Role of ESAs in adults with non-hematologic cancers

INTRODUCTION — Anemia is common in patients with malignancy and has many causes. Anemia can impair a patient's functional status, diminish physiologic reserve, cause potentially disabling fatigue, and has been associated with poor prognosis in several malignancies.

This topic discusses the indications, efficacy, and risks associated with the erythropoiesis-stimulating agents (ESAs) in anemic patients with nonhematologic malignancies, including epoetin alfa, darbepoetin alfa, and biosimilars.

Use of ESAs in hematologic malignancies is distinct and is discussed in separate topic reviews:

●MDS – (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Anemia'.)

●CLL – (See "Overview of the complications of chronic lymphocytic leukemia", section on 'Chemotherapy-induced anemia'.)

●MF – (See "Myelofibrosis (MF): Management of primary MF and secondary MF", section on 'Anemia only'.)

●Multiple myeloma – (See "Multiple myeloma: Overview of management", section on 'Other complications'.)

HOLISTIC APPROACH TO MANAGING ANEMIA — Anemia is a complication of an underlying disease process or therapy, and the treatment depends on the underlying cause and severity of the patient's symptoms.

Evaluate and treat other causes of fatigue — A holistic approach to fatigue and appropriate workup of its causes is essential to treatment.

Fatigue is a common symptom and is often the reason to decide to intervene to improve the hemoglobin.

●For some patients, control or cure of the cancer and discontinuation of cancer therapy may be sufficient to improve symptoms of fatigue.

●Fatigue is often multifactorial as well and not always (or exclusively) caused by anemia. Thus, it is not always alleviated by treatment of anemia, especially when other causes of fatigue are not addressed.

General discussions of cancer-related fatigue are presented separately:

●Evaluation of fatigue – (See "Cancer-related fatigue: Prevalence, screening, and clinical assessment".)

●Treatment of fatigue – (See "Cancer-related fatigue: Treatment".)

Evaluate and treat other causes of anemia — Multiple factors can cause or contribute to anemia in patients with malignancy, including iron deficiency, anemia of chronic disease/anemia of inflammation, and bone marrow suppression from cancer therapy. The prevalence of anemia in cancer and distribution of causes is presented separately. (See "Causes of anemia in patients with cancer".)

Before considering use of an ESA, any other treatable cause of anemia should be sought and addressed, rather than ascribing all anemia to cancer or cancer therapy. The degree to which other causes are sought depends on whether anemia was present before cancer developed or whether a specific type of anemia is suspected. (See 'Pretreatment evaluation' below.)

●Anemia prior to cancer development – Some individuals may have longstanding or hereditary anemias that require different treatments. (See "Diagnostic approach to anemia in adults".)

●Suspected hemolytic anemia (autoimmune or drug-induced) – A patient with jaundice, high reticulocyte count, high bilirubin, or receiving a drug known to cause hemolysis may have hemolytic anemia that requires a different treatment. (See "Diagnosis of hemolytic anemia in adults" and "Drug-induced hemolytic anemia".)

●Suspected nutritional deficit

•Iron deficiency – A patient with microcytic and/or hypochromic anemia may have iron deficiency, especially if blood loss has been occurring. Additionally, if an ESA is used, iron stores must be adequate to support increased red blood cell production. Thus, iron studies are appropriate in any individual who is planning to start an ESA. Subsequent monitoring is discussed below. (See 'Dosing and monitoring' below.)

-Testing for iron deficiency and interpretation of iron studies – (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

-Treatment of iron deficiency – (See "Treatment of iron deficiency anemia in adults".)

•Vitamin B12 or folate – A patient with macrocytic anemia may have vitamin B12 deficiency or folate deficiency, especially if dietary intake has not been sufficient.

-Testing – (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

-Treatment – (See "Treatment of vitamin B12 and folate deficiencies".)

ESA versus transfusion — Once other treatable causes of anemia have been excluded or addressed, the two main approaches to increasing the hemoglobin level are treatment with an ESA or red blood cell (RBC) transfusions.

The choice between these approaches should be individualized based on characteristics of the patient's underlying health status, cancer type and extent, and therapies they are receiving. General principles are summarized in the table (table 1) and include the following:

●ESA – An ESA would be indicated for a patient with all of the following:

•Chemotherapy-associated anemia

•Hemoglobin <10 g/dL

•Mildly to moderately symptomatic

•Able to wait two to four weeks or longer for a hemoglobin response

•No other potentially correctable causes of the anemia

•No prior history of thromboses

•No other major VTE risk factor, surgery, prolonged periods of immobilization, or limited activity

•Normal or controlled blood pressure

Whether ESAs should be restricted to patients being treated with palliative rather than curative intent for their cancer is controversial. (See 'Use caution in patients treated with curative intent' below.)

Some individuals have a reason other than chemotherapy-associated anemia to take an ESA such as chronic kidney disease or myelodysplastic syndrome. (See "Overview of the management of chronic kidney disease in adults", section on 'Anemia' and "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Erythropoiesis-stimulating agents (ESA)'.)

●Transfusion – RBC transfusion would be indicated for a patient with any one of the following:

•Requires an immediate or urgent (within one to two weeks) increase in the hemoglobin due to more severe symptoms (chest pain, dyspnea, extreme fatigue)

•Has cardiopulmonary compromise due to anemia

•Has severe anemia with hemoglobin <7 g/dL or below the cutoff for transfusion based on evidence from clinical trials (algorithm 1)

•Has rapidly declining hemoglobin due to bleeding or other causes and is expected to develop one of these complications

Transfusion thresholds in these individuals are similar to patients without cancer-associated anemia. (See "Indications and hemoglobin thresholds for RBC transfusion in adults".)

