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Prophylaxis and Treatment of Cancer-Related Anemia

Grading of Cancer-Related Anemia

The severity of anemia according to CTCAE is based on the hemoglobin concentration and complications:

• Grade 0: Hemoglobin within the reference range
• Grade 1: Hemoglobin below the reference range but ≥10 g/dl
• Grade 2: Hemoglobin 8 to <10 g/dl
• Grade 3: Hemoglobin <8 g/dl; transfusion may be indicated
• Grade 4: Life-threatening consequences; urgent intervention indicated
• Grade 5: Death related to complications of anemia

Epidemiology of Cancer-Related Anemia

Approximately 40% of patients with solid, nonhematologic malignancies have anemia. Advanced metastatic disease and treatment with androgen deprivation, radiation therapy, or chemotherapy increase the risk of anemia. Cancer-related anemia worsens quality of life and is associated with a less favorable prognosis.

Causes of Cancer-Related Anemia

• Nutritional deficiencies due to poor appetite and cachexia can lead to iron, vitamin B12, and folate deficiency.
• Chronic inflammation related to malignancy can cause functional iron deficiency (ferritin normal or elevated, transferrin saturation <20%).
• Blood loss: hematuria, hematochezia, and perioperative bleeding.
• Bone marrow failure due to bone marrow infiltration or treatment-related myelosuppression (e.g., chemotherapy or radiation therapy).

Diagnosis of Cancer-Related Anemia

Obtain a thorough history focused on potential causes of blood loss and anemia, and perform laboratory testing that includes a complete blood count with differential, reticulocyte count, renal function tests, iron panel (serum iron, transferrin saturation, and ferritin), CRP, vitamin B12, and folate. Depending on the clinical context, evaluation should also include stool occult blood testing and urine analysis.

Treatment of Cancer-Related Anemia

Principles of treatment include nutritional support, iron supplementation, erythropoiesis-stimulating agents (ESAs), and blood transfusions.

Erythropoiesis-Stimulating Agents

Erythropoiesis-stimulating agents (ESAs) are synthetic analogs of erythropoietin that act as growth factors to stimulate red blood cell production in the bone marrow.

Indications

In patients with chemotherapy-associated anemia, consider treatment with erythropoiesis-stimulating agents (ESAs) based on symptoms, comorbidities, and the expected duration of anemia, particularly when hemoglobin is <10 g/dl in a noncurative treatment setting.

Contraindications

Do not use ESAs in untreated iron deficiency or vitamin deficiency (replace deficiencies first), in severe symptomatic anemia (hemoglobin <8 g/dl, prefer blood transfusions), in cancer-related anemia without ongoing chemotherapy, or after completion of curative-intent therapy (lack of indication and potential risk).

Adverse Effects of Erythropoiesis-Stimulating Agents

• Injection-site reactions
• Systemic reactions: Fever, headache, nausea, vomiting, or arthralgia.
• Cardiovascular complications: The relative risk (RR) increases, particularly in patients with cardiovascular risk factors and with overly aggressive dosing leading to hemoglobin levels >12 g/dl. Reported complications include hypertension, thromboembolic events (RR 1.5), and increased cardiovascular mortality (RR 1.3), including myocardial infarction, stroke, or heart failure.
• Oncologic adverse effects: ESAs have been associated with worse tumor outcomes and reduced overall survival.
• Rare adverse effects include pure red cell aplasia due to anti-ESA antibodies and severe cutaneous reactions.

Dosing of Erythropoiesis-Stimulating Agents

ESAs are administered by subcutaneous injection; available agents include epoetin alfa (and biosimilars), epoetin beta (region-dependent), and darbepoetin alfa. The following starting doses provide general guidance and should be adjusted based on hemoglobin levels and clinical response. The goal is to achieve the lowest hemoglobin concentration that improves symptoms and reduces the need for transfusion (often approximately 10–12 g/dl). Avoid hemoglobin levels >12 g/dl by reducing the dose or holding therapy.

Epoetin alfa:

Start at 150 IU/kg subcutaneously three times per week; alternatively, start at 450 IU/kg subcutaneously once weekly.

• If the response is inadequate, increase the dose to 300 IU/kg subcutaneously three times per week after four weeks.
• Discontinue therapy if the patient does not respond despite dose escalation.
• If hemoglobin increases by more than 2 g/dl per month or exceeds 12 g/dl, reduce the dose by 25–50%.

Epoetin beta:

Start at 450 IU/kg subcutaneously every 7 days.

Darbepoetin alfa:

Start at 2.25 μg/kg subcutaneously every 7 days.

Iron Supplementation in Cancer-Related Anemia

Iron replacement is indicated in patients with cancer-related anemia and absolute iron deficiency (serum iron low, serum ferritin well below 100 ng/ml, and transferrin saturation <20%) and functional iron deficiency (serum iron low, serum ferritin normal or high, transferrin saturation <20%, and often elevated CRP). Intravenous iron is more effective than oral iron in cancer-related anemia, particularly in patients receiving ESAs or those with functional iron deficiency.

• Ferric carboxymaltose: 20 mg/kg body weight (maximum single dose 1000 mg). A typical course consists of 1–2 injections ≥7 days apart, aiming for a total dose of 1000–1500 mg of iron.
• Ferric derisomaltose: 20 mg/kg body weight as a single infusion for a total dose of 1000–1500 mg iron.

Blood Transfusions

See the section on blood transfusions. Base transfusion decisions in patients with cancer-related anemia on symptoms and clinical stability, and use a less restrictive approach than in uncomplicated postoperative anemia because rapid spontaneous recovery of hemoglobin is unlikely.

References

Aapro M, Beguin Y, Bokemeyer C, Dicato M, Gascón P, Glaspy J, Hofmann A, Link H, Littlewood T, Ludwig H, Österborg A, Pronzato P, Santini V, Schrijvers D, Stauder R, Jordan K, Herrstedt J; ESMO Guidelines Committee. Management of anaemia and iron deficiency in patients with cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2018 Oct 1;29(Suppl 4):iv96-iv110. doi: 10.1093/annonc/mdx758. Erratum in: Ann Oncol. 2018 Oct 1;29(Suppl 4):iv271. doi: 10.1093/annonc/mdy323. PMID: 29471514.

Choo u.a. 2005 CHOO, R. ; CHANDER, S. ; DANJOUX, C. ; MORTON, G. ; PEARCE, A. ; DEBOER, G. ; SZUMACHER, E. ; LOBLAW, A. ; CHEUNG, P. ; WOO, T.: How are hemoglobin levels affected by androgen deprivation in non-metastatic prostate cancer patients?
In: Can J Urol
12 (2005), Nr. 1, S. 2547–52.

Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): Supportive Therapie bei onkologischen PatientInnen https://www.leitlinienprogramm-onkologie.de/leitlinien/supportive-therapie

  Deutsche Version: Prophylaxe und Therapie der Tumoranämie

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