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Anaemia in Cancer Patients Prof. Dr. Khaled Abouelkhair, PhD Medical Oncology SCE, Royal College, UK Ass. Professor of Clinical Oncology Mansoura University, Egypt Outlines Anaemia Definition Causes Laboratory diagnosis Manifestations Clinical importance Treatment and ESAs Anaemia Anaemia is “The condition of having less than the normal number of red blood cells or less than the normal quantity of hemoglobin in the blood. The oxygen-carrying capacity of the blood is, therefore, decreased.” Anaemia can result from the tumor itself (Anaemia of cancer) as well as from cancer treatments, especially myleosuppressive chemotherapy (chemotherapyinduced Anaemia). According to The European Cancer Anaemia survey (ECAS), Anaemia affects 67% of cancer patients. The physiologic regulation of red cell production by tissue oxygen tension. Causes of Anaemia in Cancer Uncontrolled pain can cause Anaemia and through many factors one of them is decreased appetite. Decreased RBC production by treatment of cancer e.g. chemotherapy and or radiotherapy. Decreased or inappropriate endogenous erythropoietin. Decreased body stores of important factors e.g. Vit. B12, Folic acid and Iron. Increased destruction Anaemia is a major contributing factor to cancer related fatigue beside many others e.g. psychological, nutritional and disability caused by cancer. NCI Classification of Anaemia Grade 0: within normal limits, Hb values are 12.0 to 16.0 g/dL for women and 14.0 to 18.0 g/dL for men. Grade 1: mild (Hb 10 g/dL to normal limits) Grade 2: moderate (Hb 8.0 to 10.0 g/dL) Grade 3: serious/severe (Hb 6.5 to 7.9 g/dL) Grade 4: life threatening (Hb less than 6.5 g/dL). Manifestations of Anaemia Manifestation and severity of anaemia vary considerably among individual patients. Mild-to-moderate anaemia can cause typical symptoms including headache, palpitations, tachycardia and shortness of breath. Chronic anaemia may result in severe organ damage affecting the cardiovascular system, immune system, lungs, kidneys, muscles and the central nervous system. In addition to physical symptoms, the subjective impact of cancerrelated anaemia on quality of life (QoL),mental health and social activities may be substantial. Clinical studies have reported correlations between Hb levels and quality of life domains, for example mood, appetite (Leitgeb 1994), fatigue and the ability to work (Cella 1998; Thomas 1998). Clinical Importance? Its effect on the tumour itself. For malignant diseases such as Hodgkin’s Disease (HD), chronic lymphocytic leukaemia (CLL), cervical carcinoma and cancer of the head and neck, anaemia has been reported to be an independent prognostic factor. Anaemia, with the consequence of increased tumour hypoxia, results in a poorer response to radio- or chemotherapy. Severe symptoms of anaemia may also necessitate dose reduction or delay of chemotherapy. All these factors may lead to a higher tumour burden and a decreased overall survival. Evaluation…Not every anaemia in Cancer patients is related to chemotherapy The evaluation of the patient with anaemia requires a careful history and physical examination. Nutritional history related to drugs or alcohol intake and family history of anaemia should always be assessed. Certain geographic backgrounds and ethnic origins are associated with an increased likelihood of an inherited disorder of the haemoglobin molecule or intermediary metabolism. Glucose-6-phosphate dehydrogenase (G6PD) deficiency and certain haemoglobinopathies are seen more commonly in those of Middle Eastern or African origin. Laboratory studies Pay attention to…. Anisocytosis Poikilocytosis Polychromasia Reticulocytic count Sickle cells Howell-jolly bodies Reticulocytes Index Blood Smear Normal blood smear (Wright stain). Howell-Jolly bodies. Iron Deffiency Myelofibrosis Macrocytosis Target Cells Red Cell Fragmentation Reticulocytosis Burr Cell ….Uraemia Spur Cells..Acanthocytes Iron Studies The serum iron ranges from 9 to 27 μmol/L (50–150 μg/dL). While the normal TIBC is 54–64 μmol/L (300–360 μg/dL); the normal transferrin saturation ranges from 25 to 50%. A diurnal variation in the serum iron leads to a variation in the percent transferrin saturation. The serum ferritin is used to evaluate total body iron stores. Adult males have serum ferritin levels that average ∼100 μg/L, corresponding to iron stores of ∼1 g. Adult females have lower serum ferritin levels averaging 30 μg/L, reflecting lower iron stores (∼300 mg). A serum ferritin level of 10–15 μg/L represents depletion of body iron stores Reticulocytic Index The physiologic classification of anaemia. Treatment of Chemotherapy induced Anaemia For long time blood transfusions was the only way to improve anaemia, followed in early nineties by the use of Erythropoiesis stimulating agents (ESAs). The literature reports a critical degree of anaemia as a Hb level below 8 g/dL, while mild to moderate anaemia (Hb level 8-10 g/dL) usually has been left untreated (Carson 2012; Cella 1999). Although homologous blood transfusion is the fastest method to alleviate symptoms, short- and long-term risks exist. Transfusions….. Gold Standard