Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer

INTRODUCTION — Anemia is a common complication in patients with malignancy. Anemia can impair the patient's functional status, diminish physiologic reserve, cause potentially disabling fatigue, and it has been linked to a poor prognosis in several malignancies. (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment" and "Cancer-related fatigue: Treatment" and "Causes of anemia in patients with cancer", section on 'WHO and NCI CTCAE gradings of anemia'.)

Multiple factors can cause or contribute to anemia in patients with malignancy (see "Causes of anemia in patients with cancer"):

●Underlying malignancy – As can occur with other chronic inflammatory conditions, some cancer patients have anemia that is a consequence of the disease and is unrelated to treatment. This type of anemia is typically mild (ie, hemoglobin [Hb] level >10 g/dL), and the symptoms may be difficult to distinguish from those caused by the underlying malignancy. Occasionally, the anemia may be more severe, impairing functional status, diminishing physiologic reserve, and reducing quality of life. Successful resolution or remission of the underlying malignancy may address this cause of anemia. (See "Anemia of chronic disease/anemia of inflammation".)

●Cancer treatment – Anemia is often exacerbated by myelosuppressive cancer treatment, particularly in patients who are undergoing intensive chemotherapy or combined modality treatment with both chemotherapy and radiation therapy (RT) [1-5]. Anemia arising in the setting of myelosuppressive cancer treatment may also be a result of therapy-related myeloid neoplasms (myelodysplastic syndromes, acute myeloid leukemia). (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS".)

●Other causes – In addition to direct effects of the malignancy or its treatment, other causes of anemia may coexist (eg, blood loss; hemolysis; clonal cytopenias; or deficiencies of iron, folate, copper, or vitamin B12). These causes commonly coexist, and should be actively sought and treated appropriately when present, before consideration of ESA use. Determining who is "iron deficient" in the setting of anemia of chronic disease can be challenging. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Anemia of chronic disease/anemia of inflammation", section on 'Diagnostic evaluation' and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

This topic review will focus primarily on the indications, efficacy, and risks associated with the erythropoiesis-stimulating agents (ESAs) epoetin alfa, darbepoetin alfa, and biosimilars in anemic patients with nonhematologic malignancies. The issues surrounding the use of ESAs for patients with hematologic malignancies, such as myelodysplastic syndromes, are distinct and discussed separately. (See "Overview of the complications of chronic lymphocytic leukemia", section on 'Chemotherapy-induced anemia' and "Myelofibrosis (MF): Management of primary MF and secondary MF" and "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Erythropoiesis-stimulating agents'.)

MANAGING ANEMIA IN CANCER PATIENTS — Eradication of the underlying malignancy and discontinuation of anticancer therapy represents definitive therapy for cancer and cancer treatment-related anemia. However, in many cases, this is not possible. Although successful treatment of the malignancy with combinations of surgery, chemotherapy, or radiation therapy (RT) may, in the long term, improve the hemoglobin (Hb) level, short-term red blood cell (RBC) support may be needed.

ESAs versus transfusion — Hb levels can be raised with either ESAs or RBC transfusions. The choice between these approaches should be individualized. In general, the following apply:

●ESAs – ESAs are indicated for patients who have mildly to moderately symptomatic chemotherapy-associated anemia who have no other potentially correctable causes of the anemia, an Hb level ≤10 g/dL prior to therapy, and no contraindications to the use of an ESA (eg, prior history of thromboses, surgery, prolonged periods of immobilization or limited activity, or uncontrolled hypertension). Whether ESAs should be restricted to patients being treated with palliative rather than curative intent for their cancer is controversial. (See 'Indications' below and 'Should use be avoided in patients treated with curative intent?' below.)

●Transfusion – We recommend RBC transfusion rather than an ESA for patients whose clinical condition indicates the need for immediate correction of the Hb level (eg, severely symptomatic, cardiopulmonary compromise, and need for a rise in Hb before the two to four weeks or more that it may take for ESAs to take effect), and for patients who have established general risk factors for thromboembolic events or uncontrolled hypertension and thus are poor candidates for ESAs. An algorithm for RBC transfusion decisions in adults is available (algorithm 1).

Comparative efficacy and safety

●Transfusion – RBC transfusions are almost universally successful in raising Hb levels, although they have risks and availability may be limited. Transfusions can often ameliorate the patient's symptoms rapidly and improve health-related quality of life. Exceptions include patients unable to be transfused because of the presence of multiple alloantibodies and those who refuse transfusions based on religious beliefs. (See "Approach to the patient who declines blood transfusion".)

Risks of RBC transfusion include infection with transfusion-transmitted pathogens, allergic and immune transfusion reactions, volume overload, hyperkalemia, and potential for iron overload with multiple transfusions. The indications and Hb thresholds for RBC transfusions to treat anemia, and accompanying risks and complications, are discussed in more detail separately. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion" and "Indications and hemoglobin thresholds for RBC transfusion in adults".)

The risk of transfusion-transmitted infection (eg, HIV, hepatitis C virus) is lower than when ESAs were originally developed because of improvements in donor screening (table 1). (See "Blood donor screening: Laboratory testing".)

Each unit of transfused RBCs contains 200 to 250 mg of iron. Since the body has no physiologic mechanism to induce iron loss, a patient requiring 16 to 20 or more units of packed RBCs will have accumulated 4 to 5 g or more of excess body iron and may show signs of iron overload. (See "Approach to the patient with suspected iron overload", section on 'Transfusional iron overload'.)

●Epoetin and darbepoetin – The ESAs epoetin and darbepoetin are equally effective and safe in raising Hb levels and decreasing transfusion requirements in patients with chemotherapy-induced anemia [6-8]. However, use of these agents in patients with cancer has decreased over time because of evolving data linking ESA use to thromboembolic complications, inferior survival, and worse cancer outcomes, particularly when used in patients whose anemia is unrelated to chemotherapy, and in those being treated with curative intent.

While there is general agreement that ESAs are not indicated in anemic cancer patients who are not receiving chemotherapy (with the exception of myelodysplastic syndromes or coexistent renal failure), whether ESAs should be avoided in patients who are receiving myelosuppressive chemotherapy with the intent of cure remains controversial. (See 'Effect on disease control and survival' below and 'Issues related to thromboembolic risk' below.)

Biosimilars of epoetin alfa are available globally. Epoetin alfa-epbx was approved by the US Food and Drug Administration (FDA) in 2018 for the treatment of anemia caused by chronic kidney disease. Other biosimilars are available in Europe and have been used for at least 10 years with no major concerns. (See 'Epoetin alfa' below.)

Efficacy and safety outcomes do not appear to differ significantly between patients treated with the epoetin alfa originator and those treated with a biosimilar, although the bulk of the data are in patients with chronic kidney disease, and the quality of the evidence is low [9-14]. Nevertheless, 2019 updated guidelines on the use of ESAs in patients with cancer-associated anemia from the American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) consider biosimilar epoetin alfa to be similar in effectiveness and safety to epoetin alfa [7].

