Abstract
Objectives
Anemia is associated with functional disability among older adults in general. However, the relationship between anemia and functional disability has not been well characterized among older adults with cancer. Therefore, we examined the association between anemia and functional disability in patients ≥ age 65 with cancer.
Methods
We conducted cross-sectional analysis of data derived from a multi-center prospective study of 500 cancer patients aged ≥ 65 years. The primary outcome was functional disability at chemotherapy initiation, defined as the need for assistance with at least one instrumental activity of daily living. Anemia (World Health Organization criteria) was defined as hemoglobin (Hb) <12g/dl (women) and Hb <13g/dl (men). Multivariable logistic regression was used to examine the association between anemia and functional disability.
Results
Among 491 evaluable patients [median age 73.1 years (range 65-91), the prevalence of functional disability and anemia was 43% and 51%, respectively. Compared with patients without anemia, patients with anemia were more likely to report functional disability. On multivariable analysis, adjusting for sex, stage and unintentional weight loss, patients with anemia were more likely to have functional disability, [Odds Ratio = 2.40, 95% confidence interval = 1.61-3.59].
Conclusions
Anemia was highly prevalent and independently associated with functional disability in this cohort of older adults with cancer. Given the importance of functional status in cancer treatment decision-making, longitudinal studies evaluating the causal relation between anemia and functional status among older cancer patients are warranted to evaluate causality.
INTRODUCTION
Anemia, defined by the World Health Organization as Hemoglobin (Hb) less than 12g/dl in women and less than 13g/dl in men(1) is a common problem among older adults in general. The Third National Health and Nutrition Examination Survey (NHANES III) found the prevalence of anemia (WHO criteria) among community dwelling older adults ≥ 65 years to be 11% and 10% among men and women, respectively, doubling to over 20% among those >85 years of age.(2) Prevalence rates of anemia among patients with cancer have been estimated to be much higher, with rates as high as 39% among older patients at enrollment in the European Cancer Anemia Survey(3) and 100% in patients with cancer undergoing chemotherapy(4).
The etiology of chronic anemia in older adults is likely multifactorial. In the NHANES III study,(2) nutritional deficiencies, particularly iron, vitamin B12 and folate deficiency, accounted for 35% of diagnosed cases of anemia. Anemia of chronic disease or chronic inflammation and unexplained anemia each accounted for approximately a third of diagnosed cases of anemia in the same study.(2) Among older adults with cancer the etiology of chronic anemia extends to the effect of cancer per se and side effects of chemotherapy. It has also been hypothesized that aging may directly contribute to the development of anemia through age-related dysregulation of pro-inflammatory cytokines such as interleukin-6.(5)
Regardless of the etiology of anemia among older adults, uncorrected anemia has been found to be associated with poor functional status, specifically functional disability (6), and with increased mortality(7). However, the association between anemia and functional status among older adults with cancer has not been well characterized. Although a few studies in older adults with cancer have demonstrated an association between anemia and performance status(8-10) (using either the Eastern Cooperative Oncology Group Performance Scores [ECOG-PS] and Karnofsky Performance Scale [KPS] for assessment), very few studies(11) have actually examined the association between anemia and activities of daily living among older adults with cancer. This is clinically relevant because ECOG-PS and KFS may underestimate the extent of functional impairment among older adults, and self-reported activities of daily living (ADLS) and instrumental activities of daily living (IADLS) present a more comprehensive approach for assessing the functional status of older adults with cancer.(12) It is in this context that we sought to examine the association between anemia and functional disability (the need for assistance with at least one IADL) among a cohort of older adults with cancer.
PATIENTS and METHODS
Study Design and Patient Population
This study is a cross-sectional analysis of data derived from a multi-center prospective study that identified clinical and biological predictors of chemotherapy toxicity among 500 patients aged 65 years and older with cancer. Details of the study methods have been described elsewhere.(13) Briefly, between November 2006 and November 2009 study participants were recruited from ambulatory oncology clinics within seven institutions. To be eligible, study participants had to be aged 65 years and older, diagnosed with stage I-IV cancer of any tumor type, and had to be scheduled to receive chemotherapy. The current secondary analysis was limited to patients with available data on serum hemoglobin level and functional status. The study was approved by the respective Institutional Review Boards of each participating institution.
