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Benefits of Early Intervention With Erythropoiesis-Stimulating Proteins in Chemotherapy-Induced Anemia

Benefits of Early Intervention With Erythropoiesis-Stimulating Proteins in Chemotherapy-Induced Anemia

ABSTRACT: Anemia is common in patients treated with chemotherapy for both solid and hematologic malignancies, contributing to fatigue and diminished quality of life and exposing them to the inherent risks of red blood cell transfusions. Erythropoiesis-stimulating proteins have been shown to increase hemoglobin levels, reduce the need for transfusions, and improve quality of life. The current practice guidelines recommend treating moderate to severe chemotherapy-induced anemia with erythropoiesis-stimulating proteins, but the risk of transfusions may be less with earlier intervention at higher hemoglobin levels. A review of the literature suggests that treating mild chemotherapy-induced anemia with erythropoiesis-stimulating proteins reduces the risks of transfusions and the development of more-severe anemia. Weighing the clinical evidence together with other clinical and economic considerations should provide greater insight into the benefits of treating mild anemia in patients treated with chemotherapy.

Anemia is common in patients treated with chemotherapy for solid and hematologic malignancies, with an incidence ranging between 30% and 90% depending on the type of cancer and the definition of anemia being used.[1] Anemia contributes to debilitating fatigue, cardiovascular problems, shortness of breath, reduced cognitive function, and lower quality of life (QOL).[2-4] Furthermore, chemotherapy-induced anemia is associated with substantial direct medical costs[5] as well as indirect costs related to disability and lost productivity.[6]

The introduction of recombinant human erythropoietin (rHuEPO; epoetin) into clinical practice in the 1990s revolutionized the management of chemotherapy-induced anemia. Epoetin alfa (Procrit) increases hemoglobin (Hgb) levels, reduces the need for red blood cell (RBC) transfusions, and improves QOL in patients with cancer and anemia treated with chemotherapy.[7-12] Darbepoetin alfa (Aranesp) is a novel erythropoiesis-stimulating protein (ESP) that has two more N-linked carbohydrate side chains and a greater sialic acid content than epoetin alfa, which increases its serum half-life and makes less frequent dosing without loss of efficacy possible.[13] Darbepoetin alfa has also shown efficacy in patients with chemotherapy-induced anemia, with improvements in hematologic measures and QOL.[6, 14-19]

The use of ESPs has become the standard of care in the management of anemia in patients with cancer. The clinical practice guidelines of the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) recommend using ESPs routinely in patients with Hgb levels of 10 g/dL or less. The guidelines suggest that clinical circumstances should determine the use of ESPs in patients with less severe anemia (Hgb levels of 10-12 g/dL) (Table 1),[20] and a target Hgb level of 12 g/dL is suggested. Similarly, the clinical practice guidelines for cancer- and treatment-related anemia of the National Comprehensive Cancer Network (NCCN) recommend that ESPs be considered in symptomatic patients with Hgb levels of 11 g/dL or less, with a recommended target Hgb level of 11 to 12 g/dL.[21] The guidelines of the European Organisation for Research and Treatment of Cancer (EORTC) recommend ESPs in patients with Hgb levels of 9 to11 g/dL, according to their anemia-related symptoms.[22] The EORTC guidelines suggest that ESPs may also be considered in asymptomatic patients with Hgb levels of 9 to 11 g/dL to prevent a further decline in their Hgb levels. Target Hgb levels of 12 to 13 g/dL are recommended.

The guidelines were formulated on the basis of reductions in the risk of red blood cell transfusions of approximately 20% to 50% in patients treated with ESPs, as well as a favorable effect of ESPs on QOL.[10, 20-22] Determining the optimal Hgb level at which to initiate ESPs is difficult, however, because of the large variation between studies in pretreatment Hgb levels and a paucity of studies that have investigated outcomes in patients with different pretreatment levels.[22] The risk of red blood cell transfusions may be less with early intervention with ESPs at higher Hgb levels than with late intervention at lower levels (Figure 1). This is supported by statistical modeling of data in a recent subanalysis of findings from a large open-label study of darbepoetin alfa in patients with nonmyeloid malignancies treated with chemotherapy.[23] The clinical benefit of early intervention with ESPs in patients with chemotherapy-induced anemia has also been examined in a number of recent clinical trials.


Trials of Early Intervention With Erythropoietic Therapy

Early Interventionvs No Intervention

Several small studies have explored the benefits of early intervention with ESPs in cancer patients treated with chemotherapy. In patients with breast cancer, red blood cell transfusions were required in 2 (6%) of 31 patients in the control arm and in 0 of 31 patients in the ESP arm.[24] In another study, in ovarian cancer patients treated with platinum-based chemotherapy, the number of transfusions required within 6 months was less in patients treated with epoetin alfa than in those who did not receive ESP therapy (9% vs 39%).[25] Similarly, the Hgb levels fell to 10 g/dL or lower during six cycles of chemotherapy in fewer patients treated with epoetin alfa. In patients with small-cell lung cancer and pretreatment Hgb levels of 10.5 g/dL or higher, Hgb levels fell to 10 g/dL or less during treatment with chemotherapy in significantly more patients who were not treated with epoetin alfa (66%) than in those who were treated with epoetin alfa 150 IU/kg (48%; P < .05) or 300 IU/kg (39%; P = .005).[26] Transfusions were required in 59% of patients who were not treated with epoetin alfa, in 45% of those treated with epoetin alfa 150 IU/kg (P < .05), and in 20% of those treated with epoetin alfa 300 IU/kg (P < .001).[26]

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