Other factors — In addition to the potential risks described above, many factors influence the choice of an ESA or a RBC transfusion for a patient with symptomatic anemia, including the following (table 2):

●Timing of response – Clinical responses to transfusions occur almost immediately, while meaningful responses to ESAs may take weeks to months. Patients with advanced malignancy may have a relatively short life expectancy, and prompt relief of symptoms is important. In these circumstances, transfusion may be particularly appropriate in severely symptomatic patients.

●Factors impacting toxicity risks – The risk of complications with transfusion and ESAs is impacted by patient factors, including comorbidities and treatments received.

Transfusions are a preferred option for anemic patients with uncontrolled hypertension and for those at increased risk of thromboembolism (eg, prior history of thromboses, surgery, prolonged periods of immobilization or limited activity, administration of chemotherapy agents that increase thrombotic risk [eg, bevacizumab and other antiangiogenic agents, thalidomide, and lenalidomide]). (See 'Issues related to thromboembolic risk' below and "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Arterial and venous thromboembolism'.)

ESAs are an alternative for anemic patients who cannot safely receive transfusions due to volume overload or transfusion reactions. (See "Approach to the patient who declines blood transfusion", section on 'Erythropoiesis-stimulating agents (ESAs/EPO)'.)

●Accessibility – ESAs have advantages for patients who are averse to RBC transfusions or who do not have ready access to an appropriate facility for transfusion, or when RBC supplies are limited. The relative cost of ESAs versus transfusions [15], along with insurance coverage and blood availability issues [16], may become an important factor in determining which approach will be used.

CLINICAL USE OF ESAS IN CANCER PATIENTS

Indications

Minimal requirements — ESAs are indicated for the treatment of symptomatic anemia in patients with neoplasms that are nonmyeloid in origin when the anemia is due to chemotherapy. Consistent with guidelines from the American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH), cancer patients with anemia should meet all the following criteria before being treated with an ESA:

●The anemia should be symptomatic. Correctable causes of the anemia should be ruled out or treated, if present, prior to the use of an ESA.

●The patient's anemia should be associated with use of chemotherapy. Current clinical trial evidence, professional society guidelines, and product approval indications do not support the use of ESAs for the treatment of anemia due to malignancy in the absence of chemotherapy. Use of ESAs in patients with lower-risk myelodysplastic syndromes (table 3) to avoid transfusions is an exception to this recommendation. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Erythropoiesis-stimulating agents'.)

●ESAs should be instituted only if the hemoglobin (Hb) is ≤10 g/dL prior to therapy and the patient is symptomatic [7,17]. They may also be beneficial for symptomatic patients who have the need for higher Hb levels due to supply-demand mismatches (eg, coronary artery disease), but these decisions need to be individualized.

●Clinicians should carefully weigh the risks of thromboembolism in patients who are being considered for ESAs, particularly those with a heightened risk of thromboembolic events (eg, prior history of thromboses, surgery, prolonged periods of immobilization or limited activity). (See 'Issues related to thromboembolic risk' below.)

●Whether use of ESAs should be restricted to patients who are receiving palliative chemotherapy is controversial. This issue is discussed in further detail below. (See 'Should use be avoided in patients treated with curative intent?' below.)

Patients receiving chemotherapy — For all individuals considering the use of ESAs, clinicians should discuss the potential harms (thromboembolism, shorter survival) and benefits (decreased transfusions) of ESAs and compare them with the potential harms (serious infection, immune-mediated adverse reactions) and benefits (rapid Hb improvement) of red blood cell (RBC) transfusion (table 2). In addition to providing patients with the US Food and Drug Administration (FDA)-approved medication guide, ASCO/ASH guidelines suggest that the clinician discuss a number of specific issues before prescribing ESAs (table 4). (See 'Efficacy and risks in cancer patients' below.)

For patients with chemotherapy-induced anemia who meet all of the above criteria and who are well informed as to the potential risks, we suggest the use of ESAs, rather than transfusion, as long as they do not have a heightened risk for thromboembolic events (eg, prior history of thromboses, surgery, prolonged periods of immobilization or limited activity) or uncontrolled hypertension. ESAs can also be used for treatment of anemic patients where RBC transfusions cannot be provided safely (volume overload or transfusion reactions), for patients who are averse to RBC transfusions or who do not have ready access to an appropriate facility for transfusion, or when RBC supplies are limited. (See 'Other factors' above.)

We recommend RBC transfusion rather than an ESA for patients whose clinical condition indicates the need for immediate correction of the Hb level, and for patients who have established general risk factors for thromboembolic events or uncontrolled hypertension.

The data on efficacy and safety of ESAs in patients receiving chemotherapy are described in detail below. (See 'Efficacy and risks in cancer patients' below.)

Patients not receiving chemotherapy — Off-label use of ESAs in cancer patients not receiving chemotherapy was frequent in the past [18]. However, results from large clinical trials and meta-analyses support the view that ESAs are not beneficial in this setting and are potentially harmful [6,19-22], as described in the sections below. (See 'Efficacy and risks in cancer patients' below.)

For patients with anemia due to a solid tumor or nonmyeloid hematologic malignancy who are not receiving chemotherapy, we recommend not using an ESA to treat the anemia. The use of ESAs for patients with lower-risk myelodysplastic syndromes and a baseline erythropoietin level ≤500 units/L to avoid transfusions is one exception to this recommendation [7], as is use in patients with concomitant renal failure. Another potential exception is for patients who decline RBC transfusions and who have symptomatic cancer-related anemia unresponsive to other interventions. Use in this setting requires a full discussion of potential risks to their cancer outcome, other potential toxicities, as well as the possible benefits to their symptomatic anemia. (See 'Efficacy and risks in cancer patients' below and 'Recommendations from expert groups' below and "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Erythropoiesis-stimulating agents'.)

As with other exceptions, ESAs can be used for treatment of symptomatic anemic patients not receiving chemotherapy where RBC transfusions cannot be provided safely (volume overload or transfusion reactions), for patients who are averse to RBC transfusions or who do not have ready access to an appropriate facility for transfusion, or when RBC supplies are limited.

Recommendations from expert groups — Recommendations on the use of ESAs for anemic cancer patients are available from several expert groups:

●ASCO/ASH – Joint clinical practice guidelines for use of ESAs in managing cancer-associated anemia from ASCO/ASH were updated in 2019 [7] (see 'Patients not receiving chemotherapy' above and "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Erythropoiesis-stimulating agents'):

•Patient selection – ESAs may be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and whose Hb has declined to <10 g/dL. RBC transfusion is also an option, depending on the severity of the anemia or clinical circumstances. ESAs should not be offered to patients with chemotherapy-associated anemia whose cancer treatment is curative in intent.

Notably, the recommendation to limit the indication for ESAs to patients undergoing palliative chemotherapy was not based on a direct comparative analysis of data from clinical trials of ESA treatment based on the intent of any particular regimen. Rather, this recommendation was based on the known risks, such as thromboembolic events, and the short-term mortality and decreased overall survival that have been observed across patient groups. (See 'Effect on disease control and survival' below.)