For those who would benefit from an increase in hemoglobin, additional reasons to prefer transfusion over an ESA include:

•Not receiving chemotherapy.

•Possibly being treated with curative intent. (See 'Use caution in patients treated with curative intent' below.)

•Cannot receive an ESA due to a contraindication (major thromboembolic risk factors, prior thrombosis and not receiving anticoagulation, uncontrolled hypertension) (see 'Contraindications' below). However, an ESA can be considered in a patient with prior thrombosis who is receiving chronic anticoagulation, with appropriate risk-benefit discussion.

•Receiving a cancer therapy that greatly increases thrombosis risk, such as bevacizumab or other antiangiogenic agent, thalidomide, or lenalidomide. (See "Cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Arterial and venous thromboembolism'.)

Risks of transfusions include infection, allergic reactions, hemolysis, alloimmunization, volume overload, transfusion-related acute lung injury (TRALI) and potential for iron overload with multiple transfusions (after more than 15 to 20 units of RBCs). These are discussed in more detail separately. (See "Approach to the patient with a suspected acute transfusion reaction", section on 'Types of acute transfusion reactions' and "Blood donor screening: Laboratory testing", section on 'Infectious disease screening and surveillance'.)

Cost, availability, burdens of treatment, and patient values and preferences may also influence choice of therapy. Some individuals decline transfusion due to religious beliefs. (See "Approach to the patient who declines blood transfusion", section on 'Jehovah's Witnesses'.)

HIF inhibitor (daprodustat) — Daprodustat is a hypoxia-inducible factor (HIF) inhibitor approved for use in chronic kidney disease (CKD). (See "Treatment of anemia in patients on dialysis", section on 'Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHIs)' and "Treatment of anemia in nondialysis chronic kidney disease", section on 'Uncertain role for hypoxia-inducible factor prolyl hydroxylase inhibitors'.)

Randomized trials comparing daprodustat with the ESA darbepoetin for treating CKD-related anemia have enrolled small numbers of participants with cancer, but methodologic concerns have been raised [1]. More data would be required before considering a HIF inhibitor as an alternative to an ESA in cancer-related anemia.

INDICATIONS AND CONTRAINDICATIONS

Symptomatic, chemotherapy-associated anemia — In an individual with a nonhematologic cancer, an ESA can be used to treat anemia with hemoglobin <10 g/dL that is induced by chemotherapy and symptomatic. Patients may reasonably choose not to use an ESA, especially if they place a high value on avoiding the risk of venous thromboembolism (VTE) or the burdens of therapy or if they have other reasons to prefer transfusions. (See 'Informed consent and likelihood of response' below.)

The flowchart summarizes an approach to decision-making (algorithm 2).

Details include:

●Anemia severity – An ESA is generally only considered if the hemoglobin is <10 g/dL prior to therapy [2,3]. (See 'Recommendations from expert groups' below.)

An ESA may be beneficial for an individual who requires a higher hemoglobin due to supply-demand mismatch, such as with coronary artery disease; these decisions need to be individualized.

●Chemotherapy-induced – ESAs are generally considered appropriate if the anemia is caused by chemotherapy treatment. (See 'Recommendations from expert groups' below.)

•Correctable causes of the anemia should be excluded or treated, if present, prior to the use of an ESA. (See 'Evaluate and treat other causes of anemia' above.)

•Anemia caused by the tumor itself is generally not considered an appropriate use of an ESA.

●Symptoms – An ESA is generally only considered if the anemia is symptomatic. For fatigue and other symptoms, other possible causes besides anemia should be evaluated and addressed to ensure that the symptoms attributed to anemia are not due to another cause. (See 'Evaluate and treat other causes of fatigue' above.)

Data on efficacy and risks are presented below. (See 'Supporting evidence' below.)

These criteria for an ESA are consistent with guidelines from the American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH), the European Society for Medical Oncology (ESMO), and the National Comprehensive Cancer Network (NCCN) [2-4]. (See 'Recommendations from expert groups' below.)

Off-label use in non-chemotherapy anemia — In the past, ESAs were frequently used off-label in patients with cancer who were not receiving chemotherapy [5]. However, results from large clinical trials and meta-analyses suggest ESAs are potentially harmful and not beneficial in this setting. Thus, we suggest not using an ESA off-label in non-chemotherapy anemia. Evidence from clinical trials is presented below. (See 'Risks and adverse events' below.)

This approach is consistent with other guidance:

●The product information for ESAs includes a Boxed Warning stating these agents should only be used in patients with cancer to treat anemia from myelosuppressive chemotherapy [6-8]. (See 'Boxed Warnings on prescribing labels' below.)

●Guidelines from ASCO/ASH, ESMO, and NCCN are consistent with US Food and Drug Administration (FDA)-approved labeling [2-4]. (See 'Recommendations from expert groups' below.)

Exceptions (patients with non-chemotherapy anemia in whom an ESA might be used) include:

●Individuals with lower-risk myelodysplastic syndromes and baseline erythropoietin level ≤500 units/L. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS", section on 'Erythropoiesis-stimulating agents'.)

●Individuals with chronic kidney disease. (See "Treatment of anemia in nondialysis chronic kidney disease", section on 'Erythropoiesis-stimulating agents' and "Treatment of anemia in patients on dialysis", section on 'Erythropoiesis-stimulating agents (ESAs)'.)

●Individuals who would decline transfusions. (See "Approach to the patient who declines blood transfusion", section on 'Erythropoiesis-stimulating agents (ESAs/EPO)'.)

