Adjuvant chemotherapy with or without darbepoetin in node-positive breast cancer: a safety analysis from the phase III ARA plus trial.
Authors: U Nitz, C Oberhoff, T Reimer, C Schumacher, J Hackmann, M Warm, C Uleer, V Runde, O Gluz, I Zuna
Journal: Cancer Research (2009)

Abstract Abstract #4100 Background: Modern adjuvant chemotherapy regimens may cause considerable anemia. Epoetins are currently used to reduce chemotherapy-associated anemia (CAA) rates in a variety of solid tumors. The discussion of potential effects on survival rates is highly controversial. The ARA Plus trial is a prospective randomized trial comparing adjuvant chemotherapy +- darbepoetin (ARA+ / ARA-) in node-positive breast cancer patients.&amp;#x2028; Methods: Inclusions criteria were: age of 18 to 65 years, positive lymph nodes (LN) after resection of &amp;gt;10 LN, free margins , M0 status confirmed by conventional staging. At the discretion of the investigating centre patients could receive 6 cycles T75A50C500 or 6 cycles F500E100C500) q3w. They were randomized to darbepoetin (ARA+) 500μg q3w until completion of radiotherapy or to standard supportive care. Darbepoetin was started at Hb level &amp;lt;13 g/dl (amendment 01/2008 at Hb &amp;lt;12g/dl) and stopped at 14 g/dl.&amp;#x2028; Event free survival (EFS) is the primary endpoint. Overall survival, toxicity, Hb-levels and quality of life are secondary endpoints.&amp;#x2028; Results: 1234 pts (616 ARA+/618 ARA-) from 70 centres in Germany were randomized from 01/04 to 05/08. 1130 received TAC and 104 FE100C. Baseline characteristics are well balanced in ARA+ and the ARA- patients: median age 53/53, median tumor size 2.4/2.4cm, median number of + LN is 3/3, HR+. 78%/ 75% , G3 36%/40%.&amp;#x2028; Deaths: There was 1 therapy-related death due to septic fever in the ARA+ group.&amp;#x2028; SAEs: in 1234 patients 279 serious adverse events (SAE) were reported (150 ARA+ vs. 129 ARA-). Most frequent SAEs were: leucopenia, febrile neutropenia (ARA+ 14 vs. ARA- 21)., infections and thrombosis. In ARA+ patients we observe a modest higher rate of thrombosis and cardiovascular events (ARA+ 24 vs. ARA- 13),&amp;#x2028; Toxicity: In 3429 documented cycles in 624 patients, there was significantly more anemia and diarrhea in ARA- patients and leucopenia, vomiting and nausea in ARA+ patients. In the ARA+ patients Hb-levels were stable over the whole treatment period (mean values from cycle 1-6: 12.9- 12.4g/dl, median of all cycles: 12.5 g/dl). In ARA- patients Hb-levels decreased during therapy (mean values from cycle 1-6 :13.0 -11.2g/dl, median of all cycles 11.6g/dl). Overstimulation in ARA+ patients were rare (highest reported Hb 15.8g/dl).&amp;#x2028; Conclusions: The ARA plus trial is the largest prospectively randomized trial ever done in early breast cancer exclusively focusing on the impact of adjuvant darbepoetin on outcome. The majority of the patients received 6 cycles TAC. In these patients overstimulation is an rare event. Short term toxicity and safety data are reassuring. Toxicity analysis and events on 1000 intensively monitored patients will be available in 11/08. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4100.