Cancer-Related Anemia: Special Considerations in the Elderly

A common manifestation of cancer, anemia may compromise patient welfare and influence treatment outcome.[1] In older cancer patients, anemia raises special concerns for the following reasons:

• The incidence and prevalence of cancer increase with age.[2]

• 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.[5]

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.[2] 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.[8] 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.[9]

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.[2] 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.[13] 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.[3] 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[16] or early renal insufficiency, whose incidence increases with age.[17,18] In some cases, a condition called "relative erythropoietin(Drug information on 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,[25] which explains why patients with ACI have a better response to erythropoietin when provided with intravenous iron.[26]

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.[27] 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.