ESAs should not be offered to most patients with nonchemotherapy-associated anemia. One exception is that ESAs may be offered to patients with lower-risk myelodysplastic syndromes and a serum erythropoietin level ≤500 units/L or to patients with concomitant renal failure.

Caution should be exercised in the use of ESAs concomitant with treatment strategies and diseases where the risk of thromboembolic complications is increased. In all cases, blood transfusion is an option.

ESAs increase the risk of thromboembolism, and clinicians should carefully weigh this risk and use caution and clinical judgment when considering the use of these agents.

Patient counseling regarding the risks and benefits of ESA therapy is essential to ensure that patients are making an informed decision. In addition to providing a medication guide, health care providers should discuss specific issues with patients considering ESA therapy (table 4).

•Pretreatment evaluation – Before offering an ESA, clinicians should conduct an appropriate history, a physical examination, and diagnostic tests to identify alternative causes of anemia aside from chemotherapy or an underlying hematopoietic malignancy. Such causes should be addressed before considering the use of an ESA. Suggested baseline investigations are outlined in the table (table 5).

•Administration considerations – Epoetin alfa, darbepoetin, and biosimilar epoetin alfa should be considered equivalent with regard to efficacy and safety.

Hb may be increased to the lowest concentration needed to avoid or reduce the need for RBC transfusion, or ameliorate anemia-related symptoms, which may vary by patient and condition. Starting and modifying doses should follow FDA guidelines. (See 'Regulatory and fiscal policies' below.)

Treatment with an ESA should be discontinued if there is no response to treatment within six to eight weeks (as evidenced by a rise in Hb of <1 to 2 g/dL or no decrease in transfusion requirements). Patients who do not respond to ESA treatment should be reevaluated for underlying tumor progression, iron deficiency, or other etiologies of anemia.

Iron replacement may be used to improve Hb response and reduce RBC transfusions for patients receiving an ESA, with or without iron deficiency. Baseline and periodic monitoring of iron, total iron binding capacity, transferrin saturation, or ferritin levels is recommended. (See 'Iron monitoring and supplementation' below.)

Increasingly, intravenous (IV) iron formulations are used for iron supplementation instead of oral iron, although the ASCO/ASH guidelines consider both acceptable. (See 'Oral versus parenteral' below.)

●NCCN – Consensus-based guidelines on management of symptomatic anemia in cancer patients are also available from the National Comprehensive Cancer Network (NCCN) [23].

Regulatory and fiscal policies

●FDA – The results of various trials of ESAs in patients with cancer have led the FDA to restrict some aspects of ESA use in such patients:

•Patients not receiving chemotherapy – A black box safety alert from the FDA indicates that treating the anemia of cancer with an ESA in patients who are not receiving chemotherapy offers no benefit and may cause serious harm [24,25]. As noted above, ESAs increase mortality in cancer patients not receiving chemotherapy or radiation therapy (RT) when administered to a target Hb >12 g/dL. The 2019 updated guidelines from ASCO/ASH are consistent with FDA-approved labeling [7]. (See 'Patients not receiving chemotherapy' above.)

•Patients receiving chemotherapy – The FDA issued the following black box warnings and labeling revisions for ESAs based on safety concerns:

-Use the lowest possible dose of the ESA that will gradually increase the Hb concentration to the lowest level sufficient to avoid blood transfusions.

-ESAs increase the risk of death and of serious cardiovascular events when administered to a target Hb >12 g/dL.

-ESAs are not indicated in patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure [17] or when the anemia can be managed with transfusion [26,27].

-Treatment with ESAs should not begin until the Hb level drops to ≤10 g/dL. ESAs should be withheld if the Hb exceeds a level needed to avoid transfusion, but a specific Hb value was not specified. The 2008 mandate removed from the package insert the previously approved language that allowed earlier initiation of ESAs, or treatment to a higher Hb target if the patient was unable to tolerate anemia due to a comorbid condition.

The safety and efficacy of ESA use within these confines were shown in a small randomized trial in which 186 patients receiving chemotherapy for lung or gynecologic cancer who had an Hb ≤10 g/dL were randomly assigned to ESA use (epoetin beta 36,000 units) or placebo weekly for 12 weeks [28]. Weekly doses were held for Hb levels >10 g/dL, and sustained Hb levels >12 g/dL were specifically avoided. Transfusions were significantly less common in the ESA group (5 versus 20 percent of patients), and the incidence of thromboembolic events was similar, as was the one-year overall survival. While this trial provides some reassurance that the risk of thromboembolic events is not increased when ESAs are dosed according to established guidelines, it was not adequately powered to detect the magnitude of the differences in survival or disease progression that have been noted with ESAs in much larger trials. There is an FDA-approved medication guide that should be dispensed with ESAs [29,30].

Notably, epoetin beta, which is available only in a pegylated form (methoxy polyethylene glycol-epoetin beta), is neither approved nor recommended for treatment of anemia due to cancer chemotherapy.

●EMA – The same data that led the FDA to restrict approval for ESAs to palliative settings prompted the European Medicines Agency (EMA) to state in June 2008 that blood transfusions are preferred over ESAs in cancer patients who have chemotherapy-related anemia and a "reasonably long life expectancy" (otherwise not defined) [31]. The EMA has not taken further action on ESAs in cancer since 2008.

●CMS – The Centers for Medicare and Medicaid Services (CMS) restricted its coverage of ESAs in response to the controversies and safety concerns surrounding their use in patients with cancer. The CMS limits reimbursement for ESA use to patients with chemotherapy-induced anemia whose Hb level is <10 g/dL. Furthermore, treatment with ESAs is not reimbursed once the Hb level has risen to ≥10 g/dL. The CMS left coverage decisions about ESA use in myelodysplastic syndromes up to regional carriers, so there is geographic variability in reimbursement policies for ESA use in patients with myelodysplastic syndromes.

Variability in and predictors of response to ESAs — Not all patients with chemotherapy-induced anemia benefit from use of an ESA. Up to 15 to 20 percent still require RBC transfusions, and only 50 to 70 percent have an Hb increment ≥1 g/dL after 8 to 12 weeks of ESA therapy [22,32].

There are other settings in which ESAs may not be effective, including the following:

●Insufficient iron supply – A common cause of reduced responsiveness to ESAs is an impaired supply of iron to developing erythroid cells. Sufficient stores of bioavailable iron are required to achieve and maintain target Hb levels with ESAs. The concomitant use of parenteral iron may augment erythropoiesis by ensuring adequate delivery of iron to RBC precursors [33,34]. (See 'Iron monitoring and supplementation' below.)

●Extensive bone marrow involvement – With extensive malignant involvement of the bone marrow, there may be an insufficient number of erythropoietic elements to respond to the ESAs.

