Chemotherapy-Induced Anemia in Cancer Patients
The majority of cancer patients undergoing chemotherapy develop anemia during their treatment (Kitano et al., 2007). The European Cancer Anaemia Survey (ECAS), a study conducted across 24 nations in Europe, reported that about 83% of patients who received chemotherapy demonstrated anemia [defined as a hemoglobin (Hb) < 12.0 g/dL] (Barrett-Lee et al., 2006). Anemia often increases symptoms such as fatigue, weakness, and dyspnea; thus, it may worsen quality of life and performance status in cancer patients (Bremberg, Brandberg, Hising, Friesland, & Eksborg, 2007; Kosmidis & Krzakowski, 2005). Anemia can also affect prognosis in cancer patients, resulting in higher mortality (Aapro & Link, 2008); however, chemotherapy-induced anemia (CIA) in cancer patients is often underestimated and is not treated appropriately by health care providers. ECAS showed that 53% of cancer patients did not receive any treatment for their anemia. Of the 47% of cancer patients who were treated, the mean Hb level was 9.1 g/dL for epoetin and 8.5g/dL for transfusion. When considering that NCCN defines anemia as a level of hemoglobin at less than 11 g/dL, the levels reported by ECAS are obviously low. Kosmidis et al. (2005) observed that at a low level of Hb some cancer patients may experience severe anemia related-symptoms that have a profound effect on their quality of life (QOL), physical and mental functioning, and subjective sense of well being. Thus, to improve physical/non-physical functioning, QOL, and prognosis in cancer patients, it would be reasonable to take a proactive approach in identifying populations who need treatment for CIA and provide timely management. In other words, health care providers should identify high-risk patients for CIA and start treatment early, as soon as symptoms appear.
Pathophysiology and risk factors for CIA
Erythropoiesis is a dynamic process that maintains the number of circulating erythrocytes under changing physiologic conditions (Birgegard et al., 2005). In cancer patients, various factors disrupt this process. According to Birgegard et al. (2005), specific nutrients and growth factors, which are indispensable in the production and differentiation of erythroid progenitor cells, as well as malignancy itself, are associated with anemia in cancer patients. Among these factors, erythropoietin, the primary growth factor, interacts with specific receptors on erythroid progenitor cells and contributes to mitogenesis in the marrow (Birgegard et al., 2005). However, many chemotherapy agents affect erythropoietin and consequently interfere with erythropoiesis, resulting in a high incidence of anemia in cancer patients.
Among other chemo agents, alkylating agents, nitrosureas, and antitumor antibiotics damage both dividing cells and resting cells, and cause stronger myelosuppressive effects than cell-cycle-specific agents (Yabro et al., 2005). Barrette-Lee et al. (2006) found that patients who received platinum based chemotherapy have double the risk of anemia compared to patients who received non-platinum based chemotherapy.
In addition to the type of chemotherapy drug, low baseline Hb, tumor type, and concurrent treatment with chemotherapy/radiation therapy can also be risk factors for CIA. Specifically, Barrette-Lee et al. (2006) reported that cancer patients with lower baseline Hb levels (<= 12.9 g/dL in females, and <= 13.4 dL in males) have the greatest risk for anemia after chemotherapy. Furthermore, patients with tumor types such as lung cancer or gynecologic cancer have a three times greater chance of being anemic, compared to patients with gastrointestinal/colorectal cancer. Patients who received concurrent chemotherapy/radiation showed a higher risk for CIA. According to ECAS in 2004, 50% of patients with lung cancer on concomitant treatment demonstrated more severe anemia, compared to patients receiving either chemotherapy (39%) or radiation therapy (39%) separately (Kosmidis et al., 2005).
CIA patients often report fatigue as the most severe symptom. Following chemotherapy sixty-three percent of anemic cancer patients (Hb <= 11 g/dL) experience fatigue in the moderate-to-severe range (Gabrilove, Perez, Tomita, Rossi, & Cleeland, 2007). These patients may demonstrate several other symptoms simultaneously, including insomnia, anorexia, and depression (Weert, et al., 2006). During assessment, health care providers may find the following anemia-related physical symptoms: peripheral edema, sustained tachycardia, tachypnea, chest pain, dyspnea on exertion, and orthostatic light headedness (NCCN, 2009). Generally, these symptoms are reported to improve as the level of Hb improves (Gabrilove et al., 2007).
Potential differential diagnosis
It is critical to make the correct differential diagnosis, because treatment will vary depending on the etiologies of anemia, as will the urgency of treatment. Anemia in cancer patients can be caused by the cancer itself, myelosuppressive chemotherapy, and other sources, including viral/bacterial infection, thyroid disease, and renal failure etc. (Baker et al., 2007). The NCCN also points to, bleeding, hemolysis, nutritional deficiency, iron deficiency, or radiation therapy as other potential causes. When patients have CIA, it is reasonable to treat anemia with erythropoiesis-stimulating agents (ESAs), iron supplementation, or transfusion. However, if anemia is the result of other causes, treatments should be adjusted according to each problem. For example, when a patient has excessive bleeding from a trauma, transfusion would be more effective because red blood cell (RBC) transfusion has an immediate impact on low Hb level. Furthermore, it will take at least two weeks to get a therapeutic effect from the use of darbepoetin, a type of ESA.