Study Procedures and Data Collection
Patients who provided informed consent completed a brief comprehensive geriatric assessment (CGA) prior to initiation of a chemotherapy regimen. Measures completed by the healthcare provider included the Karnofsky Physician Rated Performance Rating Scale (MD-KPS)(14), and the Blessed Orientation Memory Concentration Scale (BOMC)(15), a screening instrument for cognitive function. Measures that were self-completed by patients included the KPS self-reported rating scale (PKPS)(16), Instrumental Activities of Daily Living of the Older American Resources and Services (OARS)(17). Patient self-completed measures included comorbidity (Physical Health Section of the OARS(17)), psychological state (the Hospital Anxiety and Depression Scale(18)), social support [Medical Outcomes Study (MOS) Social Support Survey(19)], social activity (MOS Social Activity Subscale(20)), MOS Physical Health Scale(21, 22), nutritional status and falls. In addition, socio-demographic data was captured using a self-reported questionnaire. Medical records were abstracted to obtain pre-treatment hemoglobin levels, and tumor and treatment characteristics.
Analytic Variables
Primary outcome variable
The primary outcome variable was functional disability prior to receiving the first cycle of chemotherapy, defined as the need for assistance with at least one IADL.(23, 24) IADLs measure the need for assistance with shopping, using the telephone, managing medications, housekeeping, laundry, transportation, ability to manage finances, and preparing meals.(17, 23) Scores range from 0-14 with lower scores denoting assistance is needed with IADLs. For the purposes of the current analyses scores were dichotomized as functional disability (Yes or No) with scores of less than the maximum of 14 points denoting functional disability.
Independent variable
The Independent variable was anemia ascertained prior to receipt of the first cycle of chemotherapy, and defined according to the World Health Organization Criteria(1) as serum hemoglobin concentration <12g/dl in women (Yes or No), and <13g/dl in men (Yes or No).
Covariates
Socio-demographic variables included age as a continuous variable; race (White, Black, Asian, other); sex; marital status (single, married, separated/divorced, widowed); educational status (≤ 8th grade, 9-12th grade, >12th grade); living companion (spouse/partner/children, alone); and job status (employed, retired, homemaker, other). Tumor characteristics included cancer type (breast, gastro-intestinal (GI), gynecologic malignancies (GYN), lung, genito-urinary (GU), other); and stage (I, II, III, IV). Geriatric variables included comorbidity count (<3, ≥ 3), unintentional weight loss ≥ 10% in the last six months (Yes or No), social support measured with the MOS Social Support sub-scale with scores dichotomized as <50 versus ≥ 50 to denote lower versus higher social support, respectively; psychological state measured with the Hospital Anxiety Depression Scale (HADS) with scores dichotomized as <15 versus ≥ 15 to denote absence versus presence of anxiety/depression respectively; and cognitive status measured with the BOMC with scores dichotomized as <11 versus ≥ 11 denoting absence versus presence of cognitive impairment, respectively. Other measures of physical function included MD-rated KPS, patient-rated KPS and MOS Physical Function with scores for all three instruments dichotomized as <70 versus ≥ 70 with higher scores denoting better function.
Analytic Strategy
We conducted descriptive analysis to examine participants’ baseline characteristics. We conducted bivariate analyses of all baseline variables comparing patients who had anemia versus patients who did not have anemia. The Chi-square test or Fisher’s exact test, when appropriate, was used to determine if a statistically significant difference existed in the distribution of baseline characteristics between the two groups.
We also examined the bivariate association between MD-KPS and MOS Physical Function scores, and anemia status to demonstrate a consistent association of anemia with other measures of physical function, other than IADL scores. Furthermore we categorized serum hemoglobin levels into quartiles and examined the relation between Hb quartiles and IADL scores.
We developed our multivariable model by first identifying potential confounders of the association between anemia and functional disability. A variable was considered a potential confounder if it was significantly associated with both functional disability and anemia at p<0.05 on bivariate analysis. We then developed a base logistic regression model with anemia as the independent variable and functional disability as the dependent variable. Potential confounders that changed the beta coefficient for anemia in the base model by at least 10% were then retained in our final multivariate logistic regression model. We did not include other measures of physical function (MD-KPS, and MOS Physical Function) in the models because of colinearity. All P values presented are two-sided. All analyses were conducted using SAS version 9.2 (SAS institute, Cary, NC).
RESULTS
Participants’ Baseline Characteristics
Baseline characteristics are displayed in Table 1. Of 491 evaluable patients, the mean age of participants was 73.1 years (S.D. = 6.1), 85% were white, 56% were female, and a majority (62%) had more than high school education. The most common types of cancer included lung (29%), and a majority had stage IV cancer (62%). Forty-four percent of participants had three or more comorbidities at the time of study enrollment. The prevalence of functional disability and anemia were 43% and 51%, respectively.
