Departments of 1Biological Psychiatry, 2General Psychiatry, 3Internal Medicine, 4Gynecology, Innsbruck University Hospital, Innsbruck; 5Department of Internal Medicine (Oncology), Vienna General Hospital, Vienna, Austria
Received 28 August 2001; revised 7 November 2001; accepted 20 November 2001.
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Abstract |
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Although fatigue is a commonly reported symptom in cancer patients its etiology is still poorly understood. The objective of the present study was to investigate the relationship between hemoglobin (Hb) levels and the subjective experience of fatigue and quality of life in cancer patients with mild or no anemia undergoing chemotherapy.
Patients and methods
Sixty-eight cancer patients (25 colorectal, 26 lung and 17 ovarian cancer) presently undergoing chemotherapy participated in the study. Fatigue was measured with the Multidimesional Fatigue Inventory (MFI-20), quality of life with The European Organization for Research and Treatment of Cancer QLQ-C30. In order to provide normative data for fatigue levels, the MFI-20 was also completed by a sex- and age-matched sample of 120 healthy controls.
Results
Compared with healthy subjects, cancer patients experienced significantly higher levels of subjective fatigue. Correlations between Hb values and subscales of the MFI-20 were moderate with a tendency to increase during chemotherapy. Hb values alone, however, do not fully account for the observed fatigue. Other symptoms, especially pain, dyspnea and sleep disturbances, also showed an association with perceived fatigue.
Conclusions
Despite significant correlations, these results indicate that Hb values only partially explain subjectively experienced fatigue and quality of life in cancer patients. It is suggested therefore that the treatment of fatigue must be multidimensional and involve all areas which contribute to the syndrome.
Key words: fatigue, quality of life, hemoglobin, cancer, chemotherapy, psychooncology
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Introduction |
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The specific etiology of cancer- or treatment-induced fatigue is still poorly understood [7]. Nevertheless, it is well known that anemia is one of the main factors causing fatigue in cancer patients [8]. Anemia is usually diagnosed by clinical signs and low hemoglobin (Hb) values and may be the result of either advanced disease or aggressive therapy. Where anemia results from the myelosuppressive effects of therapy, it is generally reversible, with little post-treatment morbidity, although the fatigue associated with anemia can be quite disruptive to patients, affecting their QoL [9, 10].
The effect of low Hb values (<10 g/dl) on fatigue has been the subject of considerable research, and severe anemia (especially with Hb values <8 g/dl) is known to give rise to a wide variety of fatigue-related symptoms such as exercise intolerance, tachycardia, palpitations or dyspnea at rest, anorexia, dizziness, headaches, sleep disturbances, concentration difficulties, pallor and hypersensitivity to cold.
Mild anemia (female, 1012 g/dl; male, 1014 g/dl) is associated with few specific clinical symptoms and is usually diagnosed on the basis of Hb level [11]. Nevertheless, the lack of manifest clinical symptoms does not mean that it can be surmised that there are no negative consequences for the patients perceived well-being. The relationship between Hb values in the mildly anemic range and fatigue has received little attention so far [12, 13].
The symptoms of both anemia and fatigue, and the negative impact of these on QoL and their anticipated interrelation have fostered attempts to counteract these symptoms by treating patients with either erythropoietin or blood transfusion.
Treatment of this nature has become widely accepted and popular, although little information on potential correlations between Hb values, fatigue and QoL is available. As these interventions also contribute considerably to the costs of cancer treatment, data are badly needed to support evidence-based and cost-effective treatment [14, 15].
The present study attempted to address the effects of mild anemia on fatigue and QoL by investigating the association between Hb levels, the subjective experience of fatigue and QoL in cancer patients with an Hb level >10 g/dl. The study was conducted in patients with three different types of cancer (colorectal, lung and ovarian) all of whom underwent chemotherapy. A group of healthy controls was evaluated for comparative purposes.
