Anemia: A prevalent condition among patients with cancer
For oncologists, the importance of recognizing the presence of anemia is clear, given that anemia is the most common hematologic abnormality in patients with cancer.1 Depending on the tumor type, between 32% and 49% of patients are anemic at the time of cancer diagnosis,2 and approximately 50% of all patients will develop anemia at some point.1
Anemia in patients with cancer reflects multiple possible etiologic factors. The type of cancer present, the patients underlying medical issues, and the treatment itself all may act independently or interact to result in anemia.3 In patients with cancer, anemia may result from a combination of noncancer-related and cancer-related etiologies. Noncancer-related etiologies include underlying comorbidities (eg, bleeding, hemolysis, nutritional deficiencies, hemoglobinopathies) or infection.1,2 The malignancy itself can contribute to or exacerbate a preexisting anemia, and anemia can also develop as a side effect of cancer treatments (chemotherapy-induced anemia).2
Due to the numerous potential etiologies of anemia in patients with cancer, the evaluation may be complex.2 Thus, understanding the pathophysiology behind cancer and chemotherapy-induced anemia is an important step in gaining a more thorough understanding of cancer-related anemia.
Anemia in patients with cancer
Oncologists will most often see anemia resulting from chemotherapy or anemia primarily due to the malignancy itself. Nutritional anemias, particularly those resulting from iron deficiency, as well as deficiencies in folate or vitamin B12, are more common in noncancer populations but may also be present in patients with cancer.1,3,4 The goal of the anemia evaluation is to characterize the anemia and identify any underlying comorbidity that can be potentially corrected; therefore it is important to understand how the various anemias can develop.2
Anemia of cancer
Anemia of cancer may also be evident at initial diagnosis. Activation of the immune system appears to be the driving force for a global diminution of erythropoiesis, analogous to chronic inflammatory conditions observed in anemia of chronic disease.3,5 It is postulated that the immune system may be mobilized to stimulate production of inflammatory cytokines that can impede erythropoiesis. Consequently, there is insufficient differentiation and proliferation of erythroid precursors, leading to anemia.3 Inflammatory cytokines can also impair iron metabolism which can result in reduced serum iron levels and iron retention within the reticuloendothelial system.3 Tumors can also produce cytokines, which induce iron sequestration, thereby decreasing RBC production. Shortened RBC survival may also result from overexpression of inflammatory cytokines.3 Furthermore, chronic blood loss at tumor sites can exacerbate anemia from cancer.2,5 Anemia can result from bone marrow invasion by leukemia or solid tumors. Myelophthisis, resulting from bone marrow replacement of solid tumors or hematologic malignancies, may manifest as anemia or pancytopenia. Breast cancer, prostate cancer, small cell lung cancer, and lymphoma are among the most common tumors associated with bone marrow replacement.1
While anemia in patients with cancer is often produced by the cancer itself, the addition of chemotherapy significantly increases the proportion of patients with anemia.6 The myelosuppressive effects of cytotoxic chemotherapy agents on erythropoiesis are generally cumulative in nature and up to 50% of patients with cancer may develop chemotherapy-induced anemia over the course of chemotherapy.1,7 A steady increase in the rate of anemia occurs with additional cycles of chemotherapy as evidenced by data from the European Cancer Anaemia Survey (ECAS). This study showed that the rate of anemia (hemoglobin [Hb] <12 g/dL) increased from 19.5% in cycle 1 to 46.7% by cycle 5. The percentage of patients with more severe anemia (grades 2 and 3) also increased with greater numbers of chemotherapy cycles.7 Patients can also become anemic within the first 2 cycles of chemotherapy as evidenced by data from a separate analysis of ECAS data in patients who were not anemic (Hb >12 g/dL) prior to initiating chemotherapy. In this analysis, 62% of patients experienced a Hb decline by 1.5 g/dL within a median time of 6.1 to 7.2 weeks and 51% experienced a Hb decline by 2 g/dL within a median time of 7.3 to 8.9 weeks.8
Depending on the chemotherapeutic agent or regimen, anemia may be mild in degree (grade 1 or 2) in about 10%85% of patients. Moderate or severe anemia will develop in about 2%55% of patients and require intervention (Table).2,9 An individual patients ability to tolerate anemia will vary depending on the presence of preexisting conditions and comorbidities; the decisions for correction of anemia should be based on an assessment of individual patient characteristics, severity of anemia, symptoms, comorbidities and clinical judgment of the physician.2
Chemotherapy may cause anemia in multiple ways. First, some chemotherapeutic agents will affect the production of new RBCs. For example, chemotherapy can damage normal bone marrow precursor hematopoietic cells. When these cells are damaged, the ability of the bone marrow to produce new RBCs is impaired. Some drugs, such as platinum-containing agents, are nephrotoxic, and can also affect the development of new RBCs by interfering with erythropoietin production by the kidneys.2
Based on in vitro studies, the production of an RBC from its stem cell precursor takes approximately 26 days.10-13 In culture, stem cells differentiate into burstforming unit-erythrocyte (BFU-E) cells, which are stimulated by erythropoietin to mature into colonyforming unit-erythrocyte (CFU-E) cells. These cells mature through the proerythroblast stage into erythroblasts and then reticulocytes. Reticulocytes are released into the bloodstream and take approximately 24 hours to terminally differentiate into mature RBCs. Reticulocytes are generally slightly larger than the mature RBC.10-13