●High endogenous erythropoietin – Although most patients with anemia due to cancer have a serum erythropoietin level that is inappropriately low for the degree of anemia [35], some cancer patients synthesize large amounts of endogenous erythropoietin in response to anemia (ie, >500 units/L). These patients are unlikely to respond to pharmacologic doses of an ESA, although there are no data addressing this issue in patients receiving chemotherapy for solid tumors. Furthermore, a 2003 meta-analysis highlighted the lack of sensitivity or specificity for erythropoietin levels in selecting anemic cancer patients for ESA treatment [36] (see 'Minimal requirements' above). In patients with lower-risk myelodysplastic syndromes, serum erythropoietin levels >500 units/L strongly predict the lack of an ESA response [37].

●Erythropoiesis-inhibiting cytokines – In patients with anemia from chronic disease, the bone marrow may respond poorly to ESAs because of the presence of erythropoiesis-inhibiting cytokines (eg, tumor necrosis factor-alpha, interleukin-6) [38]. (See "Anemia of chronic disease/anemia of inflammation", section on 'Pathogenesis'.)

●Pure RBC aplasia – Cases of pure RBC aplasia due to anti-erythropoietin antibodies have been reported in patients treated with ESAs; this is rare, however, and most cases have been in patients treated with Eprex, an epoetin alfa product used outside of the United States. (See "Pure red cell aplasia (PRCA) due to anti-erythropoiesis-stimulating agent antibodies".)

The ASCO/ASH Expert Panel on use of ESAs in adult patients with cancer concluded that starting doses and dose modifications of ESAs after response or nonresponse should follow the FDA-approved labeling guidelines (table 6), and that ESAs should be discontinued after eight weeks in nonresponders (ie, a <1 to 2 g/dL increase in Hb or no diminution of transfusion requirements) [7]. (See 'Regulatory and fiscal policies' above.)

Formulations and dosing

Epoetin alfa — Epoetin alfa is indicated for the treatment of chemotherapy-induced anemia in nonmyeloid malignancies. Epoetin alfa can be administered weekly or three times weekly (table 6).

When epoetin alfa was initially approved for patients with chemotherapy-associated anemia, a starting dose of 100 to 150 units/kg administered subcutaneously was recommended three times weekly along with supplemental oral iron. Responders were expected to show an increase in reticulocyte count within one week and a rise in Hb concentration of at least 0.5 g/dL by two to four weeks [39,40].

However, a subsequent meta-analysis of data from four randomized trials in 604 patients with nonmyeloid malignancies concluded that up to 46 percent of those without a rise in Hb by two to four weeks ultimately respond to ESA therapy [36]. Accordingly, most patients are treated for at least eight weeks before treatment is considered a failure.

The FDA-approved starting dose for epoetin is 150 units/kg three times weekly or 40,000 units weekly (table 6). When a weekly single-dose schedule was employed in anemic patients, results were similar to those with administration three times weekly, with an increase in mean Hb concentration, a reduction in transfusion requirements, and an improvement in quality of life measures for patients receiving chemotherapy [41] or chemoradiotherapy [42].

Less frequent administration of higher doses of epoetin (ie, every two or three weeks) may be similarly effective but more convenient [32,43].

If Hb levels have not increased by four weeks in the setting of adequate iron stores, the schedule can be intensified or the dose raised (table 6). FDA-approved labeling guidelines suggest not continuing ESAs beyond eight weeks in the absence of a response (a <1 to 2 g/dL increase in Hb or no diminution in transfusion requirements). (See 'Iron monitoring and supplementation' below.)

A biosimilar form of epoetin alfa (epoetin alfa-epbx, Retacrit) is approved in the United States for treatment of anemia caused by chemotherapy [44]. The approved dose is the same as that for epoetin alfa [45]. Other biosimilar products are also approved in Europe (eg, HX575 epoetin alfa, Binocrit) and Asia. (See 'Comparative efficacy and safety' above.)

Darbepoetin — Darbepoetin is indicated for the treatment of chemotherapy-induced anemia in nonmyeloid malignancies. Darbepoetin is effective when given as infrequently as once every three to four weeks (table 6) [46-49].

Darbepoetin is a biochemically distinct form of erythropoietin that has a longer in vivo half-life than erythropoietin and modestly lower erythropoietin receptor binding activity (figure 1). These properties are due to an altered glycosylation pattern compared with native erythropoietin and with epoetin.

The FDA-approved starting dose for darbepoetin is 2.25 mcg/kg weekly [50,51] or 500 mcg every three weeks [48] subcutaneously (table 6). Other guidelines for the use of darbepoetin in patients with chemotherapy-induced anemia recommend an initial dose of 200 mcg every two weeks, a dose and schedule that are included in NCCN guidelines [23]. At least four randomized trials of the treatment of chemotherapy-induced anemia in patients with a variety of malignancies found that this dose and schedule of darbepoetin achieved comparable clinical and hematologic outcomes compared with epoetin given at a dose of 40,000 units once per week [22,51-53].

As with epoetin, if there is no increase in the Hb concentration after four weeks in the setting of adequate iron stores, the dose can be increased (table 6).

Maintaining adequate iron stores

Iron monitoring and supplementation — Sufficient stores of bioavailable iron are required to achieve and maintain target Hb levels with ESAs. The availability of iron can limit the Hb response following treatment with ESAs in patients with cancer-related anemia as well as in those with renal failure. (See 'Variability in and predictors of response to ESAs' above.)

●Monitoring iron stores – Serum iron, total iron binding capacity, and serum ferritin should be assayed at baseline in all anemic patients who are being considered for an ESA, in patients who fail to respond to ESA therapy within six to eight weeks, and in those who initially respond and then lose response.

The most widely available markers reflecting the iron status of the body are transferrin saturation (serum iron divided by total iron binding capacity [transferrin]) and serum ferritin, although transferrin saturation is strongly influenced by daily variations in serum iron, and ferritin is an acute phase reactant protein that may be increased during acute inflammation [54].

●Supplementation – For all patients treated with ESAs, we suggest supplemental iron. We target a transferrin saturation ≥20 percent and a serum ferritin ≥100 ng/mL.

Iron deficiency may develop quickly in ESA-treated patients who had borderline iron levels at the onset of therapy. Furthermore, even normal subjects and cancer patients with adequate iron stores may have difficulty adequately mobilizing iron to respond to ESA therapy, a phenomenon that has been termed "functional iron deficiency" or "iron-restricted erythropoiesis" [54-59]. Anemic cancer patients treated with ESAs may have additional difficulties with iron mobilization, due to cytokine-mediated inhibition of the transfer of iron from macrophages to the developing erythron. (See "Anemia of chronic disease/anemia of inflammation", section on 'Pathogenesis'.)

The available data from randomized trials support a significant benefit of iron supplementation with ESAs over ESAs alone in terms of hematopoietic response (ie, increasing the Hb by ≥2 g/dL above baseline or to 12 g/dL without transfusion), reducing the need for blood transfusion [60]. Assuming a baseline risk of transfusion of 7 to 40 percent without iron supplementation, between 10 and 57 patients would need to be treated with iron to avoid an RBC transfusion in one patient.

