Anemia raises special concerns in older cancer patients. This review addresses the prevalence, causes, and mechanisms of anemia in older individuals, the complications of anemia in this population (including its impact on cancer treatment), and the appropriate management of anemia in the elderly.
A common manifestation of cancer, anemia may compromise patient welfare and influence treatment outcome. In older cancer patients, anemia raises special concerns for the following reasons:
• The incidence and prevalence of cancer increase with age.
• The incidence and prevalence of anemia increase with age.[3,4]
• Anemia—even mild anemia—is associated with a number of unfavorable outcomes in older individuals.
This article explores the causes, consequences, and management of anemia in older individuals, and the influence of anemia on cancer treatment.
Prevalence, Causes, and Mechanisms
Definition of Anemia
According to the World Health Organization (WHO), anemia is defined as hemoglobin levels lower than 12 g/dL in women and 13 g/dL in men. Recent findings have called into question this definition, which nevertheless remains the gold standard for epidemiologic and clinical studies, as well as for clinical practice.
A critical issue concerns whether it is justified to use different normal values for postmenopausal women and men. The Women's Health and Aging Study (WHAS) followed 667 home-dwelling women aged 65 and older for 11 years and established that hemoglobin values lower than 13 g/dL were an independent risk factor for mortality and disability.[6,7] Similar results were reported from the Invecchiare in Chianti (InChianti) study, a cross-sectional look at the older population in the Italian region of Chianti. In addition, several years ago, the fatigue coalition reported that the highest increment in energy, both in men and women with cancer, was obtained when hemoglobin levels were raised from 11 to 13 g/dL, suggesting that hemoglobin levels around 13 g/dL may be optimal for both sexes, at least in the later years of life.
Another problem with the WHO definition is its failure to account for ethnicity. In the United States, the National Health and Nutrition Examination Survey (NHANES) III confirmed previous reports that hemoglobin levels in healthy African-Americans may be lower than in Caucasians. It has not been established whether a higher prevalence of hemoglobinopathies among African-Americans is responsible for this difference.
Individual variations in hemoglobin levels may also be present irrespective of ethnicity and sex. While hemoglobin levels lower than 12 g/dL are probably abnormal for everybody, it is possible that levels between 12 and 13 g/dL are abnormal for some women and men and normal for others. In the following discussion, we will use the WHO definition as reference, recognizing that it may lead to underdiagnosis of anemia and its causes especially in older women.
Incidence and Prevalence of Anemia
Incidence and prevalence of anemia increase with age[3,4] and are highest in the institutionalized population.[4,10-12] According to cross-sectional studies, average hemoglobin levels remain constant throughout all age groups at least up to age 90. Anemia appears not to be a consequence of aging, but the incidence and prevalence of chronic diseases causing anemia increase with age.
In the NHANES III study, anemia was more common among women up to age 50, was equally prevalent in the two sexes up to age 65, and became more common in men after age 65. This finding is dependent on the definition of anemia. If the lower-normal levels of hemoglobin in women were set at 13 g/dL instead of 12 g/dL, incidence and prevalence of anemia would be higher in women throughout the age spectrum.
Causes and Mechanism of Anemia
Common causes of anemia in older individuals are reported in Table 1.[3,14,15] In all reviews, so-called "idiopathic anemia" accounted for 15% to 30% of cases. Undoubtedly some of these cases were due to inadequate investigations and might have involved early myelodysplasia or early renal insufficiency, whose incidence increases with age.[17,18] In some cases, a condition called "relative erythropoietin insufficiency" might have been present. Several investigators have found circulating levels of erythropoietin to be more elevated in older individuals than in their younger counterparts for hemoglobin levels ≥ 12 g/dL.[19,20] For hemoglobin < 12 g/dL, the levels of erythropoietin were lower in the older individuals (Figure 1). These data suggest that:
• The erythropoietic precursors become resistant to erythropoietin with aging. Thus, higher levels of erythropoietin are needed to maintain a normal hemoglobin level. It is also possible that reduced capillary blood flow causes tissue hypoxia, which is responsible for elevating erythropoietin levels to achieve a normal hemoglobin count.
