When should Erythropoiesis-Stimulating Agents (ESAs) be used in patients with anemia?

ESAs Should Be Used Selectively in Cancer Patients on Chemotherapy and CKD Patients, With Strict Hemoglobin Targets and Contraindications in Curative-Intent Treatment

ESAs are indicated for chemotherapy-induced anemia in cancer patients with hemoglobin ≤10 g/dL who are receiving palliative (not curative) chemotherapy, and for anemia in chronic kidney disease patients, but should never target hemoglobin levels above 12 g/dL due to increased mortality and thrombotic risks. 1, 2

Primary Indications for ESA Use

Cancer Patients on Chemotherapy

• ESAs may be considered only in patients receiving myelosuppressive chemotherapy with Hb ≤10 g/dL to prevent transfusions and improve quality of life. 1
• The goal is to increase Hb by <2 g/dL or prevent further decline, not to normalize hemoglobin. 1
• ESAs are absolutely contraindicated in patients receiving chemotherapy with curative intent (e.g., early-stage breast cancer, non-small cell lung cancer, lymphomas, testicular cancer), as they increase mortality and tumor progression risk. 1, 2
• Patients with solid tumors and those on platinum-based chemotherapy benefit more than other tumor types. 1

Chronic Kidney Disease Patients

• ESAs are indicated for anemia in both dialysis and non-dialysis CKD patients. 3, 2
• Target hemoglobin should be 10-12 g/dL in CKD patients—higher targets increase risk of death, myocardial infarction, stroke, and thromboembolism. 3, 2
• Intravenous route is preferred for hemodialysis patients; subcutaneous is acceptable for non-dialysis CKD patients. 2

Absolute Contraindications

Do not use ESAs in the following situations:

• Uncontrolled hypertension 1, 2
• Known hypersensitivity to ESAs 1, 2
• Pure red cell aplasia (PRCA) from prior ESA exposure 1, 2
• Cancer patients NOT receiving chemotherapy (increased mortality risk with Hb targets 12-14 g/dL) 1
• Patients receiving curative-intent cancer treatment 1, 2
• When anemia can be managed by transfusion alone 2

High-Risk Situations Requiring Extreme Caution

ESAs increase thromboembolic risk by 67% (RR 1.67,95% CI 1.35-2.06), so carefully reconsider use in: 1

• Previous history of thrombosis
• Recent surgery or prolonged immobilization
• Multiple myeloma patients on thalidomide/lenalidomide with doxorubicin and corticosteroids 1
• Patients with impaired liver function 1

Dosing and Monitoring Algorithm

Initial Dosing for Cancer Patients

Epoetin alfa: 1, 3

• 150 U/kg subcutaneously 3 times weekly, OR
• 40,000 U subcutaneously once weekly

Darbepoetin alfa: 1, 3

• 2.25 mcg/kg subcutaneously weekly, OR
• 500 mcg subcutaneously every 3 weeks

Response Assessment at 4 Weeks

• If Hb increase ≥1 g/dL: Continue same dose or decrease by 25-50% 1
• If Hb increase <1 g/dL: Increase dose per protocol (see dosing tables) 1
• If Hb rises >2 g/dL in 4 weeks OR exceeds 12 g/dL: Reduce dose by 25-50% 1
• If Hb exceeds 13 g/dL: Discontinue until Hb falls below 12 g/dL, then restart at 25% lower dose 1

Discontinuation Criteria

• Stop ESAs if no response (Hb increase <1 g/dL) after 8-9 weeks of therapy—continuing is not beneficial. 1, 3
• Discontinue 4 weeks after completion of chemotherapy in responders. 1, 3

Mandatory Iron Monitoring and Supplementation

• Baseline and periodic monitoring of iron, transferrin saturation (TFS), ferritin, and C-reactive protein is necessary. 1
• Intravenous iron supplementation in iron-deficient patients leads to higher Hb increments than oral or no iron and reduces transfusion requirements. 1
• Functional iron deficiency (ferritin >100 ng/mL but TFS <20%) should be corrected before or during ESA therapy. 1

Critical Safety Considerations

Mortality and Tumor Progression Risk

• Meta-analyses show ESAs increase overall mortality (cHR 1.17,95% CI 1.06-1.30) when given to cancer patients overall. 1
• However, patients treated with chemotherapy had no increased mortality (HR 0.97,95% CI 0.85-1.1). 1
• Studies targeting Hb >12 g/dL or including patients with baseline Hb >11 g/dL showed decreased survival and poorer disease control. 1

Special Populations

CKD patients with cancer: 4

• Use lowest ESA doses to achieve maximum Hb of 10 g/dL
• Patients with remote or active malignancy require particularly cautious dosing

Patients refusing transfusions: ESAs may be considered even in contexts where otherwise contraindicated, with careful risk-benefit discussion. 1

Common Pitfalls to Avoid

1. Never target hemoglobin >12 g/dL—this increases mortality, cardiovascular events, and tumor progression without additional benefit. 1, 2
2. Do not continue ESAs beyond 6-8 weeks without response—this wastes resources and exposes patients to unnecessary risks. 1
3. Do not use ESAs in curative-intent settings—the mortality signal is strongest here. 1, 2
4. Do not ignore iron status—functional iron deficiency limits ESA effectiveness. 1
5. Do not use ESAs as substitute for urgent transfusion—they take weeks to work. 2

Cost-Effectiveness Warning

ESAs profoundly increase healthcare costs with an estimated cost per quality-adjusted life-year of €208,000, as there is no survival benefit. 1 This economic consideration should factor into shared decision-making, particularly in resource-limited settings.