Sequential vs concurrent epirubicin and docetaxel as adjuvant chemotherapy for high-risk, node-negative, early breast cancer: an interim analysis of a randomised phase III study from the Hellenic Oncology Research Group

Abstract

Background:Sequential anthracyclines and taxanes are standard adjuvant chemotherapy for patients with high-risk axillary node-positive breast cancer. We compared a sequential to a concurrent regimen in high-risk node-negative early breast cancer.Methods:Patients were eligible if they had tumours >2 cm or T1c with two of the following characteristics: no oestrogen receptor (ER) and progesterone receptor (PR) expression, histological grade III, Ki67 >40% and vascular, lymphovascular or perineural invasion. They were randomised to receive four cycles of epirubicin 90 mg m−2 followed by four cycles of docetaxel 75 mg m−2 (sequential regimen) or six cycles of epirubicin 75 mg m−2 plus docetaxel 75 mg m−2 (concurrent regimen). All chemotherapy cycles were administered every 21 days with G-CSF prophylaxis only for the concurrent arm. The primary endpoint was disease-free survival (DFS).Results:Between 2001 and 2013, 658 women received the sequential (n=329) or the concurrent (n=329) regimen. The median age was 53 years, 43.9% of the patients were premenopausal and of the tumours 44.2% were ⩽2 cm, 52.7% histological grade 3 and 35.3% hormone receptor-negative. After a median follow-up of 70.5 months, there were 29 (8.8%) vs 42 (12.8%) disease relapses (P=0.102) and 11 (3.3%) vs 19 (5.8%) deaths (P=0.135), in the sequential and concurrent arm, respectively. The 5-year DFS rates were 92.6% vs 88.2% for sequential and concurrent arm, respectively (hazard ratio (HR): 1.591; 95% confidence interval (CI): 0.990–2.556; P=0.055). Toxicity included grade 2–4 neutropenia in 54% vs 41% (P=0.001), febrile neutropenia 2.7% vs 6.1% (P=0.06), nausea/vomiting 18.5% vs 12.4% (P=0.03) of patients in the sequential and concurrent arm. There were no toxic deaths.Conclusions:Sequential compared with the concurrent administration of anthracyclines and taxanes is associated with a non-significant but possibly clinically meaningful improvement in DFS. In the era of molecular selection of patients for adjuvant chemotherapy, this study offers valuable information for the optimal administration of anthracyclines and taxanes in patients with node-negative disease.

Prognostic Significance of TWIST1, CD24, CD44, and ALDH1 Transcript Quantification in EpCAM-Positive Circulating Tumor Cells from Early Stage Breast Cancer Patients

“…Peripheral blood (20 mL) was obtained from all these patients two weeks after the removal of the primary tumor and before the initiation of adjuvant chemotherapy. The chemotherapeutic adjuvant treatment for these patients has been previously reported [34]. The clinical characteristics for these patients at the time of diagnosis are shown in Supplementary Table S1.…”

Sequential Vs Concurrent Adjuvant Chemotherapy for Operable Breast Cancer: A Meta-analysis

“…This is consistent with other reports that "lower doses" (30mg/m 2 ) of doxorubicin are correlated with inferior survival compared with "higher doses" (60 and 40mg/m 2 ) [14,15].Secondly, the dose intensitywashigher in both doxorubicin validated the nding from NEAT trial [16] that a higher dose intensity confers a greater favorable long-term outcome. The principle behind dose density relates to the Gompertzian model and Norton-Simon hypothesis that smaller tumor grows faster so that the regrowth rate is higher between treatment cycles [17,18], and as tumor shrinks, the regrowth rate increases to make the chemotherapy level capable of initiating regression be insu cient to maintain this regression and produce cure, indicating the regression rate may be overcome by switching to alternative cytotoxic therapy [19].On the contrary, the left four trials [8,[11][12][13]did not indicate any signi cant better survival in sequential regimens than that in concurrent treatment. Given these trials'patients assigned to the concurrent treatment were administrated higher cumulative dosethanBig02-98 [10] and NSABP-30 [9], it may be inferredthatperhaps once the threshold of total dose is surpassed, higher cumulative doses do not add to e cacy.…”

“…Secondly, heterogeneity, which may affect the result, exists in several trials. HE 10/00 trial [13]included patients with pathological stage T4, while HORG trial [11]focused on patients with early breast cancer as well as node-negative and high risk. Besides, the choice of anthracyclines and the cycles of treatment in the 6 trials are different.…”

“…Eligible patients in HORG trial [11]were early breast cancer patients with high risk and node-negative, while the other trials included patients with node-positive.We conducted a sub-analysis according to the axillary lymph node status. The pooled estimate showed that there wasa signi cant better DFS in patients with node-positive administrated with sequential regimens (RR: 1.08;95%CI:1.02-1.14, P=0.004, Figure 5A),yet the OS were approximate between both regimens (RR: 1.07;95%CI:0.96-1.19, P=0.24, Figure 5B).…”

Adjuvant chemotherapy provided survival benefit for stage T2N0 gastric cancer with high-risk factors

“…These included high grade and large tumors, older age and lymphatic vessel and nerve invasion [9,10]. These high-risk factors were not only demonstrated to be indepen-dent poor prognostic markers for survival, but also markers for adjuvant chemotherapy in various kinds of solid tumor, such as non-small cell lung cancer [11], colorectal cancer [12] and breast cancer [13]. It is believed that the high-risk groups from T2N0 GC potentially benefit from adjuvant chemotherapy.…”