Background: Reductions in adjuvant chemotherapy dose <85% for historical regimens (ie, cyclophosphamide/methotrexate/fluorouracil) are known to affect breast cancer survival. This threshold, in addition to early versus late dose reductions, are poorly defined for third-generation anthracycline/taxane-based chemotherapy. In patients with breast cancer receiving adjuvant 5-fluorouracil/epirubicin/cyclophosphamide followed by docetaxel (FEC-D), we evaluated the impact of chemotherapy total cumulative dose (TCD), and early (FEC) versus late (D only) dose reductions, on survival outcomes. Patients and Methods: Women with stage I–III, hormone receptor–positive/negative, HER2-negative breast cancer treated with adjuvant FEC-D chemotherapy from 2007 through 2014 in Alberta, Canada, were included. TCD for cycles 1 to 6 of <85% or ≥85% was calculated. Average cumulative dose was also calculated for early (cycles 1–3) and late (cycles 4–6) chemotherapy. Survival outcomes (disease-free survival [DFS] and overall survival [OS]) were estimated using Kaplan-Meier and multivariate analysis. Cohorts were evaluated for uniformity. Results: Characteristics were reasonably balanced for all cohorts. Overall, 1,302 patients were evaluated for dose reductions, with 16% being reduced <85% (n=202) relative to ≥85% (n=1,100; 84%). Patients who received TCD ≥85% relative to <85% had superior 5-year DFS (P=.025) and OS (P<.001) according to Kaplan-Meier analysis, which remained significant on univariate and multivariate analyses. In stratified late and early dose reduction cohorts, DFS and OS showed a significant inferior survival trend for dose reduction early in treatment administration in 5-year Kaplan-Meier (P=.002 and P<.001, respectively) and multivariate analyses (hazard ratio [HR], 1.46; P=.073, and HR, 1.77; P=.011, respectively). Dose delays of <14 or ≥14 days and granulocyte colony-stimulating factor use did not affect outcomes. Conclusions: Chemotherapy TCD <85% for adjuvant FEC-D affects breast cancer survival. Late reductions (D only) were not shown to adversely affect DFS or OS. Conversely, early reductions (FEC±D) negatively affected patient outcomes.
Submitted October 24, 2018; accepted for publication February 21, 2019.Author contributions:Study concept: Veitch, Tang, King, Lupichuk. Study design: Veitch, Khan, Tang, King, Lupichuk. Data acquisition: Veitch, Khan. Quality control of data and algorithms: Veitch, Khan, Tilley. Data analysis and interpretation: Veitch, Tilley, Tang, Stewart, King, Lupichuk. Statistical analysis: Veitch, Tilley, Kostaras. Manuscript preparation: Veitch, Tilley, Tang, Lupichuk. Manuscript editing: Veitch, Tilley, Lupichuk. Manuscript review: All authors.Disclosures: Dr. Stewart has disclosed that he is a consultant for and receives consulting fees/honoraria from Apobiologix, Sandoz, and Amgen. The remaining authors have disclosed that they have not received any financial considerations from any person or organization to support the preparation, analysis, results, or discussion of this article.Correspondence: Zachary Veitch, MSc, MD, FRCPC, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Email: Zachary.Veitch@uhn.ca