• The ability to produce erythropoietin declines with age, and the erythropoietin response to anemia is inadequate in older individuals. Declining renal function may account in part for this inadequacy.[17,18] Other mechanisms may include increased circulating levels of inflammatory cytokines[21,22] and exhaustion of the ability to produce erythropoietin.
The pathogenesis of this type of anemia is interwoven with the pathogenesis of anemia of chronic inflammation (ACI), in which relative erythropoietin deficiency has been repeatedly described.[15,22-24] Aging is a form of chronic and progressive inflammation, and the concentration of circulating inflammatory cytokines that inhibit erythropoiesis increases with age.[20,21] Among these, interleukin (IL)-6, IL-2, interferon-gamma, and tumor necrosis factor (TNF) are known to modulate the production of erythropoietin and to reduce the sensitivity of the erythropoietic progenitors to erythropoietin (Figure 2).[20,21,23] The idiopathic anemia that one finds in older individuals may just represent a form of ACI. Another important characteristic of ACI is reduced mobilization of iron from stores. Hepcidin, a protein whose hepatic production is enhanced by IL-6, is responsible for reduced mobilization of iron and impaired absorption of this element from the intestine, which explains why patients with ACI have a better response to erythropoietin when provided with intravenous iron.
Iron deficiency is common in older individuals. This may be due to bleeding from the gastrointestinal or genitourinary tract, from cancer, peptic ulcer, nonsteroidal anti-inflammatory drug-induced gastritis, diverticular disease of the colon, or angiodysplasia. Helicobacter pylori gastritis may cause iron deficiency, as the bacterium utilizes food iron for its own growth. In some cases, the cause of iron deficiency is not found. Some of these cases may be nutritional, as age-related gastric atrophy may prevent the reduction of food-bound iron necessary for its absorption.
Cobalamin deficiency may be present in as many as 15% of individuals aged 60 and older.[28,29] Cobalamin deficiency is most commonly due to an inability to digest food-bound B12 because of gastric atrophy. Crystalline cobalamin is absorbed normally in this situation, and oral preparations of B12 may correct the deficiency. If folate deficiency is not present as well, cobalamin deficiency may not cause anemia but may cause peripheral neuropathy and dementia.
Myelophthisis is more common in hematologic malignancies, but it may be observed in patients with solid tumors metastatic to the bones, especially breast cancer, prostate cancer, and small-cell lung cancer. Myelophthisis may present as pancytopenia with increased concentration of immature blood cells in the circulation.
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Stasi R, Amadori S, Littlewood TJ, et al: Management of cancer-related anemia with erythropoietic agents: Doubts, certainties, and concerns. Oncologist 10:539-554, 2005.
2. Balducci L, Ershler WB: Cancer and ageing: A nexus at several levels. Nat Rev Cancer 5:655-661, 2005.
3. Guralnik JM, Eisenstaedt RS, Ferrucci L, et al: Prevalence of anemia in persons 65 years and older in the United States: Evidence for a high rate of unexplained anemia. Blood 104:2263-2268, 2004.
4. Beghe C, Wilson A, Ershler WB: Prevalence and outcomes of anemia in geriatrics: A systematic review of the literature. Am J Med 116(suppl 7A):3S-10S, 2004.
5. Balducci L, Hardy CL, Lyman GH: Hemopoiesis and aging. Cancer Treat Res 124:109-131, 2005.
6. Chaves PH, Sumba RD, Leng SX, et al: Impact of anemia and cardiovascular diseases on frailty status of community dwelling women. The Women Health and Aging Studies I and II. J Gerontol A Biol Sci Med Sci 60:729-735, 2005.
7. Chaves PH, Xue QL, Guralnik JM, et al: What constitutes normal hemoglobin concentration in community dwelling disabled older women? J Am Ger Soc 52:1811-1816, 2004.
8. Cesari M, Penninx BW, Lauretani F, et al: Hemoglobin levels and skeletal muscle: Results from the InCHIANTI study. J Gerontol A Biol Sci Med Sci 59:249-254, 2004.
9. Curt GA, Breitbart W, Cella D, et al: Impact of cancer-related fatigue on the lives of patients: New findings from the Fatigue Coalition. Oncologist 5:353-360, 2000.
