	Practicing clinicians and healthcare administrators face many challenges in treating cancer patients, including management of chemotherapy-induced anemia. Information on how to best treat these patients comes from a variety of sources: clinical guidelines provide direction based on evidence-based literature, the US Food and Drug Administration (FDA) provides guidance on safe administration and use of erythropoiesis-stimulating agents (ESAs), and insurance providers drive treatment based on evidence and policy. With all of the directives on how to treat chemotherapy-induced anemia, integration of concepts and current data must be completed to determine the appropriate use of ESAs in cancer. The landscape surrounding erythropoietin agents is shifting as questions surround the safety and appropriate use of these agents in cancer patients. The clinical decision between blood transfusions and use of ESAs has become more difficult, as there are safety warnings concerning ESAs and questions regarding the safety of blood transfusions.

	The American Society of Hematology (ASH)/American Society of Clinical Oncology (ASCO) has called for a meta-analysis of data to determine factors contributing to (1) the risks surrounding transfusions or adverse event of ESAs, or both; (2) faster tumor progression or shorter survival in some ESA-treated patients; and (3) a better understanding of effectiveness of ESAs for anemia not related to chemotherapy (anemia of cancer) and eventually help guide the design of new clinical trials. The Erythropoiesis Stimulating Agents in Cancer Patients: Individual Patient Data Meta-Analysis Collaborative Group presented a meta-analysis at the December 2008 ASH meeting. Their timely efforts analyzed data for 13,933 patients from 53 studies. ESAs increased on-study mortality by 17% (hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.06-1.30; 

= .002) and worsened overall survival by 6% (HR, 1.06; 95% CI, 1.00-1.12; 

= .005). Chemotherapy patients also had worse outcomes, with on-study mortality increasing by 10% (HR, 1.10; 95% CI, 0.98-1.24; 

= .12) while overall survival decreased by 4% (HR, 1.04; 95% CI, 0.97-1.11; 

= .26). Since the CI crossed 1 in the chemotherapy subset, it appears from this meta-analysis that ESAs decrease survival in chemotherapy patients, but caution should be used in all patients using ESAs.

	From the meta-analysis, Bohlius et al2 determined the number needed to harm (NNH) for cancer patients with various prognoses. For low-risk patients who have a 5% chance of mortality within the next 4 months, the NNH was 121 (95% CI, 69-343). For medium-risk patients who have a 20% risk of mortality within months, the NNH was 34 (95% CI, 19-94). Finally, for high-risk patients with a 70% risk of mortality within 4 months, the NNH was 24 (95% CI, 14-67).

	These data confirmed the FDA warnings issued in March 2007 and proposed a framework for the ASH/ASCO 2007 guidelines. The guidelines included warnings derived from prior published or presented data that were then solidified as black box warnings in ESA labeling which: (1) shortened the time to tumor progression in patients with advanced head and neck cancers receiving radiation therapy when administered to target a hemoglobin level >12 g/dL (Ezetimibe and Simva&shy;statin in Hypercholesterolemia Enhances Atherosclerosis Regres&shy;sion [ENHANCE] and Danish Head and Neck Cancer Study [DAHANCA] Group, 10 trials); (2) shortened overall survival and increased mortality attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a hemoglobin level >12 g/dL (Breast Cancer Erythropoietin Trial [BEST]); and (3) increased the risk of death when administered to target a hemoglobin level of 12 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy (Randomized Trial of Epoetin Alfa in Patients With Advanced Non-Small Cell Carcinoma of the Lung [EPO-CAN-20] and Amgen 20010103 trials). The FDA warning established that treating patients to a hemoglobin level >12 g/dL can lead to negative consequences.

	The Oncology Drug Advisory Committee (ODAC) of the FDA met after the letter in March 2007 to further analyze the safety data and clarify safety directives. It restated that patients with advanced breast, head and neck, lymphoid, and non—small-cell lung cancers (when hemoglobin levels are targeted at 

12 g/dL), survival can be shortened and tumor progression more likely. Further warnings of changes in survival and tumor progression were made for ESAs at any targeted hemoglobin level (specifically <12 g/dL). Dosing should be targeted at the lowest dose to avoid blood transfusions. Anemia as a result of chronic disease is addressed as a nonindication. In March 2008, this information was added to the product labeling.

	In August 2008, a medication guide was drafted for epoetin alfa and darbepoetin alfa. The accompanying letter also stated that patients should not be started on ESAs unless their hemoglobin level is <10 g/dL. A warning was also added about not using ESAs when the expected outcome of chemotherapy is cure, as well as instructions on how to report an adverse event. The FDA plans to create a new Risk Minimization Action Plan or Risk Evaluation and Mitigation Strategy program for ESAs to better assess the true risks using these agents in anemia caused by chemotherapy. The overall risks and benefits of red blood cell transfusions (

) should be outlined in addition to those outlined in the medication guides for the ESA products.

	When treating patients for anemia related to chemotherapy, the possibility that ESAs may help improve hemoglobin levels and avoid the need for transfusion must be taken into consideration. Witzig et al

demonstrated that weekly epoetin alfa significantly increased hemoglobin levels (10.9 g/dL for placebo, which was a change of 0.9 g/dL and 12.6 g/dL for epoetin alfa, a change of 2.8 g/dL by week 4 of the study; 

<.001). Significant reductions in the percentage of patients undergoing transfusions was also described in a subset (110/329) of patients (27% transfused in the epoetin alfa arm, 40% in the placebo arm; 

= .012). Patients were transfused at a median hemoglobin level of 8 g/dL, but transfusion triggers may differ in individual institutions and clinical situations, so the true benefit of the reduction in transfusions is difficult to determine.