Table 1. Baseline Characteristics by Anemia Status.
| Baseline Characteristics | TOTAL (N=491) |
NO ANEMIA (N=240) | ANEMIA (N= 251) |
P-value |
|---|---|---|---|---|
| Age | ||||
| Mean (Std Dev) | 73.1 (6.12) | 72.4 (5.89) | 73.7(6.28) | .02 |
|
| ||||
| Race | ||||
| White | 420 (85.5) | 212 (88.3) | 208 (82.9) | |
| Asian | 25 (5.1) | 9 (3.8) | 16 (6.4) | |
| Black | 40 (8.2) | 14 (5.8) | 26 (10.4) | |
| Other | 6 (1.2) | 5 (2.1) | 1 (0.4) | .05 |
|
| ||||
| Sex | ||||
| Female | 276 (56.2) | 159 (66.2) | 117 (46.6) | |
| Male | 215 (43.8) | 81 (33.8) | 134 (53.4) | <.001 |
|
| ||||
| Education | ||||
| Less than high school | 17 (3.5) | 6 (2.5) | 11 (4.4) | |
| High school graduate | 171 (34.9) | 76 (31.8) | 95 (37.9) | |
| Associate/bachelor’s degree | 199 (40.6) | 103 (43.1) | 96 (38.3) | |
| Advanced degree | 103 (21.0) | 54 (22.6) | 49 (19.5) | |
| Missing | 1 | 1 | .29 | |
|
| ||||
| Cancer Type | ||||
| Breast | 56 (11.4) | 42 (17.5) | 14 (5.6) | |
| GI | 133 (27.1) | 49 (20.4) | 84 (33.5) | |
| Gyn | 85 (17.3) | 44 (18.3) | 41 (16.3) | |
| Lung | 140 (28.5) | 68 (28.3) | 72 (28.7) | |
| GU | 50 (10.2) | 22(9.2) | 28 (11.2) | |
| Other | 27 (5.5) | 15 (6.3) | 12 (4.8) | .002 |
|
| ||||
| Stage | ||||
| I | 22 (4.5) | 19 (7.9) | 3 (1.2) | |
| II | 59 (12.0) | 31 (12.9) | 28 (11.2) | |
| III | 106 (21.6) | 62 (25.8) | 44 (17.5) | |
| Limited | 2 (0.4) | 2 (0.8) | 0 (0) | |
| IV | 302 (61.5) | 126 (52.5) | 176 (70.1) | <.001 |
|
| ||||
| Total Comorbidities | ||||
| <3 | 275 (56.0) | 140 (58.3) | 135 (53.8) | |
| ≥ 3 | 216 (44.0) | 100 (41.7) | 116 (46.2) | .31 |
|
| ||||
| Unintentional Weight Loss | ||||
| Yes | 258 (52.5) | 104 (43.3) | 154 (61.4) | |
| No | 233 (47.5) | 136 (56.7) | 97 (38.6) | <.001 |
|
| ||||
| IADL Score | ||||
| <14 | 207 (42.5) | 73 (30.9) | 134 (53.4) | |
| =14 | 280 (57.5) | 163 (69.1) | 117 (46.6) | <.001 |
| Missing | 4 | 4 | 0 | |
| Mean | 12.9 | 13.3 | 12.6 | <.001 |
|
| ||||
| MOS Physical Function Score | ||||
| Mean | 68.5 | 74.9 | 62.3 | |
| Median | 75.0 | 80.0 | 70.0 | |
| Range | 0-100 | 0-100 | 0-100 | <.001 |
|
| ||||
| MD KPS Score | ||||
| Mean | 84.7 | 88.1 | 81.6 | |
| Median | 90.0 | 90.0 | 80.0 | |
| Range | 50-100 | 60-100 | 50-100 | <.001 |
|
| ||||
| Self-rated KPS | ||||
| Mean | 85.7 | 88.6 | 82.9 | |
| Median | 90.0 | 90.0 | 90.0 | |
| Range | 40-100 | 40-100 | 50-100 | <.001 |
|
| ||||
| Social Support (MOS) | ||||
| Mean | 85.3 | 85.9 | 84.7 | |
| Median | 95.8 | 95.8 | 95.8 | |
| Range | 0-100 | 0-100 | 0-100 | .67 |
|
| ||||
| HADS | ||||
| < 15 | 406 (84.4) | 209 (88.6) | 197(80.4) | |
| ≥ 15 | 75 (15.6) | 27 (11.4) | 48 (19.6) | .01 |
| Missing | 10 | 4 | 6 | |
| Mean | 8.2 | 7.6 | 8.9 | .04 |
|
| ||||
| Blessed OMC | ||||
| < 11 | 461 (94.1) | 234 (97.9) | 227 (90.4) | |
| ≥ 11 | 29 (5.9) | 5 (2.1) | 24 (9.6) | <.001 |
| Missing | 1 | 1 | ||
| Mean | 4.8 | 4.1 | 5.4 | .001 |
Participants’ Baseline Characteristics According to Anemia Status
The bivariate association between anemia and baseline characteristics is displayed in Table 1. Compared with participants who did not have anemia prior to receiving the first cycle of chemotherapy, participants who had anemia were more likely to be older [mean age =73.7 years (SD=6.3) vs. 72.4 years (SD=5.9), p= 0.02); to be Black (10% vs. 6%, p=0.05); to be male (53% vs. 39%, p<0.0001); to have a GI malignancy (34% vs. 20%, p=0.0002); to have stage IV disease (70% vs. 53%, p<0.0001); to have unintentional weight loss (61% vs. 43%, p<0.0001); to score ≥ 15 on the HADS (20% vs. 11%, p=0.02); and to score ≥ 11 on the Blessed OMC (10% vs. 2%, p=0.0005).
Anemia and Functional Disability
Compared with participants who did not have anemia, participants who had anemia were more likely to be have functional disability (53% vs. 31%, p<0.001), see Table 1. In addition, compared with participants who did not have anemia, participants with anemia had a lower mean IADL score 12.6 vs 13.3 p<0.001). Figure 1 demonstrates that progressively increasing hemoglobin quartiles were associated with increasing IADL scores, (P-trend <0.001), and further supports the strong association between anemia and functional status.
