Annals of Oncology Advance Access originally published online on October 26, 2005
Annals of Oncology 2006 17(1):146-150; doi:10.1093/annonc/mdj038
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© 2005 European Society for Medical Oncology
Correlation between anemia and functional/cognitive capacity in elderly lung cancer patients treated with chemotherapy
1 5th Pneumo-Oncology Unit, Department of Lung Diseases, S. Camillo-Forlanini Hospital, Rome, Italy; 2 FoRO (Fondazione per la Ricerca Oncologica), Rome, Italy
* Correspondence to: Dr F. De Marinis, 5th Pneumo-Oncology Unit, Department of Lung Diseases, San Camillo and Forlanini Hospitals, V. Portuense 332 – 00149 Rome, Italy. Tel/Fax: +39-06-55552565; E-mail: f.demarinis{at}oncpneumo.it
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionReferences |
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Background: Elderly cancer patients are often excluded from clinical trials and no data are available on the impact of chemotherapy-related anemia on their functional status and cognitive functions. This observational study investigates the association between hemoglobin (Hb) level and comprehensive geriatric assessment (CGA) variables (MMSE, ADL/IADL, GDS, CIRS and VAS).
Patients and methods: We enrolled 42 consecutive lung cancer elderly patients undergoing chemotherapy that were evaluated at baseline and after each CT cycle at least until cycle 2. Hb association with CGA indexes was expressed using Spearman's non-parametric coefficient r.
Results: Higher Hb values were significantly associated with more favourable values of all indexes measuring mental and functional capacity, depression and comorbidities. For all indexes except IADL, improvements from baseline were significantly related with concomitant Hb increases. In 14 patients given erythropoietin during the first two cycles, mean Hb increased from 9.2 to 10.8 g/dl, and the mean values of all CGA indexes were improved. On the contrary, in 18 patients not given erythropoietin, Hb varied from 13.0 to 11.2 g/dl and a parallel worsening in all CGA indexes was observed.
Conclusions: Chemotherapy-related anemia is associated with impairment of functional status and cognitive functions. In elderly cancer patients anemia correction or maintenance could be useful to preserve functional independency and protect from mental decay. However, the study results need to be confirmed on a larger series of patients within a controlled clinical trial.
Key words: anemia, chemotherapy, elderly, geriatric assessment
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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The older population is undergoing a continuous expansion and currently 60% of all cancers occur in persons over 65 years of age. Cancer in older individuals is expected to become progressively more common, with 80% of all cancers occurring in this population by the year 2050 [1
]. Among the common age-related cancers non-small-cell lung cancer (NSCLC) must be considered a disease of older adults: the median age of newly diagnosed lung cancer patients in developed countries is approximately 68 years, and as many as 40% of patients may be older than 70 years at diagnosis [2]. Evidence from earlier clinical trials suggests that platinum-based chemotherapy regimens offer patients with advanced NSCLC modest quality of life and survival advantages compared with best supportive care [3]. Subgroup analyses of these trials and retrospective studies suggest that the relative survival benefits of chemotherapy are maintained in older age groups. One of the major issues in the management of NSCLC in elderly patients is the high prevalence of comorbidity that may affect the function, the functional reserve, the quality of life, the life expectancy and the tolerance of treatment by older individuals [4, 5].
Anemia is a common finding in cancer patients and its prevalence increases after 65 years [6]. Anemia has a negative impact on the majority of organs but in an elderly cancer population the consequences can be even more invalidating due to its contribution to the ‘fragility syndrome’ [7]. Moreover, in this setting cardiac functionality is often compromised and anemia contributes to increased workload, being associated with increased heart rate in a recently published survey of 78 974 patients [8].
Anemia and fatigue might precipitate functional dependence in the elderly considering that higher mobility difficulties have been reported in women aged 
70 years with lower Hb level [9]. Furthermore, anemia causes energy imbalance and emotional distress (fatigue) [10].
