We evaluated the survival benefit, safety, feasibility, and tolerability of dose-dense (DD) adjuvant chemotherapy with epirubicin and paclitaxel for women with node-positive primary breast cancer. Randomised patients (n ¼ 216) received DD or conventionalschedule (CS) chemotherapy. Dose-dense regimen patients (n ¼ 108) received epirubicin 90 mg m À2 plus paclitaxel 175 mg m À2 in four 14-day cycles, then cyclophosphamide 600 mg m À2 , methotrexate 40 mg m À2 , and fluorouracil 600 mg m À2 (CMF 600/40/600) in three 14-day cycles, plus filgrastim 5 mg kg day À1 as growth support in every cycle. Conventional-schedule regimen patients (n ¼ 108) received epirubicin 90 mg m À2 plus cyclophosphamide 600 mg m À2 in four 21-day cycles, then CMF 600/40/600 in three 21-day cycles, plus filgrastim if required. After a median follow-up of 38.4 months, 71 patients (33%) relapsed or died: DD, 33 patients (15 deaths); CS, 38 patients (22 deaths). Dose dense showed a trend for improved disease-free survival (DFS) and overall survival (OS). Four-year rates of DFS and OS were 64 and 85% for DD, and 58 and 75% for CS. All seven cycles were administered to 208 patients (96%). Rates of cycle delay, discontinuation, dose reduction, and adverse events were similar in both groups. Dose-dense sequential chemotherapy with epirubicin/paclitaxel then CMF, supported by filgrastim, is safe and improves survival for patients with node-positive breast cancer.

Purpose: Although dose-dense (dd) chemotherapy plays a fundamental role in the treatment of breast cancer (BC), a variety of trials have presented divergent survival results. Here, we present data of patients with more than 3 positive axillary lymph nodes (+aLN) receiving dd chemotherapy after a median follow-up period of 12.3 years. Methods: In the years 1996-2000, 231 patients with invasive BC, ≥pN2a and no evidence of distant metastases were recruited to receive treatment A, i.e. dd 3 × epirubicin (E, 90 mg/m2) + paclitaxel (P, 175 mg/m2) every 2 weeks (q2w) followed by 3 × cyclophosphamide (C)/methotrexate/5-fluorouracil (CMF, 600/40/600 mg/m2, q2w), or treatment B, i.e. 4 × E + C (C, 600 mg/m2) q3w followed by 3 × CMF q3w. Results: 113 patients in arm A and 113 patients in arm B were analysed after an updated median follow-up of 12.3 years. The median age was 55 years, with a median number of 6 +aLN, 50.4% had a T2 and 79.2% hormone receptor-positive BC. The disease-free survival (DFS) rate was 53.1% in arm A and 42.5% in arm B (adjusted p = 0.027). The overall survival (OS) rate was 54.9% in arm A and 48.7% in arm B (adjusted p = 0.058). In the multivariable analysis, the tumour burden was a significant predictor for DFS and OS. Conclusion: The adjuvant use of dd chemotherapy led to a statistically significant improvement of DFS after a follow-up of 12.3 years.

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Background Dose dense chemotherapy (DDT) has shown improvements of disease-free survival (DFS) and overall survival for primary breast cancer patients with a high risk of relapse. There are much less data about the effect of DDT in patients with intermediate risk of recurrence (1-3 positive axillary lymph nodes). Aim of this prospectively randomized trial was to investigate the superiority of a DDT schedule over a standard chemotherapy (ST) in primary breast cancer patients with 1-3 positive axillary lymph nodes. Methods The ASG1-3 study is a prospectively randomized, open label phase III study of the Adjuvant Study Group of the NOGGO association. Patients were eligible for the trial, if they had a primary invasive breast cancer (pT1-3) with 1-3 positive axillary lymph nodes and no evidence of distant metastases. Patients were randomized to an adjuvant therapy with either 4 cycles epirubicin (90mg/m2 body surface area, BSA) and cyclophosphamide (600mg/m2 BSA) q3w, followed by 4 cycles of paclitaxel (175mg/m2 BSA) referred to as ST or to a therapy with 4 cycles of epicubicin (120 mg/m2 BSA) q2w and primary G-CSF support followed by 4 cycles of paclitaxel (175mg/m2 BSA) q2w and primary G-CSF support referred to as DDT. Trastuzumab was not given in this study. The study was designed to show an increase of 70% DFS (ST) to 80% DFS (DDT) 5 years after randomization. Comparisons were conducted using Kaplan Meier estimates, log rank tests and Cox regression analyses. In an exploratory way, subgroup analyses were performed for HER2, hormone receptor status and grading using Cox regression models with interaction terms. Results A total of 936 patients were eligible for survival analysis, of which 465 were randomized to ST and 471 to DDT from 2001 to 2004. Patient characteristics were mainly well balanced, with patients being 52.5/52.1 years old, 71.9/78.1% being hormone receptor positive, 24.4/24.6% being HER2 positive and 38.6/38.8% having a tumor grade of 3 in the ST arm and DDT arm respectively. 53 events occurred after ST and 46 after DDT. Adjusted hazard ratio (HR) was 0.87 (95%CI: 0.57-1.35; p=0.54). 5 year DFS rates were 85% (ST) vs. 87% (DDT). Hematological toxicities were the most common grade 3 or 4 adverse events. Grade 3/4 neutropenia occurred in 57.2 vs. 28.0%, grade 3/4 anemia in 15.3% vs. 17.1% and grade 3 /4 pain symptoms were seen in 13.2 vs. 12.4% of the patients in the ST arm vs. DDT arm respectively. Other grade 3/4 toxicities were less frequent than 10%. Subgroup analysis showed a significant interaction (p<0.001) between HER2 status and randomization arm with regard to DFS. In HER2 negative patients the HR was 1.53 (95%CI: 0.91-2.59), whereas in HER2 positive patients the HR was 0.22 (95%CI: 0.09-0.55). Patients with HER2 positive disease and DDT had a similar prognosis like HER2 negative patients. Conclusion In the overall population a statistically significant improvement of DFS could not be shown for the DDT arm. In patients with HER2 positive breast cancer DDT chemotherapy improved the disease-free survival to a prognosis which was similar to patients with HER2 negative disease. Citation Format: Fasching PA, Eggemann H, Krocker J, Häberle L, Volz B, Kleine-Tebbe A, Blohmer J-U, Kittel K, Hufnagel M, Janni W, Emons G, Simon E, Köhler U, Thomssen C, Kohls A, Beckmann MW, Hielscher C, Krabisch P, Zeiser T, Brodkorb T, Baier F, Nabieva N, Kellner S, Untch M, Stadie S, Budner M, Breitbach G-P, Keller M, Stickeler E, Kühn T, Tolkmitt M, Belau AK, Schmidt M, Ulm K, Kümmel S. Final results of the ASG1-3 study, a randomized phase III study comparing a standard dose chemotherapy with epirubicin/cyclophosphamide and paclitaxel with a dose dense regimen with epirubicin and paclitaxel [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-13-01.

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