Hematopoietic progenitor cells divide rapidly regardless of their developmental stage.Thus, chemotherapy, which interferes with cell division, can clearly impede RBC production. Finally, certain chemotherapeutic treatments, such as alkylating agents or nitrosureas, can damage dividing and resting cells, causing harm to more cells, including hematopoietic stem cells, than those chemotherapeutic agents that are cell-cycle specific.14
Anemia due to nutritional deficiency
Patients with cancer may develop anemia secondary to poor nutrition in general or due to reduced function in the gastrointestinal (GI) tracts to absorb nutrients.1-3 Folate deficiency may develop in anorexic patients with cancer, while vitamin B12 deficiency can arise in patients who have undergone gastric or small bowel resection or bypass or have atrophy of stomach parietal cells, which produce intrinsic factor necessary for vitamin B12 absorption.1,15 Iron deficiency anemia due to blood loss or the inability to absorb iron in the GI tract often occurs in patients with malignancies of the GI tract, including colorectal cancers.1,3 Nutrient deficiencies in folate, vitamin B12 or iron may lead to anemia because all of these nutrients are essential to red blood cell (RBC) production and development.10,15
Prevalence by cancer type
The type of cancer that a patient has can also contribute to the risk of developing anemia. On a broader level, patients with hematologic malignancies are more likely to have anemia at the time of diagnosis, with about half of patients presenting with anemia. In contrast, about one third of patients with solid tumors will be anemic at diagnosis.16
A retrospective study conducted by Wu and colleagues in 2009 shed some additional light on the variations in prevalence of anemia by cancer type. In the observational cohort study of 47,159 adult patients with cancer, anemia was defined as an Hb less than 11 g/dL at any time during chemotherapy. Information was obtained from electronic medical records from community- and hospital-based clinical oncology practices between 2000 and 2007. At baseline 20.9% of the 42,923 patients evaluated were anemic.17
The results indicated that about 56.3% of patients with ovarian cancer were anemic during chemotherapy. The next highest prevalence for anemia was 53.3% among patients with breast cancer, and 50.9% among patients with non-small cell lung cancer (NSCLC).17 Many factors may alter the prevalence of anemia among these patients. For example, patients with NSCLC may be more commonly diagnosed with anemia because of their reduced lung function, which results in a limited ability to tolerate anemia and more prominent symptoms of anemia (such as dyspnea).18 This reduced tolerability and increased severity of symptoms may bring anemia to the attention of the health care team. To date, the distinct mechanisms underlying the development of anemia in patients with different cancer types is unknown.
Prevalence by treatment type
The type of chemotherapy and the length and intensity of the treatment can affect the prevalence of anemia.
Platinum-based regimens, including cisplatin or carboplatin, are well recognized for causing anemia in patients with cancer.9 These agents are often used to treat cancers of the lung, ovary and GI tract. They reduce erythropoietin production via direct negative effects on bone marrow and the kidneys.2,6 In general, all myelosuppressive agents are likely to result in anemia to some degree.6
In their study, Wu and colleagues also reported the percentage of patients who develop anemia according to chemotherapy regimen. A chemotherapy regimen was defined as more than 1 administration of a drug, with no more than 45 days between consecutive administrations.17
The results indicated that patients receiving gemcitabine-based (59% of patients), platinum-based (50.7%), and anthracycline-based (50.8%) regimens were the most likely to develop anemia. Platinum-based regimens comprised the most common regimens among patients receiving chemotherapy in this study. In fact, platinum-based regimens were used in 27.8% of all patients treated, including 76.8% of patients with head and neck cancers and 66.6% of patients with non-small cell lunch cancer. For patients with lung, ovarian, head and neck, and colorectal cancers, platinum-based regimens were most common; however, anthracycline-based regimens were more common for patients with breast and hematologic cancers.17
The intensity of chemotherapy may also contribute to the severity of anemia.9 In the Wu study, of the 60.5% of patients who experienced cycle delays, anemia occurred during 51.9% of the delayed chemotherapy cycles. The largest proportion of delayed cycles occurred in patients receiving platinum-based regimens (45.3%), followed by anthracycline-based (13.9%), gemcitabine-based (8.6%), and taxane-based regimens (7.6%).17 Additionally, as we move into an era of targeted therapies, including biologics and small molecule inhibitors, there may be a greater risk for the development of anemia.2,9 For example, imatinib therapy for GI stromal tumors resulted in almost 90% of patients developing anemia, with 10% experiencing grade 3 or 4 anemia.19 Patients with metastatic renal cell carcinoma, receiving the newer agent sunitinib as monotherapy, experienced an increased rate of clinically significant anemia compared with patients receiving temsirolimus (26% vs. 9%).20,21
Anemia in patients with cancer is multifactorial in its etiology. It is highly prevalent, whether a result of nutritional deficiency, a consequence of the effects of the tumor itself on RBC production, or as a side effect of chemotherapy. Chemotherapy-induced anemia is frequent, as a result of myelosuppressive cytotoxicity of the chemotherapeutic regimens.2 The incidence and severity of chemotherapy-induced anemia and its symptoms depend on a variety of factors, including the tumor type and chemotherapy regimen (including the schedule and intensity of therapy).17 The health care team must always be vigilant regarding the possibility of anemia and be alert for signs and symptoms associated with this common disease associated with cancer and chemotherapy.
