Second interims analysis of the ARA Plus study – Breast Cancer (BC) adjuvant chemotherapy (CT) with and without darbepoetin alfa (Aranesp®) – Analysis serious adverse events

Adjuvant chemotherapy improves survival in node positive breast cancer. TAC is one of the most effective regimens, but it is associated with higher frequency of anemia and chemotherapy-induced neutropenia (CIN). The erythropoiesis stimulating factor (ESF) support of chemotherapy, its complications and survival effect remain unclear. Erythropoetins do prevent chemotherapy-associated anemia (CAA) and subsequent fatigue syndrome but their potential influence on survival is still unclear. Two aims of this analysis are to investigate the amount of hemoglobin (Hb) response and the correlation between CT, growth factor support and toxicity. The goal of the Aranesp® (ARA) therapy in the ARA Plus trial was an increase of the mean Hb value of 2g/dl.

Methods: This ARA Plus phase III trial compare chemotherapy +/-ARA in breast cancer patients >18 years old, with positive lymph nodes and with M0 disease. Pts get six cycles of of 5-fluoro-uracile 500mg/m2, epirubicine 100mg/m2 and cyclophosphamide 500mg/m2, (FEC, Bonneterre), 3-weekly or six cycles of docetaxcel 75mg/m2, adriamycin 50mg/m2 and cyclophosphamide 500mg/m2, (TAC, BCIRG) and are randomized to ARA 500µg q3w if Hb<13g/dl or standard support care. Toxicity, hemoglobin responses, transfusion requirements were measured. Here are the results of the SAEs

Results: A total of 749 pts (194 + ARA/182 -ARA) from 53 sites were enrolled since January 2004, there are 1234 pts. planned up to January 2008. 185 serious adverse events (SAE) are reported. Of these 185 SAE's 100 (54%) had an ARA-therapy. Most frequent SAE's were: leucopenia, febrile neutropenia, thrombosis and infections. In 9 (31%) out of the 29 febrile neuropenia SAE's, ARA was given. 30 thromboses were reported (23+ARA/7-ARA s.) but only 10at the verty time ARA was given. In 31 severe infections 16 (51,6%; n.s.) were reported in patients receiving ARA Therapy. Fever of unknown origin could be seen in 6 pts., ARA was given only to one out of these. From 43 patients with intestinal SAEs like Diarrhea/Mucositis/Nausea to 30 pts. (69,8%) ARA eas given. Over all there were 1 death in each group.

Conclusion: The combination of CT and ARA is safe concerning febrile neutopenia and furthermore appears to be protective factor of this SAE when combined with TAC. These findings are in contrast to recent news about erythropoiesis-stimulating agents. On the other hand there seem to be more SAEs concerning thrombosis and intestinal difficulties. These results allow to hypothesize that ARA therapy which induces a well tolerated and beneficial Hb level in BC pts is associated with higher toxicity concerning thrombosis which could make the use of heparin necessary but on the other side it shows significant reduced neutropenia. Actually complete data on anaemia and toxicity will be presented.