The most common symptom of illness, whether mental or physical, is fatigue. It is often the first indication of the presence of some abnormality and affects the totality of an individual. 1 Fatigue is a major concern in patients with cancer. 2 It is becoming increasingly realized that quality of life in patients with cancer is affected by fatigue, partly as a result of longer cancer survival. 3 In a recent study in the Netherlands, patients with cancer (suffering from various types of cancer) stated that fatigue had a greater effect on their daily life than pain. 4 The National Comprehensive Cancer Network (NCCN) reported that fatigue affects 70% to 100% of patients with cancer. 5
Everyone experiences fatigue on a daily basis. Although fatigue is normally relieved by a good night’s sleep, this is often not the case for patients with cancer, for whom it may become a chronic and unpleasant sensation. 6 Although fatigue can be a symptom of the disease itself, it can also be expected to accompany cancer treatment. 7 Patients with cancer who are receiving chemotherapy may experience a variety of side effects such as pain, nausea, vomiting, hair loss, weight changes, fatigue, and anxiety, with fatigue being one of the most commonly reported side effects.
Since 1992, breast cancer has been the most common type of cancer in the Netherlands. In 1995, breast cancer in women accounted for one third of the total number of cancer cases. 8 In the period from 1986 to 1995, 18% of the patients with breast cancer received adjuvant chemotherapy.
The purpose of this article is to critically review the literature with respect to fatigue in patients with breast cancer who are receiving adjuvant chemotherapy.
This study addressed the following questions:
- To what extent do patients with breast cancer who are receiving adjuvant chemotherapy experience fatigue?
- How does this change in the course of time?
- What are the factors relating to fatigue?
Published articles were found by means of a CD-ROM search of MEDLINE (1989 to July 2001): using the search terms fatigue, breast cancer, and chemotherapy. The snowball method was used for additional literature.
The Concept of Fatigue
Fatigue is a multicausal, multidimensional, and complex concept, 9–11 and it is difficult to define or describe. 10,12–14 Many disciplines are interested in the concept of fatigue, including medicine, psychology, physiology, nursing science, and ergonomics. 10,15 No widely accepted definition of fatigue exists, and the concept has been associated with many other terms, such as tiredness, exhaustion, weariness, malaise, weakness, and asthenia. 10,16 In addition, differences in cultural values, meanings of words and concepts, and translation problems have influenced the meaning of fatigue. 17 The concept is used at different levels: as a symptom, a diagnosis, and a syndrome. 10
Despite complexities and difficulties, Ream and Richardson proposed the following definition of fatigue for nursing purposes based on a concept analysis: “Fatigue is a subjective, unpleasant symptom which incorporates total feelings ranging from tiredness to exhaustion creating an unrelenting overall condition which interferes with individuals’ ability to function to their normal capacity.”18(p527) To supplement this general definition of fatigue, NCCN recently convened a panel of fatigue experts to define cancer-related fatigue. The panel defined cancer-related fatigue as “A n unusual, persistent, subjective sense of tiredness related to cancer or cancer treatment that interferes with usual functioning. ”5(p152) This definition emphasizes the unusual character of cancer fatigue, which differentiates it from the type of fatigue that healthy individuals may experience. Fatigue in patients with cancer is more severe, more distressing, and less likely to be relieved by rest. Compared with the definition proposed by Ream and Richardson, 18 it seems to be the unusual character of fatigue that is specific for patients with cancer. Holley 19 also reported the unusual character of cancer-related fatigue. She reported that cancer-related fatigue had a more rapid onset and was more energy-draining, more intense, longer lasting, more severe, and more unrelenting than typical fatigue. 19 Important characteristics of cancer-related fatigue in the NCCN definition are the subjectivity of the sensation and the interference with usual functioning. These characteristics correspond with the definition proposed by Ream and Richardson. 18
Prevalence and Course of Fatigue in Patients With Breast Cancer Who Are Receiving Chemotherapy
The literature search resulted in the identification of a number of publications reporting on patients with breast cancer who were receiving or had received adjuvant chemotherapy. Table 1 presents an overview of the methodological details of these studies, and Table 2 presents sample characteristics, main results, and limitations of the studies.
Fatigue During or During and After Receiving Chemotherapy
STUDIES WITH TIMING OF MEASUREMENTS ADJUSTED TO THE DIFFERENT CYCLES OF CHEMOTHERAPY
Sitzia and Huggins 20 studied side effects in patients with breast cancer (n = 52) who were receiving 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). Data were collected after each treatment cycle using the reliable and valid Worthing Chemotherapy Questionnaire 75 (WCQ-75). This self-reporting questionnaire features a list of 61 problems. The incidence of fatigue was approximately 90%, and fatigue severity remained stable throughout the treatment cycles. The strengths of this study include the use of a homogeneous group of patients with breast cancer who were receiving only chemotherapy without radiation therapy and the use of a valid and reliable tool.
