Erythropoiesis-stimulating agents—benefits and harms in the treatment of anemia in cancer patients

Anemia is a common finding in patients with solid or hematological malignancies. The underlying causes of cancer-related anemia can be multifactorial, including toxicity of cancer therapy, raised inflammatory conditions by the cancer, chronic bleeding and malnutrition. Therapeutic approaches for the treatment of chemotherapy induced anemia encompass red blood cell (RBC) transfusions and erythropoietin-stimulating agents (ESAs). The latter are approved for the treatment of patients with symptomatic anemia caused by palliative chemotherapy to reduce the number of RBC transfusions and gradually improve anemia-related symptoms. Before the treatment with ESA, a baseline Hb level < 10 g/dl is mandatory and iron deficiency must be ruled out. ESAs are linked to an increase in thromboembolic events and potentially raised mortality. Therefore, the risk-benefit ratio should be carefully assessed.


Background
Anemia and its resulting symptoms like fatigue have a great impact on the quality of life (QoL) of patients suffering from cancer.According to the European Cancer Anemia Survey in 2004, the prevalence of anemia in patients with a solid or hematological malignancy was about 39% [1].Elevated inflammatory cytokines from cancer cells or toxicity of cancer treatment may be reasons for impaired iron homeostasis and erythropoietic activity.Further causes like chronic bleeding (e.g., occult gastrointestinal bleeding from tumors) or malnutrition can occur simultaneously and should be ruled out during the diagnostic process or treated adequately (e.g., malnutrition).In some patients with cancer, causes of anemia remain unclear or are inevitable (e.g., myelotoxic chemotherapy).In this scenario, supportive treatment to raise hemoglobin levels and diminish symptoms from anemia, including erythropoiesis-stimulating agents (ESAs), may become necessary.This short review focuses on indications, advantages, and risks of ESAs in patients with chemotherapy-associated anemia that develops during treatment of nonhematologic malignancies.

Indication
ESAs can be used in patients with symptomatic anemia (hemoglobin [Hb] < 10 g/dL) associated with myelosuppressive chemotherapy given with palliative intention to reduce the number of red blood cell (RBC) transfusions ( [2,3]; Table 1).In addition, treatment-naïve lower-risk myelodysplastic syndromes with low endogenous erythropoietin (EPO) levels (< 500 IU/L) and patients with concomitant chronic kidney disease may benefit from erythropoiesis-stimulating drugs [4].Evaluating EPO levels to screen K Erythropoiesis-stimulating agents-benefits and harms in the treatment of anemia in cancer patients 259 short review for patients with chemotherapy-associated anemia is not recommended due to its lack of sensitivity and specificity [5].

Management
Iron deficiency in patients with cancer must be ruled out (ferritin > 100 µg/L and transferrin saturation > 20%) before treatment with ESA and supplementing ESA therapy with intravenous iron is recommended.
If there is no response after 6-8 weeks (change in Hb < 1-2 g/dl or absent reduction of transfusion requirements), iron stores should be checked again.There is suggestive evidence that combining an ESA with granulocyte colony-stimulating factor (G-CSF) improves chances of erythroid responses in patients presenting with lower-risk myelodysplastic syndromes with low erythropoietin levels and low transfusion needs [6].Further analysis did not show any difference regarding erythroid response rates between higher doses of ESA and ESA plus G-CSF [7,8].Available ESAs such as epoetin, darbepoetin, and epoetin alfa biosimilars seem to be equal in effectiveness and safety ( [2,9]; Table 2).Responses to ESA therapy takes weeks to months and therefore RBC transfusion should be used in patients where prompt relief of symptoms is necessary.