Oral versus parenteral — For most patients, we suggest parenteral (IV) rather than oral iron. Although a few cancer patients will respond to the use of oral iron, such replacement is likely less effective in patients receiving ESAs and is associated with a high incidence of gastrointestinal adverse effects. Parenteral iron may augment erythropoiesis by providing iron in a more rapidly bioavailable form. (See "Treatment of iron deficiency in patients with nondialysis chronic kidney disease (CKD)" and "Treatment of iron deficiency in patients on dialysis".)

Multiple randomized trials in patients with chemotherapy-induced anemia have been conducted comparing IV iron versus oral iron or no iron, and the results are disparate:

●Multiple trials show that parenteral iron supplementation (compared with either oral iron or no iron) increases the proportion of patients achieving an adequate Hb response to ESA therapy and decreases the percentage of patients requiring transfusion [33,34,57,61,62]. This benefit has been seen both in iron-deficient and in iron-replete patients.

●On the other hand, two trials, including the largest randomized trial to date of ESAs with or without parenteral iron, conducted in 502 patients receiving chemotherapy who had an Hb <11 g/dL, failed to show any benefit for IV, as compared with oral iron [63,64].

This issue was addressed in two 2022 Cochrane analyses, one in 2016, and the second, a network meta-analysis, in 2022 [65], neither of which provides a definitive answer:

●A subgroup analysis in the 2016 Cochrane review examining the role of iron in the management of chemotherapy-induced anemia addressed IV versus oral supplementation [60]. They concluded that randomized controlled trials that used IV iron favored the addition of iron to an ESA, compared with an ESA alone, in terms of hematopoietic response (risk ratio [RR] 1.20, 95% CI 1.10-1.31), a benefit that was not seen with oral iron (RR 1.04, 95% CI 0.87-1.24); however, the difference between subgroups was not statistically significant (test for interaction p = 0.16), and the conclusion was that the route of iron administration did not significantly modify hematopoietic response. On the other hand, when the outcome measure was mean change in Hb, randomized trials that used IV iron also favored the addition of iron to an ESA (mean difference 0.84, 95% CI 0.21-1.46, p = 0.009), a benefit that was not seen with oral iron (mean difference 0.07, 95% CI -0.19 to -0.34, p = 0.59), and the difference between subgroups was statistically significant (test for interaction p = 0.03). The endpoint of needing transfusions according to the route of iron administration was not addressed.

●Data are also available from a year 2022 network meta-analysis of a variety of treatments (IV iron versus oral iron versus no iron with or without ESAs) for cancer patients with anemia; the analysis was based on 96 trials, and 25,157 participants [65]. Compared with no treatment, the use of ESAs alone or with oral or IV iron all significantly improved hemoglobin response, with the highest relative risk (ie, greatest effect on the hemoglobin value) attributed to ESAs plus IV iron, although all the 95 percent confidence intervals overlapped. In the ranking of treatments, ESA plus IV iron was ranked highest. For the end point of need for RBC transfusions, compared with no treatment, the use of ESAs alone or with oral or IV iron also significantly reduced the need for RBC transfusions; although the greatest reduction in the risk for RBC transfusion was with ESA plus oral iron, all the 95 percent confidence intervals overlapped. In the ranking of treatments, ESA plus oral iron was ranked highest compared with no treatment. Comparison between direct and indirect evidence for the outcome of RBC transfusion did not reveal inconsistencies between IV versus oral iron when considering direct estimates (RR for IV versus oral iron 1.23, 95% CI 0.72-2.09), indirect estimates (RR 0.80, 95% CI 0.27-2.61), or the network estimate (RR 0.90, 95% CI 0.56-1.43, p test for disagreement 0.8487). The certainty of the evidence for most outcomes was assessed as moderate.

Widespread adoption of parenteral iron in patients receiving ESAs has been slow. In the past, anaphylactic reactions have been a major problem for IV iron administration, particularly with high-molecular-weight iron dextran preparations (eg, Imferon and Dexferrum, which are no longer available). In addition to low-molecular-weight iron dextran, iron sucrose, and ferric gluconate, several newer formulations (ferumoxytol, ferric carboxymaltose, and ferric derisomaltose) are available that can be administered as a full or near-full replacement dose in as short an infusion as 15 minutes (at least 20 minutes is recommended for ferric derisomaltose). With the exception of high-molecular-weight iron dextran, there appears to be little difference among the available parenteral agents in terms of efficacy [60] and safety, although low-molecular-weight iron dextran is less costly. The use of these agents is discussed separately. (See "Treatment of iron deficiency anemia in adults", section on 'Intravenous iron'.)

Another issue is that, in the United States, Medicare rules do not allow the administration of an ESA and parenteral iron on the same day.

Available guidelines — Available guidelines from expert groups are variable regarding iron supplementation during ESA therapy:

●NCCN – NCCN guidelines recommend either oral or IV iron in patients with absolute iron deficiency (ferritin <30 ng/mL and transferrin saturation <20 percent), but they recommend consideration of IV iron with erythropoietic therapy in patients who are intolerant of or unresponsive to oral iron therapy and when iron therapy is indicated for functional iron deficiency (defined as serum ferritin between 30 and 800 ng/mL and transferrin saturation between 20 and 50 percent) [66]. In this setting, the NCCN guidelines state that IV iron has superior efficacy and should be considered for supplementation.

●ASCO/ASH – Year 2019 updated guidelines from the ASCO/ASH Expert Panel state that iron replacement may be used to improve Hb response and reduce RBC transfusions for patients receiving an ESA, with or without iron deficiency. The guidelines consider oral and IV iron formulations to both be acceptable options for supplementation [7].

●ESMO – For anemic patients with iron deficiency, the European Society for Medical Oncology (ESMO) considers IV iron in conjunction with ESAs to lead to a higher Hb increment in comparison with either oral or no iron supplementation, with level II, grade A evidence [67].

EFFICACY AND RISKS IN CANCER PATIENTS

Meta-analyses — Randomized clinical trials have consistently demonstrated that use of ESAs raises hemoglobin (Hb) levels and reduces the frequency of red blood cell (RBC) transfusion in anemic cancer patients who are receiving chemotherapy [6]. With few exceptions [68,69], most of these trials have not shown that ESAs prolong survival or improve quality of life (QOL) or patient-reported outcomes, including fatigue [19]. Furthermore, these trials have also raised questions about serious side effects, including an increased incidence of thromboembolic events, and the possibility of adverse cancer outcomes and higher death rates [70].

