A study published in the July 17, 2013 issue of Journal of the National Cancer Institute (JNCI) [1]shows that the addition of the erythropoiesis-stimulating agent (ESA) epoetin alfa (Epogen?, Amgen;Eprex?, Janssen-Cilag;Procrit?, Janssen Products)to the chemotherapy regimen in patients with high-risk breast cancer may help avoid a decrease in hemoglobin levels and resulting anemia often seen in these patients. Adding epoetin alfa also resulted in a decrease of red blood cell (RBC) transfusions.

In this study, designed to investigate the safety and efficacy of epoetin alfa, Volker Moebus, M.D., of the Department of Gynecology and Obstetrics, at the Klinikum Frankfurt H?chstin Frankfurt, Germany, and colleagues, conducted a second randomized study of patients in the intense dose-dense (IDD) chemotherapy arm of the AGO-ETC trial (NCT01690702).


…ESAs appear to be safe drugs for the treatment of chemotherapy-induced anemia in patients with IDD chemotherapy regimens…


No negative impact
The outcome of this second randomized study suggest that adding epoetin alfa to the chemotherapy regimen doesnot negatively affect relapse-free (RFS) or overall survival (OS). However, the study authors note that it can increase the risk of thrombotic events.

Anemia
Anemia, an abnormally low hemoglobin concentration in the blood (female: < 120 g/l, male < 1340 g/l),is frequent in cancer patients, especially in patients receiving chemotherapy or radiotherapy. Themulti-symptom syndrome involves both physical and emotional problems that can be evaluated for their negative impact on the patient’s quality of life.Fatigue is the cardinal symptom of anemia, reported by three of four cancer patients using the general version of the Functional Assessment of Cancer Therapy (FACT-G) questionnaire.

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Chemotherapy
Standard adjuvant chemotherapeutic regimens of breast cancer patients lead to a clinically significant degree of anemia. Studies have shown that the anthracycline-containing regimen such as the French FEC regimen (5-fluorouracil, epirubicin, cyclophosphamide), for example, induces anemia grades 1 to 3 in 42.4% of patients [2]. Other treatment options, such as dose-dense combination regimens with granulocyte colony-stimulating factor (G-CSF) support [3], includered blood cell (RBC) transfusions in 13% of the patients and intense dose-dense regimens such as intense dose-dense (IDD) sequential chemotherapy with epirubicin (E), paclitaxel (T), and cyclophosphamide (C) (IDD-ETC) or doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) (IDD-ATC) include RBC transfusions in 25% to 67% of patients. [4][5]

Trial results

In the trial (n=643) patients receiving the sequential chemotherapy regimen of epirubicin, paclitaxel, and cyclophosphamide, 324 were randomly assigned to receive the ESA epoetin alfa and 319 were assigned to the non-ESA group. The authors compared change in hemoglobin level, percentage of subjects requiring red blood cell (RBC) transfusion, incidence of thrombotic events, and, after a median follow-up of 62 months, OS, RFS and intra-mammary relapse in the two groups.

The researchers found that the patients in the non-ESA group had statistically significant reduction in hemoglobin levels and required more RBC transfusions than those in the ESA treatment group (28.1% vs 12.8%). ESA treatment had no impact on OS, RFS or intra-mammary relapse. However, patients treated with epoetin alfa were approximately twice as likely to experience thrombotic events compared with patients in the non-ESA group (7% vs 3%). The authors conclude that “?ESAs appear to be safe drugs for the treatment of chemotherapy-induced anemia in patients with IDD chemotherapy regimens.”

In an accompanying editorial, Chau Dang, M.D., Clifford Hudis, M.D., and Larry Norton, M.D., of the Memorial Sloan-Kettering Cancer Center in NY, write that the study of Moebus et al. “provides important evidence that ESAs may be safe in the curative treatment of cancer.” However, they cite some limitations of the study, ie, a much larger sample size would be needed to unequivocally conclude that epoetin alfa had no effect on OS or RFS; the still unacceptably high transfusion rate (13%) in the ESA group; the high cost of ESAs given that they do not improve OS or RFS, and the approximately two-fold rate of thromboembolic events in the ESA group.[6]

In a second editorial, Brian Leyland-Jones, M.B. B.S., Ph.D., of Edith Sanford Breast Cancer Research in SD, attempted to put this article into the context of the significant controversy surrounding this field, in terms of the effect of ESAs on overall survival, tumor progression and risk of thrombosis. [7] He especially focused on trials where ESAs were prescribed within label. He noted that these drugs are powerful pharmacological tools, and in an era dominated by personalized medicine, should be prescribed according to individualized risk-benefit ratio.

For more information:
[1] Moebus V, Jackisch C, Schneeweiss A, Huober J, Lueck HJ, Du Bois A, et al. Adding Epoetin Alfa to Intense Dose-Dense Adjuvant Chemotherapy for Breast Cancer: Randomized Clinical Trial. JNCI J Natl Cancer Inst (2013) 105 (14): 1018-1026. doi: 10.1093/jnci/djt145 [Full Article][PDF]
[2] Bonneterre J, Roch? H, Kerbrat P, et al. Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node- positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol. 2005;23:2686?2693. [Abstract]
[3] Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of intergroup trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21:1431?1439.[Abstract]
[4] Moebus V, Heilmann V, Schneeweiss A, et al. Supportive therapy with epoetin-alpha in breast cancer patients (pts) receiving dose-dense sequential chemotherapy with epirubicin, paclitaxel and cyclophosphamide (ETC). Eur J Cancer. 2001;37(Suppl6):S171.
[5] Hudis C, Fornier M, Riccio L, et al. 5-year results of dose-intensive sequential adjuvant chemotherapy for woman with high-risk node-positive breast cancer: a phase II study. J Clin Oncol. 1999;17:1118?1126.[Abstract]
[6] Dang C, Hudis C, Norton L. Epoetin Alfa: To Give or Not to Give
JNCI J Natl Cancer Inst (2013) 105 (14): 1001-1003 doi:10.1093/jnci/djt172 [Abstract]
[7] Brian Leyland-Jones Erythropoiesis Stimulating Agents: A Personal Journey JNCI J Natl Cancer Inst (2013) 105 (14): 999-1001 doi:10.1093/jnci/djt171 [Abstract]

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