Inflammatory and tumor anemia

The term "paraneoplastic syndrome" was introduced by Boudin in 1961 (Stemmler 2010). In the late 1990s, the treatment of cancer-associated anemia with erythropoiesis-stimulating agents (ESA [Gilreath 2020]) began after the first recombinantly produced erythropoietin from the Amgen company was launched in 1989 (Krämer 2008).

Inflammatory and tumor anemia (ACD) is a normochromic, normocytic hyporegenerative anemia that can occur in the course of severe, acute or chronic inflammation, solid tumors, lymphomas and leukemias (Herold 2022). According to WHO, the lower limit of anemia is characterized by a Hb- value depending on age in Central European non-pregnant women at 12 g / dl (7.45 mmol / l) and in men 13 g / dl (8.07 mmol / l) (Jordan 2020).

Tumor an emia: Tumor anemia is one of the paraneoplastic syndromes (Stemmler 2010). According to the guideline, tumor anemia is defined as follows:

- Tumor anemia: It results from activation of the immune system.

- Tumor therapy induced anemia: This is caused by chemotherapy and / or radiotherapy.

- Chemotherapy-induced anemia: In this case, the anemia is caused by chemotherapy alone (Jordan 2020).

Tumor anemia: According to WHO and Common Terminology Criteria of Adverse Events (CTCAE), the classification of tumor anemia is divided into the following grades depending on the hemoglobin concentration:

• Grade 1: Women Hb 11.9 - 10.0 g / dl Men Hb 12.9 - 10.0 g / dl
• Grade 2: Women Hb 9.8 - 8.0 g / dl Men Hb 9.9 - 8.0 g / dl
• Grade 3: Women Hb ≤ 7.9 g / dl Men Hb ≤ 7.9 g / dl
• Grade 4: women: life-threatening consequences men: life-threatening consequences (Gilreath 2020).

see also inflammatory anemia

Tumor anemia: At diagnosis, about 50% of all patients with solid tumors already show ACD and 60-70% of patients with hematologic neoplasms (Szeimies 2010). The prevalence of tumor anemia can increase to 90%, depending on treatment (Gilreath 2020).

In patients with carcinomas, ACD was found in 63.4% in studies (Fränkel 2017). Jordan even speaks of 75% (2020). Patients with gynecological tumors (77 %) and lung carcinomas (77 - 83 %) are predominantly affected.

In the case of radiatio, about 38 % are affected by anemia, and in the case of combined radio- and chemotherapy, about 62 % (Jordan 2020).

Patients present with tumor-related anemia Hb- values between 7 - 11 g / dl. Of these, 18 - 34 % require transfusion (Link 2006).

Inflammatory anemia: see d.

Triggering factors are:

• acute and chronic infections
• advanced malignant disease (Fränkel 2017) autoimmunological diseases (Kaltwasser 2009).

An older age and renal failure have an unfavorable effect (Fränkel 2017). Tumor anemia is caused by 3 main factors:

1. Hemolysis
2. ineffective erythropoiesis
3. Blood loss (Gilreath 2020).

Tumor anemia is most often iatrogenically caused by chemotherapy or radiotherapy (Demetri 2001). In addition, nephrotoxic effect with decreased EPO- production plays a role with some cytostatic drugs (Dicato 2010).

The polypeptide hepcidin, which is primarily formed in the liver and excreted via the kidneys (Nemeth 2014), inhibits the ability of the intestine to absorb iron. In chronic inflammation, it is increased by inflammatory toxins, especially interleukin. In addition, iron absorption by duodenal enterocytes is downregulated. Thus, a state of functional iron deficiency develops (Cullis 2013). Erythropoietin (EPO), which is produced in the kidney, promotes the formation of erythrocytes. In inflammatory anemia, the increase in EPO that normally follows a drop in Hb- levels is attenuated (Cullis 2013).

Positive effects of anemia: The reduced availability of iron blocks the growth of invading pathogens. In addition, the deprivation of iron leads to a strengthening of the immune defense mechanisms of macrophages (Weiss 2009).

Tumor anemia: In tumor anemia, on the one hand, the comorbidities such as hemolysis, coagulation disorders, renal insufficiency, malnutrition, etc. play a role.

On the other hand, the malignant disease especially by inflammatory cytokines such as interleukin- 1 alpha and beta, interleukin- 6, interferon gamma and tumor necrosis factor alpha (Jordan 2020) can lead to:

- Suppression of hematopoiesis by bone marrow infiltration.

- Production of cytokines that bind iron

- reduction of erythrocyte production

- Iatrogenic due to therapeutic interventions such as chemotherapy, radiotherapy (Dicato 2010).

