The use of erythropoietic growth factors to treat chemotherapy-induced anemia (CIA) has been increasing as clinicians become more aware of the ability of these drugs to improve the quality of life of patients with cancer. The cost associated with erythropoietic growth factor therapy makes its appropriate use a practical issue for physicians and hospitals. Clinical practice guidelines can benefit physicians by increasing practice efficiency, reducing medical errors, increasing the quality of medical care, and decreasing reimbursement problems. The American Society of Clinical Oncology and the American Society of Hematology, the European Organisation for Research and Treatment of Cancer, and the National Comprehensive Cancer Network (NCCN) have all published guidelines for using erythropoietic growth factors to treat CIA, and this article reviews and summarizes those guidelines. Of the three guidelines for the use of erythropoietic growth factors in CIA, the NCCN guidelines are based on the most recent data. Current evidence indicates that erythropoietic growth factors can increase hemoglobin levels, reduce the need for red blood cell transfusions, and improve quality of life; the effect of erythropoietic therapy on outcomes in patients with CIA is still being investigated.
Clinical practice guidelines can benefit physicians by increasing practice efficiency, reducing medical errors, increasing the quality of medical care, and decreasing reimbursement problems. The use of erythropoietic growth factors to treat chemotherapy-induced anemia (CIA) has been increasing as clinicians become more aware of the ability of these drugs to improve the quality of life of patients with cancer. The cost of erythropoietic growth factor therapy makes its appropriate use a practical issue for physicians and hospitals. Three practice guidelines for the use of erythropoietic growth factors to treat CIA have been published. In this article, the guidelines and current recommendations for treating CIA are summarized and discussed.
In 1997, the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) began discussions on developing clinical practice guidelines for the use of erythropoietic therapy in patients with cancer. At that time, epoetin was the only erythropoietic growth factor available. The two organizations established a panel of experts to develop guidelines that were based on the Agency for Healthcare Research and Quality topic review of epoetin, which was released in 2001.
That review covered the medical literature on erythropoiesis-stimulating agents published between January 1985 and October 1999; epoetin alfa (Procrit) was the primary drug evaluated. Evidence was weighted such that the results of large randomized controlled trials and meta-analyses were given greater weight. In the absence of compelling evidence, panel conclusions were reached by consensus. The resulting ASCO/ASH guidelines, published in 2002 and summarized in Table 1, are "a blend of evidence, the opinion of experienced practitioners, and their interpretation of the evidence."
Epoetin alfa was recommended in patients with CIA and a hemoglobin (Hgb) level less than 10 g/dL, administered according to the prescribing information—150 U/kg tiw, escalated to 300 U/kg tiw if there is no response after 4 weeks—or at the recommended dose of 40,000 U/wk, with dose escalations in nonresponders. The target Hgb level was established at (or near) 12 g/dL, with the dose of epoetin alfa adjusted to maintain it at that level. In patients who do not respond to escalated doses, the guidelines suggest that iron deficiency be evaluated.
More recently, the European Organisation for Research and Treatment of Cancer (EORTC) published its guidelines for the use of erythropoietic growth factors in patients with cancer and CIA. The EORTC literature search covered the years 1996 through 2003; epoetin alfa, epoetin beta, and darbepoetin alfa (Aranesp) were reviewed. The evidence levels and weighting methods were similar to those used by ASCO and ASH. The EORTC panel focused on addressing specific questions, including the threshold Hgb level for initiating therapy, the target Hgb level, the utility of dose escalation, the prevention of red blood cell transfusions, the effects on quality of life and survival, the optimal regimens, and the adverse effects of erythropoietic growth factors. The EORTC guidelines, summarized in Table 2, were published in 2004.
Erythropoietic growth factor therapy was recommended to improve quality of life and prevent red blood cell transfusions in patients with cancer and anemia. It was suggested that treatment be initiated at Hgb levels of 9 to 11 g/dL, on the basis of the patient's symptoms. The target Hgb level was 12 to 13 g/dL. There was support in the literature for the use of all three growth factors (epoetin alfa, epoetin beta, and darbepoetin alfa). The risks for pure red cell aplasia and thrombosis were discussed, but the latter risk appeared to be related to the Hgb level achieved.
The National Comprehensive Cancer Network (NCCN) is an alliance of 19 major cancer centers in the United States whose primary focus is on disseminating information on cancer care to patients and health-care workers. To this end, it has developed numerous practice guidelines in oncology, including guidelines for supportive care. The most recently published guidelines (in 2006) for the management of cancer- and treatment-related anemia are available on the NCCN website (www.nccn.org) and onCD-ROM. Panel members from NCCN institutions reviewed an updated Cochrane database on the use of erythropoietic growth factors in patients with cancer as the basis for the 2006 guidelines. Most of the recommendations in the guidelines are based on categories of consensus, either level 1-uniform consensus based on high-level evidence (large randomized controlled trials and meta-analyses)—or level 2A-uniform consensus based on low-level evidence, including clinical experience. The NCCN guidelines are summarized in Table 3.
Dr. Rodgers is on the speakers bureau of and has participated in clinical trials for Amgen.
1. Sackett DL, Rosenberg WM, Gray JA, et al: Evidence based medicine: What it is and what it isn't. Br Med J 312:71-72, 1996.
2. Littlewood TJ, Bajetta E, Nortier JW, et al: Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: Results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 19:2865-2874, 2001.
3. Rizzo JD, Lichtin AE, Woolf SH, et al: Use of epoetin in patients with cancer: Evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. Blood 100:2303-2320, 2002.
4. Procrit (epoetin alfa) prescribing information. Raritan, NJ, Ortho Biotech Products, LP, 2005.
5. Bokemeyer C, Aapro MS, Courdi A, et al: EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 40:2201-2216, 2004.
6. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Cancer and treatment-related anemia. Version 1.2006. Available at http//:www.nccn.org. Accessed March 3, 2006.
7. Crawford J, Cella D, Cleeland CS, et al: Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer 95:888-895, 2002.
8. Aranesp (darbepoetin alfa) prescribing information. Thousand Oaks, Calif, Amgen Inc, 2006.
9. Auerbach M, Ballard H, Trout JR, et al: Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: A multicenter, open-label, randomized trial. J Clin Oncol 22:1301-1307, 2004.
10. Schwartzberg LS, Yee LK, Senecal FM, et al: A randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer. Oncologist 9:696-707, 2004.
11. Waltzman R, Croot C, Justice GR, et al: Randomized comparison of epoetin alfa (40,000 U weekly) and darbepoetin alfa (200 microgm q2w) in anemic patients with cancer receiving chemotherapy. Oncologist 10:642-650, 2005.
12. Glaspy J, Berg R, Tomita D, et al: Final results of a phase 3, randomized, open-label study of darbepoetin alfa 200 mcg every 2 weeks (Q2W) versus epoetin alfa (40,000 U weekly (QW) in patients with chemotherapy-induced anemia. J Clin Oncol 23(16s):760s, 2005.
13. Senecal FM, Yee L, Gabrail N, et al: Treatment of chemotherapy induced anemia in breast cancer: Results of a randomized controlled trial of darbepoetin alfa 200 microg every 2 weeks versus epoetin alfa 40,000 U weekly. Clin Breast Cancer 6:446-454, 2005.
14. Locatelli F, Pisoni RL, Akizawa T, et al: Anemia management for hemodialysis patients: Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines and Dialysis Outcomes and Practice Patterns Study (DOPPS) findings. Am J Kidney Dis 44(5 suppl 3):27-33, 2004.