Medical treatment for CIA
As untreated CIA can cause negative prognoses, it is important to differentiate patients who need urgent treatment with transfusion. NCCN guidelines (2009) recommend transfusion of packed red blood cell (PRBC) for patients who need immediate correction of CIA. However, this guideline states that there is no standard Hb threshold for RBC transfusion. Therefore, patients who need PRBC transfusion cannot be screened simply based on certain Hb levels. Comparatively, EORTC guidelines (2007) recommend that cancer patients with Hb less than 9 g/dL should be evaluated for transfusion, although an individualized approach may be needed. (Aapro et al., 2008). That is, even if a cancer patient has an Hb level of 9.9 g/dL, if he/she shows prominent anemia-related symptoms, it should be reasonable to consider transfusion of PRBC. In addition, preexisting cardiovascular disease may affect patients' tolerance of an anemic state (Paul, Wilfred, Woodman, & DePasquale, 2008). Accordingly, the decision as to whether a patient should be transfused or not should be based on an assessment of the individual patient, preexisting pulmonary/cardiovascular cormorbidities, and clinical judgment. Transfusion is an effective way to replace depleted Hb within a short period, but the effect of RBC transfusion is unfortunately temporary, and can cause serious adverse risk such as thromboembolism and increased mortality (Mercadante et al., 2009; Khorana et al., 2008).
Erythropoietic stimulating agents
For the above reasons, another form of treatment, such as an ESA, is used for symptomatic CIA patients. According to Clinical Practice Guidelines from the American Society of Clinical Oncology/American Society of Hematology, ESA treatment is typically recommended for CIA patients whose Hb concentration has declined to a level of less than 10 g/dL (as cited in Charu, et al., 2007). As explained previously, erythropoietin is an endogenous hormone, which is involved in the maturation, proliferation, and differentiation of red blood cells (Birgegard et al., 2005). Myelosuppression from chemotherapy can result in reduction of erythropoietin, and in turn cause anemia. Thus, ESA treatments aim at replacing endogenous erythropoietin.
Epoetin alfa and darbepoetin alfa are commonly used ESAs. Compared with epoetin alfa, darbepoetin alfa can be administered less frequently without changes in efficacy and with a longer half-life and greater biologic activity (Canon et al., 2006). NCCN guidelines (2009) recommend epoetin alfa with initial dosing of 150 unit/kg three times weekly administered subcutaneously, or 40, 000 units once weekly subcutaneously. Another ESA, darbepoetin alfa can be initiated subcutaneously, either with a dose of 2.25 mcg/kg every week or 500mcg every three weeks. If the Hb level improves by 1 g/dL within four to six weeks, the dose of epoetin alfa or darbepoetin alfa can be titrated. For these drugs, NCCN (2009) suggests close monitoring of therapeutic response and weekly measurements of Hb levels, as decisions regarding further treatment depend on a gradual increase in Hb levels. If the Hb level increases more than 1 g/dL over a two-week period, the ESA dose should be reduced by 25% to 50%.
Despite ESAs' effectiveness in reducing transfusions in patients with CIA, the use of these drugs often causes concern over severe adverse reactions. Pirker et al. (2008) reported that darbepoetin alfa is associated with cardiovascular/thromboembolic adverse events in extensive-stage small-cell lung cancer treated with platinum based therapy. Compared to patients who received placebo (15%), patients who received darbepoetin alfa (22%) had a higher incidence of cardiovascular/thromboembolic events. On the other hand, a randomized controlled study by Gordon et al. (2008) found that darbepoetin alfa is not related to a higher incidence of cardiovascular/thromboembolic adverse effects. What is more, darbepoetin alfa was not shown to be effective in reducing the frequency of transfusions (Gordon et al., 2008). As these inconsistent findings show, while ESAs are proven to increase Hb levels, there is debate over the safety of ESAs and their effectiveness in reducing transfusions. In several studies, ESAs were found to shorten overall survival or time to tumor progression in patients when the Hb level achieved is more than 12 g/dl. These studies included patients with breast cancer, non-small cell lung cancer, head and neck cancer, lymphoid, and cervical cancer, yet the risk likely exists in other tumor types as well. The effect on survival and tumor progression with lower achieved Hb levels is less clear given that some patients in the studies with decreased survival or tumor progression had Hb levels under 12. Recommendations from the U.S. Food & Drug Administration include only using ESAs to treat anemia while a patient is receiving myelosuppressive chemotherapy and discontinue them when chemotherapy is completed. Therefore, NCCN (2009) recommends health care providers discuss the risks and benefit of ESAs with their patients prior to starting ESA therapy.
