In cancer patients, anemia is multifactorial, resulting from cancer treatment, anemia of malignancy, blood loss, impaired production of or response to erythropoietin, and dysregulation of iron metabolism (decreased dietary iron intake, absorption, and utilization). Clinical studies have found that erythropoietin stimulating agents (ESAs) increase hemoglobin (Hb) levels and reduce the need for blood transfusions by 40%, with ESA-treated patients receiving an average of 1 unit less of red blood cells (RBCs) than non-ESA-treated anemic cancer patients.[1,2]
Epoetin alfa (Procrit) and darbepoetin alfa (Aranesp) are approved to treat anemia in cancer patients receiving chemotherapy.[3,4] However, in everyday practice, ESAs are often prescribed not only at FDA-approved doses for cancer patients receiving chemotherapy but also for other cancer patients, or using unapproved dosing regimens. ESAs are now leading drugs used in oncology, with $11.9 billion in worldwide sales in 2006. Anemia has been associated with decreased overall survival in cancer patients. It was hypothesized that correction of anemia by ESAs would improve tumor oxygenation and thus the response to chemotherapy and radiation, resulting in improved overall survival.
Early studies evaluating use of ESAs to correct anemia were not powered to measure overall survival, but a meta-analysis summarizing the data from 27 clinical trials from 1985–2001 found a nonsignificant trend toward improved overall survival in ESA-treated patients. In 2006, a repeat meta-analysis which included additional trials conducted from 2001–2005 summarized the results of 57 clinical trials in which 9,353 cancer patients with anemia were randomized to an ESA or RBC transfusions alone.[1,2]
The impact of ESAs on overall survival was inconclusive, however there was evidence that ESAs could, in certain circumstances, adversely affect survival in cancer patients. In addition, there were significant risks associated with ESA use, including thromboembolic complications (eg, transient ischemic attacks, stroke, pulmonary emboli, deep vein thrombosis, and myocardial infarction) and hypertension.[1,2]
EMERGING safety CONCERNS
Two large trials specifically designed to measure overall survival in cancer patients treated with ESAs to maintain Hb higher than the recommended level of 12 g/dL concluded ESAs had an adverse effect. Henke and colleagues demonstrated that patients with advanced head and neck cancer receiving radiation therapy had a higher risk of tumor progression if treated with an ESA to achieve a target Hb >14 g/dL in women and >15 g/dL in men. The BEST trial showed maintenance of an Hb of 12–14 g/dL in metastatic breast cancer patients undergoing first-line chemotherapy was associated with decreased overall survival.
In the past year, four additional clinical trials found a higher incidence of serious adverse effects and/or death with use of ESAs in unapproved dosing regimens or in patients not receiving chemotherapy.
In January 2007, the FDA was notified of the interim analysis of a clinical trial evaluating the use of ESAs to achieve a target Hb level of 12 g/dL in 989 patients with cancer-related anemia not receiving chemotherapy. In this study, the use of an ESA did not reduce the need for RBC transfusions, and it increased overall mortality (hazard ratio 1.25; 95% confidence interval: 1.04, 1.51).
1. Bohlius J, Wilson J, Seidenfeld J, et al: Recombinant human erythropoietins and cancer patients: Updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 98(10):708–714, 2006.
2. Bohlius J, Wilson J, Seidenfeld J, et al: Erythropoietin or darbepoetin for patients with cancer. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD003407. DOI: 10.1002/14651858.CD003407.pub4.
3. Procrit (epoetin alfa) Full Prescribing Information. Ortho Biotech Products, LP, Raritan, New Jersey, June 2007. Available at: http://www.orthobiotech.com/common/prescribing_information/PROCRIT/PDF/ProcritBooklet.pdf.
4. Amgen: Aranesp prescribing information, 2007. Available at: http://www.aranesp.com/pdf/aranesp_PI.pdf.
5. U.S. Food and Drug Administration: Information for Healthcare Professionals. Erythropoiesis Stimulating Agents (ESA) [Aranesp (darbepoetin), Epogen (epoetin alfa), and Procrit (epoetin alfa)]. FDA Alert 2:16, 2007. Available at http://www.fda.gov/cder/drug/InfoSheets/HCP/RHE2007HCP.htm.
6. Top 20 Biologics. In: PipelineReview.com. La Merie Business Intelligence, Barcelona, Spain (www.lamerie.com). Available at: http://www.pipelinereview.com/Top_20_Biologics_by_La_Merie.pdf.
7. Leyland-Jones B, Semiglazov V, Pawlicki M, et al: Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: A survival study. J Clin Oncol 23:5960–5972, 2005.
8. Bohlius J, Langensiepen S, Schwarzer G, et al: Recombinant human erythropoietin and overall survival in cancer patients: Results of a comprehensive meta-analysis. J Natl Cancer Inst 97:489–498, 2005.
9. Henke M, Laszig R, Rube C, et al: Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. Lancet 362:1225–1260, 2003.
10. U.S. Food and Drug Administration: 2007 Safety Alert: Aranesp (darbepoetin alfa). Available at: http://www.fda.gov/medwatch/safety/2007/Aranesp_DHCP_012707.htm.
11. Wright JR, Ung YC, Julian JA, et al: Randomized, double-blind, placebo-controlled trial of erythropoietin in non–small-cell lung cancer and disease-related anemia. J Clin Oncol 25:1027–1032, 2007.
12. Danish Head and Neck Cancer Group. Interim analysis of DAHANCA 10, 12:1 2006. Available at http://www.dahanca.dk/get_media_file.php?mediaid=125.
13. Hoffmann-La Roche Limited. Recruitment Temporarily Suspended Into C.E.R.A. Phase II Oncology Trial. Roche Media News 2:23, 2007. http://www.roche.com/med-cor-2007–02-23c.
14. Acs G, Acs P, Beckwith SM, et al: Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res 61:3561–3565, 2001.
15. National Comprehensive Cancer Network. Cancer- and Treatment-Related Anemia, V.2.2007. Available at http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf.
16. Centers for Medicare and Medicaid Services (CMS): Decision Memo for Erythropoiesis Stimulating Agents (ESAs) for non-renal disease indications (CAG-00383N). Available at: http://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=203.
17. American Society of Clinical Oncology Letter, August 3, 2007. Available at: http://www.asco.org/ASCO/Downloads/Cancer%20Policy%20and%20Clinical%20Affairs/MMA%20Regulations%20and%20Resources/ASCO%20Letter%20to%20CMS%20on%20ESA%20Decision%2008-03-07%20final%20lthd.pdf Accessed September 20, 2007
18. American Society of Hematology Letter, August 8, 2007. Available at: http://www.hematology.org/policy/testimony/ASHltr_CMS_Scenarios_08082007.pdf