This prospective randomized controlled trial was approved by the Ethics Committee of West China Hospital of Sichuan University. Written informed consent was obtained from all participants. The study was registered with the Chinese Clinical Trial Register on September 21, 2014 (Registration number: ChiCTR-TRC-10001043).
Women aged 18–70 years old with locally advanced breast cancer confirmed by core needle biopsy were eligible for our study. Locally advanced breast cancer was classified as clinical stage IIB or III according to the American Joint Committee on Cancer staging system. Before randomization, baseline chest radiography, abdominal computed tomography (CT) or magnetic resonance imaging, and bone scintigraphy were performed to exclude distant metastases. Other eligibility criteria were an ECOG performance status of 0–1; normal cardiac function; no history or evidence of abnormal hematologic, renal, or hepatic function; and no history of other neoplasm (except non-melanoma skin cancer or curatively treated carcinoma in situ of the cervix).
Patients were excluded if they were pregnant; had received prior breast cancer surgery or systemic therapy; had uncontrolled concurrent illness such as serious viral, bacterial, or fungal infections, peptic ulcers or diabetes, or autoimmune diseases; had a history of severe hypersensitivity reactions to chemotherapeutic regimens; or had any other illness deemed by the physician to affect chemotherapy tolerability.
With simple randomization, the participants were randomly assigned to the PE arm or the FEC arm. In the PE arm, intravenous infusion of epirubicin 30–40 mg/m2 and paclitaxel 70–80 mg/m2 were administered concurrently on days 1, 8, and 15 of every 4-week cycle. In the FEC arm, intravenous infusion of 5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2 were administered on day 1 of every 3-week cycle. Antimimetic drugs were administered prophylactically 30 min before the chemotherapeutic regimen was administered. During NACT, granulocyte colony-stimulating factor (G-CSF) support was required if the neutrocyte count dropped to <1.0 × 109/L.
Surgery was undertaken within 1–2 weeks of NACT completion. According to the tumor characteristics and patient preference, women underwent BCS or mastectomy. Those considered eligible for BCS had a single tumor <3 cm in diameter, with the distance between the tumor edge and nipple being ≥3 cm, had no diffuse lesion or skin involvement, and were not contraindicated for radiotherapy. All patients who underwent BCS also underwent postoperative radiotherapy. All these patients underwent axillary lymph node dissection for nodal assessment.
All study visits were completed at the Breast Cancer Center of West China Hospital. At the beginning of each cycle, history taking, physical examination, and hematologic assessment were conducted to evaluate safety. The NACT schedule was delayed if the left ventricle ejection fraction (LVEF) decreased by 15% or if the patient showed symptoms of congestive heart failure, a severe hypersensitive reaction, or other adverse events during treatment. In the PE arm, if the patients had severe neutropenia (neutrophil count <1.0 × 109/L), febrile neutropenia (grade 2 and above), or peripheral neuropathy (grade 2 and above), the dose of epirubicin and paclitaxel was reduced by 15%.
Participants were withdrawn if they had disease progression or developed severe adverse events (e.g., grade 3 or 4 non-hematologic toxicity), or at their request.
Physical examination and imaging data (ultrasonography for tumor response assessment and CT scan for metastasis monitoring) were carefully recorded for clinical assessments before treatment, every two cycles during NACT, and before surgery. The tumor response was assessed by experienced oncologists and was classified as clinical complete response (cCR), partial response (cPR), stable disease (cSD), or progressive disease (cPD). In particular, the clinical tumor response was defined as the achievement of cCR and cPR. Any controversy was solved by discussion with a third oncologist. Tumor responses were used to dictate management strategies. Those showing a cCR, defined as the disappearance of the breast tumor and enlarged nodes on clinical assessments, could undergo surgery. Those showing a cPR, defined as a reduction of ≥30% in the three largest perpendicular tumor diameters, could complete at least four NACT cycles and then undergo surgery. Those with cSD, defined as a tumor reduction of <30%, or those with cPD, defined as an increase of ≥20% in the target tumor diameter or the emergence of a new tumor, could switch NACT regimens or undergo surgery as desired.
Postoperative pathologic assessments were conducted by pathologists at the Pathology Department of West China Hospital. A pCR was defined as the complete disappearance of the invasive tumor in the breast and lymph nodes. Residual ductal carcinoma in situ (DCIS) alone was also classified as pCR. Before the assessments and data analysis, the two groups were renamed as group 1 or 2 without detailed information on the NACT provided. Therefore, the surgeons who assessed the suitability for BCS, the pathologists who assessed the postoperative specimens, and the statisticians who performed the analysis were all blinded.
All adverse events were recorded and graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0). All women who underwent at least 1 cycle of chemotherapy were included in the safety analysis. Only grade 3–4 adverse events were analyzed.
The sample size was estimated to detect a pCR rate difference of 25% for the PE arm and 10% for the FEC arm. The assumed dropout rate was 10%. A sample size of 218 participants was sufficient to provide an 80% power to detect a pCR improvement of 15% in each arm with a type I error rate of 0.05.
All data were analyzed based on the intent-to-treat principle at randomization. Descriptive data were used to analyze patient characteristics. Quantitative data were compared using an independent sample t test, and qualitative data were compared using the Chi square test. Ranked data were compared using a non-parametric test. Statistical tests were considered significant with a two-sided P value of <0.05. All data were analyzed using SPSS version 16.0 (SPSS Inc., Chicago, IL, USA).