Fatigue, particularly common after 65 years of age, may contribute to progressive functional decline, delayed cancer treatment and suboptimal cancer control and may substantially increase the costs of managing these patients [11]. The prevention of fatigue and anemia may reduce the risk of functional dependence and its correction in this setting of patients results in improved quality of life (QoL) and energy levels [12–17]; this effect is partly independent from the response of cancer to chemotherapy [15]. A correlation between anemia and risk of Alzheimer's disease was first identified by Beard et al. [18]. A large number of cognitive and emotional complications of anemia, including headaches, loss of concentration and depression, have been reported in cancer patients [19–21]. In patients undergoing dialysis, anemia was associated with confusion, inability to concentrate, decreased mental alertness and impaired memory [22]. A direct correlation between hemoglobin levels and cognition was established by Pickett et al. [23] and they reported that increasing the hematocrit of chronic dialysis patients above 33%–36% with blood transfusions improved attention span, learning ability and memory.
With the aim of systematizing all these data, using CGA variables, we have investigated in this prospective study whether any association exists between Hb levels and functional capacity, cognitive impairment and comorbidities in elderly lung cancer patient treated with CT. CGA may improve the knowledge base in determining which older patients with cancer may benefit from active cancer treatment and who may benefit from clinical oncologic and geriatric co-management.
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patients and methods |
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patients selection
This prospective observational study was conducted in the department of respiratory diseases, 5th Pneumo-Oncology Unit, San Camillo-Forlanini Hospital, Rome, Italy, between July 2003 and January 2004. Patients enrolled in the study were required to be
70 years old and to have a confirmed diagnosis of lung cancer, for which they were undergoing chemotherapy. Patients with symptomatic brain metastases were excluded, as were those with pre-existing major neurological or psychiatric problems. Also excluded were patients who could not speak Italian or had a history of substance abuse or were unable to provide a written informed consent. Table 1 shows patients' characteristics and cancer specific treatments. All patients were evaluated before the initiation of chemotherapy (baseline) and before each subsequent cycle (after 21 days) for quality of life, mental capacity, functional status, depression and comorbidities.
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instruments
Evaluation scales were taken from the Comprehensive Geriatric Assessment (CGA), a multidimensional, interdisciplinary diagnostic process to determine the medical, psychological and functional capabilities of a frail elderly person.
Cognitive function was measured with the Mini-Mental State Examination (MMSE), a widely used brief screening test for cognitive deficit [24, 25]. It covers a number of domains in orientation, registration, attention and calculation, recall, language and copying. The standard MMSE maximum score is 30. A score <24 is usually used to distinguish between normal and abnormal cognitive function. Functional status was established using Activity Daily Living (ADL) and Instrumental Activity Daily Living (IADL) scales. The basic ADLs are composed of self-care activities of dressing, bathing, transferring to and from chair, bed and standing position, going to the toilet and eating. A dichotomous rating (dependent/independent) of six ADL functions assesses the physical functioning of elderly or chronically ill patients. In addition to the required daily activities, IADLs (score ranging between 0 and 8) include activities that one may do for oneself or may customarily be done by other members of the household (e.g. housework or other domestic chores, managing money, using the telephone, shopping) [26]. Depression was tested using the Geriatric Depression Scale (GDS) designed to help identify depression in elderly patients by a 15-item questionnaire. A score (0 or 1) is related to each question and scoring intervals indicate the absence or the severity grade of depression (scoring intervals: 0–4, no depression; 5–10, mild depression; 11+, severe depression) [27, 28]. In elderly patients with cancer, the number and severity of comorbid conditions can be assessed with the Cumulative Illness Rating Scale-Geriatric (CIRS-G) [29]. The CIRS-G offers a more far-reaching assessment with respect to other tools. Conditions that affect any organ system are rated on a scale of 0, indicating no problems, to 4, indicating a severe or life-threatening condition. The QoL/fatigue outcome was measured by a visual analogue scale (VAS). The VAS consisted of a 10-cm line with ‘no fatigue at all during the 21 days’ at one end and ‘extreme fatigue during the last 21 days’ at the other end. Patients were asked to indicate the severity of fatigue by placing a marking on the line. A higher score represents increased fatigue.
statistical methods
Data were summarized using frequencies and proportions or mean ± standard deviation (SD) and 95% confidence interval (CI), as appropriate. As the score variables used to measure functional and cognitive capacity were definitely not normally distributed, the association between these indexes and Hb level (or their changes) was expressed using Spearman's rank-order (non-parametric) coefficient r. Associated P values were calculated at the visits, which were completed by all patients (V0–V2) and for changes from V0 to V1 and V2. To account for multiple testing, only P values <0.01 were considered as statistically significant and those <0.002 as highly significant (equivalent to an overall type-I error of about 0.05 for each of the six indexes and for all indexes, respectively, under the highly conservative assumption of total independence between measures).
