Oncology Unit, General Hospital, Latisana, Italy
Received 19 June 2003; revised 12 December 2003; accepted 19 December 2003
ABSTRACT
Fatigue is a subjective experience that affects everybody. In healthy individuals, it can be considered a physiological response to physical or psychological stress. In people with specific diseases, however, fatigue often represents one of the most significant problems. Fatigue can be caused by many factors, both intrinsic to the patient and extrinsic, such as therapeutic interventions. This review, based on published studies, has been conducted with the aim of presenting a critical discussion of the available information on the characteristics, causes and potential treatments of fatigue in cancer patients receiving chemotherapy. The incidence of fatigue in these patients, the methods for measuring and evaluating fatigue, and possible therapeutic options are discussed. An appraisal of the toxicity of various chemotherapeutic agents is also presented. Although fatigue is now an ever more considered aspect of the toxicity of chemotherapy, it remains difficult to establish what standard should be used to make a quali-quantitative evaluation of this symptom. Furthermore, in the absence of a clear demonstration of the efficacy of some therapies, the management of cancer-related fatigue remains poorly defined (except for the treatment of anemia-related fatigue). New randomized clinical trials are necessary to indicate the best strategies for tackling this important problem.
Key words: chemotherapy, fatigue, toxicity
Introduction
Fatigue is a common problem in patients receiving treatment for cancer. This type of fatigue, defined as cancer- or therapy-related, is different from everyday tiredness, which can be reversed by rest or sleep. Until recently cancer-related fatigue has been overlooked by patients and health-care personnel, and only the growing attention to the quality of life of patients with cancer has begun to contribute to a re-evaluation of this symptom. In recognition of its importance, cancer-related fatigue was recently classified as an independent nosological entity in the 10th revision of the International Classification of Diseases (year 2000). Nevertheless, knowledge about this condition remains fragmentary and scarce. The aim of this review is to present a critical discussion of the available information on the characteristics, causes and potential treatments of fatigue.
Through careful analysis of the documentation, we have quantified the impact of fatigue, maintained or caused by chemotherapeutic agents administered alone or in association, to categorize them in the therapeutic management algorithm for cancer patients.
Fatigue has been described in the literature as tiredness, exhaustion, depression, feeling unwell, loss of motivation and limitations of mental state [13]. Furthermore, it has been demonstrated that fatigue reduces the individual resources of patients [4], influences their nutritional state, increases morbidity [5] and can negatively affect the dose intensity of some forms of oncology therapy [6].
Fatigue is a multifaceted, subjective condition. It can be described using a range of general characteristics (severity, negative sensations, temporal features) and specific weaknesses (lack of energy, weakness, somnolence, difficulty in concentrating). Fatigue can be defined as a multidimensional phenomenon which evolves over time, compromising physical energy, mental capacity and the psychological condition of the patient with cancer (Table 1) [7].
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There are various factors which potentially predispose to or cause cancer-related fatigue (Table 2). Several studies have shown a correlation between fatigue and different types of oncological therapy. It is known that fatigue is the commonest side-effect of chemotherapy and radiotherapy: it has been shown that 65100% of patients undergoing radiotherapy [911] and up to 8296% of those receiving chemotherapy [12, 13] suffer from fatigue during their treatment.
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Two investigations on the impact of fatigue on the quality of life of cancer patients were carried out by the Fatigue Coalition, a multidisciplinary group whose aim was to examine the importance of fatigue in patients and their caregivers, and to draw up guidelines on the diagnosis and treatment of the fatigue syndrome. Vogelzang et al. carried out a telephone investigation in 419 randomly selected patients who had received chemotherapy or radiotherapy, and also in their caregivers and oncologists [15]. Fatigue was reported by 78% of the patients during the course of their disease or during treatment, and about one-third reported daily fatigue and difficulty in carrying out normal daily activities.
From a different perspective, fatigue was noticed by 86% of the patients caregivers, while 76% of the oncologists recorded this syndrome in their patients. Furthermore, 80% of the oncologists considered that fatigue was ignored or not adequately treated, while 74% of the patients considered that it was a symptom that had to be put up with. Fifty per cent of the patients did not discuss therapeutic options with their oncologists, and only 27% said that their oncologist had prescribed or advised them on some sort of treatment for the fatigue.
A second telephone survey by the Fatigue Coalition confirmed that fatigue was common in patients who received chemotherapy, and that it had detrimental physical, psychosocial and financial consequences (Table 3) [16].
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Incidence of fatigue in patients undergoing chemotherapy
Only in relatively recent times has the clinical picture of fatigue been assimilated into the field of oncology, and indeed its evaluation is still often not included among the parameters normally used to describe the toxicity of chemotherapy. With these limitations, we have identified recently published articles that report fatigue (or symptoms similar to it, such as asthenia) among the descriptors of toxicity of chemotherapeutic agents, dividing the various articles according to the underlying malignancy (Tables 4, 5, 6, 7, 8, 9).
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Methods of evaluating and measuring fatigue
Over the last few years, various methods of evaluating and measuring fatigue have been proposed or introduced.
The Brief Fatigue Inventory is one of the methods developed to study fatigue [17]. This instrument evaluates fatigue over 24 h using a scale from 1 to 10 (1 indicates absence of, and 10 the worst imaginable fatigue). Studies have shown that values of 7 or above are strongly correlated with a clinically relevant level of difficulty.
Another instrument for evaluating fatigue is the MFI-20, a 20-item questionnaire which examines the following parameters: general, physical and mental fatigue, decreased motivation and reduced activity, through five subscales of five items each [18]. Using this method, Holzner et al. recently confirmed the correlation between hemoglobin levels, fatigue and quality of life in cancer patients [19].
