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The causes of cancer-related fatigue and approaches to its treatment

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Evidence suggests that fatigue may affect over half of all patients with cancer (Ream et al, 2002). But, although it is often classed as a single entity, the term can encompasses a wide range of symptoms that will have a combination of biological, psychological or iatrogenic origins.

Tonks N. Fawcett, BSc (Hons), MSc, RN, RNT, ILTHE

Senior Lecturer, Nursing Studies, University of Edinburgh

 

Growing recognition of fatigue in cancer may be leading health-care professionals to overstate the likelihood of it occurring (Tanghe et al, 1998; Okuyama et al, 2001; De Jong et al, 2002) and, by so doing, unwittingly give rise to a self-fulfilling prophecy in a proportion of cancer patients who might not otherwise have experienced it as a significant side-effect. At the same time, research has found that assessment and treatment of cancer fatigue is, at best, patchy and, at worst, may be absent (Knowles et al, 2000; Fletchner and Bottomley, 2003).

Therefore, while acknowledging patients’ need for honest, accurate information, we must avoid raising the spectre of fatigue, and then abandoning patients to face it alone, without support.

This paper aims to examine the basis of cancer-related fatigue and outline some of the approaches to help alleviate this complex symptom.

Definitions of fatigue

Fatigue is a widespread phenomenon, as is pain, but it is similarly not a single entity but a complex, subjective and multidimensional concept with many causes, modes of expression and means for alleviation (Morrow et al, 2002). In a healthy person, it can be seen as a short-term protective, and even pleasant regulatory experience, in response to some form of exertion or activity, which dissipates after a period of rest or sleep, leaving the individual to feel refreshed.

However, when fatigue emanates from either a disease or treatment regimen, or is of unknown or uncertain origin (Aylett and Fawcett, 2003), it can be a major life-altering experience. Ream and Richardson (1996) define this type of fatigue as ‘a subjective unpleasant symptom that incorporates total body feelings ranging from tiredness to exhaustion, creating an unrelenting overall condition which interferes with an individual’s ability to function to their normal capacity’.

This definition would seem particularly apposite in the case of cancer-related fatigue. But it has been suggested that cancer fatigue is a phenomenon in itself, being described by Morrow et al (2002) as an ‘unusual excessive whole-body experience that is disproportionate or unrelated to activity or exertion and is not relieved by rest or sleep’. Holley (2000) describes it as ‘more energy draining, more intense, longer lasting, more severe and more unrelenting than typical fatigue’.

Because researchers use a range of definitions or different inventories of fatigue - with varying degrees of reliability and validity - there is little consistency between studies; some do not appear to use any measures. This lack of uniform criteria to define fatigue makes it difficult to evaluate the patient experience and the plethora of research in the area (Nail, 2002; Stone, 2002). But nurses seeking to find the most effective and sensitive ways to care for patients with cancer fatigue must neither approach the concern with too simplistic or superficial an understanding, nor feel daunted by its complexity.

Fatigue as a symptom of cancer

It is difficult to take a single view of cancer fatigue and its prevalence because of the differences in how each researcher, and each patient, chooses to interpret its meaning. Fatigue is a common problem that affects not only those with specific conditions, but also the population of the developed world as a whole (Bultmann et al, 2000).

Many people who juggle work, family and relationship commitments feel fatigued and the rise in the awareness or legitimacy of fatigue as a symptom of cancer, seems to share its ascent with a greater appreciation in the media and among general public of the negative effects of chronic fatigue conditions and ‘stress’.

A search for the term ‘cancer fatigue’ in databases such as Cinahl, Medline and Cancerlit brings up a large volume of papers and research. Stone (2002) reported a tenfold increase in the number of articles on cancer fatigue in the past 10 years. It appears that fatigue has gone from being a symptom somewhat ignored by doctors, nurses and researchers to one recognised as being central to the experience of having cancer. However, comparatively few qualitative papers attempt to look at the experience of cancer fatigue from the patient’s perspective and this area requires further research.

