Abstract S3-4: Ten year follow-up analysis of intense dose-dense adjuvant ETC (epirubicin (E), paclitaxel (T) and cyclophosphamide (C)) confirms superior DFS and OS benefit in comparison to conventional dosed chemotherapy in high-risk breast cancer patients with ≥ 4 positive lymph nodes.

Abstract

Background: The 5-year analysis of adjuvant chemotherapy with intense dose-dense (IDD) ETC had shown a significant improved DFS (HR 0.72; p < 0.001) and OS (HR 0.76; p = 0.29) in comparison with conventional dosed chemotherapy (J Clin Oncol 28: 2874–2880, 2010). In contrast to other dose-dense trials the ETC regimen is dose-dense and dose-intensified. Long-term results are essential to evaluate the impact of dose-dense chemotherapy in the adjuvant treatment of breast cancer patients (pts). We now report the final analysis of DFS, OS, and long-term safety including the application of epoetin alfa after 10 years of follow-up. Patients and Methods: A multi-center phase-III trial of the German AGO Breast Study Group recruited 1284 pts from 12/98 until 4/03. Pts below 65 years of age were eligible if at least 4 axillary lymph nodes were infiltrated. In the experimental arm, pts were assigned to receive three courses each of epirubicin (150 mg/m2), paclitaxel (225 mg/m2) and cyclophosphamide (2500 mg/m2) at 2-week intervals (q2w) (ETC) with G-CSF support (5µg/kg/SC day 3–10). In the standard arm 4 courses of conventional dosed epirubicin/cyclophosphamide (90/600 mg/m2) followed by 4 courses of paclitaxel (175 mg/m2) were given (EC→T). All cycles were administered in 3-week intervals without growth factor support. A second randomization ± epoetin alfa was performed in the IDD-ETC arm only (150IU/kg/sc three times weekly) to reduce the number of red blood cells (RBC's) transfusion and to evaluate the impact of epoetin alfa on DFS and OS in the adjuvant setting. Results: 58% and 42% of the pts presented with 4–9 and ≥ 10 positive nodes with a median number of 8 involved nodes. The median age was 51 years and median follow-up was 122 months. We observed 604 DFS events (282 with IDD ETC; 322 with EC→T) (p = 0.00014, one-sided; HR 0.74; 95% CI, 0.63 to 0.87). IDD ETC improved DFS irrespective of nodal status, HER2 and ER status. 446 pts. have died (201 events in the IDD ETC arm vs. 245 events in the standard arm). 10 year OS rates were 69% with IDD ETC and 59% with EC→ T (p = 0.0007; two-sided; HR, 0.72; 95% CI, 0.60–0.87). Nine cases of acute myeloid leukemia or myelodysplastic syndrome occurred in the IDD ETC arm vs. two cases in the standard arm. 28% of pts in the IDD ETC arm vs. 13% in the IDD ETC arm plus epoetin alfa (p < 0.0001) received RBC's transfusions. There was no difference between the IDD ETC arm alone and the IDD ETC + epoetin alfa arm regarding 10-year DFS and OS ((57% vs. 55% (p = 0.69) and 70% vs. 68% (p = 0.45)). Conclusion: Intense dose-dense ETC remains significantly superior compared to standard chemotherapy after 10 years of follow-up. The risk of secondary leukemia/MDS in the IDD ETC arm (1.3% of pts) is comparable to that of the Cancadian CEF regimen. The prevention of RBC's transfusions and anemia by the application of epoetin alfa in the IDD ETC-arm had no impact on DFS and OS. IDD ETC is a highly effective and safe regimen in the adjuvant treatment of high-risk breast cancer pts. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S3-4.

Updated Survival Analysis after a Median Follow-up of 12 Years of an Anthracycline-Containing Adjuvant Prospective Multicentre, Randomised Phase III Trial on Dose-Dense Chemotherapy in Primary Node-Positive, High-Risk Breast Cancer Patients

“…The studies mentioned above have only published data after follow-up periods of 3-5 years. The AGO-ETC study [5,20] presented comparable dose-dense long-term follow-up data of at least 10 years. The AGO-ETC trial used an anthracyclines/taxane(AT)-based combination chemotherapy regimen with dose-dense and dose-intense 3 × E(150)/P(225)/C(2500) q2w versus the standard regime 4 × EC (90/600) q3w -4 × P(175) q3w.…”

“…The long-term follow-up data after 10 years of the dose-dense and dose-intense AGO-ETC study (AGO = Arbeitsgemeinschaft Gynäkologische Onkologie; Working Group Gynaecological Oncology) were presented, showing a persistent advantage for the dose-dense, dose-intense approach with epirubicin/paclitaxel/cyclophosphamide (ETC) q2w, leading to a relapse-free survival (RFS) rate of 56% and an OS of 69% compared to EC-P q3w with an RFS of 47% and an OS of 59% for the whole cohort (p = 0.00014, HR 0.74, 95% CI 0.63-0.87; p = 0.0007, HR 0.72, 95% CI 0.60-0.87, respectively) [20]. The CALGB 9741 data presented after 12 years of follow-up support the long-term benefit of dose-dense chemotherapy [12].…”

Adjuvant Dose-Dense Chemotherapy in Breast Cancer: Standard of Care in High-Risk Patients

“…The iddETC trial recruited only high-risk patients with ≥ 4 positive lymph nodes and is the only trial which reports long-term survival data [5]. With 10 years of follow-up, event-free survival was significantly longer for the iddETC arm with 56 vs. 47% and a HR of 0.74.…”

“…Whereas meta-analyses [1,2] persistently describe a significant superiority for dose-dense treatment, the results of large phase III trials remain contradictory [3,4,5,6,7,8,9]. Some of these trials showed important differences between the dose-dense and conventional groups regarding number of cycles, type of drug, and total dose.…”

If Chemotherapy Is Indicated, Give the Optimal Regimen!

“…Although subgroup analyses are considered as hypothesis generating only, they may have consequences for clinical routine. Only (intense) dose-dense trials, which recruited exclusively high-risk patients, showed a significant benefit for ER+ and ER- patients [8,9]. …”