Multiple meta-analyses have addressed the issues of benefit and adverse effects from ESAs [6,8,71-73]. A 2012 Cochrane review of 91 trials with 20,102 participants came to the following conclusions [6]:

●Fewer transfusions – ESAs significantly reduced the use of RBC transfusions (relative risk [RR] 0.65, 95% CI 0.62-0.68). Patients treated with an ESA received 1 unit less of RBCs on average than the control group. For patients at a low risk of needing transfusion, this translated into a decrease from 300 to 195 participants needing transfusion per 1000 patients (range 186 to 204), while for those with a high risk of needing transfusion, this translated into a decrease from 700 to 455 participants needing transfusion per 1000 patients (range 434 to 476).

●Increased venous thromboembolism – The risk of venous thromboembolism was increased in patients receiving ESAs (RR 1.52, 95% CI 1.34-1.74). For patients with a low risk of venous thromboembolism at baseline, this translated into an increase from 20 to 30 events per 1000 patients (range 27 to 35), while for those with a high baseline risk of venous thromboembolism, this translated into an increase from 100 to 152 events per 1000 patients (range 133 to 173). The risk was significantly elevated regardless of the Hb level at baseline (<10, 10 to 12, or >12 g/dL); the impact of target Hb level was not addressed. Additional information on thromboembolic risk and the relationship between target Hb and venous thromboembolism risk are addressed in detail below. (See 'Influence of target and threshold hemoglobin levels' below.)

●Unclear impact on QOL – There was suggestive evidence that ESAs improve QOL (mean change in the 13-item Functional Assessment of Cancer Therapy-Fatigue [FACT-F] scale was 2.08 points [95% CI 1.43-2.72] on a scale of 0 to 52 points). This improvement was less than the 3.0-point increase considered to be a clinically important difference [74]. A similar conclusion was drawn in a second meta-analysis that assessed fatigue and anemia-related symptoms, as measured by the FACT-F subscale and the Functional Assessment of Cancer Therapy-Anemia (FACT-An) subscale, in 37 placebo-controlled randomized trials of ESAs in cancer patients [19]. Although use of ESAs had a clinically meaningful impact on anemia-related symptoms (which included dizziness, chest discomfort, headache, trouble walking, and fatigue), the mean difference in the FACT-F scale was not clinically meaningful.

●Impact on mortality – There was strong evidence that ESAs increase mortality during active therapy (on-study mortality hazard ratio [HR] 1.17, 95% CI 1.06-1.29) and modest evidence that they increase overall mortality (HR 1.05, 95% CI 1.00-1.11). However, when the analysis was restricted to trials of patients receiving chemotherapy, there was only a trend toward higher on-study (odds ratio [OR] 1.10, 95% CI 0.98-1.24) and overall mortality (OR 1.04, 95% CI 0.98-1.11), neither of which was statistically significant. In trials of no antineoplastic therapy, use of ESAs significantly increased both on-study (OR 1.34, 95% CI 1.07-1.66) and overall mortality (OR 1.23, 95% CI 1.04-1.45). Additional information on the effect of ESAs on survival is provided below. (See 'Effect on disease control and survival' below.)

When analyzed according to baseline Hb levels, there was a significant increase in overall (OR 1.17, 95% CI 1.06-1.29) and on-study mortality (OR 1.37, 95% CI 1.12-1.68) among patients with baseline levels >12 g/dL, but not at lower levels. The impact of target Hb levels was not addressed.

●Increased risk of hypertension – Use of ESAs significantly increased the risk of hypertension (RR 1.30, 95% CI 1.08-1.56) and thrombocytopenia/hemorrhage (RR 1.21, 95% CI 1.04-1.42).

These conclusions were largely the same in a 2013 comparative effectiveness update of 41 trials comparing epoetin with control, eight trials comparing darbepoetin with control, and five trials directly comparing darbepoetin with epoetin from the Agency for Healthcare Research and Quality (AHRQ) [8], with a couple of notable exceptions:

●There were no meaningful differences between epoetin and darbepoetin regarding efficacy or adverse event endpoints.

●There were fewer thromboembolic and on-study mortality adverse events when ESA treatment was delayed until the baseline Hb was <10 g/dL than when treatment was initiated at higher Hb levels, although the difference in effect compared with early treatment was not significant, and the evidence was judged to be of low quality. (See 'Influence of target and threshold hemoglobin levels' below and 'Effect on disease control and survival' below.)

A later year 2022 Cochrane network metanalysis of IV iron versus oral iron versus no iron with or without ESAs for cancer patients with anemia also concluded that relative to no treatment, treatment with an ESA alone or with IV or oral iron probably decreases the number of blood transfusions, and may slightly increase the number of thromboembolic events; the impact on mortality was less clear [65]. (See 'Oral versus parenteral' above.)

The findings from both of these analyses are consistent with published guidelines from the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH), which state that patients who are not receiving chemotherapy should not receive ESAs, and that use of an ESA is recommended as a treatment option for patients with chemotherapy-associated anemia and an Hb level that has decreased below 10 g/dL. (See 'Patients not receiving chemotherapy' above and 'Recommendations from expert groups' above.)

Issues related to thromboembolic risk — As noted above, randomized trials and systematic reviews demonstrate an approximately 50 percent increased RR of thromboembolism in patients receiving ESAs [6,8,75]. (See 'Efficacy and risks in cancer patients' above.)

The magnitude of risk was addressed in the meta-analysis conducted by the AHRQ [8]. Combining the results from 31 trials of epoetin versus control and six trials of darbepoetin versus control, the pooled RR of a thromboembolic event with ESA use was 1.51 (95% CI 1.30-1.74). The absolute event rates ranged from 0 to 30.8 percent in the treatment arms (pooled 5.8 percent) and from 0 to 14.5 percent in the control arms (pooled 3.2 percent).

Influence of target and threshold hemoglobin levels — An excessively high Hb level, either prior to treatment with an ESA or as an ESA treatment target, may have contributed to a higher incidence of thromboembolic events. In many of these trials of an ESA versus control, Hb target levels were supraphysiologic, in the range of 13 to 15 g/dL. At least when ESAs are used in patients with end-stage kidney disease, higher target Hb levels increase the incidence of thrombotic and vascular events. (See "Treatment of anemia in patients on dialysis", section on 'Target Hb levels'.)

The data in anemic cancer patients are less extensive, and the relationship between baseline/target Hb levels and incidence of thrombotic/vascular events is incompletely described [76,77]:

●The Cochrane meta-analysis of 60 controlled trials of ESAs documented a significantly elevated risk of thrombotic events regardless of the baseline Hb levels (for Hb <10 g/dL, RR 1.41, 95% CI 1.06-1.99; for Hb 10 to 12 g/dL, RR 1.64, 95% CI 1.33-2.03; for Hb >12 g/dL, RR 1.44, 95% CI 1.15-1.80) [6].

●An updated analysis of five trials of an ESA versus control by the AHRQ concluded that there was a trend toward fewer thromboembolic events when ESA treatment was delayed until the baseline Hb was <10 g/dL (RR for thromboembolic events for early versus late ESA 1.61, 95% CI 0.85-3.05), but the quality of the evidence was low [8].

