therapy, was associated with more asthenia (36% versus 29%, difference = 7%, 95% CI = 2% to 12%; P =.01), bone pain (33% versus 4%, difference = 29%, 95% CI = 25% to 33%; P<.001), anemia (38% versus 19%, difference = 19%, 95% CI = 14% to 24%; P<.001), and thrombocytopenia (8% versus 2%, difference = 6%, 95% CI = 4% to 9%; P<.001), but with less leukopenia (12% versus 45%, difference = 33%, 95% CI = 28% to 37%; P<.001). No acute myelogenous leukemia or myelodysplastic syndrome was observed. At a median follow-up of 10.4 years, no statistically significant difference in the hazard of death (hazard ratio [HR] = 0.87, 95% CI = 0.67 to 1.13) or recurrence (HR = 0.88, 95% CI = 0.71 to 1.08) was found between FEC14 and FEC21 groups after adjustment by multivariable analysis. Although the study was underpowered for subset analysis, we found no evidence that the effect of the treatment type was associated with any of the potential prognostic factors. Conclusion: Our results support the long-term safety of FEC14 chemotherapy as an adjuvant treatment of breast cancer. However, this therapy was not associated with improved outcome, but because of the limited statistical power of our study, we cannot rule out a modest improvement in outcome associated with FEC14 therapy.