Introduction
Anemia happens when a patient has a low red blood cell (RBC) count. Apart from other functions, RBCs deliver oxygen to the body. An anemic patient has a pale complexion, dyspnea (shortness of breath), chest pain, and headaches.
Cancer (the development of abnormal cells in the body) deteriorates the patient’s iron and hemoglobin (Hb) profile. As a result, anemia can negatively impact the anticancer treatment efficacy and patient survival. Cancer-related anemia (CRA) may accompany cancer and is primarily diagnosed in patients at advanced disease stages. CRA is characterized by low circulating iron and transferrin saturation (transferrin binds to iron and mediates its transport through the blood). The iron stores are adequate in CRA. Hence, CRA originates from issues in iron homeostasis (self-regulatory process) and additional factors such as chronic inflammation due to cancer. Therefore, it is crucial to identify the existing chronic inflammatory and oxidative state and correctly diagnose anemia before initiating anticancer treatment.
What Is the Pathogenesis of Cancer-Related Anemia?
The pathogenesis (disease process) of CRA is multifactorial and can be a result of cancer invasion (anemia secondary to cancer; ASC), cancer treatment (radiation, chemotherapy), or chronic kidney disease (CKD).
ASC results from cancer invading normal tissues causing blood loss and bone marrow infiltration, which inhibits RBCs. Chemotherapy alone or combined with radiotherapy commonly contributes to the development of anemia (chemotherapy-induced anemia) as it is myelosuppressive (suppresses RBC production by the bone marrow).
The kidneys produce erythropoietin (EPO, a hormone that prompts the bone marrow to produce RBCs). CKD (a result of kidney injury from chemotherapy) can be diagnosed in many elderly patients with cancer. Additionally, malnutrition, lack of nutrients (iron, vitamins, and folic acid are needed for RBC production), eating disorders, inactivity, and other lifestyle factors may contribute to CRA pathogenesis.
Certain cancers, such as leukemia, lymphoma, and multiple myeloma, damage bone marrow. Nausea, vomiting, and loss of appetite can also cause nutrient loss. In cancer, one can lose RBCs faster than their production. It may happen after surgery or when cancer causes bleeding in the body.
CRA is also due to oxidative stress (imbalance between free radicals and antioxidants in the body that causes tissue and organ damage) and chronic inflammation (refers to the immune system response that persists long after an infection or injury). Hence, cancer-induced chronic activation of the immune response results from the suppression of erythropoiesis (RBC formation) by cytokines (immune mediators). In CRA, a strong correlation has been found between the prevalence and severity of anemia and the cancer stage.
Further, there is a direct link between inflammatory markers, including C-reactive protein (CRP), fibrinogen, interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, erythrocyte sedimentation rate (ESR), and reactive oxygen species (ROS) and the stage of cancer. Hence, CRA is a cytokine-mediated disorder resulting in interactions between cancer cells and the immune system. Overexpression of the inflammatory cytokines results in decreased RBC survival, suppression of parent RBCs, impaired iron utilization, and insufficient EPO production. Hence, to summarize, the main pathogenic mechanisms by which inflammation may cause CRA are:
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Shortened RBC survival and increased RBC destruction.
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Suppressed erythropoiesis in the bone marrow.
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Effects of chronic inflammation on EPO production.
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Alterations in iron metabolism that result in iron-restricted RBC formation.
What Is the Clinical Relevance of Cancer and Anemia?
CRA has a significant clinical impact on cancer patients. It leads to a decline in patient survival and quality of life (QoL). Further, it is due to impaired brain function and energy-activity levels. Patients with CRA exhibit fatigue, lethargy, dyspnea, and anorexia (an eating disorder marked by restriction of food intake). All these compromise the overall functional status and reduce adherence to anticancer treatment. CRA-related fatigue can particularly affect QoL and restricts patients from receiving adequate treatment, impairing the therapeutic response.
Moreover, CRA affects the central nervous system (CNS). EPO-specific receptors are expressed in the CNS, and EPO exerts a crucial role in preventing cell death and favoring the survival of brain neurons. CRA can also affect the immune system causing immunosuppression, which increases susceptibility to infection and further decreases treatment efficacy.
How Is Cancer-Related Anemia Managed?
CRA is associated with multiorgan failure that occurs in advanced cancer. Thus, CRA carries a negative prognosis. Treatment strategies should target the multiple causes and include blood transfusions, erythropoiesis-stimulating agents (ESAs), iron supplementation, nutritional supplementation, and anti-inflammatory therapies.
Blood transfusions are an effective therapeutic intervention to improve the symptoms by rapidly boosting Hb. Blood transfusions are convenient in severe or life-threatening anemia. Several studies reveal improved survival in cancer patients receiving transfusions. Moreover, they are useful in treating breathlessness and fatigue. However, blood transfusions have risks such as fever, allergic reactions, the transmission of infectious diseases, and immunosuppression.
The United States Food and Drug Administration (US FDA) approved recombinant human erythropoietin (rHuEPO) in 1993 for CRA. Hence, various short- and long-acting formulations of rHuEPO (ESAs) are available. Furthermore, several ESAs have been developed and introduced in clinical practice. Examples of ESAs are Epoetin alfa and Darbepoetin, which work well for treating CRA.
Intravenous (IV) iron administration can improve QoL and decrease the need for blood transfusions in CRA patients. It is because oral iron (used for treating anemia) is inappropriate for treating inflammation-related anemia (the basis of CRA) due to inadequate absorption, metabolic disorders, and gastrointestinal complications. On the contrary, IV iron can be captured directly by immune cells counteracting absorption problems. Currently, there is no standard therapy for IV iron (alone or in combination with EPO agents) in CRA. Future strategies include chelate-iron therapy, cytokines, or hormones that can modulate erythropoiesis under severe inflammation. Hence, it warrants further studies on CRA patients.
Although conventional therapies help many patients, some need a novel multitarget approach as the anemia remains uncorrected. Some examples are diet modifications (including probiotics, polyphenols, lipoic acid, and green tea), vitamin supplementation, and exercise.
Conclusion
In recent years, new evidence on integrated approaches for CRA is emerging. However, a successful clinical approach is still lacking. Currently, oral iron is the primary therapy for CRA. However, it can impair the gut microorganisms and cause serious problems, such as diarrhea. On the contrary, evidence shows that adequately prescribed functional supplements and regular moderate or low-intensity physical activity can significantly improve patients’ general health, metabolic profile, and immune system. The above-mentioned treatment plan can also reduce oxidative stress and inflammation, which are the underlying mechanisms of CRA. Still, more studies are required to explore the relevance of the integrated approach in CRA.
In conclusion, the patient’s physiological status should be assessed. Further, the clinician, nutritionist, and exercise specialist should work as a multidisciplinary team targeting the anemia pathogenesis and the patient’s clinical state.