Potential complications associated with blood transfusion are transmission of infectious diseases, transfusion reactions, allo-immunisation, over-transfusion and immune modulation This method remains the best way of rapidly ameliorating anaemic symptoms and target to maintain Hb between 8 – 10 and decrease anaemia related symptoms However, the effect of the treatment is short-lived and there are several risks involved even with the widespread testing of donors. This is why ESAs were introduced to clinical practice. ESAs…. A hope turned into a hill What we expect to be this Turned in reality to be that ESAs Recombinant human erythropoietin is a treatment option for cancer- related anaemia. Human erythropoietin is an acidic glycoprotein hormone. Approximately 90% of the hormone is synthesised in the kidney and 10% in the liver (Koury 1988; Koury 1991). Basal production maintains a relatively constant plasma concentration of erythropoietin in individuals, within a range from 9 to 26 mU/mL. Tissue hypoxia is the most important trigger for increased synthesis. ESAs The effects of erythropoietin in the bone marrow are mediated by a specific surface receptor located mainly on erythroid progenitor and precursor cells (D´ Andrea 1989; Spivak 1994b). Two major functions of erythropoietin are described: stimulating progenitor cell proliferation and maintaining their viability. In 1985, Lin et al isolated EPO and coded its gene sequence Several short- and long-lasting forms of recombinant human erythropoiesis-stimulating agents (ESAs) are available: Types of ESAs Epoetin-a and Epoetin-ß and darbepoetin-a (Darbepo) (Glaspy 2003; Halstenson 1991;Hedenus 2002; Joy 2002; Storring 1998; Vansteenkiste 2002). Recently: Novel ESA molecules, such as continuous erythropoietin receptor activator (CERA) (Gascon 2008) Biosimilars (epoetin theta, epoetin delta) have been developed (Jelkmann 2010). Clinical trials directly comparing Epo and Darbepo have been published and suggest that Epo and Darbepo are similarly effective with regard to Hb response and proportion of patients transfused. Impact of ESAs In the early 1990s ESAs were shown to alleviate Anaemia in cancer patients receiving chemotherapy. Hence ESAs were used extensively in clinical practice and high Hb levels up to 16 Gm/dl were targeted. Earlier Studies ESAs were found to: Increase Haemoglobin (Hb) levels Reduce the need for red blood cell transfusions Improve quality of life (QoL) through alleviation of anaemic symptoms e.g. fatigue Increase overall survival ESAs However…further researches proved a decrease in overall survival and association with tumor progression, thromboembolic events, hypertension and even death. Failed to show improvement of patient’s well being, enhance quality of life or alleviate fatigue. Not indicated for cancer patients not on myleosuppressive chemotherapy…RT, Hormone or biologic. Not used as a substitute for urgent PRBCs transfusion to rapidly correct anaemia. Epoetin Alfa (Eprex) Prefilled Syringe Dose 150U/Kg IV/SC 3 times weekly or 40,000 U SC once weekly until completion of chemotherapy course. Needs Iron supplement and weekly monitor of Hb levels. Target of treatment is increase of Hb level by 1 Gm/4 weeks treatment. Stop if Hb reaches 10 Gm and the patient is asymptomatic. If target level not reached after 4 weeks; increase to 60,000 U once weekly and keep monitoring. if Hb increased by more than 1Gm in any 2-weeks period reduce by 25%. Eprex….Side Effects Hypertension is common…15-25% VTE is serious……8% Fever…..25% Pruritus rash and headache about 15% each Increased risk of serious cardiovascular events. Rare but fatal…red cell aplasia, Seizures, severe allergic reactions. Recent Guidelines: Restricted ESAs use to only one indication chemotherapy induced anaemia with restrict precautions: Lower target Hb levels to 10-12 Gm/dl. Meticulous and continuous follow up of Hb levels. Only if the patient’s treatment of palliative intent. Anaemia in cancer but not myeloid cancers. DVT prophylaxis is advised especially in high risk patients. FDA currently requires these agents to be prescribed only under REMS (risk evaluation and mitigation strategy for ESAs). With full explanation to the patients about the side effects and risk of tumour progression. What is your Role? Read your patient’s CBC and symptoms carefully. Define the type of anaemia: Size, normo or hypochromic. If microcytic hypochromic ask for Iron studies i.e Iron, TIBC, Ferritin. Give Iron…relation to food…tea and Coffee. Give Folic and Vit B12. If chemotherapy for cure…Do not hold chemotherapy if Hb 8-10 and the patient is asymptomatic…proceed with chemotherapy and start Iron supplement +/transfusions. Case Study A 38 y.o female recently diagnosed with early stage breast cancer presented for her 3rd cycle of chemotherapy, however, she is complaining of fatigue and her Hb level is 8 Gm/dl decreasing from 11 Gm/dl at diagnosis. What you will do? A. B. C. D. Give her Iron supplement and delay her treatment for one week. Start ESAs plus iron and give her cycle. Start ESAs with Iron and delay her cycle till Hb is at least 10 Gm/dl. Transfuse with PRBCs and give her cycle once Hb is 10 Gm/dl.