	Although the efficacy of ESAs is well established, because safety issues have been raised, adjunctive therapy could be more crucial to treatment of chemotherapy-related anemia. Auerbach et al18 conducted a trial evaluating the addition of intravenous and oral iron to ESAs. The study did not enroll enough patients to achieve the required statistical power, but the results provided compelling evidence for the use of intravenous iron. Of the patients who received intravenous iron, 68% responded (defined as an increase in hemoglobin 

12 g/dL). In the no iron and oral iron therapy groups, 25% (

<.01) responded, respectively. This evidence shows that iron could potentially provide overall improvement in hemoglobin levels and possibly lessen the need for blood transfusions. The ASH/ASCO guidelines have not completely addressed intravenous iron therapy, but the data discussed appear to support concomitant use with ESAs.

 The Mayo Clinic Cancer Research Consortium is completing a larger trial that should provide insight as to the use of oral iron and intravenous iron gluconate.

	Current clinical guidelines by ASH and ASCO were published after the safety warning by the FDA in March 2007, the ODAC meeting in May 2007, and the Centers for Medicare & Medicaid Services (CMS) National Coverage Decision (NCD) in July 2007.1,

 The hemoglobin level clinicians need to be aware of is 10 g/dL for Medicare patients, according to the new NCD, but the ASH/ASCO guidelines leave the limit for treating chemotherapy-induced anemia at 12 g/dL. Some private insurers follow the ASH/ASCO guidelines as opposed to the CMS decision. Clinicians have shown their frustration over the new limit of 10 g/dL set by the CMS NCD. In May 2007, a total of 2600 patients, physicians, and other parties responded to the new NCD. Some concessions were made, but the limits to chemotherapy-related anemia and a restriction of treatment for patients with a hemoglobin level of <10 g/dL endured the suggestions.

 The ASH/ASCO guidelines support the dosing for epoetin alfa at 150 U/kg subcutaneously 3 times weekly and 40,000 units subcutaneously weekly. For darbepoetin alfa, they recommend 2.25 mcg/kg subcutaneously weekly or 500 mcg subcutaneously every 3 weeks. Alternative dosing can be utilized following the guidelines, which our clinic uses but continues to evaluate because of specific wording on dosing. New long-term studies are needed to evaluate whether giving ESAs on the same day of chemotherapy has a tumor progression benefit or adverse effect.

	As to when to increase or decrease doses of ESAs, dosing should be reduced once the hemoglobin level approaches 11 g/dL and stopped once it is >12 g/dL to hopefully prevent any thrombo&shy;embolic events. Increases in doses can be made at week 4 for epoetin and week 6 for darbepoetin, and clinicians must take this into account prior to stopping therapy. Physicians should also consider erythropoietin levels to determine which patients will respond, as this may help to make better decisions as to who should receive therapy.

	The other unanswered question is the use of the data concerning quality of life (QOL). This is a “soft” end point and difficult to measure. The objective end point of transfusion avoidance is much easier to assess. Future studies should focus on QOL outcomes so clinicians have better information to share with patients on the actual benefits of treatment. The QOL data do help in practice, but the actual impact is difficult to quantify. To further help clinicians answer questions about QOL benefits, this concept should continue to be a secondary end point in trials.

	Guidelines from the National Comprehensive Cancer Network have addressed the risks and benefits of ESAs and transfusion medicine. The critical question for evaluating patients and creating institution policies surrounds the intent of the chemotherapy goals. If it is for curative intent, then ESAs are not indicated/appropriate. If the patient requires immediate resolution of symptoms from anemia (fatigue, chest pain, dsypnea, lightheadedness, syncope, and/or tachycardia), then a transfusion should be considered. If they are not symptomatic or do not require immediate attention, then iron studies should be completed and ESAs should be considered. Dosing and titration are similar to previous versions of the guidelines and to the ASH and ASCO guidelines. The risks and benefits of both ESAs and transfusions should be considered as outlined in 

	After stepping back and taking in the impact of the last 2 years of new data analyses, guidelines, and safety updates, it appears that treating patients for chemotherapy-induced anemia can be difficult. Reducing the number of transfusions with a limited blood supply is the current primary goal of therapy. Patients provide feedback as to what they hope to receive from supportive care therapy, but with current guidelines and safety data, clinicians must continually re-evaluate the literature and treat with the patient’s best interests in mind. Patients in our clinic have read the warnings from the FDA concerning the discontinuation of ESA therapy 8 weeks following the last course of chemotherapy. For a variety of rationales, they cite that they “feel better” and wish to “avoid transfusions.” Future studies must take this into account (particularly the avoidance of transfusions) postchemotherapy. To quantify the impact of ESA therapy on transfusion avoidance, postchemotherapy trials need to continually consider the risks and benefits of supportive care therapy. Another question to take into account is the length of therapy beyond chemotherapy that would be safe and appropriate. With the mass of data in nonchemotherapy-related anemia, we must make heads or tails of the clinical conundrum in which we are now practicing. Administrators should work closely with clinicians to determine the appropriate course of action to help ensure that patients receive the best possible care as new data and guideline updates emerge.

Articles

Practicing clinicians and healthcare administrators face many challenges in treating cancer patients, including management of chemotherapy-induced anemia.

Rickey C. Miller, PharmaD, BCPS, BCOP

Articles

Challenges in Treating Chemotherapy-Induced Anemia