●Individuals who could not tolerate transfusions due to lack of venous access, an appropriate way to receive transfusions, or significant volume overload or transfusion reactions. (See "Transfusion-associated circulatory overload (TACO)".)

Use caution in patients treated with curative intent — Whether ESAs should be avoided in patients receiving chemotherapy for a potentially curable cancer remains controversial, and caution is advised (algorithm 2).

We generally do not use an ESA when the goal of treatment is curative, with exceptions detailed below. The main reason for concern is the lack of survival benefit and possible increased mortality with ESAs, although much of these data are based on older studies targeting a higher hemoglobin than is presently used. (See 'Effects on survival' below.)

However, determining the goals of treatment requires clinical judgment and incorporation of an individual patient's circumstances, values, and preferences. Whether individuals are receiving curative- or palliative-intent therapy is not always a clear distinction. A well-informed patient who is being treated with curative intent may reasonably choose to take an ESA if they are aware of the risks associated with ESAs and consider them to be acceptable given benefits of avoiding transfusion or allowing full chemotherapy dosing. (See 'Informed consent and likelihood of response' below.)

ESA product information 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. (See 'Recommendations from expert groups' below.)

Contraindications — There are few absolute contraindications, mainly uncontrolled hypertension and previous venous thromboembolism (VTE) not currently receiving anticoagulation. If a prior VTE arose in a provoked setting and prior anticoagulation was of limited duration without recurrence after stopping anticoagulation, an ESA could be used.

Other possible reasons to avoid an ESA include:

●Individuals with VTE risk factors (surgery, high body mass index, immobility) may reasonably choose not to use an ESA. (See 'Thromboembolic complications' below.)

●Whether use of ESAs should be restricted to patients who are receiving palliative chemotherapy is controversial. (See 'Use caution in patients treated with curative intent' above.)

Recommendations from expert groups — Recommendations on the use of ESAs for anemic cancer patients are available from several groups, which are largely consistent with recommendations discussed herein.

●ASCO/ASH – Joint clinical practice guidelines for use of ESAs in managing cancer-associated anemia from the American Society of Clinical Oncology and the American Society of Hematology were updated in 2019 [2]. Key recommendations include:

•ESA indications – An ESA may be offered to patients with chemotherapy-associated anemia whose cancer treatment is not curative in intent and who have hemoglobin <10 g/dL.

An ESA should not be offered to patients with chemotherapy-associated anemia whose cancer treatment is curative in intent or to patients with anemia not caused by chemotherapy.

Thromboembolism risk should be considered. Patient counseling regarding risks and benefits is essential (table 2).

•Choice of ESA and dosing – All available ESAs (darbepoetin, epoetin alfa, or epoetin alfa biosimilars) are considered equivalent in safety and efficacy.

Dosing should follow FDA guidelines. Discontinue if no response by six to eight weeks.

•Target hemoglobin – Target the lowest hemoglobin needed to avoid or reduce transfusions, which may vary by patient and condition.

•Iron – Iron replacement may be used to improve response to an ESA in patients with or without iron deficiency. Oral or intravenous iron may be used, although emerging data suggest intravenous iron is more effective. Iron studies should be monitored.

●ESMO – The European Society for Medical Oncology updated their guidelines for management of cancer-associated anemia and iron deficiency in 2018 [3]. Key recommendations include:

•ESA indications – An ESA should be considered in patients receiving chemotherapy (or combined chemotherapy and radiation therapy) who have symptomatic anemia and hemoglobin <10 g/dL or those who are asymptomatic with hemoglobin <8 g/dL. Iron deficiency and any other underlying reversible causes of anemia should be corrected.

ESAs are not recommended for patients who are not receiving chemotherapy.

•ESA dosing – Should follow approved labels. Discontinue therapy if no response in four to eight weeks.

•Target hemoglobin – Stable hemoglobin of approximately 12 g/dL without RBC transfusions.

•Iron – Treat with intravenous iron if the patient is receiving chemotherapy and has anemia (hemoglobin ≤11 g/dL or decrease of 2 g/dL or more from baseline of ≤12 g/dL) with evidence of absolute iron deficiency (ferritin <100 ng/mL) or functional iron deficiency (transferrin saturation [TSAT] <20 percent). Do not give intravenous iron on the same day as cardiotoxic chemotherapy.

•Transfusions – Give RBC transfusion for hemoglobin <7 to 8 g/dL and/or severe anemia-related symptoms and the need for immediate improvement in hemoglobin or symptoms.

●NCCN – The National Comprehensive Cancer Network published updated consensus-based guidelines on management of symptomatic anemia in cancer patients in 2024 [4]. Key recommendations include:

•ESA indications – May be appropriate based on FDA guidance in a patient undergoing palliative treatment, a patient who declines transfusions, or selected individuals with anemia who are receiving myelosuppressive chemotherapy and lack other identifiable causes of anemia.

For patients with cancer not receiving therapy, patients receiving nonmyelosuppressive therapy, or patients being treated with curative intent, there is insufficient evidence to support ESA use, and an ESA is not recommended.

•Iron – Treat absolute iron deficiency (ferritin <30 ng/mL, TSAT <20 percent) with intravenous or oral iron.

In patients receiving an ESA, treat functional iron deficiency (ferritin 30 to 500 ng/mL and TSAT <50 percent) with intravenous iron.

•Transfusions – Transfuse per Association for the Advancement of Blood & Biotherapies (AABB) guidelines for symptomatic anemia (sustained tachycardia, tachypnea, chest pain, dyspnea on exertion, lightheadedness, syncope, or severe fatigue preventing usual activity).