Figure 1. Anemia Quartiles and Proportion of Older Cancer Patients with IADL Independence.
Anemia and Other Measures of Physical Function
We undertook additional analyses to determine if the association between anemia and other measures of physical function would be consistent with the association between anemia and functional disability, see Table 1. Compared with participants who did not have anemia, participants who had anemia had a lower mean score on the MOS Physical Function subscale (62 vs. 75, p<0.001); on the MD-KPS (82 vs. 88, p<0.001), and on the patient self-rated KPS (83 vs. 87, p<0.001). These results demonstrate a consistent and robust association between anemia and physical function irrespective of whether physical function is patient self-reported or provider-rated.
The independent association between anemia and functional disability is displayed in Table 2. Baseline characteristics that had a significant bivariate association with both anemia and functional disability and also accounted for a 10% change in the crude odds ratio of the association between anemia and functional disability included sex, stage and unintentional weight loss (data not shown). These three variables were considered potential confounders and were therefore included in the final model that examined the independent association between anemia and functional disability. Accounting for sex, stage and unintentional weight loss in the final model, participants with anemia relative to those without anemia had an increased odds of reporting functional disability at chemotherapy initiation, (OR = 2.40, CI=1.61-3.59).
Table 2. Association Between Anemia and Functional Disability.
| Odds Ratio | 95% CI | P-Value | |
|---|---|---|---|
| Anemia vs no anemia | 2.56 | 1.76-3.71 | <.001 |
| Anemia vs no anemia | 2.40* | 1.61-3.59 | <.001 |
Adjusted for sex, stage, and unintentional weight loss
DISCUSSION
In this cohort of older patients from multiple academic centers with stage I-IV cancer, anemia defined by the WHO criteria, was highly prevalent. In addition, we found that anemia was independently associated with functional disability and that the independent association between anemia and functional disability was not explained by sex, cancer stage or unintentional weight loss within the last six months. Older cancer patients with anemia (compared to those without anemia) were more than twice as likely to have functional disability.
Our study results showing that anemia is independently associated with functional disability is consistent with results from studies conducted among non-cancer patients. In a cross-sectional study of 1156 community dwelling older adults, aged 65 years and older, Penninx, et al,(6) demonstrated an independent association between anemia (WHO criteria) and functional disability. However, results from prospective studies have been mixed. While the longitudinal association between anemia and physical performance (hand grip and knee extensor strength) was demonstrated in a population based study of community dwelling older adults in the InCHIANTI Study(25) and in the EPESE Study(7), a prospective cohort study conducted among 562 community dwelling older adults aged 85 years and older failed to show an association between anemia and functional decline.(26) Among older adults with cancer, few studies have demonstrated an association between anemia and physical performance, and most of these studies have not specifically evaluated the association between anemia and functional status.(8, 10, 11, 27) In a cross-sectional study of 3523 women with breast and gynecological cancers, women with anemia relative to women without anemia were more likely to have poor performance status (ECOG-PS of 3 or 4).(27) Our study results demonstrate that the association between anemia and physical performance among older adults with cancer extends to functional disability.