10. Artz AS, Fergusson D, Drinka PJ, et al: Mechanisms of unexplained anemia in the nursing home. J Am Geriatr Soc 52:423-427, 2004.
11. Dunn A, Carter J, Carter H: Anemia at the end of life: Prevalence, significance, and causes in patients receiving palliative care. J Pain Symptom Manage 26:1132-1337, 2003.
12. Kalchthaler T, Tan ME: Anemia in institutionalized elderly patients. J Am Geriatr Soc 28:108-113, 1980.
13. Inelmen EM, D'Alessio M, Gatto MR, et al: Descriptive analysis on the prevalence of anemia in a randomly selected sample of elderly people living at home. Aging (Milan) 6:81-89, 1994.
14. Anía BJ, Suman VJ, Fairbanks VF, et al: Incidence of anemia in older people: An epidemiologic study in a well defined population. J Am Geriatr Soc 45:825-831, 1997.
15. Joosten E, Van Hove L, Lesaffre E, et al: Serum erythropoietin levels in elderly in-patients with anemia of chronic disorders and iron deficiency anemia. J Am Geriatr Soc 41:1301-1304, 1993.
16. Balducci L: Transfusion independence in patients with myelodysplasia: Impacts on outcome and quality of life. Cancer 106:2087-2094, 2006.
17. Cumming RG, Mitchell P, Craig JC, et al: Renal impairment and anaemia in a population-based study of older people. Intern Med J 34:6-7, 2004.
18. Ble A, Fink JC, Woodman RC, et al: Renal function, erythropoietin, and anemia in older persons: The inCHIANTI study. Arch Intern Med 65:2187-2189, 2005.
19. Ershler WB, Sheng S, McKelvey J, et al: Serum erythropoietin and aging: A longitudinal analysis. J Am Geriatr Soc 53:1360-1365, 2005.
20. Ferrucci L, Guralnik L, Woodman RC, et al: Proinflammatory state and circulating erythropoietin in persons with and without anemia. Am J Med 118:1288, 2005.
21. Ferrucci L, Corsi A, Lauretani F, et al: The origin of age-related proinflammatory state. Blood 105:2294-2299, 2005.
22. Weiss G, Goodnough LT: Anemia of chronic disease. N Engl J Med 352:1011-1023, 2005.
23. Miller CB, Jones RJ, Piantadosi S, et al: Decreased erythropoietin response in patients with anemia of cancer. N Engl J Med 322:1689-1692, 1990.
24. Spivak JL, Barnes DC, Fuchs E, et al: Serum immunoreactive erythropoietin in HIV-infected patients. JAMA 261:3104-3107, 1989.
25. Ganz T: Hepcidin: A key regulator of iron metabolism and anemia of inflammation. Blood 102:783-788, 2003.
26. Auerbach M; Ballard H; Trout JR, et al: Intravenous iron optimizes the response to recombinant human erythropoietin in chemotherapy-induced anemia. A multicenter open label randomized clinical trial. J Clin Oncol 22:1301-1307, 2004.
27. Cardenas VM, Mulla ZD, Ortiz M, et al: Iron deficiency and Helicobacter pylori infection in the United States. Am J Epidemiol 163:127-134, 2006.
28. Norman EJ, Morrison JA: Screening elderly populations for cobalamin (vitamin B12) deficiency using the urinary methylmalonic acid assay by gas chromatography mass spectrometry. Am J Med 94:589-594, 1993.
29. Clarke R, Grimely Evans J, Scheenke J, et al: Vitamin B12 and folate deficiency in later life. Age Ageing 33:34-41, 2004.
30. Laurberg P, Andersen S, Bulow Pedersen I, et al: Hypothyroidism in the elderly: Pathophysiology, diagnosis and treatment. Drugs Aging 22:23-38, 2005.