Consider transfusion per AABB guidelines for progressive decline in hemoglobin with recent intensive chemotherapy or radiation or comorbidities (cardiac, pulmonary, cerebrovascular disease).

PRACTICAL ASPECTS OF ADMINISTRATION

Pretreatment evaluation — Before offering an ESA, clinicians should conduct an appropriate history, 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 3).

Informed consent and likelihood of response — For all individuals who are considering an ESA, clinicians should discuss the potential harms (risk of thromboembolism and hypertension, possible reduced survival) and benefits (decreased need for transfusions, improved symptoms) relative to available alternatives such as RBC transfusion, which also has potential harms (infection, allergic reaction, hemolysis, fluid overload, transfusion-related acute lung injury), burdens (travel time and time spent in an infusion center), and benefits (rapid improvement in hemoglobin). (See 'ESA versus transfusion' above.)

The table summarizes discussion points suggested in the 2019 joint guideline from the American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) (table 2) [2].

There is also a medication guide available from the US Food and Drug Administration (FDA) [9].

●Likelihood of response – Not all patients with chemotherapy-induced anemia benefit from an ESA. Up to 15 to 20 percent still require RBC transfusions, and only 50 to 70 percent have a hemoglobin increment ≥1 g/dL after 8 to 12 weeks of ESA therapy [10,11].

●Predictors of response – Conditions that may reduce the efficacy of an ESA include:

•Iron availability – A common and treatable cause of reduced responsiveness is insufficient iron. (See 'Maintain adequate iron stores' below.)

•Bone marrow involvement – Extensive involvement of the bone marrow by cancer may reduce erythroid reserve. (See "Causes of anemia in patients with cancer", section on 'Bone marrow infiltration'.)

•Endogenous erythropoietin – Most patients with cancer-associated anemia have inappropriately low serum erythropoietin [12]. However, some patients may have high endogenous erythropoietin (eg, >500 units/L). Although data are lacking in individuals with nonhematologic cancers, it seems likely that these individuals will not have as good a response. Extrapolation from individuals with myelodysplastic syndrome indicates a low likelihood of response when serum erythropoietin levels are >500 units/L [13]. However, a 2003 meta-analysis highlighted the lack of sensitivity or specificity for erythropoietin levels in selecting anemic cancer patients for ESA treatment [14].

•Cytokines – Inflammatory cytokines due to cancer or infection may reduce bone marrow responsiveness due to functional iron deficiency [15]. (See "Anemia of chronic disease/anemia of inflammation", section on 'Pathogenesis'.)

Choice of ESA — The ESAs epoetin alfa and darbepoetin are equally effective and safe in raising hemoglobin and decreasing transfusion requirements in patients with chemotherapy-induced anemia [2,16,17]. Darbepoetin has a longer half-life than epoetin alfa, as illustrated in the figure (figure 1). This allows less-frequent administration of darbepoetin.

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.

Dosing and monitoring

Epoetin alfa dosing and expected response — Epoetin alfa is given subcutaneously.

●Starting dose – The initial dose can be administered as 150 units/kg three times per week or 40,000 units once per week, as summarized in the table (table 4). For outpatients, once per week dosing is significantly more convenient and less burdensome. This is supported by observational studies that suggest similar benefits with the three times per week or once per week schedules [18,19]. Less frequent administration of higher doses of epoetin alfa (ie, every two or three weeks) may be similarly effective but more convenient [11,20].

●Biosimilar epoetin alfa products – A biosimilar form of epoetin alfa (epoetin alfa-epbx, Retacrit) was approved in the United States in 2018 and carries an indication for treatment of anemia caused by chemotherapy, with the same dosing as that for the branded epoetin alfa [6]. The 2019 guideline from the American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) consider biosimilar epoetin alfa to be similar in effectiveness and safety to epoetin alfa [2]; efficacy and safety in chronic kidney disease appear similar, although the quality of the evidence is low [21-26]. Other biosimilar products are approved in Europe (HX575 epoetin alfa, Binocrit) and Asia.

●Monitoring – Following initiation of therapy and after each dose adjustment, monitor the hemoglobin weekly until it stabilizes. Hemoglobin is repeated prior to each ESA dose. Serum iron parameters are monitored every one to three months depending on the baseline iron status at the start of treatment.

●Expected response – When epoetin alfa was initially approved for patients with chemotherapy-associated anemia, criteria predictive of a response were an increase in reticulocyte count within one week and a rise in hemoglobin concentration of at least 0.5 g/dL by two to four weeks [27,28]. 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 hemoglobin by two to four weeks ultimately did have a hemoglobin response to ESA therapy [14]. Accordingly, most patients are treated for at least eight weeks before treatment is considered ineffective.

●Dose adjustments – The package inserts for ESAs lists dose adjustments for hemoglobin responses outside the desired ranges [6-8]:

•Dose reduction for large hemoglobin increase – If the hemoglobin increase is >1 g/dL in any two-week period or reaches a level needed to avoid transfusion, the dose can be reduced by 25 percent.

If the hemoglobin exceeds a level needed to avoid transfusion, the dose is held, and when the hemoglobin approaches a level at which transfusions may be required, the ESA can be restarted at a 25 percent dose reduction.

•Dose increase for lack of response – After the first four weeks of therapy, if the hemoglobin increase is <1 g/dL and the hemoglobin remains <10 g/dL, the dose may be increased to 300 units/kg three times per week or 60,000 units once weekly. Adequate iron stores should be affirmed.

