Patients receiving chemotherapy for cancer often develop anemia, which can contribute to increased morbidity and reduced quality of life. It is important for clinicians to be aware of current clinical studies in the treatment of chemotherapy-induced anemia. In patients with nonmyeloid malignancies, chemotherapy-induced anemia can be successfully treated using erythropoiesis-stimulating agents (ESAs). The application of these agents has evolved from more frequent to less frequent administration and from weight-based to single, fixed doses. Emerging data show that ESAs can be given safely on the same day as chemotherapy without loss of efficacy, and that these agents may be administered as infrequently as every 3 weeks.[3,4] The every-3-week schedule is convenient and may reduce the burden on patients and their caregivers by reducing the number of visits to the clinic.
This commentary summarizes the latest studies of ESAs approved or under investigation in the United States for the treatment of chemotherapy-induced anemia (with a focus on every-3-week dosing). In addition, we offer clinicians a practical guide that incorporates and builds on current evidence-based anemia guidelines.[5,6]
Patients with cancer often suffer from chemotherapy-induced anemia, which is a debilitating condition resulting in increased transfusion requirements, increased fatigue, and reduced quality of life. Historically, red blood cell (RBC) transfusions were the standard of care for the treatment of anemia and still may be utilized for patients with severe anemia (ie, hemoglobin levels < 8 g/dL, see Figure 1). Although transfusions can provide a quick correction of anemia, this correction is temporary and associated with potentially serious health risks such as transfusion reactions and infection, and over time with multiple transfusions, can predispose the patient to iron overload and secondary end-organ failure. Transfusions are time-consuming and expensive, and deplete an important resource that is often in limited supply. Reducing requirements for RBC transfusions may lower these risks for patients with cancer-induced anemia.
ESAs can effectively treat anemia in patients undergoing chemotherapy by increasing hemoglobin concentrations and reducing or eliminating the requirements for RBC transfusions (see Key Points sidebar).[4,8-13] In addition, patients may have significantly improved quality of life and better physical and functional well-being after treatment with ESAs.[10,13-18] These agents act via the same mechanism as endogenous erythropoietin to stimulate RBC production in the bone marrow.
The first recombinant human erythropoietin (rHuEPO) product was epoetin alfa, approved by the US Food and Drug Administration (FDA) as Epogen in 1989 and as Procrit in 1990. This agent dramatically changed the treatment of anemia and became one of the cornerstones of oncology supportive care. In 2002, a second-generation ESA, darbepoetin alfa (Aranesp), was approved for the treatment of cancer-induced anemia. Darbepoetin alfa stimulates RBC production to increase and maintain hemoglobin levels by the same mechanism as epoetin alfa. However, darbepoetin alfa has a unique amino acid sequence and a greater sialic acid content, leading to a longer terminal half-life (approximately 74 hours in cancer patients), a longer duration of action, and greater biologic activity than rHuEPO (approximately 40 hours in cancer patients).[2,19,20]
Another next-generation, long-acting ESA is the pegylated form of rHuEPO (Peg-EPO) that is said to have an erythropoietin receptor activator mechanism for stimulating erythropoiesis in a continuous manner. Peg-EPO is currently under phase II clinical trial investigation for its application in chemotherapy-induced anemia, using weekly and every-3-week administration.
Epoetin alfa was originally approved for three-times-weekly administration. Today, epoetin alfa is most often given as a weekly 40,000-unit dose. To date, one study has examined an extended dosing schedule of epoetin alfa in mildly anemic cancer patients using a front-loading approach (ie, 40,000 units weekly for 3 weeks followed by 120,000 units every 3 weeks vs 40,000 units weekly). This showed no difference in overall transfusion rate between the treatment groups, but patients receiving the weekly dose were more likely to have greater than a 2 g/dL rise in hemoglobin; more likely to have their epoetin alfa dose held secondary to high hemoglobin; and had a higher final hemoglobin than the treatment group receiving 120,000 units every 3 weeks. Epoetin alfa currently does not have a label indication for extended dosing.
Darbepoetin alfa was initially approved for a weight-based weekly dosing of 2.25µg/kg. However, emerging data showed that darbepoetin alfa could be administered less frequently. Today, darbepoetin alfa is most commonly administered in clinical practice as a fixed 200-µg dose every 2 weeks.
The every-3-week schedule is becoming more common.[2-4,22-26] Last year, the weight-based 6.75 µg/kg every-3-week dosing regimen was approved for the treatment of chemotherapy-induced anemia in Europe. In the United States, every-3-week darbepoetin alfa (500 µg) for chemotherapy-induced anemia recently received FDA approval. The every-3-week dosing schedule has received attention because it coincides with the schedule for many common chemotherapy regimens. A retrospective review of nearly 3,000 patient records from 65 US oncology clinics revealed that 40% of chemotherapy was given on an every-3-week basis and 23% given on a weekly basis. Thus, 63% of these patients were receiving weekly or every-3-week chemotherapy regimens. Consequently, the every-3-week dosing schedule may lead to increased convenience for health-care providers and their patients and have a favorable impact on clinical resource utilization.
Several studies have been published describing the optimal every-3-week dose. One double-blind, placebo-controlled, dose-response study showed that multiple weight-based doses of every-3-week darbepoetin alfa were effective (4.5, 6.75, 9, 12, 13, or 15 µg/kg), with 4.5 µg/kg determined to be the minimally effective every-3-week dose (approximately 300 µg for a 74-kg patient). Limited incremental benefit was observed at doses above 6.75 µg/kg every 3 weeks. A recent study of 81 anemic patients provided further evidence of the effectiveness of darbepoetin alfa at 6.75 µg/kg (approximately 500 µg for a 74-kg patient) every 3 weeks regardless of the timing of administration relative to concurrent chemotherapy. For ease in dosing, ESA therapy is increasingly being given to patients using fixed rather than weight-based doses.
Single, fixed doses of ESAs have been shown to be safe and effective.[12,14,18,24] The fixed-dose approach is commonly used in practice for weekly epoetin alfa at 40,000 units and for every-2-week darbepoetin alfa at 200 µg. Recently, a clinical trial of darbepoetin alfa comparing the approved 2.25 µg/kg weekly dose to the every-3-week 500-µg dose showed comparable efficacy in achieving the targeted hemoglobin (77% vs 84%).[3,28] Furthermore, this study showed that roughly 75% of patients in both arms required a 40% dose reduction. The dose reduction was required to maintain hemoglobin levels in the desirable 11 to 13 g/dL range,[29,30] consistent with evidence-based practice guidelines.[5,6,31,32] Darbepoetin alfa is increasingly used every 3 weeks as a 300-µg dose in our practice (see the Case Study sidebar). The 500-µg and 300-µg doses correspond to the optimal and minimally effective every-3-week doses, respectively, for an average-weight patient of approximately 74 kg.
Currently, there is some debate concerning the level of hemoglobin at which ESAs should be initiated. Subset analyses from several darbepoetin studies evaluated patient outcomes depending on whether ESAs were started when the hemoglobin was greater than or less than 10 g/dL.[33-35] In all of the studies, there was greater than a 50% reduction between the two groups in transfusions if ESAs were initiated at a hemoglobin > 10 g/dL In addition, a study administering darbepoetin alfa 300 µg every 3 weeks showed that patients who started receiving darbepoetin alfa therapy in week 1 of chemotherapy maintained their hemoglobin levels within the National Comprehensive Cancer Network (NCCN) target range throughout the course of their treatment. However, those who began darbepoetin alfa at 300 µg later in their treatment course after hemoglobin levels fell below 10 g/dL had a delay in achieving their target range generally after two doses (6 weeks).
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