Inflammatory anemia: s. d.

Tumor anemia: Clinically, the symptoms of the underlying disease are usually in the foreground. The symptoms of ACD are often masked or concealed by the symptoms of the underlying disease (Herold 2022). The most common symptom is fatigue, which is particularly detrimental to quality of life (Demetri 2001). In a study by Curt (2000), 91% stated that fatigue prevented them from leading a "normal" life. Other symptoms may include:

- decreased cognitive and muscular performance

- general feeling of weakness

- dizziness

- depression

- palpitations

- headaches

- exertional dyspnea

- syncope (Jordan 2020)

- tachycardia

- Paleness of the skin and mucous membranes (Szeimies 2010)

Inflammatory anemia: s. d.

The diagnosis is made on the basis of a detailed history, physical examination, and laboratory chemistry findings (Gaspar 2015).

- Decrease in hemoglobin value (Kasper 2015)

- MCH normal to slightly decreased

- MCV normal to slightly decreased

- Transferrin saturation (TfS) decreased (Herold 2022)

- Serum iron decreased (< 50 µg / dl [Kasper 2015])

- transferrin elevated

- lack of storage iron in bone marrow (Herold 2022)

- Serum transferrin receptor (sTfR) slightly decreased or unchanged (Cullis 2013)

- Hypochromia of reticulocytes

- Ferritin elevated

- Erythropoietin may be elevated

There is a linear correlation between Hb- value and erythropoietin- value. However, in tumor anemia and additionally enhanced by chemotherapy, erythropoietin does not increase in sufficient amount and relative deficiency occurs. The erythropoietin can nevertheless be above the normal value (for a normal Hb value), but below the Hb-dependent target value without anemia (Jordan 2020).

see also inflammatory anemia

- Other forms of anemia, especially iron deficiency anemia.

No Prussian blue stained iron can be detected in bone marrow macrophages in iron deficiency anemia. However, this test has since been replaced by serum ferritin determination, as a decreased serum ferritin value is highly specific for iron deficiency anemia (Nemeth 2014).

Further differentiation is possible by determining the serum transferrin receptor (sTfR), which increases in iron deficiency anemia and remains slightly decreased or unchanged in ACD (Cullis 2013).

The best treatment option is to treat the underlying condition, as this usually also leads to an improvement in the anemia (Cullis 2013). However, if clinical symptoms are present, the anemia should also be treated (Jordan 2020).

Blood transfusions, agents to stimulate erythropoiesis such as epoetin [Cullis 2013]), intravenous iron therapy (Fränkel 2017), and vitamin D- treatment are helpful in this regard (Icardi 2013).

Blood transfusions: Blood transfusions are indicated for life-threatening degrees of anemia with an Hb< 6.5 g / dl and likewise before surgical procedures in patients with ACD (Kaltwasser 2009).

Erythropoietin: Among the erythropoiesis-stimulating substances, drugs such as darbepoetin, epoetin alpha and epoetin beta are available. With these drugs, there is 100% therapeutic success provided that iron is simultaneously substituted in the case of functional iron deficiency (recognizable by adequate storage iron in combination with an increase in hypochromic erythrocytes in the peripheral blood) (Kaltwasser 2009). Dosage recommendation:

• Epoetin alpha: 150 IU / kg bw s. c. 3 x weekly. If this does not achieve therapeutic success (increase in Hb- value after 4 weeks by ≥ 1 G / dl [Demetri 2001]), the dose should be increased to 300 IU / kg bw s. c. 3x weekly. If the patient does not respond even to doubling the dose, therapy should be discontinued (Demetri 2001).
• Epoetin beta: 450 IU / kg bw s. c. every 7 days.
• Darbepoetin: 2.25 µg / kg bw s. c. every 7 days (Manski 2020).

Iron substitution: Iron substitution should be given to ACD- patients with completely depleted iron stores (Kaltwasser 2009).

In addition, iron therapy may be necessary if functional iron deficiency occurs during the course of treatment with erythropoietin. In this context, this is recognizable by sufficient storage iron in combination with an increase in hypochromic erythrocytes in the peripheral blood.

Therapy should be parenteral, as this is superior to oral administration in terms of effectiveness (Kaltwasser 2009).

Dosage recommendation:

- Ferrous gluconate 125 mg over 60 min by infusion. Repeat dose over 2 - 3 weeks up to a total dose of 1,000 mg (Dicato 2010).

- Iron carboxymaltose 750 mg over 7.5 min slowly i. v. or by infusion. Repeat dose is possible after ≥ 7 days (Dicato 2010).