●Discontinuation for lack of response – After eight weeks of therapy, persistent requirements for transfusions or lack of an increase in hemoglobin are considered to be a lack of response and a reason to discontinue therapy. This presumes that there are no other causes of anemia that could be preventing a response and that all other causes of anemia, including insufficient iron stores, have been addressed. (See 'Evaluate and treat other causes of anemia' above and 'Maintain adequate iron stores' below.)

Darbepoetin dosing and expected response — 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.

Darbepoetin is given subcutaneously.

●Starting dose – Darbepoetin can be administered once weekly or once every three weeks, as summarized in the table (table 4) [29-32]. The once every three week dosing is more convenient and can sometimes be adjusted to every four weeks based on hemoglobin response. Some insurers mandate using erythropoietin prior to using darbepoetin.

The FDA-approved starting dose for darbepoetin is:

2.25 mcg/kg weekly [33,34]

or

500 mcg every three weeks [31]

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 [4]. (See 'Recommendations from expert groups' above.)

●Monitoring and dose adjustments – Monitoring is similar to epoetin, including hemoglobin prior to each ESA dose and serum iron parameters every one to three months depending on the baseline iron status at the start of treatment. As with epoetin, if there is no increase in the hemoglobin concentration after four weeks in the setting of adequate iron stores, the dose can be increased (table 4).

●Expected response and evidence for efficacy – 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 produced comparable clinical and hematologic outcomes to epoetin given at a dose of 40,000 units once per week [10,34-36].

Target hemoglobin — The goal is to increase the hemoglobin enough to reduce symptoms and decrease the need for transfusions, not to raise the hemoglobin into the normal range. Raising the hemoglobin too high increases the risk of thromboembolic complications.

Fewer data are available to determine the ideal target hemoglobin that maximizes efficacy and minimizes adverse events. However, clinical trials taking into account the target hemoglobin have generally shown that the risk of adverse events, especially thromboembolic complications, is higher when higher target hemoglobins have been used. This is the rationale for using the lowest possible hemoglobin that resolves symptoms and reduces the need for transfusion.

We generally target a hemoglobin that reduces symptoms and is no higher than 11 g/dL. If the hemoglobin rises to >11 g/dL, we hold the ESA and make subsequent dose adjustments as needed.

The 2018 ESMO guidelines recommend targeting a stable hemoglobin of approximately 12 g/dL without RBC transfusions [3]. The 2024 NCCN guidelines note that survival is decreased when the target hemoglobin is >12 g/dL, but risks of shortened survival and tumor progression have not been excluded with a target hemoglobin <12 g/dL [4]. The 2019 ASCO/ASH guidelines recommend targeting the lowest hemoglobin needed to avoid or reduce transfusions, which may vary by patient and condition [2]. (See 'Recommendations from expert groups' above.)

Maintain adequate iron stores — Sufficient bioavailable iron is required to increase the hemoglobin with an ESA [37]. The concomitant use of parenteral iron may augment erythropoiesis by ensuring adequate delivery of iron to RBC precursors [38,39].

●Monitoring iron stores – Iron studies, including serum ferritin, iron, total iron binding capacity, and calculated transferrin saturation (TSAT) should be assayed at baseline in all patients who are being considered for an ESA, as well as in patients for whom ESA therapy does not produce an increase in hemoglobin within six to eight weeks, and in individuals who have an initial response followed by a decline in hemoglobin. During ESA therapy, iron studies are monitored every one to three months.

Ferritin and TSAT are most useful for indicating body iron stores. Ferritin <30 ng/mL and TSAT <20 percent are consistent with absolute iron deficiency, and TSAT <20 percent with normal ferritin is consistent with iron-restricted erythropoiesis. In cancer therapy-associated anemia, a ferritin >100 ng/mL is ideal.

There are caveats for both measures.

•TSAT can be influenced by variation in serum iron caused by iron administration.

•Ferritin is an acute phase reactant that may increase due to inflammation caused by cancer or infection.

Interpretation of results and alternative testing such as soluble transferrin receptor (sTfR) are discussed separately. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Iron studies (list of available tests)'.)

●Supplementation – Iron deficiency may develop rapidly during ESA treatment in individuals who had borderline iron stores at the start of therapy.

Furthermore, many individuals with cancer who have adequate iron stores can have a block to iron mobilization, referred to as anemia of chronic disease/anemia of inflammation (ACD/AI), functional iron deficiency, or iron-restricted erythropoiesis [40-42].

For all patients treated with an ESA, we suggest supplemental iron, provided they do not have iron overload. Some individuals may decline iron therapy if their iron stores are adequate, and they wish to determine whether the ESA is effective without iron replacement therapy.

When providing supplemental iron, we target a TSAT ≥20 percent (but not higher than 45 percent) and a serum ferritin ≥100 ng/mL (but not higher than 500 ng/mL), as long as the assessments are made no sooner than four to six weeks after intravenous iron administration.

Data from randomized trials support a significant benefit of adding iron to an ESA in raising the hemoglobin and reducing the need for transfusion [43,44].

In a randomized trial from 2008 involving 149 patients with breast, gynecologic, lung, or colorectal cancer and 12 or more weeks of planned chemotherapy who had anemia (hemoglobin ≤11 g/dL) without absolute or functional iron deficiency and were treated with the ESA darbepoetin, those who were also treated with intravenous iron had a higher hemoglobin response (77 percent, 95% CI 65-86%, versus 62 percent in the no iron group, 95% CI 50-73%; p = 0.0495) [44]. Safety was comparable in the iron and no iron groups.

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.