The National Comprehensive Cancer Network (NCCN) Fatigue Practice Guidelines Panel reviewed the available evidence and the consensus of doctors managing fatigue to produce guidelines for clinical practice. Five factors were identified as being associated with fatigue: anemia, pain, emotional stress, sleep disturbances and hypothyroidism [20].
Using the Functional Assessment of Cancer TherapyGeneral (FACTG) questionnaire, which measures overall quality of life (QoL), as a basis, 20 new questions have recently been developed concerning the impact of fatigue and other symptoms associated with anemia in cancer patients. Thus two new instruments have been constructed: FACTFatigue (FACTF), made up of FACTG and an additional 13 questions on fatigue (the fatigue subscale) and FACTAnemia (FACTAn), comprising FACTF and a further seven questions on other aspects relevant to anemia but not to fatigue.
FACTAn, FACTF and the fatigue subscale have been shown to be able to discriminate successfully between cancer patients on the basis of their levels of hemoglobin and performance status. Dividing the patients into two groups according to their levels of hemoglobin, those who had levels of hemoglobin >12 g/dl reported less fatigue and fewer symptoms of anemia, better physical and functional wellbeing, as well as a higher overall QoL [21].
The Linear Analog Scale Assessment (LASA) was recently used to measure the effect of therapy with epoetin on parameters relating to QoL. Patients reported their level of energy, capacity to carry out daily activities and overall QoL on a scale from 0 (lowest value) to 100 (highest value). LASA is a unidimensional scale that is easy to use in clinical practice, and its results correspond well (>70%) with those of the multidimensional FACTAn scale.
Pipers fatigue scale was the first validated multidimensional scale; it addresses the severity, distress and impact of fatigue using a 40-item questionnaire [22].
The Multidimensional Fatigue Symptom Inventory (MFSI) evaluates global, somatic, affective, cognitive and behavioral symptoms of fatigue through 83 items. It was administered to women who had received or were undergoing treatment for breast cancer. The MFSI appears to be sensitive to fatigue, accurately discriminating cancer patients from control subjects and between patients with varying levels of performance status [23].
Treatment of cancer-related fatigue
The potentially useful treatments for cancer-related fatigue are as follows: varying the patients therapeutic regime; correcting metabolic disorders; and treating depression and insomnia. Furthermore, many physicians advise light physical exercise (a loss of muscle mass has been hypothesized to be a concausal mechanism of fatigue).
Recent controlled studies have shown that aerobic exercises prevent worsening fatigue and psychological stress in patients receiving high-dose therapy [24]. Furthermore, in women with breast cancer receiving chemotherapy, exercise can significantly reduce the level of fatigue, and as the duration of exercise increases, the intensity of fatigue declines [25]. In patients with melanoma receiving interferon-, the combination of exercise and methylphenidate showed a positive effect on interferon-induced fatigue [26].
Other non-pharmacological therapeutic approaches include modifications in periods of activity and rest, cognitive therapy, behavioral therapy to modify sleep (sleep hygiene) and nutritional support.
Pharmacological treatments include central nervous system stimulants and corticosteroids. The use of the former is essentially empirical; there are no published studies in which the reduction of the level of fatigue was the primary end point. Recently, a psychostimulant, methylphenidate (Ritalin), has shown some activity in improving fatigue, sedation and pain in cancer patients [26, 27]. It has been hypothesized that the use of antidepressants, such as selective serotonin re-uptake inhibitors, could play a role in the treatment of fatigue, but again, there are no published data confirming this.
All this has led to a growth in the parallel market of alternative therapies. Many patients take chemical supplements of unproven efficacy. A recent study in HIV-positive patients reported that the two factors predicting use of these supplements were high educational level and marked degree of fatigue [28]. A similar investigation in cancer patients would probably find the same results. This highlights the need for controlled clinical studies which correctly evaluate the therapeutic approaches adopted for fatigue.
Anemia is recognized as one of the main potential causes of cancer-related fatigue: a review of the data of patients undergoing anticancer therapy showed that most of them were anemic or developed anemia during treatment [29]. Numerous clinical studies have shown that the administration of epoetin- is a safe and effective way to correct anemia and significantly improve QoL in cancer patients [30].
Indeed, as demonstrated by LASA and FACT-An, both QoL and fatigue showed improvements which were proportional to hemoglobin increase and to response to chemotherapy in an independent manner [31]. Multivariate regression analyses from double-blind trials also confirm the benefit in QoL obtained increasing hemoglobin levels with epoetin- [32].
Conclusions
In conclusion, although fatigue is now an increasingly considered aspect of the toxicity of chemotherapy, in part because of its impact on patients QoL, it remains difficult to establish what standard should be used for the quali-quantitative evaluation of this symptom. Furthermore, in the absence of clear demonstration of the efficacy of some therapies and the present climate of empirism, therapeutic management of fatigue remains poorly defined (except for the treatment of anemia, which in its turn is a possible concause of fatigue).
More efforts, in the form of randomized clinical trials, are necessary so that in the near future the best strategies for tackling this important problem can be indicated.
Acknowledgements
This work was supported by a grant from Ortho Biotech, Italy.
FOOTNOTES
* Correspondence to: Dr A. Iop, Oncology Unit, General Hospital, 33053 Latisana, Udine, Italy. Tel: +39-0431-529298; Fax: +39-0431-520478; E-mail: onco-lat{at}ass5.sanita.fvg.it
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