Vitamin D: Administration of native or analog vitamin D improved anemia and reduced the need for erythropoiesis-stimulating agents in studies by Icardi (2013) in patients with chronic renal failure .

Tumor anemia: Tumor anemia in particular is often inadequately treated (Dicato 2010).

The short-term goal should be to correct the quantitative Hb and erythrocyte deficiency so that the oxygen requirements of all tissues can be met (Dicato 2010).

Treatment options available are:

- Transfusions

The administration of red cell concentrates represent a reliable and rapid method to correct anemia. However, because of the existing risks such as transfusion-related reactions, bacterial contamination, viral infection, decompensated heart failure, iron overload, venous and arterial thromboembolism, etc. (Dicato 2010), they are usually administered only when anemia is life-threatening (Demetri 2001). Manski (2020) recommends transfusions from a Hb- value < 8g / dl.

However, in patients with malignant diseases, red blood cell transfusions show a 10-fold higher risk of severe complications than IV iron. From there, Gilreath (2020) recommends transfusing only when other therapies fail and tumor anemia grade 2 - 4 is present. Jordan (2020) recommends decision making for transfusion from a Hb- value < 8 g / dl (5 mmol / l) or a hematocrit between 24 - 21% (5.0 - 4.3 mmol /l).

- Erythropoiesis stimulating agents (ESA: Recombinant human erythropoietin (rHuEPO) has shown good immediate efficacy in increasing Hbs in studies in 50 - 60% of patients and should be used in chemotherapy. Of the remaining 40%, a proportion usually show a response only after 4 weeks at the earliest. The Hb value 2 weeks after the start of therapy has proven to be a prognostic predictor. If this value does not increase by at least 0.5 g/dl, the patient will not respond to erythropoietin with a prediction probability of 80% (Demetri 2001). However, a meta-analysis by Böhlius (2006) showed that caution should be exercised with ESAs in combination with thrombogenic chemotherapeutic agents or in cancer patients at high risk of embolism, as there is an increased risk of venous thromboembolism in these patients (Böhlius 2006) and tumor progression (Dicato 2010). Because ESAs may thus potentially decrease survival, Gilreath (2020) recommends them exclusively in patients with nonmyeloid malignancies and iron-resistant anemia or for patients with decreased quality of life due to anemia after progressive cycles of palliative myelosuppressive antineoplastic therapy (ANT).

ESAs are approved for the treatment of anemia in malignant tumors during chemotherapy (Szeimies 2010).

The use is subject to a strict indication: the Hb- value should be ≤ 10 g / dl (6.2 mmol / l). The target value is 12 g / dl (7.5 mmol / l). The patient should be informed about the benefits and risks (especially thromboembolic complications and arterial hypertension) of ESA- therapy (Jordan 2020).

Dosage recommendation:

- Epoetin alpha: 150 IU / kg bw s. c. 3 x weekly. If this does not achieve therapeutic success (increase in Hb- value after 4 weeks by ≥ 1 G / dl [Demetri 2001]), the dose should be increased to 300 IU / kg bw s. c. 3x weekly. If the patient does not respond even to doubling the dose, therapy should be discontinued (Demetri 2001).

- Epoetin beta: 450 IU / kg bw s. c. every 7 days.

- Darbepoetin: 2.25 µg / kg bw s. c. every 7 days (Manski 2020).

- Biosimilars: A statement on biosimilars and originator drugs cannot be made due to lack of comparative studies (Jordan 2020).

- Iron substitution: In case of additionally existing functional iron deficiency, a therapy with iron i. v. should be performed. In several studies, the combination of iron i. v. with ESA- treatment has been shown to be beneficial in patients receiving chemotherapy (Jordan 2020). Dosage Recommendation:

• - Iron gluconate 125 mg over 60 min by infusion. Repeat dose over 2 - 3 weeks up to a total dose of 1,000 mg (Dicato 2010).
• - Iron carboxymaltose 750 mg over 7.5 min slowly i. v. or by infusion. Repeat dose is possible after ≥ 7 days (Dicato 2010).

Course: The course is usually determined by the underlying disease (Herold 2022). According to Cooper's 2012 CRIT study, severe anemia (Hb < 9 g / dl) in the setting of ACD is a predictor of increased mortality (Cooper 2012).

In the presence of malignancy, anemia is generally associated with a worse prognosis (Avancini 2021).

Tumor growth is experimentally enhanced by hypoxemia, as there is a positive correlation between anemia and tumor hypoxia (Gaspar 2015).

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