●Intravenous versus oral iron – For patients with chemotherapy-induced anemia receiving supplemental iron during ESA therapy, we suggest intravenous rather than oral iron. If iron stores are low (ferritin <100 ng/mL), it makes sense to replete iron before starting the ESA and then continuing during ESA therapy.

Intravenous iron may augment erythropoiesis by providing iron in a more rapidly bioavailable form, is more likely to be effective, and does not cause gastrointestinal side effects. This is especially relevant for patients receiving chemotherapy due to cancer therapy-induced nausea, diarrhea, or constipation. (See "Treatment of iron deficiency anemia in adults", section on 'Side effects (oral iron)' and "Treatment of iron deficiency anemia in adults", section on 'Uses for IV iron'.)

The block to iron mobilization is generally attributed to cytokine-mediated inhibition of iron release from macrophages, mediated by hepcidin. Evidence suggests this block is better overcome by intravenous iron than by oral iron. (See "Anemia of chronic disease/anemia of inflammation", section on 'Pathogenesis' and "Anemia of chronic disease/anemia of inflammation", section on 'Hepcidin level' and "Treatment of iron deficiency anemia in adults", section on 'Oral versus IV iron'.)

Multiple randomized trials have compared intravenous and oral iron for chemotherapy-induced anemia, with somewhat disparate results:

•Many trials have demonstrated better efficacy with intravenous iron [38,39,45,46].

•Two trials showed comparable efficacy with intravenous and oral iron [47,48].

•A 2022 Cochrane review and network meta-analysis concluded that, compared with no treatment, hematologic response was increased with ESA alone, ESA plus oral iron, or ESA plus intravenous iron, with the best likelihood of response with ESA plus intravenous iron [49]:

-ESA alone – Relative risk (RR) of hematologic response 5.19, 95% CI 4.02-6.71

-ESA plus oral iron – RR 5.85, 95% CI 4.06-8.42

-ESA plus intravenous iron – RR 6.71, 95% CI 4.93-9.14

A similar general pattern was seen for transfusions, although the magnitude of differences was smaller.

Despite these data, widespread adoption of intravenous iron in patients receiving ESAs has been slow. This may be due to concerns about adverse effects of intravenous iron seen with a previous formulation (high molecular weight iron dextran) that is no longer available. Newer formulations are considered to have a low risk of anaphylaxis, and several can be given as a single dose infusion, as discussed separately. (See "Treatment of iron deficiency anemia in adults", section on 'Intravenous iron'.)

Guidelines from expert groups recommend iron supplementation but vary in the details of which parameters on which to base therapy, what cutoffs to use, and whether they prefer intravenous iron or consider oral iron sufficient. (See 'Recommendations from expert groups' above.)

SUPPORTING EVIDENCE

Efficacy

Reduced need for transfusions — Randomized trials and associated meta-analyses have consistently demonstrated that ESAs raise hemoglobin and reduce the need for red blood cell (RBC) transfusion in patients with cancer who have chemotherapy-induced anemia.

●A 2012 Cochrane review of 91 trials with 20,102 participants reported that ESAs significantly reduced the use of RBC transfusions (relative risk [RR] 0.65, 95% CI 0.62-0.68) [16]. On average, patients treated with an ESA received 1 unit less of RBCs 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).

•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).

●A 2022 Cochrane network meta-analysis of 96 trials with 25,157 participants that evaluated ESAs in patients with cancer and anemia concluded that an ESA alone or with oral or intravenous iron decreases the number of transfusions [49].

Symptom relief — The impact of ESAs on quality of life (QOL) is unclear and, if present, likely to be small.

●A 2012 Cochrane review of 91 trials with 20,102 participants reported suggestive evidence that ESAs improve QOL, with a mean change in the 13-item Functional Assessment of Cancer Therapy-Fatigue (FACT-F) scale of 2.08 points (95% CI 1.43-2.72 points) on a scale of 0 to 52 points [16]. However, this improvement was less than the 3.0-point increase considered to be a clinically important difference [50].

●A 2014 meta-analysis that assessed anemia-related symptoms and fatigue in 37 randomized trials with 10,581 patients with cancer using the FACT-An and FACT-F subscales found that ESAs had a clinically meaningful impact on anemia-related symptoms including dizziness, chest discomfort, headache, trouble walking, and fatigue, but the mean difference in the FACT-F fatigue scale was not clinically meaningful [51].

●Two earlier trials in breast cancer patients (587 patients total) found that ESA treatment did improve QOL [52,53].

Risks and adverse events

Boxed Warnings on prescribing labels — The prescribing information for ESAs includes a Boxed Warning that specifies the following when used in cancer treatment [6-8]:

●ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers.

●The lowest possible ESA dose to avoid RBC transfusions should be used.

●The ESA should only be used to treat anemia from myelosuppressive chemotherapy.

●ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure.

●The ESA should be discontinued following the completion of the course of chemotherapy.

Effects on survival — The effect of ESAs in patients with cancer is incompletely understood, although concerns exist about a possible increase in mortality.

●Association of anemia with reduced survival – Anemia is associated with shortened survival in a variety of solid tumors [54-56]. However, it has been unclear whether anemia is a marker of other adverse prognostic factors or whether it has a causative role that could be addressed by raising the hemoglobin.

A hypothetical mechanism by which anemia could adversely affect outcomes is by reducing cytotoxicity of cancer therapies (some chemotherapeutic agents and ionizing radiation therapy) that depend on oxygen delivery. Observational studies in patients with non-small cell lung cancer (NSCLC) and head and neck cancer who had improved survival with higher hemoglobin levels supported this idea [57,58]. (See "Methods to overcome radiation resistance in head and neck cancer".)