The following questions were addressed in this study. (i) Can subjective fatigue be observed in cancer patients with Hb values in the normal range (1216 g/dl female, 1418 g/dl male) and in the mildly anemic range (1012 g/dl female, 1014 g/dl male)? (ii) Are there differences in the fatigue scores [Multidimensional Fatigue Inventory (MFI-20)] between the three diagnostic groups (colorectal, lung and ovarian cancer)? (iii) Is there a relationship between subjective fatigue (MFI-20), QoL [assessed with The European Organization for Research and Treatment of Cancer (EORTC) Core Questionnaire QLQ-C30] and Hb values in patients with mild or no anemia? (iv) Do variables other than (degree of) anemia have an influence on subjective fatigue? (v) What is the relationship between subjective fatigue (MFI-20) and QoL (EORTC QLQ-C30)?
In answering these questions implications for possible treatment strategies are also considered.
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Patients and methods |
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Twenty-five of the patients had colorectal cancer, 26 lung cancer and 17 ovarian cancer. All patients were receiving chemotherapy according to their diagnoses (colorectal cancer: 72.0% 5-fluorouracil/leucovorin, 8.0% oxaliplatin/irinotecan, 8.0% mitomycin/irinotecan, 8.0% mitomycin, 4.0% oxaliplatin/mitomycin; lung cancer: 23.1% vinorelbine/gemcitabine, 30.8% paclitaxel/cisplatin, paclitaxel/carboplatin, 19.2% cisplatin/vinorelbine, 11.5% vincristine/doxorubicin/cyclophosphamide, 7.7% etoposide/cisplatin, 7.7% gemcitabine; ovarian cancer: 17.6% carboplatin/cyclophosphamide, 82.4% cisplatin/cyclophosphamide).
Immediately before each chemotherapy cycle patients were asked to fill out the EORTC QLQ-C30 (for QoL) and the MFI-20 (for fatigue). After the questionnaires had been completed, blood samples were collected and sociodemographic and clinical data were obtained from the medical charts.
Only the data of the first three chemotherapy cycles are considered in this study, since there were too many missing values in subsequent chemotherapy cycles.
During the first three chemotherapy cycles, eight patients (three colorectal cancer, two lung cancer, three ovarian cancer) showed Hb values <10 g/dl at any time of measurement. These patients received treatment for anemia (four patients received a blood transfusion and four patients erythropoietin). All were subsequently excluded from further analysis. Consequently only data from patients with Hb values within the normal range and in the mildly anemic range (1012 g/dl female, 1014 g/dl male) were included in statistical analysis.
In order to provide normative data for fatigue levels of the general population for the purpose of comparison, we collected MFI-20 scores of 120 age- and sex-matched healthy controls.
Assessment of fatigue (MFI-20)
The MFI-20 is a 20-item self-report instrument designed to measure fatigue [5, 7, 1619]. It covers the following dimensions: General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Motivation and Reduced Activity.
Physical Fatigue refers to the physical sensations related to the feeling of tiredness. Possible somatic symptoms of fatigue such as light-headedness or sore muscles are not included in this scale in order to exclude contamination with the symptoms of somatic illness that are independent of fatigue. Reduction in activities and lack of motivation are covered by the scales Reduced Activities and Reduced Motivation, respectively. Finally, cognitive symptoms such as having difficulty concentrating are included in the scale for Mental Fatigue. Each subscale contains four items which have to be rated on a five-point Likert scale (higher subscores indicate greater fatigue). The use of a total score over all 20 items is not recommended. When a total score is needed as a comprehensive indicator of fatigue, the developers recommend use of the subscore General Fatigue which measures comprehensive aspects of fatigue. The MFI-20 has shown good psychometric properties [19].
QoL instrument: EORTC QLQ-C30
QoL was assessed using the EORTC QLQ-C30, which is widely employed in Europe and whose validity is well established [2024]. This questionnaire has a modular structure and consists of a core questionnaire (EORTC QLQ-C30 [24]) and additional modules developed specifically for cancer patients of different diagnostic groups [2529].
The patient is requested to rank each of the items on a scale ranging from 1 (not at all) to 4 (very much). The 30 individual items of the EORTC QLQ-C30 can be summarized in five functioning scales, Physical Functioning, Role Functioning, Emotional Functioning, Social Functioning and Cognitive Functioning (0, minimum QoL; 100, maximum QoL) and nine symptom scales, e.g. Pain, Dyspnea, Sleep Disturbance, Appetite Loss and Diarrhea (0, no symptoms; 100, severe symptoms).