Efficacy and risks
The use of ESA in patients meeting the above-mentioned criteria lowers the number of RBC transfusions by about 35% [10] and 50-70% of patients undergoing treatment with ESA achieve an Hb increment ≥ 1 g/dL [7,8].ESAs may be an alternative for patients with anemia-associated symptoms, in whom RBC transfusions should be administered with caution (e.g., patients at risk of volume overload or transfusion reac-tions in the past).Patients who do not have easy access to transfusion (long distances to appropriate facility) or who refuse transfusion because of personal or religious beliefs (e.g., Jehovah's Witnesses) should be considered for treatment with ESA if indicated.Whether use of ESAs can significantly improve QoL remains controversial.Although treatment with ESA in patients with chemotherapy-associated anemia improves anemia-related symptoms like dizziness, chest discomfort, and headache, the impact on fatigue-related symptoms was not clinically relevant [11][12][13][14].
During treatment with ESA, the risk of thromboembolic complications increases and it is supposedly associated with higher mortality through accelerated tumor growth [9,[15][16][17][18][19][20][21][22].The use of ESAs was related to an adverse impact on survival in certain tumor entities (e.g., non-small-cell lung cancer [NSCLC], head and neck cancer receiving radiotherapy, cervical cancer receiving chemoradiotherapy, and metastatic breast cancer receiving chemotherapy), as shown by several controlled trials [19,20,[23][24][25][26]. High target Hb levels, deaths from thromboembolism, and adverse impact on tumor progression are among the possible explanations for that observation.However, high Hb levels (before or during treatment with ESA) may be a possible explanation for the increased risk of thromboembolic events, as seen in patients with end-stage kidney disease [27].Based on these trials, several experts and regulatory groups (e.g., European Medicines Agency, US Food and Drug Administration) only recommend the use of ESAs in patients receiving treatment with palliative intention [2,28].However, there are still no results from clinical trials or meta-analysis that have compared the use of ESAs in patients undergoing chemotherapy with different treatment goals (cure vs. palliation).A small randomized trial comparing the administration of epoetin beta (Hb target < 12 g/dl) to placebo in patients with lung and gynecologic cancers showed no difference in the incidence of thromboembolic events between the two groups [10].Nevertheless, clinicians should carefully reconsider the use of ESA in patients with a high risk of thromboembolism (e.g., immobilization or history of thrombosis) [16].

Role of hemoglobin levels
According to a Cochrane meta-analysis, the higher number of thromboembolic events in patients receiving ESA was unrelated to baseline Hb levels [9], but available data also indicated a trend towards fewer thromboembolic events when treatment with ESA was initiated in patients with baseline Hb levels < 10 g/dl [29].
The current literature does not provide information about the optimal target Hb level.A meta-analysis of 12 randomized trials comparing epoetin beta with placebo could not provide evidence that high Hb values among patients treated with epoetin beta were associated with a higher risk of thromboembolic rates, disease progression, or mortality [30].Although there is a lack of data concerning the optimal target Hb levels in anemic cancer patients receiving myelosuppressive chemotherapy [17,30], a target Hb > 12 g/dl might increase the risk of death and serious cardiovascular events.There is still a need of further clinical trials to determine target Hb levels in the use of ESAs in patients undergoing chemotherapy.Therefore, Hb levels should be raised to the lowest level necessary to achieve a reduction of RBC transfusion and relieve anemia-associated symptoms.

Conclusion
Erythropoiesis-stimulating agents (ESAs) are approved for the treatment of symptomatic anemia caused by treatment with myelosuppressive chemotherapy in patients with nonhematologic neoplasms in order to reduce the frequency of red blood cell (RBC) transfusions.Several randomized clinical trials have demonstrated that the use of ESAs is accompanied by serious side effects, such as an increase in thromboembolic events, mortality, and inferior outcomes.In order to decrease these risks, a baseline hemoglobin (Hb) level < 10 g/dl is mandatory before treatment initiation and Hb levels > 12 g/dl should be strictly avoided during administration.Clinicians must be aware of these issues and should carefully weigh the risks of ESAs against transfusion risks when considering the administration of these drugs in the individual patient.

Table 1
Key facts regarding the use of erythropoiesisstimulating agents (ESA)