However, data in patients without cancer suggest that once the hemoglobin is in a safe range (variously defined as >7 to 8 g/dL in most populations), raising the hemoglobin higher does not improve outcomes. (See "Indications and hemoglobin thresholds for RBC transfusion in adults", section on 'Impact of anemia on morbidity and mortality'.)

●Reduced survival with ESAs – Despite suggestive data from observational studies, subsequent randomized trials suggested that ESAs might in fact be adversely affecting survival in certain cancer patient populations such as people with [59-64]:

•Head and neck cancer receiving radiation therapy

•NSCLC

•Cervical cancer

•Metastatic breast cancer receiving chemotherapy

These have subsequently been confirmed in several large meta-analyses of randomized trials that have documented reduced survival with ESAs [16,65-68]. The magnitude of the increase varies. In one of the larger meta-analyses from Cochrane that evaluated 70 trials including 15,935 participants, the hazard ratio (HR) for death was 1.17 (95% CI 1.06 to 1.29) [16].

Among the hypotheses to explain this potentially detrimental impact on survival with ESA use were an adverse effect on disease progression, excessively high target hemoglobin, and an increase in deaths from thromboembolism.

●Possible exception for some patients with chemotherapy-induced anemia – Additional analyses restricted to randomized trials of patients receiving chemotherapy suggest that ESAs do not appear to significantly increase mortality, especially when given for a short duration and using a lower target hemoglobin than in earlier trials.

As examples:

•A 2023 meta-analysis that evaluated randomized trials of ESA use in nearly 7000 patients with breast cancer receiving chemotherapy for either curative intent or metastatic disease found a higher risk of death in individuals receiving an ESA than in controls (relative risk [RR] 1.07, 95% CI 1.01-1.13) [68]. However, subgroup analysis according to duration of therapy found the increased risk of death was only statistically significant when the ESA was given for six months or more:

-ESA use for ≤6 months – RR of death, 1.04 (95% CI 0.98-1.10)

-ESA use for >6 months – RR of death, 1.27 (95% CI 1.05-1.55)

•The 2012 Cochrane analysis that found increased mortality with ESAs did multiple subgroup analyses, and the increased mortality was only statistically significant for certain populations, such as individuals with baseline hemoglobin >12 g/dL [16]. Patients with lower baseline hemoglobin values did not have a statistically significant increase in mortality. When the analysis was restricted to trials of patients receiving chemotherapy, there was only a trend toward higher mortality that did not reach statistical significance (OR 1.04, 95% CI 0.98-1.11).

•In a 2020 randomized trial in 2516 patients receiving chemotherapy for advanced NSCLC, overall and progression-free survival were similar with darbepoetin alfa (dosed to a target hemoglobin ≤12 g/dL) and placebo [69].

•In a 2011 trial, 186 patients receiving chemotherapy for lung or gynecologic cancer who had a hemoglobin ≤10 g/dL were randomly assigned to epoetin beta (36,000 units) or placebo weekly for 12 weeks [70]. Doses were held for hemoglobin >10 g/dL, and sustained hemoglobins >12 g/dL were specifically avoided. Transfusions were significantly less common in the ESA group (5 versus 20 percent); the rate of thromboembolic events was similar; and one-year survival was similar. However, the trial was not adequately powered to detect the differences in survival or disease progression that have been noted with ESAs in larger trials.

Additional data are needed. In the meantime, these results support a cautious use of an ESA in selected individuals such as those receiving chemotherapy for a shorter duration and using as low as possible target hemoglobin, as discussed above. (See 'Indications and contraindications' above.)

●Mechanism of survival reduction – The mechanism of reduced survival with ESAs is unclear. Effects on tumor progression have been hypothesized but not clearly demonstrated. Increased thromboembolic events are observed but often at an insufficient rate to explain the differences in survival [59,71]. (See 'Thromboembolic complications' below.)

Thromboembolic complications — Cancer-associated risk factors for venous thromboembolism (VTE) include patient, tumor, and treatment-related factors. (See "Cancer-associated hypercoagulable state: Causes and mechanisms".)

●Risk of VTE – Among patients with cancer, randomized trials and systematic reviews indicate an approximately 50 percent increase in the risk of VTE in patients receiving ESAs.

In a 2012 Cochrane analysis that evaluated 20,102 patients with cancer participating in 91 randomized trials, use of an ESA increased the risk of VTE (RR 1.52, 95% CI 1.34-1.74) [16].

•For patients with a low VTE risk at baseline, this translated into an increase from 20 to 30 events per 1000 patients (range 27 to 35).

•For patients with a high baseline VTE risk, 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 baseline hemoglobin level (<10, 10 to 12, or >12 g/dL). The impact of target hemoglobin level was not addressed.

The risk was similar in a meta-analysis restricted to patients with breast cancer (RR 1.53, 95% CI 1.27-1.86) [68].

A 2014 meta-analysis involving 12,115 patients with cancer participating in 51 randomized trials also found a higher VTE risk in patients who received an ESA (RR 1.75, 95% CI 1.50-2.05) [72]. The highest risk was in patients with ovarian and cervical cancers (RR 2.45, 95% CI 1.12-5.33].

●Effect of hemoglobin – An excessively high baseline hemoglobin or target hemoglobin may contribute to a higher incidence of thromboembolic events.

•In many of these trials of an ESA versus control, hemoglobin targets were higher than current recommendations, in the range of 13 to 15 g/dL.