The core questionnaire fulfills all essential psychometric criteria and demands little time for completion (1015 min). A full description of the inventory can be found in the key references [24].
Statistical methods
Subscores of the MFI-20 and the EORTC QLQ-C30 were computed according to the instructions of the developers.
The MannWhitney U test for independent samples was employed for comparing groups of patients and healthy controls as well as diagnostic subgroups with respect to fatigue variables (subscales). To quantify differences between groups, effect sizes were determined (difference of group means divided by the standard deviation of the group of healthy controls).
Correlations between MFI-20 subscales and Hb values as well as EORTC QLQ-C30 subscales were evaluated by Pearson correlation coefficients.
The effect of specific symptoms (e.g. Pain, Sleep Disturbances, Dyspnea) on the MFI-20 subscale General Fatigue was determined using partial correlations adjusting for Hb values.
The size of the study sample (n = 60) was determined such that a correlation coefficient of r = 0.35 or higher can be detected with a power of 80% at a two-sided significance level of = 0.05.
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Results |
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A detailed description of the sociodemographic and clinical data is given in Table 1.
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Very similar Hb values were observed for the three groups and the three cycles investigated (Table 1). A detailed analysis is given in the next subsection.
The sample of healthy controls consisted of 120 subjects (age, 59.2 years ± 10.6; sex, 45.5% female).
Relationship between fatigue, QoL and Hb values
Question 1: Can subjective fatigue be observed in cancer patients with Hb values in the normal range (1216 g/dl female, 1418 g/dl male) and in the mildly anemic range (112 g/dl female, 1014 g/dl male)?
Patients with Hb values both in the normal range and in the mildly anemic range had significantly higher MFI-20 scores than the reference group of healthy controls. Results for the first chemotherapy cycle are presented in Table 2. The effects sizes for the subscales General Fatigue, Physical Fatigue, Reduced Activity and Reduced Motivation were fairly high ranging from 0.67 to 1.49. Smaller effect sizes were observed for the Mental Fatigue subscore.
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Question 2: Are there differences in the MFI-20 scores between the three diagnostic groups
In all of the chemotherapy cycles the majority of the MFI-20 subscales displayed significantly higher values for lung cancer patients than for patients with colorectal or ovarian cancer (Table 3).
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Question 4: Do variables other than (degree of) anemia have an influence on subjective fatigue?
In colorectal cancer, Pain and Diarrhea and in ovarian cancer Pain and Sleep Disturbances were found to be correlated with subjective fatigue (MFI-20 subscale General Fatigue) after the effect of Hb had been partialed out. This is displayed for cycle 1 in Table 5.
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Question 5: What is the relationship between subjective fatigue and QoL?
As shown in Table 6, the correlations between the two instruments were generally fairly high (cycle 1). MFI-20 subscales correlated best with the EORTC QLQ-C30 subscale Physical Functioning. Only the MFI-20 subscale Mental Fatigue had a slightly higher correlation with the EORTC QLQ-C30 Cognitive Functioning subscale. The same correlation pattern was observed in cycles 1 and 3.
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Discussion |
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The aim of the present study was to investigate the influence of Hb and other factors on subjective fatigue in cancer patients with Hb values in the normal or mildly anemic range.
Our results show that cancer patients undergoing chemotherapy who are suffering from mild anemia or are even not anemic report markedly more subjective fatigue than healthy controls. These findings extended to all of the dimensions of fatigue that were assessed, namely Physical Fatigue, Reduced Activity, Reduced Motivation, Mental Fatigue and General Fatigue. Similar findings were reported by Smets et al. [19], Glaus [32], Glaus and Muller [12] and Cella [33].
The group of lung cancer patients reported a considerably higher degree of subjective fatigue than the groups of colorectal and ovarian cancer patients. This is in accordance with the previous findings of Hickok et al. [34], Hopwood and Stephens [35], Hurny et al. [36], Krishnasamy [37] and Stone et al. [38]. Differences were especially pronounced in the physical dimension of fatigue, although it seems to extend to other aspects such as Reduced Activity and Reduced Motivation. It would seem highly likely that subjective fatigue is higher in lung cancer patients because the location of the cancer may have a detrimental effect on respiratory function or the patients perception of their respiratory function.