Prevalence

The evidence on the prevalence of cancer fatigue presents a contradictory picture. Although the link between cancer and fatigue is undeniable, the precise relationship is unclear. Akechi et al (1999) found that fatigue among ambulatory chemotherapy patients was no more prevalent than among the general population. Bower et al’s (2000) study focused on patients who had had cancer who were disease free at the time of the study and were not receiving treatment; they found that fatigue was no more severe and only slightly more prevalent than in the reference population.

This finding contrasts with that of Andrykowski et al (1998) who found that fatigue persisted for several years following treatment. Irvine et al (1994) compared fatigue levels in patients undergoing chemotherapy and radiotherapy with that in auxiliary staff. Similar levels were recorded at the outset but, after treatment, the patients reported a significant increase in levels of fatigue compared with levels before chemotherapy.

Stone et al (2000) suggest that people with cancer perceive fatigue as a real and pervasive problem. It is also frequently cited by authors as the most common symptom or side-effect experienced by patients with cancer and/or receiving chemotherapy and/or radiotherapy (Barnes and Bruera, 2002; De Jong et al, 2002; Okuyama et al, 2000; Curt, 2000). CancerBACUP (2001) reports that people with cancer find fatigue the symptom or side-effect that is ‘most disruptive to their daily life’.

A framework for fatigue

Piper et al (1987) sought to identify the possible causes of fatigue in specific patient situations using a fatigue framework. This provides a tool for assessing fatigue and selecting appropriate interventions for each individual on the basis of subjective and objective fatigue indicators. This framework recognises that the subjective perception is crucial to understanding how fatigue varies between healthy individuals and those with cancer and its multidimensional nature allows for person-specific relief of fatigue to be recognised (Wu and McSweeney, 2001)

Krishnasamy (2000) argues that, rather than placing these concepts under the umbrella term ‘fatigue’, it might be more helpful to view each as a separate symptom. It might also help to explain the apparent paradoxical findings of a study by Schwartz (2000). The research examined patterns of fatigue and the effect of exercise in women with breast cancer: it found that, although most women commonly rated their energy levels as low while having high levels of fatigue, some participants reported feeling fatigued yet having energy. This challenges the idea that there is a commonality of experience among patients and reinforces the need to identify individual patients’ symptoms more specifically.

Cancer fatigue includes non-specific disease-related fatigue as well as that caused by treatments such as surgery, radiotherapy and chemotherapy (Richardson and Ream, 1996). Many biological and psychosocial causes can contribute to a patient’s experience of cancer fatigue. Andrykowski et al (1998) report that many cancer patients, for reasons not fully understood, may experience fatigue not only from the time of diagnosis and through treatment but also for several years following treatment.

The causes of fatigue

Biological factors - Fatigue precedes, accompanies and follows many diseases, and may be seen as part of any disease process that causes the accumulation of abnormal metabolites, alters energy substrates, impairs the essential oxygenation of tissues or interferes with fluid and electrolyte levels or optimal neurotransmission (Souhami, 2002). Cancer can affect an individual’s fatigue levels in a number of ways. The causes of fatigue include specific tumour location, anaemia and cachexia (general weight loss and wasting), but there are also many unknown causes (Okuyama et al, 2000).

Tumour location - The fatigue status of a patient will be affected by the specific location and grade of tumour, as well as its stage of progression. Although there is no clear evidence, fatigue does appear to be associated with specific cancer types and locations (Richardson and Ream, 1996). For example, it appears to be prevalent in patients with lung cancer or where primary tumours have metastasised to the lungs (Smets et al, 1998; Okuyama et al, 2001). This may be explained by the associated dyspnoea and the complication of pleural effusions secondary to the disease, which further increases the work of breathing and reduces blood oxygenation.

Anaemia - Fatigue associated with anaemia is well recognised. Anaemic patients have been shown to have higher levels of fatigue compared with non- anaemic patients (Cella, 1997).

In cancer, anaemia may be secondary to:

  • Anorexia and malnutrition
  • Bleeding due to tumour vascularity
  • A low platelet count
  • Myelosuppression, a symptom of many of the haematological malignancies.

