The clinical impact of adjuvant dose-dense sequential chemotherapy (dds-CT) in patients with high-risk operable breast cancer (BC): Pooled analysis of 6 clinical trials

Abstract

Background: The principles of dose-dense (dd) and sequential (s) chemotherapy (CT) were introduced in the adjuvant setting by HeCOG in 1997. We aimed to explore the long-term clinical benefit and safety of treatment of adjuvant dds-CT in patients (pts) with high-risk BC. Methods: We performed a pooled analysis from 6 HeCOG-initiated clinical trials (3 randomized and 3 observational). Patients with operable, early-stage breast cancer received adjuvant treatment with epirubicin, taxane and cyclophosphamide/methotrexate/ fluorouracil (CMF), except from 297 patients included in one study who did not receive taxanes. Granulocyte colony-stimulating factor was given prophylactically with all treatment regimens. The primary study endpoint was 10-year disease-free survival (DFS) rate. Results: Between 06/1997 and 04/2013, 4,767 pooled pts were treated with dds-CT (median age 52.9, range 20.9-82.7, postmenopausal: 54%). Patients presented with Hormone receptor (HR)-positive/HER2-negative tumors (56%), HER2-positive tumors (29%) or triple negative breast cancer (TNBC, 15%). Overall, 92.2% of pts completed CT according to study protocol. Grade 4 adverse events were recorded in 356 (8%) pts, mostly neutropenia (81%). Grade 3-4 cardiac adverse events were reported in 6 (0.1%) pts. Six pts succumbed from toxicity during CT including febrile neutropenia (2 pts), acute myocardial infarction (1 pt), infection (1 pt), pulmonary embolism (1 pt) and acute respiratory failure (1 pt). In total, 134 (3%) pts were diagnosed with a secondary cancer; 126 (2.8%) with solid tumors and 16 (0.4%) with a hematologic malignancy. Median follow-up time was 8.9 years (95% CI 8.8-9.1). The 10-year DFS rate was 76% for pts with HR-positive/HER2-negative tumors, 73% with TNBC and 74% for those with HER2-positive tumors (62% and 82% in the pre-and post-trastuzumab era, respectively (p<0.001). Conclusions: dds-CT with epirubicin, taxane and CMF in the adjuvant setting was well-tolerated and was associated with favorable clinical outcomes.