Fewer data are available on target Hb levels:

●In a meta-analysis of 12 randomized trials totaling 2297 cancer patients in which epoetin beta was compared with placebo (all but three involving chemotherapy), the overall risk for a thromboembolic event was significantly increased (HR 1.62, 95% CI 1.13-2.31) in patients receiving epoetin compared with those receiving placebo [77,78].

In the analysis based on maximum achieved Hb level during treatment, there was no evidence for an increased risk of thromboembolic events or mortality when maximum Hb levels were >13 g/dL as compared with lower levels in the entire cohort of 12 trials [77]. When the analysis was restricted to the four trials with long-term follow-up, there was a statistically significant higher mortality rate in patients with a maximum Hb in the 10 to 13 g/dL range compared with patients with a maximum Hb <10 g/dL, but the mortality rate was not further elevated in those patients with a maximal Hb >13 g/dL.

The results of this analysis need to be interpreted with caution because of methodologic limitations and potential confounders. As an example, for the subgroup of patients with a maximum achieved Hb ≥13 g/dL, the comparison was between those patients who were treated to beyond 13 g/dL with epoetin and those who either achieved an Hb ≥13 g/dL without treatment or who were enrolled with a baseline Hb ≥13 g/dL. On the assumption that an increase in Hb independent of epoetin treatment is a good prognostic factor, these analyses would be biased in favor of the control group.

In its 2019 updated guidelines for use of ESAs in adult patients with cancer, the ASCO/ASH Expert Panel concluded that the use of ESAs to decrease transfusions is recommended for patients with chemotherapy-induced anemia and an Hb concentration that has decreased to <10 g/dL [7]. Furthermore, given that an optimal target Hb could not be definitively determined from the available literature, the panel recommended that the Hb be increased to the lowest concentration needed to avoid transfusion, a level that may vary by patient and condition. (See 'Recommendations from expert groups' above.)

Other risk factors — Specific risk factors for thromboembolism were not defined in these trials, and clinicians must use caution and clinical judgment when considering the use of one of these agents. Established general risk factors for thromboembolism include a history of thromboses, surgery, and prolonged periods of immobilization or limited activity. Some disease and treatment regimens have also been associated with a higher risk of thromboembolic events (eg, multiple myeloma treated with an immunomodulatory agent plus an anthracycline or high-dose corticosteroid). (See "Cancer-associated hypercoagulable state: Causes and mechanisms".)

Effect on disease control and survival — The presence of anemia has been linked to shortened survival in a variety of solid tumors [79-81], an effect attributed in part to a poorer response to anticancer treatments that are dependent on oxygen delivery for cytotoxicity (eg, ionizing radiation therapy [RT] and some forms of chemotherapy). It was hypothesized that normalizing Hb levels through the use of ESAs might reduce the degree of tumor hypoxia, improving response to chemotherapy and/or RT and prolonging disease-free and overall survival. This hypothesis was generally supported by observational studies, which suggested that raising Hb levels to >12 or 14.5 g/dL improved survival in non-small cell lung cancer (NSCLC) and head and neck cancer, respectively [82,83]. (See "Methods to overcome radiation resistance in head and neck cancer".)

However, safety data from some subsequent, individual controlled trials suggested that use of ESAs might in fact be adversely affecting survival in certain cancer patient populations (head and neck cancer receiving RT only, NSCLC receiving neither chemotherapy nor RT, cervical cancer, and breast cancer receiving chemotherapy for metastatic disease) [20,84-88]. Among the hypotheses to explain this potentially detrimental impact on survival with ESA use were an adverse effect on disease progression, excessively high target Hb levels, and an increase in deaths from thromboembolism.

●Safety data from some individual controlled trials suggest that ESA use might affect disease progression in certain cancer patient populations (eg, head and neck cancer receiving RT only) [23,89-91]. However, several different meta-analyses of controlled trials that reported disease progression outcomes have failed to show that disease progression or tumor response rates are significantly different in patients who do versus who do not receive ESAs [6,8,73,77,92]. Furthermore, several meta-analyses have examined the effects of ESAs on overall survival in patients with various tumor types. Among patients with chemotherapy-induced anemia, the labeled indication for ESA use in the United States and elsewhere, there has been no significant effect of ESA use on overall survival [6,72,73]. In the same analyses, patients receiving RT only or no cancer therapy (anemia of cancer) have modestly but significantly higher mortality risks with the use of ESAs.

●An excessively high Hb level, either prior to treatment with an ESA or as an ESA treatment target, may have contributed to a higher mortality rate [93], possibly by accelerating tumor growth [20,84,85,94,95]. In many of these trials, Hb target levels were in the range of 13 to 16 g/dL, levels that are substantially higher than those recommended by professional society guidelines or approved by the US Food and Drug Administration (FDA). At least one meta-analysis found no increase in mortality risk when ESA treatment was delayed until the baseline Hb level was <11 g/dL (as compared with starting earlier at higher baseline Hb levels) [8].

Unfortunately, subsequent randomized trials specifically designed to test the hypothesis that cancer outcomes would not be compromised if ESA use for chemotherapy-induced anemia was restricted to achieving Hb levels <12 g/d have come to different conclusions:

•A potentially detrimental impact of ESA use, even when published guidelines were adhered to, was suggested in a noninferiority trial in which 2098 women with metastatic breast cancer were randomly assigned to epoetin alfa versus best standard of care; the target Hb level was ≤12 g/dL, and ESA treatment was delayed until the Hb fell to <11 g/dL [88].

•On the other hand, a second randomized, double-blind, phase III, noninferiority trial of darbepoetin alfa (dosed to an Hb ≤12 g/dL Hb ceiling) versus placebo in patients receiving chemotherapy for advanced NSCLC did not show inferior outcomes for overall or progression-free survival in the darbepoetin arm [96].

●Another potential mechanism by which ESA therapy might result in inferior survival is through promotion of thromboembolic events. However, in the trials described above, the incidence of thromboembolic and other adverse events was only minimally elevated and was insufficient to explain the observed differences in survival [84,97]. In addition, the events would not explain the reduction in survival related to enhanced tumor progression in some of the studies. (See 'Issues related to thromboembolic risk' above.)

Should use be avoided in patients treated with curative intent? — Whether ESAs should be avoided in patients receiving chemotherapy for a potentially curable cancer remains controversial. No study or meta-analysis has evaluated outcomes of ESA therapy by subgroups defined by chemotherapy intent. Furthermore, determination of the goal of treatment requires clinical judgment of an individual patient's circumstances; whether individuals are receiving curative- or palliative-intent therapy is not always a clear distinction. In our view, if, after discussion with a well-informed patient who is being treated with curative intent, the risks are felt to be counterbalanced by the benefits of avoiding transfusion (table 2) or reducing the chemotherapy dose(s), then use of ESAs is appropriate. (See 'Indications' above.)