31. Goodnough LT, Skikne B, Brugnara C: Erythropoietin, iron and erythropoieisis. Blood 96:823-833, 2000.
32. Cook JD, Flowers CH, Skikne BS, et al: The quantitative assessment of body iron. Blood 101:3359-3364, 2003.
33. Izaks GJ, Westendorp RGJ, Knook DL: The definition of anemia in older persons. JAMA 281:1714-1719, 1999.
34. Kikuchi M, Inagaki T, Shinagawa N: Five-year survival of older people with anemia: Variation with hemoglobin concentration. J Am Geriatr Soc 49:1226-1228, 2001.
35. Zakai NA, Katz R, Hirsch C, et al: A prospective study of anemia status, hemoglobin concentration and mortality in an elderly cohort. The Cardiovascular Health Study. Arch Intern Med 165:2214-2220, 2005.
36. Denny SD, Kuchibhatla MN, Cohen HJ: impact of anemia on mortality, cognition and function in community dwelling elderly. Am J Med 119:327-334, 2006.
37. Pickett JL, Theberge DC, Brown WS, et al: Normalizing hematocrit in dialysis patients improves brain function. Am J Kidney Dis 33:1122-1130, 1999.
38. Donovan KA, Small BJ, Andrykowski MA, et al: Cognitive function after adjuvant chemotherapy and/or radiotherapy for early stage breast cancer. Cancer 104:2499-2507, 2005.
39. Atti AR, Palmer K, Volpato S, et al: Anemia increases the risk of dementia in cognitively intact elderly. Neurobiol Aging 27:278-284, 2006.
40. Joosten E, Lemiegre J, Nelis T, et al: Is anemia a risk factor for delirium in an acute geriatric population? Gerontology 32:382-385, 2006.
41. Silverberg DS, Wexler D, Iaina A, et al: The Interaction between heart failure and other heart diseases, renal failure and anemia. Semin Nephrol 26:296-306, 2006.
42. Akran K, Pearlman BL, Parker M, et al: Congestive heart failure related anemia and a role for erythropoietin. Int J Cardiol. In press.
43. Wu WC, Rathore SS, Wang Y, et al: Blood transfusions in elderly patients with acute myocardial infarction. N Engl J Med 345:1230-1236, 2001.
44. Inzitari M, Carlo A, Baldereschi M, et al: Risk and predictors of motor performance decline in a normally functioning population-based sample of elderly patients. The Italian Longitudinal Study on Aging. J Am Geriatr Soc 54:318-324, 2006.
45. Penninx BW, Pahor M, Cesari M, et al: Anemia is associated with disability and decreased physical performance and muscle strength in the elderly. J Am Geriatr Soc 52:719-724, 2004.
46. Extermann M, Chen A, Cantor AB, et al: Predictors of tolerance from chemotherapy in older patients: A prospective pilot study. Eur J Cancer 38:1466-1473, 2002.
47. Schrijvers D, Highley M, DeBruyn E, et al: Role of red blood cell in pharmacokinetics of chemotherapeutic agents. Anticancer Drugs 10:147-153, 1999.
48. Dunst J, Kuhn T, Strauss HG, et al: Anemia in cervical cancers: Impact on survival, patterns of relapse, and association with hypoxia and angiogenesis. Int J Radiat Oncol Biol Phys 56:778-787, 2003.
49. Weitz J, D'angelica M, Gonen M: Interaction of splenectomy and perioperative blood transfusions on prognosis of patients with proximal gastric and gastroesophageal junction cancer. J Clin Oncol 21:4597-4603, 2003.
50. McDougall JC: CERA (Continuous Erythropoietin Receptor Activator): A new erythropoiesis stimulating agent for the treatment of anemia. Curr Hematol Rep 4:436-440, 2005.
51. Osterborg A: New erythropoietic proteins: Rationale and clinical data. Semin Oncol 31(3 suppl 8):12-18, 2004.
52. Bohlius J, Langersiepen S, Schwarzer G, et al: Recombinant human erythropoietin and overall survival in cancer patients. Results of a comprehensive meta-analysis. J Natl Cancer Inst 97:489-498, 2005.
53. Food and Drug Administration, Oncologic Drugs Advisory Committee: Presentations on erythropoietin products in cancer patients, May 4, 2004. Available at www.FDA.gov/ohrms/dockets/ac/04/slides/4037s2.htm. Accessed December 7, 2006.