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.
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).
In another study designed to evaluate whether ESAs improved quality of life, 70 patients with non–small-cell lung (NSCLC) cancer with an Hb < 12 g/dL who were not receiving chemotherapy were randomized to treatment with ESAs to maintain an Hb level of 12–14 g/dL. Although it initially planned to accrue 300 patients, the study was closed after enrolling only 70 patients because interim analysis showed a significant decrease in median survival (68 days) compared with placebo (131 days, P = .04), and the majority of deaths were reported as due to disease progression. Also, treatment with ESAs did not significantly reduce the need for RBC transfusion or improve quality of life.
The Danish Head and Neck Study Group Trial randomized 484 patients with advanced head and neck cancer receiving radiation therapy to placebo or treatment with an ESA to maintain an Hb level of 14–15.5 g/dL. Interim results indicated a 10% increase (P < .01) in locoregional tumor progression and a trend towards decreased overall survival in the patients treated with an ESA.
Lastly, in February 2007, the FDA was notified that Hoffmann-La Roche suspended its study of a new pegylated epoetin beta product in anemic patients with stage IIIB or IV NSCLC receiving first-line chemotherapy. The new ESA was compared with darbepoetin administered to achieve an Hb level of 11–13 g/dL. Although the study results have not been formally released, the company stated that the reason for the trial closure involved safety concerns.
The aggregate of data raises concern that ESAs may enhance thrombosis, tumor growth, and tumor angiogenesis. For many years it was assumed that erythropoetin acts exclusively on erythroid progenitor cells in the bone marrow; however, there is accumulating evidence that erythropoietin receptors are also found on some tumor cells, and that ESAs may stimulate both angiogenesis and tumor growth.
In response to emerging safety concerns, the FDA issued a health-care professional alert and added a black box warning to the prescribing information for ESAs on March 9, 2007. The new prescribing information warns that serious cardiovascular, arterial, and venous thromboembolic events; increased risk of tumor progression; and decreased overall survival can occur with the use of ESAs to achieve a target Hb level > 12 g/dL in cancer patients.
The FDA alert reminds health-care providers that ESAs are not FDA-approved to treat anemia in cancer patients not receiving chemotherapy, as there is no proven benefit and ESAs may shorten the time to death. The FDA also concluded that ESAs do not improve cancer treatment outcome, alleviate fatigue, increase energy, or improve quality of life. ESAs should only be administered to avoid RBC transfusions in cancer patients undergoing chemotherapy.
To minimize risks associated with ESAs, the FDA recommends that health-care professionals prescribe the lowest dose that will gradually raise the Hb concentration to the lowest level sufficient to avoid the need for blood transfusions. The National Comprehensive Cancer Network anemia guidelines suggest considering ESA therapy when the Hb level is < 10 g/dL for asymptomatic patients and < 11 g/dL for symptomatic patients.
The FDA recommends that the dose of epoetin alfa or darbepoetin be reduced by 25% when the Hb approaches 12 g/dL or increases > 1 g/dL in any 2 weeks. If the Hb exceeds 12 g/dL, the dose should be withheld until the Hb falls below 11 g/dL and it should be restarted at 25% less than the previous dose.[3,4] The Hb level should be measured twice a week for 2 to 6 weeks after any dose adjustment.
In July 2007, the Centers for Medicare and Medicaid Services (CMS) revised their national coverage guidelines to limit reimbursement of ESAs. The new guidelines are more restrictive and limit coverage for ESAs to cancer patients receiving chemotherapy whose Hb level is < 10 g/dL prior to initiation of ESA treatment and during maintenance of ESA treatment.
If the Hb level is > 10 g/dL at any time after the first 4 weeks of therapy, ESAs will not be covered. If the Hb rise is > 1 g/dL during any 2-week period, ESAs will not be covered. Additionally, the Hb level must be documented prior to every ESA dose and the duration of ESA treatment is limited to 8 weeks following the last dose of chemotherapy.
The American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) have raised concerns about the breadth of the new CMS restrictions.[17,18] Although it is reasonable to initiate ESA treatment when the Hb level is < 10 g/dL, it is of concern that ESAs will no longer be covered if the Hb level is > 10 g/dL while the patient is on maintenance therapy with ESAs. This is not consistent with revised FDA labeling for ESAs or with published ASH and ASCO guidelines for ESA use which recommend maintenance with an ESA as long as the Hb level is < 12 g/dL.
Because ESAs may take 2–6 weeks to exert their full effect, limiting coverage to patients only when the Hb is < 10 g/dL could result in stopping and restarting treatment several times during a course of therapy. Also, patients will be burdened with additional laboratory work to document the Hb level prior to every ESA dose. ASCO and ASH continue to appeal to CMS to reconsider their policy. An updated version of the ASH-ASCO guidelines for epoetin use is due to be published in Blood and in the Journal of Clinical Oncology.
Anemia is a common clinical problem in cancer patients. Though epoetin alfa and darbepoetin effectively reduce the need for blood transfusions in anemic cancer patients undergoing chemotherapy, the benefits and risks of these agents should be considered for each patient, and they should be prescribed according to FDA guidelines.
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