Cachexia - Although in many cancers the pathological processes that affect nutritional intake and status may explain cachexia, there are many instances where cancer cachexia cannot be fully explained. The high demands on the body caused by the disease biomodulation of metabolism, whereby calories cannot be used in the normal way, result in marked and rapid weight loss of both fat and muscle, with associated general weakness (Haslett et al, 2002).

In addition, tumours produce proteins called cytokines. These (such as interleukin-1) act as mediators between cells and may affect conditions that contribute to anaemia and cachexia (Kurzrock, 2001). There is, therefore, simply less ‘physical’ energy available. The catabolism of muscle inevitably leads to muscle weakness and reduced exercise tolerance (Barnes and Bruera, 2002). Loss of activity may result in muscle atrophy, further exacerbating the problem.

Psychosocial factors - The diagnosis of cancer and the uncertain experience that ensues will provoke intense psychosocial distress, threatening the person’s very existence and all that they value (Ferrell et al, 1996). Mood disturbance arising from the stress of diagnosis has been identified as one of the more potent predictors of fatigue (Berger and Noble, 2001).

Even with the best support and optimal coping strategies, such a stressor can precipitate fatigue. For some, fatigue may mask depression but, although there is a strong correlation between the two, cause and effect in either direction cannot be assumed (Bower et al, 2000). Normal patterns of activity become inextricably part of the fatigue experience. Sleep is disrupted and the resulting weariness reduces activity that predisposes to a vicious cycle of further weariness and sleep disruption.

Treatment-related factors

All treatments, including surgery, radiotherapy, chemotherapy and hormone therapies, place additional stress on the body and thus have the potential to cause fatigue in varying degrees. The physical demands of attending appointments and treatments may also be exhausting for patients. Surgical trauma can cause postoperative fatigue as the body copes with repair (Smith, 1992; Horvath, 2003).

Radiation exposure may cause fatigue but fatigue is especially associated with chemotherapy (Richardson and Ream, 1996). Although different agents have separate methods of action and degrees of toxicity, all share the disadvantage of non-specific cell death. Because the cytotoxic action cannot be targeted at the tumour, treatment can cause cell death throughout the body (Souhami, 2002). Although modern cancer therapies are beginning to overcome this major complication, traditional chemotherapies remain the first-line treatment in many cases.

Damage to healthy cells is most noticeable in areas of rapid cell division such as bone marrow and the gastrointestinal tract (Byrne, 2000). This is the cause of the most common side-effects of chemotherapy: bone marrow suppression (and therefore anaemia), mucositis, and vomiting and diarrhoea. However, the increasing availability of more effective anti-emetic medication should make nausea and vomiting less of a contributing factor to patient fatigue.

It is difficult to report the pattern and prevalence of chemotherapy-induced fatigue, owing to the vast number of drugs and combinations of drugs that are used to treat patients. Fatigue patterns arising as a result of treatments for breast cancer - such as commonly used chemotherapy regimens that include cyclophosphamide, methotrexate and 5-fluorouracil - appear to have been more thoroughly researched than other regimens. Studies report fatigue occurring in peaks and troughs throughout treatment cycles, with intensity levels often at their lowest at the midpoint in the cycle (Berger, 1998; Schwartz, 2000).

As already stated, fatigue may linger long after the chemotherapy has finished and cell counts have recovered. Longitudinal studies report patients experiencing fatigue months later (Longman et al, 1997) although, as time goes by, it appears uncertain whether this can be attributed to chemotherapy, the disease itself or a combination of the two (Richardson and Ream, 1996; Ream et al, 2002).

Whatever the direct effects of treatments on fatigue, the subjective experience will be influenced by the psychosocial factors present in patients’ lives. While the effects of the treatment and the disease itself can only be partially ameliorated or modified, much can be achieved by nursing intervention to help minimise and modify therapeutically the psychosocial factors precipitating fatigue.