- Marks PW, Rosenthal, DS. Hematologic manifestations of systemic disease: infection, chronic inflammation, and cancer. In: Hoffman R, Benz EJ, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 5th ed. Philadelphia, PA: Churchill Livingstone Elsevier. 2009;2309-2319.
- The NCCN Clinical Practice Guidelines in Oncology. Cancer- and Chemotherapy-Induced Anemia. Version 2.2012. National Comprehensive Cancer Network website. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed August 5, 2011.
- Birgegård G, Aapro MS, Bokemeyer C, et al. Cancer-related anemia: pathogenesis, prevalence and treatment. Oncology. 2005;68(suppl 1):3-11.
- Brittenham GM. Disorders of iron metabolism: iron deficiency and overload. In: Hoffman R, Benz EJ Jr, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 4th ed. Philadelphia, PA: Churchill Livingstone; 2005:481-497.
- Spivak JL. The anaemia of cancer: death by a thousand cuts. Nat Rev Cancer. 2005;5:543-555.
- Bridges KR, Pearson HA. Cancer and anemia. In: Bridges KR, Pearson HA, eds. Anemias and Other Red Cell Disorders. New York, NY: McGraw-Hill Medical Publishing Division; 2008:58-80.
- Ludwig H, Van Belle S, Barrett-Lee P, et al. The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patient. Eur J Cancer. 2004;40:2293-2306.
- Barrett-Lee PJ, Ludwig H, Birgegård G, et al; for European Cancer Anaemia Survey Advisory Board and Participating Centers. Independent risk factors for anemia in cancer patients receiving chemotherapy: results from the European Cancer Anaemia Survey. Oncology. 2006;70:34-48.
- Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst. 1999;91:1616-1634.
- Guyton AC, Hall JE. Red blood cells, anemia, and polycythemia. In: Guyton AC, Hall JE, eds. Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Saunders; 2006:419-428.
- Papayannopoulou T, DAndrea AD, Abkowitz JL, Migliaccio AR. Biology of erythropoiesis, erythroid differentiation, and maturation. In: Hoffman R, Benz EJ Jr, Shattil SJ, et al, eds. Hematology: Basic Principles and Practice. 4th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2005:267-294.
- Dessypris EN. Erythropoiesis. In: Richard-Lee GL, Foerster J, Lukens J, Wintrobe MM, eds. Wintrobes Clinical Hematology. London, UK: Lea & Febiger; 1998:169-172.
- Bunn HF. Pathophysiology of the anemias. In: Isselbacher K, ed. Harrisons Principles and Practice of Internal Medicine. 13th ed. New York, NY: McGraw Hill Inc; 1994:1717-1721.
- Camp-Sorrell D. Chemotherapy toxicities and management. In: Yarbro CH, Wujcik D, Gobel BH, eds. Cancer Nursing: Principles and Practice. 7th ed. Sudbury, MA: Jones and Bartlett; 2011:458-503.
- Kaushansky K, Kipps TJ. Hematopoietic agents: growth factors, minerals, and vitamins. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilmans The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: The McGraw Hill Companies; 2005. http://www.accessmedicine.com/content.aspx?aID=952126. Accessed June 21, 2011.
- Ludwig H, Birgegard G, Barrett-Lee PJ, Krzakowski M. Prevalence and management of anemia in patients (pts) with hematologic malignancies (HMs) and solid tumors (STs): results from the European Cancer Anaemia Survey (ECAS). Blood. 2002;100:234a. Abstract 884.
- Wu Y, Aravind S, Ranganathan G, Martin A, Nalysnyk L. Anemia and thrombocytopenia in patients undergoing chemotherapy for solid tumors: a descriptive study of a large outpatient oncology practice database, 2000-2007. Clin Ther. 2009;31:2416-2432.
- Kosmidis P, Krzakowski M; the ECAS Investigators. Anemia profiles in patients with lung cancer: what have we learned from the European Cancer Anaemia Survey (ECAS)? Lung Cancer. 2005;50:401-412.
- Duffaud F, Lecesne A, Ray-Coquard I, et al. Erythropoietin for anemia treatment of patients with GIST receiving imatinib. J Clin Oncol. 2004;22:145. Abstract 9046.
- Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006;295:2516-2524.
- Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004;22:909-918.