There are two types of iron deficiency anemia: absolute and functional. An absolute iron deficiency anemia (AIDA) (ferritin < 30 ng/ml, transferrin < 15 %) develops from a lack of available iron. NCCN guidelines (2009) recommend that patients who are going to start ESA therapy have their iron level tested (including serum iron, total iron binding capacity (TIBC), and serum ferritin) because AIDA can be treated with oral or intravenous iron supplementation. Iron supplementation can also be helpful in treating functional iron deficiency anemia (FIDA) (ferritin < 300 ng/ml, transferrin < 20%), because the body cannot supply sufficient iron for bone marrow erythropoiesis, despite enough total body iron stores. Even patients under treatment with ESAs without preexisting FIDA will need iron supplementation due to continuous ESA-stimulated RBC production. As a result, stored iron is depleted due to continuing erythropoiesis.
Oral iron supplementation is commonly used with ESA treatment for the sake of convenience, but intravenous iron has greater efficacy (Bastit et al, 2008). Bastit et al. (2008) reported that adding intravenous iron supplementation to darbepoetin alfa every three weeks significantly reduced RBC transfusion and lag time to respond. In this randomized controlled study, only 9 % of patients who received combination therapy with intravenous iron and ESAs had RBC transfusion, whereas patients treated with non-intravenous iron therapy showed a significantly higher RBC transfusion rate (20%). In addition, patients who received intravenous iron responded more rapidly to ESA therapy (50 days) than did patients receiving non-intravenous iron treatment (64 days). Therefore, health care providers should consider the use of parenteral iron preparations such as iron dextran, ferric gluconate, or iron sucrose, with ESA treatments, in accordance with clinical guidelines.
Patient education & non-medical intervention
Patient education is one of the most crucial roles of nurses. Knowledge about physical/psychological symptoms and treatments related to CIA may give patients confidence for self-care. In addition, patient education increases patients' compliance to treatments, and in turn improves clinical outcomes. NCCN guidelines (2009) for cancer-related fatigue also include anemia as the secondary cause of fatigue. Many anemic cancer patients commonly demonstrate fatigue and functional impairment. They can cope with fatigue by using energy conserving strategies, such as scheduling rests between activities, using energy saving tools, planning for efficient activity, and maintaining a regular sleeping pattern (NCCN, 2009). Functional QOL is also an important issue for patients. According to a recent study, a decreased level of functioning is more distressful to CIA patients than anemia alone, even though anemia may ultimately affect fatigue, and in turn, functional status (Bremberg et al., 2007). Therefore, with appropriate medical treatment, patients should try to maintain their functional status as well as they can to improve QOL.
If CIA patients have either absolute or functional iron deficiency, knowledge about appropriate diet or vitamin supplementation would be helpful. Zimmermann, Chaouki, and Hurrell (2005) found that low iron bioavailability from legume- and cereal-based diets can cause iron deficiency anemia. Thus, patients can address their iron deficiency by intake of iron-containing food such as meat and leafy green vegetables. Even with sufficient iron levels, though, a patient with low copper levels can experience macrocytic anemia; in this case, a multi-vitamin including copper will also be helpful (Angotti et al., 2008).
Fatigue may cause anxiety and depression in CIA patients (Romito, Montanaro, Corvasce, Bisceglie, & Mattioli, 2007). If patients are depressed or are under excessive stress, health care providers should consider psychological counseling or cognitive behavioral therapy. As another non-medical intervention, exercise with prophylactic ESA therapy may be helpful to increase Hb level and reduce RBC transfusion rate. Coleman et al. (2008) found that multiple myeloma patients who received aerobic and strength-resistant exercise combined with epoetin alfa treatment had significantly fewer transfusions during nadir (Bonferoni, adjusted p < 0.025).
Based on the needs of the individual patient, health care providers should provide information on energy conservation strategies, diet, and exercise to CIA patients. If CIA patients know how they can modify their life pattern or diet, it would be helpful to increase the efficacy of medical treatments.
CIA is a common problem in cancer patients who are treated with myelosuppressive chemotherapy. However, many patients with CIA tend to be under treated clinically. Untreated CIA is reported to increase fatigue and have a negative effect on prognosis, QOL, and functional/psychological well being in cancer patients. NCCN guidelines (2009) recommend screening and treatments including RBC transfusion, ESAs treatments, and iron supplementations for these patients depending on the severity and type of anemia. According to these clinical guidelines, health care providers should identify patients who need CIA therapy and treat them in a timely manner. Along with these pharmacological treatments, if CIA patients know how to manage their symptoms and participate in their own care, their adherence to treatment and its therapeutic effects may improve. Therefore, health care providers should support CIA patients with knowledge of non-medical management strategies, which can enhance the therapeutic effect of CIA treatment.
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