The underlying mechanism through which anemia may affect muscle strength, physical performance, and functional disability have not been well examined. However, one hypothesis is that anemia may result in diminished muscle oxygenation leading to impaired muscle strength, poor physical performance, and subsequently to functional disability. Another hypothesis suggests that the association between anemia in older adults and poor functional outcomes may be partly explained by chronic subclinical inflammation. Aging is accompanied by increasing serum levels of inflammatory cytokines and acute-phase proteins, and chronic diseases which may all contribute to chronic subclinical inflammation.(28, 29) Evidence from cross sectional studies have shown an inverse association between biomarkers of inflammation and sarcopenia (loss of skeletal muscle mass and strength), slower walking speed and functional disability.(30-33) Prospective studies have also shown that interleukin-6 (IL-6) and C - reactive protein (CRP) levels and other inflammatory markers independently predict incident mobility limitations and decreases in physical function in older adults.(34, 35) Additionally, with increasing frailty, levels of IL-6, and CRP increase.(36) A plausible explanation for the association between inflammation and functional outcomes is the catabolic effect of inflammation on muscle. Several specific cytokines up-regulate the inflammatory response(37) which then induce hypercatabolism, stimulate protein breakdown, suppress muscle synthesis, leading to sarcopenia, impaired physical performance, and functional disability. Although the direct causal link between anemia and chronic subclinical inflammation remains to be firmly established, older adults with anemia (relative to those without anemia) have been shown to have higher serum levels of inflammatory biomarkers such as CRP and IL6.(6) In light of this background, chronic subclinical inflammation, a condition commonly found among older anemic adults, might be a key biological mechanism contributing to the functional disability among older adults with anemia.
Our study has several limitations that deserve comment. First, the study design is cross-sectional which precludes us from inferring that anemia causes functional disability. Longitudinal studies and randomized controlled trials conducted among older adults with cancer are warranted to address this question. Second, our study did not determine the level of hemoglobin that was associated with functional disability. Prior work, completed by Chaves, et al (38), suggest that mildly low and even low-normal hemoglobin level, levels considered normal by the current WHO definition, may not be benign, and could be associated with increased mortality. Third, all study participants were recruited from academic centers, majority were non-Hispanic White and had an associate degree, suggestive that our patient population were of higher socio-economic status. This may limit the generalizability of our results. However, our results are consistent with existing data from older community dwelling adults, and therefore, our results can be deemed generalizable. Fourth, the heterogeneity of the patient population may have introduced unmeasured confounders into the study and may make it difficult to draw conclusions regarding specific tumor types. Last, our study did not collect any data on biomarkers of inflammation, or on fatigue and therefore could not account for the mediating role of chronic subclinical inflammation or fatigue on the association between anemia and functional disability in this patient population. Hardy, et al(39), demonstrated in a study of older community dwelling adults that fatigue was independently associated with functional deficits that persisted for years.
In conclusion, our study shows that anemia was highly prevalent and independently associated with functional disability among this cohort of older adults with cancer. Longitudinal studies among older adults with cancer would be helpful in establishing a causal link between anemia and functional disability. In addition, given that functional status is a key factor for treatment tolerance, randomized controlled trials are warranted to evaluate whether treating anemia can improve functional status and treatment tolerance among older adults with cancer. Although 30% of all anemias in older adults may be unexplained(2) and therefore not readily corrected, and the use of erythropoietin in cancer patients may be associated with increased mortality(40, 41) and is therefore not recommended by current guidelines, a significant proportion of anemia in older adults are due to nutritional deficiencies(2) and are readily modifiable. Modifiable causes of anemia offer an opportunity to evaluate whether treating anemia can improve functional status and treatment tolerance among older adults with cancer.
Acknowledgments
Funding Source: This study was supported by K23 AG026749-01 (Author J) and American Society of Clinical Oncology--Association of Specialty Professors--Junior Development Award in Geriatric Oncology (Author J).
Footnotes
Conflict Of Interest: The authors made no disclosures.
Presented at the 48th meeting of the American Society of Clinical Oncology, Chicago, Illinois, June 2012.
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