•However, in the 2012 Cochrane meta-analysis, risk of VTE remained elevated for all baseline hemoglobin values (hemoglobin <10 g/dL, RR 1.41 [95% CI 1.06-1.99]; for hemoglobin 10 to 12 g/dL, RR 1.64 [95% CI 1.33-2.03]; for hemoglobin >12 g/dL, RR 1.44 [95% CI 1.15-1.80]) [16].

•An updated analysis of five ESA trials by the Agency for Healthcare Research and Quality concluded that there was a trend toward fewer thromboembolic events when ESA treatment was delayed until the baseline hemoglobin 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 [17].

•Higher target hemoglobin levels are also associated with increased thromboembolic events in patients receiving an ESA to treat anemia in end-stage kidney disease. (See "Treatment of anemia in patients on dialysis", section on 'Target Hb levels'.)

These findings support the practice of using a lower target hemoglobin. (See 'Target hemoglobin' above and 'Recommendations from expert groups' above.)

Other adverse effects

●No major effect on disease progression – Several meta-analyses of randomized trials have failed to show significant differences in disease progression or tumor response rates with or without ESAs [16,17,67,73,74].

●Hypertension – In the 2012 Cochrane meta-analysis, use of an ESA 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) [16].

●Pure RBC aplasia – Cases of pure RBC aplasia due to anti-erythropoietin antibodies have been reported in patients with chronic kidney disease (CKD) treated with ESAs, and in theory, this could occur in patients with cancer as well. However, this complication is rare, 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".)

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 fatigue and anemia – Fatigue and anemia are common in patients with cancer, and a holistic approach is required to evaluate the cause(s) of both. Details are summarized in the table (table 3) and discussed in topics listed above. (See 'Evaluate and treat other causes of fatigue' above and 'Evaluate and treat other causes of anemia' above and "Cancer-related fatigue: Prevalence, screening, and clinical assessment".)

●ESA versus transfusion – Once other treatable causes of anemia are excluded or addressed, two main approaches to increasing the hemoglobin are an erythropoiesis-stimulating agent (ESA) or red cell transfusions. The table summarizes advantages and disadvantages (table 1). (See 'ESA versus transfusion' above.)

●ESA indications and contraindications – The flowchart summarizes decision-making (algorithm 2), which includes the following:

•For patients with chemotherapy-induced anemia who meet all of the following criteria, we suggest an ESA rather than transfusions (Grade 2C):

-Nonhematologic cancer

-Receiving myelosuppressive chemotherapy, not with curative intent

-Symptomatic

-Hemoglobin <10 g/dL

and

-Can wait two to four weeks for an increase in hemoglobin

These individuals may reasonably avoid ESAs, especially if they are concerned about reduced survival, venous thromboembolism or burdens of therapy, if they require a rapid increase in hemoglobin, or if they prefer transfusions for other reasons. (See 'Symptomatic, chemotherapy-associated anemia' above and 'Supporting evidence' above.)

•For patients with non-chemotherapy anemia, we generally do not use an ESA. However, an ESA may be appropriate for chronic kidney disease or if transfusions are declined or not tolerated. (See 'Off-label use in non-chemotherapy anemia' above.)

•The main absolute contraindications are uncontrolled hypertension and previous venous thromboembolism not currently receiving anticoagulation. Whether ESAs should be avoided in patients receiving chemotherapy with curative intent remains controversial; caution is advised. (See 'Contraindications' above and 'Use caution in patients treated with curative intent' above.)

•Our approach is similar to available guidelines, which restrict use to chemotherapy-induced anemia in patients not being treated with curative intent. (See 'Recommendations from expert groups' above.)

•Recommendations for patients with hematologic malignancy are discussed in topics listed above. (See 'Introduction' above.)

●Informed consent – For individuals considering an ESA, informed consent includes discussion of harms and benefits (table 2). Only 50 to 70 percent have a hemoglobin increment ≥1 g/dL after 8 to 12 weeks of ESA. Bone marrow involvement by cancer, high endogenous erythropoietin, and conditions that cause high cytokine levels may interfere with response. (See 'Informed consent and likelihood of response' above and 'Supporting evidence' above.)

●Choice of drug, dosing, and target hemoglobin – Available ESAs including biosimilars have equivalent safety and efficacy. Starting doses and dose modifications should follow US Food and Drug Administration (FDA)-approved labeling (table 4). We target the lowest hemoglobin that reduces symptoms, and we hold the ESA and adjust the dose if the hemoglobin is >11 g/dL. Some individuals may use different hemoglobin values. (See 'Choice of ESA' above and 'Dosing and monitoring' above and 'Target hemoglobin' above.)

●Iron stores – Sufficient bioavailable iron is required. Iron studies (ferritin, iron, total iron binding capacity, calculated transferrin saturation [TSAT]) are assayed prior to starting an ESA, during therapy, and when the hemoglobin does not increase. (See 'Maintain adequate iron stores' above.)

•Patients with iron deficiency (ferritin <30 ng/mL or TSAT <20 percent) require supplemental iron. (See "Treatment of iron deficiency anemia in adults", section on 'Indications for treatment'.)

•For all patients treated with ESAs, we suggest supplemental iron (Grade 2C).

•For most patients receiving supplemental iron with an ESA, we suggest intravenous rather than oral iron (Grade 2C).

●Adverse events – Prescribing information for ESAs includes a Boxed Warning stating a risk shortened overall survival and/or tumor progression or recurrence in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers. ESAs increase the risk of venous thromboembolism approximately 1.5-fold. (See 'Risks and adverse events' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Stanley L Schrier, MD, David P Steensma, MD, and Charles L Loprinzi, MD, who contributed to an earlier version of this topic review.