Recommendations of expert and regulatory groups — Despite the reassuring data when ESA use is restricted to patients with chemotherapy-related anemia, current ESA labels and clinical guidelines continue to recommend avoidance of ESAs when cure is the goal of therapy, due to lingering concerns about an adverse effect on disease outcomes:

●In June 2008, the European Medicines Agency (EMA) stated that blood transfusions are preferred over ESAs in cancer patients who have chemotherapy-related anemia and a "reasonably long life expectancy" [31]. (See 'Regulatory and fiscal policies' above.)

●Review of the same data also led the FDA to mandate a label change for ESAs, stating that their use was not indicated in patients receiving myelosuppressive chemotherapy when the anticipated outcome was cure, regardless of the specific type of malignancy [17]. (See 'Regulatory and fiscal policies' above.)

●The consensus-based National Comprehensive Cancer Network (NCCN) guidelines for cancer and chemotherapy-related anemia state that there is not enough evidence to support ESA use in patients with potentially curable cancers (eg, early-stage breast cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, testicular cancer, early-stage NSCLC, small cell lung cancer), and ESAs are not recommended in these patients [66], similar to the FDA language.

●Year 2019 updated guidelines for the use of ESAs from the ASCO/ASH consider ESAs to be indicated in the setting of palliative chemotherapy and suggest that the agents not be used for patients whose treatment intent is cure of the cancer [7]. However, they also acknowledge that the recommendation to limit the indication for ESAs to patients undergoing palliative chemotherapy was not based on a direct comparative analysis of data from clinical trials of ESA treatment based on the intent of any particular regimen. Rather, this recommendation was based on the known risks, such as thromboembolic events, and the short-term mortality and decreased overall survival that have been observed across patient groups. (See 'Recommendations from expert groups' above.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: When your cancer treatment makes you tired (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Multifactorial nature of anemia in cancer patients – Anemia is a common complication in patients with malignancy and is linked to adverse outcomes. Multiple factors can contribute, including the underlying malignancy and cancer treatment. (See 'Introduction' above.)

●Transfusion versus ESA

•Hemoglobin (Hb) levels can be raised with either erythropoiesis-stimulating agents (ESAs) or red blood cell (RBC) transfusions. The choice between these approaches must be individualized; the risks and benefits of either approach are outlined in the table (table 2). (See 'ESAs versus transfusion' above.)

On average, the available data suggest that (see 'Meta-analyses' above):

-ESAs significantly reduce the use of RBC transfusions by about 35 percent (relative risk [RR] 0.65, 95% CI 0.62-0.68). For patients at a low risk of needing transfusion, this translates into a decrease from 300 to 195 participants needing transfusion per 1000 (range 186 to 204), while for those with a high risk, this translates into a decrease from 700 to 455 participants needing transfusion per 1000 (range 434 to 476).

-The impact on quality of life is unclear.

-The risk of venous thromboembolism (VTE) is increased by 50 percent in patients receiving ESAs (RR 1.52, 95% CI 1.34-1.74). For patients with a low risk of VTE at baseline, this translates into an increase from 20 to 30 events per 1000 (range 27 to 35), while for those with a high baseline risk of VTE, this translates into an increase from 100 to 152 events per 1000 (range 133 to 173).

-When the analysis is restricted to trials of patients receiving chemotherapy, ESAs do not appear to significantly increase mortality.

●Our suggested approach

•Exclude other treatable causes – Other treatable causes of anemia (eg, blood loss, hemolysis, nutritional deficiency [eg, iron, vitamin B12, folate]) should be excluded or treated if present. (See 'Managing anemia in cancer patients' above.)

•Indications and contraindications to ESA use

-Risks and harms of ESAs and RBC transfusions should be discussed with patients (table 2 and table 4). Contraindications to use of an ESA include predisposition to thromboembolism (eg, prior history of thromboses, surgery, prolonged periods of immobilization or limited activity, multiple myeloma treated with an immunomodulatory agent plus an anthracycline or high-dose corticosteroid) or uncontrolled hypertension. (See 'Indications' above.)

-RBC transfusion is required in patients whose clinical condition indicates immediate correction of anemia (algorithm 1). (See 'Other factors' above.)

-For patients with anemia due to a solid tumor or nonmyeloid hematologic malignancy who are not receiving chemotherapy, we recommend not using an ESA (Grade 1B). Such patients are appropriately transfused according to Hb level, symptoms, and comorbidities. (See 'Patients not receiving chemotherapy' above.)

As exceptions, ESAs can be used for treatment of symptomatic anemic patients not receiving chemotherapy where RBC transfusions cannot be provided safely (volume overload or transfusion reactions), for patients who are averse to or refuse RBC transfusions or who do not have ready access to an appropriate facility for transfusion, when RBC supplies are limited, or in patients with lower-risk myelodysplastic syndrome to avoid transfusion. (See 'Efficacy and risks in cancer patients' above and "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Erythropoiesis-stimulating agents'.)

-For patients with chemotherapy-induced symptomatic anemia (Hb <10 g/dL) and a nonhematologic malignancy, we suggest the use of ESAs rather than transfusion as long as there is no contraindication to ESA (Grade 2C). We do not distinguish between chemotherapy given for curative versus palliative intent; some experts consider ESA treatment only for patients receiving chemotherapy for noncurative intent. (See 'Minimal requirements' above and 'Should use be avoided in patients treated with curative intent?' above.)

However, ESAs may also be beneficial for symptomatic patients who need higher Hb levels (eg, coronary artery disease). The decision to use an ESA for a Hb level between 10 and 12 g/dL requires clinical judgment, consideration of the risks/benefits of ESAs, and the patient preferences.

RBC transfusion is an appropriate alternative if there are contraindications to ESA (risk factors for thromboembolic events, uncontrolled hypertension).

•Choice of ESA – Epoetin, darbepoetin, and epoetin alfa biosimilars appear to be similarly effective. Darbepoetin may be more convenient than epoetin. Starting doses and dose modifications should follow US Food and Drug Administration (FDA)-approved labeling guidelines (table 6). (See 'Formulations and dosing' above.)

•Iron stores and supplementation

-Sufficient stores of bioavailable iron are needed to achieve and maintain target Hb levels with ESAs. (See 'Iron monitoring and supplementation' above.)

Serum iron, total iron binding capacity, and serum ferritin should be assayed at baseline in all anemic patients who are being considered for an ESA, in patients who fail to respond to ESA therapy within six to eight weeks, and in those who initially respond and then lose response.

-For all patients treated with ESAs, we suggest supplemental iron (Grade 2B). We target a transferrin saturation ≥20 percent and a serum ferritin ≥100 ng/mL. (See 'Iron monitoring and supplementation' above.)

For most patients receiving ESAs, we suggest intravenous (IV) rather than oral iron supplementation (Grade 2C). Decisions should be individualized based on the benefits, burdens, and harms of each route. (See 'Oral versus parenteral' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Stanley L Schrier, MD (deceased), who contributed to an earlier version of this topic review.

The UpToDate editorial staff acknowledges David P Steensma, MD, who contributed to an earlier version of this topic review.