The Significance of Anemia in Elderly Patients with Cancer

Advanced age adversely affects the prognosis of patients with hematologic malignancies and solid tumors. The lower survival rates of older patients with cancer compared with those of their younger counterparts are attributed to poorer-risk disease, multidrug-resistance mechanisms, low bone marrow reserves that prevent or delay recovery of hematopoiesis after treatment, and higher rates of comorbidities. Additionally, anemia may play an important role in the outcomes of elderly patients with cancer. The incidence of anemia increases with age[1] and ranges from 3% to 11% in individuals older than 65 years.[2,3]

The significance of anemia in elderly patients with cancer is evidenced by increased mortality rates, reduced cognitive function, increased risk of congestive heart failure, fatigue, and dependence, increased risk of chemotherapy-induced complications, reduced response of some cancers to certain treatment modalities, and increased number of red blood cell transfusions.

Arbitrary Guideline?

In this issue of ONCOLOGY, Balducci reviews the definition, incidence, and pathogenesis of anemia and its complications in the elderly. Balducci argues that the World Health Organization definition of anemia (hemoglobin levels lower than 12 g/dL in women and 13 g/dL in men) is arbitrary, does not account for ethnic differences, and may lead to the underdiagnosis of anemia and its causes, particularly in older women. The latter position is supported by studies demonstrating that a hemoglobin level of 13 g/dL in women is an independent risk factor for mortality and disability.[4,5]

Balducci and others attribute the increase in the incidence and prevalence of anemia in the elderly not only to aging but also to the incidence and prevalence of chronic diseases causing anemia.[6] Idiopathic anemia reportedly accounts for 15% to 30% of cases.

Mechanisms of Anemia

The current paper also attempts, in part, to determine the mechanisms and causes of anemia in older patients. The author suggests that the following mechanisms are responsible for anemia in the elderly: the development of resistance of erythropoietic precursors to erythropoietin with aging and a decrease in the production of erythropoietin, which may be attributed to declining renal function, increased circulating cytokine levels, and exhaustion of erythropoietin production capability. The remaining cases of anemia in patients with cancer are caused by iron, cobalamine, and folate deficiency, hypothyroidism, chronic inflammation, and renal insufficiency. In particular, anemia in patients with cancer is attributed to six main causes: infection (13%-23%), chronic disease (17%-33%), iron deficiency (8%), nutritional deficiency (8%), chronic renal disease (8%-12%), and unexplained causes (18%-38%).

Other investigators have reported that the expected inverse linear relationship between serum erythropoietin levels and hemoglobin was absent in cancer patients.[6] They also showed that low erythropoietin levels may contribute to the development of cancer-related anemia. However, adequate erythropoietin production was restored in hypoxic patients with cancer.[6]

Indications for Erythropoietic Therapy

Although the author recommends that the therapeutic goal in cancer patients with anemia should be to maintain hemoglobin levels of at least 12 g/dL, one is left with the question of whether it is reasonable to treat anemia in all older cancer patients with erythropoietic growth factors, given the increased risk of thromboembolic events. Further research is needed to determine specific indications for these growth factors in cancer patients. Previous reports have shown that although these agents have an established efficacy in reducing the need for red blood cell transfusions and improving the rates of hematologic response, their use is associated with an increased risk of thomboembolic events (eg, transient ischemic attacks, stroke, pulmonary emboli, deep-vein thrombosis, and myocardial infarction).[7]

In a meta-analysis of 35 trials and 6,769 patients, these complications were observed in 229 of the 3,728 patients treated with epoetin or darbepoetin (median incidence = 4.5%, range = 0%-30%) and in 118 of the 3,041 untreated control patients (median incidence = 1.4%, range = 0%-22.6%), resulting in a relative risk of a thromboembolic event of 1.67 (95% confidence interval = 1.35-2.06) in the treated group compared with the control group.[7] Although a negative impact on survival rates could not be confirmed, these findings indicate that epoetin or darbepoetin should be used with caution in cancer patients treated with thrombogenic chemotherapeutic agents or those who are at increased risk for thromboembolic events.[7] Notably, the use of intravenous iron has been shown to improve hemoglobin levels and reduce erythropoietin dosage requirements in cancer patients with anemia.[8]

These observations indicate that it is important to determine patients at risk for developing severe anemia who might benefit from erythropoietic growth factors. This could partially be addressed with the use of a previously published model that predicts the rate of chemotherapy-induced severe anemia.[9] The model was validated in test and training sets in a total of 1,092 cancer patients with chemotherapy-induced severe anemia. A baseline hemoglobin level less than 12 g/dL, performance status greater than 1, and baseline lymphocyte count ≤ 700/µL were identified as independent risk factors for severe anemia requiring red blood cell transfusions. These three factors were given arbitrary risk coefficients of 3, 1, and 1, respectively, and a risk score for each patient was obtained by adding the coefficients. The probabilities that red blood cell transfusions would be required in patients with scores of 0, 1, 2-3, and ≥ 4 were 1%, 4%, 11%, and 30%, respectively. This model may identify patients who will benefit from prophylactic erythropoietin treatment.[9]

Conclusions

In summary, this article reviews the prognostic significance of anemia in older patients with cancer. It notes that anemia has a negative impact on survival, increases the risk of heart failure and functional and cognitive decline, and increases the risk of therapeutic complications. Balducci recommends that all patients with hemoglobin levels lower than 13 g/dL be evaluated for the cause of their anemia. The available data suggest that the risks and benefits of erythropoietic growth factors for all older patients need to be validated in randomized clinical trials.

—Apostolia-Maria Tsimberidou, MD, PHD

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

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2. Nilsson-Ehle H, Jagenburg R, Landahl S, et al: Blood haemoglobin declines in the elderly: Implications for reference intervals from age 70 to 88. Eur J Haematol 65:297-305, 2000.

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. Chaves PH, Semba RD, Leng SX, et al: Impact of anemia and cardiovascular disease on frailty status of community-dwelling older women: The Women's Health and Aging Studies I and II. J Gerontol A Biol Sci Med Sci 60:729-735, 2005.

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6. Weiss G, Goodnough LT: Anemia of chronic disease. N Engl J Med 352:1011-1023, 2005.

7. Bohlius J, Wilson J, Seidenfeld J, et al: Recombinant human erythropoietins and cancer patients: Updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 98:708-714, 2006.

8. Auerbach M, Ballard H, Trout JR, et al: Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: A multicenter, open-label, randomized trial. J Clin Oncol 22:1301-1307, 2004.

9. Ray-Coquard I, Le Cesne A, Rubio MT, et al: Risk model for severe anemia requiring red blood cell transfusion after cytotoxic conventional chemotherapy regimens. The Elypse 1 Study Group. J Clin Oncol 17:2840-2846, 1999.