More detailed analyses also revealed correlations between subjective fatigue and Hb values during the course of chemotherapy (cycles 2 and 3) but not before the first chemotherapy cycle.
This may be because before the first chemotherapy cycle patients may also have been feeling the after-effects of surgery, the stress of hospitalization as well as the symptoms of the disease itself. Under such circumstances these additional stresses may have outweighed the effects of low Hb on fatigue. In the course of the chemotherapy the cancer- and/or surgery-related symptoms decrease and therefore the effect of Hb becomes more prominent.
Given the findings of correlations between subjective fatigue and Hb in the present sample it could then be argued that medical treatment to increase Hb levels be extended to those patients with Hb >10 g/dl. Such patients could derive considerable benefit from erythropoietin during chemotherapy as this has been shown to lead to a reduction of transfusion requirements, improved QoL and lowered subjective fatigue [3942].
As has already mentioned above, however, our findings indicate that Hb values alone do not fully account for the perceived fatigue. In addition to Hb levels, several symptoms, especially Pain, Dyspnea and Sleep Disturbances, also showed an effect on fatigue. Similar results were reported by Okuyama et al. [1] who found fatigue to be correlated with dyspnea, insufficient sleep and depression [43, 44]. As a consequence the management of fatigue must go beyond a mere correction of anemia. Comprehensive treatment regimens will include measures addressing aspects of fatigue other than anemia [8, 45].
Considering the fact that fatigue may also be a symptom of depression or of an adjustment disorder [46], psychological treatment of these syndromes is one obvious possible line of treatment. This could take the form of increasing the patients autonomy by strengthening coping mechanisms and helping them develop new perspectives. Positive effects of such psychotherapeutic interventions on perceived fatigue have been shown in several studies for both group [47] as well as individual therapy [48]. A further treatment strategy which may be of benefit to a cancer patients fatigue is the use of educational measures. Although there are no specific studies investigating the role of providing better patient information on fatigue, Rainey [49] and Johnson et al. [50] reported positive effects of detailed patient information on normal daily activities. In some cases pharmacological intervention with psychostimulants, corticosteroids or antidepressants, depending on the chief complaint, may also be indicated [5, 46].
As our study has shown that fatigue and hence QoL is associated with somatic complaints a further category of treatment could focus on somatic issues that affect fatigue. In this context physiotherapy could be considered. A reduction of fatigue as a result of exercise during chemotherapy has been reported by Dimeo et al. [51] and Schwartz [52]. Mock et al. [53] found similar results in early-stage breast cancer patients undergoing post-operative radiotherapy.
We also analyzed the association between fatigue and QoL. The results basically replicated previous findings that fatigue (as measured by the MFI-20) is generally found to be highly correlated with QoL and is reflected in particular by restrictions in the domain of Physical Functioning. This relationship has been discussed in detail in other investigations [54] and will therefore not be elaborated further.
One limitation in interpreting our findings lies in the fact that we were only able to study three chemotherapy cycles. A longer study duration would clearly have been desirable. Although we had originally planned for a longer evaluation period, high attrition rates, mostly due to premature termination of chemotherapy and tumor progression, rendered meaningful statistical analyses beyond the third chemotherapy cycle impossible. Similar problems were also encountered by other investigators [5556].
In summary it has been shown that a high level of fatigue is reported by cancer patients with mild or even no anemia. In order to improve QoL of these patients a multidimensional concept of the treatment of fatigue should be established. The present data indicate that in the course of chemotherapy benefit might be gained from increasing Hb in patients with mild anemia. This should be supported by concurrent psychological and physical treatments.
It is suggested that the area would benefit from further intervention studies investigating in detail the effect that medical treatment of mild anemia as well as other pharmacological, physical and psychological interventions will have on fatigue and QoL.
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Disclosure information |
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Acknowledgements |
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Footnotes |
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References |
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