Assessment and management of fatigue

The growing volume of research on the topic might lead to the expectation that patients will receive increasingly better treatment and advice. This is not necessarily the case: a study by Stone et al (2000) found that, although 58% of participants experienced fatigue, only 14% received treatment advice about fatigue and only 33% reported that it had been well managed.

Fatigue can be difficult to assess and manage, in large part because of the many ways it can manifest itself. Patients may also feel embarrassed to complain to health-care professionals about such a comparatively trivial symptom. Equally, doctors and nurses may focus on treating the cancer and the more established physical side-effects such as nausea and vomiting, for which there are effective interventions. Practitioners may also feel uncomfortable about addressing those areas of patient concern for which there is no obvious medical ‘fix’ and may convey to the patient that fatigue is something they will simply have to accept.

Not all patients experience significant fatigue as evidenced by Stone et al’s (2000) study findings, where 42% of participants did not experience fatigue. To overemphasise this symptom might in itself be a self-fulfilling prophecy, in that a certain number of people might experience fatigue because they have been warned to expect it.

A nursing assessment of the subjective and objective indicators can be a delicate balancing act. While it would be irresponsible not to inform patients of a potential side-effect of cancer and its therapy, it would be equally irresponsible to emphasise the likelihood of developing fatigue should the side-effects not be managed effectively. Perhaps the best approach would be to warn patients of the possibility that they may experience fatigue, while simultaneously making them aware of how the symptoms can be alleviated. This demands not only having a one-to-one therapeutic relationship with the patient, but also taking a collaborative approach within the multidisciplinary team to address the issue.

Interventions and supportive treatment

The complexity of this side-effect means that patients may require a variety of interventions to alleviate fatigue. Research on the efficacy of the available interventions is in its infancy and there are few long-term follow-up studies (De Jong et al, 2002). Taking the time to deconstruct the patient’s understanding and personal definitions of fatigue and how they are experiencing it may prove beneficial. The use of a comprehensive fatigue scale, such as the Cancer Related Fatigue Scale (Holley, 2000), to help patients describe and rate their symptoms may be a beneficial way of addressing the problem. Identifying contributing and relieving factors can help the patient make sense of their fatigue and help them to cope with it themselves. For example, in addition to fatigue scales the use of fatigue assessment instruments such as a fatigue diary may help identify times of the day when the patient generally feels at his or her best. This could help patients to balance rest and activity, and to plan events such as spending time with their family and friends.

The impact of psychological factors such as depression (Bower et al, 2000) must not be neglected: for example, giving patients time to talk may be sufficient to improve their mood. But expert psychological and pharmacological intervention may also be necessary.

The management of objective physiological indicators of fatigue is another facet of holistic care. For example, a patient’s nutritional well-being should be maximised and may require the advice of a dietitian. The patient might also benefit from controlled aerobic exercise which, when considered against the particular assessment strategies, has been shown to improve fatigue (Dimeo et al, 1996; Porock et al, 2000)

Careful monitoring of blood counts may also help. Nail (2002) identifies that various studies - at different levels of evidence (Level 1-5) - suggest that improving haemoglobin levels reduces fatigue. There are a number of ways to treat anaemia, but research has focused on the use of erythropoietin (Henry and Abels, 1994). This stimulates the formation of red blood cells without the need to resort to blood transfusions, which can have adverse effects. The use of stimulant drugs such as amphetamines or perhaps steroids may be considered, but the efficacy of these is, as yet, unproven in the treatment of cancer fatigue.

Conclusion

Fatigue has been identified as a concept that has received increasing attention in the past decade. It has been shown to have a multifactorial aetiology, making effective treatment challenging and time-consuming. This is reflected in the research, which suggests that it is often poorly managed. This paper suggests that the increased recognition of this debilitating symptom and often inadequate treatment may result in nurses overemphasising fatigue.

To enable patients to benefit from the rapidly expanding body of research, health-care professionals must take shared responsibility for the systematic assessment and treatment of fatigue, to help improve the experience of cancer and the effects of its treatments for patients.

 

 

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