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results |
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Forty-two lung cancer patients aged
70 were enrolled in the study (Table 1). After the baseline evaluation (V0), patients were visited before each therapy cycle (21 days) at least until V2. Nineteen of them were controlled again at V3 and 11 further to V5. Spearman's correlation coefficients r between functional/cognitive capacity measures and Hb at each of the visits completed by all patients (V0, V1, V2), along with the nominal associated P values, have been calculated (Table 2). All coefficients showed that higher Hb values were associated with higher (better) values of the upward scales ADL, IADL and MMSE (i.e. a positive correlation) and with lower (better) values of the downward scales VAS, CIRS and GDS (i.e. a negative correlation). For all indexes, statistical significance was attained at one or more of the time points. Overall (V0–V5), r coefficients were similar to those calculated at each visit (Figure 1).
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The association between Hb changes from V0 to V1 and V2 and the concomitant index changes have also been studied (Table 2). All coefficients were in the direction showing that Hb increase was associated with improvement of the indexes. Statistical significance at V1, V2 or both was attained for all scales except IADL (Table 3).
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In 14 patients given erythropoietin in the interval V0–V2, mean Hb increased by 1.6 g/dl (95% CI 0.8–2.3) and all indexes were improved as shown by mean (95% CI) changes: VAS, –1.4 (–2.5 to –0.2); CIRS, –1.7 (–5.4 to 2.0), ADL, 0.57 (0.03–1.11); IADL, 0.86 (0.08–1.64); MMSE, 3.4 (0.6–6.1); GDS, –2.1 (–3.7 to –0.4). On the contrary, in 18 patients not given erythropoietin where mean Hb decreased by –1.8 g/dl (95% CI –2.6 to –1.0), a parallel worsening has been observed for all indexes: VAS, 1.4 (0.3–2.6); CIRS, 6.2 (2.9–9.6); ADL, –0.94 (–1.47 to –0.42); IADL, –0.61 (–1.38 to 0.15); MMSE, –3.3 (–6.0, –0.6); GDS, 2.1 (0.7–3.4). Roughly parallel changes of Hb and mean values of all associated parameters tested in the interval V0–V2 were also observed in 10 patients given erythropoietin for part of this interval (Figure 2).
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discussion |
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Anemia may adversely influence the management of older cancer patients receiving chemotherapy with or without radiotherapy by limiting the dose intensity and the dose density of the treatment and thus preventing adequate cancer control. In addition, anemia may increase the cost of treating cancer by causing prolonged disability and more frequent hospitalizations.
Our prospective survey analysed correlations between anemia and CGA principal parameters, revealing functional decline, cardiovascular and central nervous comorbidity, and risk of therapeutic complications as well as QoL.
In our elderly cancer patients Hb level was associated to QoL, functional capacity, mental decline, presence of comorbidities and depression. Moreover the change in Hb level was associated with the change in all the above parameters although not significantly for IADL. This suggests that the treatment of anemia or maintenance of adequate Hb levels could be useful to preserve or improve quality of life and overall health status in elderly cancer patients undergoing chemotherapy. These results are one of the clinical evidences of guidelines (ASCO-ASH, NCCN, EORTC) that recommend the treatment of mild anemia level (Hb 10–12 g/dl) in an elderly population with comorbidities [30]. In interpreting the results of this study, however, one should be aware that other factors, such as patient's performance status, chemotherapy regimen and response to chemotherapy, may have interacted with the Hb level and the other variables examined. Investigating the role of these factors in an observational study would require a larger patient population and complex analysis models. Therefore, notwithstanding these promising results, further larger controlled clinical studies are needed to confirm the role of CGA and to establish more clearly when anemia correction becomes absolutely necessary to avoid functional and mental decay.
Received for publication June 8, 2005. Revision received August 8, 2005. Accepted for publication September 5, 2005.
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