Berger described patterns of fatigue in 72 patients with breast cancer receiving CMF, doxorubicin and cyclophosphamide (A/C), or cyclophosphamide, doxorubicin, and fluorouracil (CAF). 21 The Piper Fatigue Scale, a reliable and valid multidimensional subjective fatigue measure established for patients with cancer, was used to measure fatigue 48 hours after each treatment and at treatment cycle midpoints during 3 cycles. Berger’s results showed that fatigue levels 48 hours after each of the first 3 chemotherapy cycles were not significantly different over time. The common perception that fatigue increases with time as patients receive further courses of chemotherapy is not supported by this study, which confirms the findings of Sitzia and Huggins. 20 Jacobsen et al found similar results in their study of 54 patients with breast cancer who were receiving adjuvant chemotherapy. 22 Patients had to complete the Memorial Symptom Assessment Scale (MSAS) in the clinic immediately before the start of each of the first 4 chemotherapy cycles. The MSAS assesses symptoms commonly associated with cancer and its treatment in terms of their prevalence, severity, and distress. Fatigue increased after the start of chemotherapy but did not increase further during the first 3 treatment cycles. The prevalence rates of fatigue at the 4 measurement points were 72%, 92%, 94%, and 91%, respectively. Their study also compared patients with breast cancer with women with no cancer history using the Fatigue Scale from the Profile of Mood States (POMS-F) and the Fatigue Symptom Inventory (FSI). The patients completed these questionnaires at home on 3 occasions: before the start of chemotherapy, between the second and third cycles, and between the third and fourth cycles. The noncancer comparison subjects who agreed to participate were mailed the POMS-F and FSI 3 times at 3-to 6-week intervals. Women receiving adjuvant chemotherapy for breast cancer experienced significantly worse fatigue than the age-matched comparison group of women with no cancer history. Jacobsen et al used 3 measuring instruments for fatigue and assessed data at 7 measurement points. The use of a control group in this study strengthens its validity and enhances the comparison of results. The large number of questionnaires administered to patients may, however, have led to inaccurate and incomplete information because respondents may have become tired of answering so many questionnaires, which is known to adversely influence the results.
STUDIES WITH UNCLEAR TIMING OF MEASUREMENTS RELATIVE TO THAT OF ADMINISTRATION OF CHEMOTHERAPY
Longman et al studied side effects in 307 women receiving treatment for breast cancer. 23 They found fatigue to be the most common (83%) as well as the most problematic side effect. The Side Effects Checklist used in this study consisted of 16 common side effects of breast cancer treatment and was developed during a pilot study among 24 women who each cited specific side effects experienced after 2 to 4 weeks of adjuvant therapy and again 6 weeks later. A limitation of this checklist is the lack of reliability and validity data. The prevalence rate of fatigue was assessed without distinguishing between the types of treatment patients underwent, and a combination of treatments could have influenced the experience of fatigue and therefore biased the results. Likewise, the timing of the measurements in this cross-sectional study was doubtful, with measurements performed at a designated point in time after the start of medical treatment to allow for the appearance of treatment-related side effects. It is difficult, sometimes even impossible, to determine such a designated point. Longman et al subsequently extended their study with a longitudinal design in which 53 of the 307 respondents were interviewed during a 4- to 5-month period. Data were collected at 3 points: a designated point in time after the medical treatment had started to allow for the appearance of treatment-related side effects, then 6 to 8 weeks later, and again 3 months later. 24 They found prevalence rates of fatigue at the points of 70%, 77%, and 79%, respectively. Despite its limitations, the longitudinal design of this study reveals more details about the prevalence rate of fatigue. It appears to indicate that more patients experience fatigue with time. Hoskins also studied side effects in a longitudinal design. 25 Data were collected from 93 women diagnosed with breast cancer at 6 points in time: 7–10 days, 1 month, 2 months, 3 months, 6 months, and 1 year after surgery. In this study, fatigue was one of the most prominent side effects. The investigators developed their own checklist, the Treatment Recovery Inventory, whose content validity was only verified by one clinical oncology nurse, making its value doubtful. The prevalence values of fatigue at the 6 data collection points were 8%, 26%, 35%, 22%, 14%, and 1%, respectively. Just as in the study by Longman, 24 a limitation of this study was the lack of clarity on fatigue and the timing of the chemotherapy.
Wyatt and Friedman investigated the patterns of functional and psychosocial adjustment of midlife and older women after surgery for breast cancer. 26 They compared women who received follow-up adjuvant therapy (n = 30) with those who did not (n = 16). The presence and severity of the symptoms were measured at 3 time points after surgery (6 weeks, 3 months, 6 months). Fatigue and pain were the most frequently reported symptoms in both groups. In the group with adjuvant treatment, 70% of the patients experienced fatigue after 6 weeks, 53% after 3 months, and 56% after 6 months. In the surgery-only group the corresponding percentages were 44%, 32%, and 38%, respectively. Women reported relatively low levels of severity of fatigue and this symptom did not improve over time. Differences between the two groups were not analyzed because of small sample sizes. The study by Wyatt and Friedman 26 and the study by Hoskins 25 shared two of their measurement points: 3 months and 6 months after surgery. Nevertheless, their findings were very different, which may have been caused by the different measuring instruments and age ranges of the populations.
STUDIES WITH MEASUREMENTS WITHIN TWO CYCLES OF CHEMOTHERAPY
Berger found that reported fatigue intensities were significantly lower at the midpoint of each cycle than they were 48 hours after each of the first 3 treatments. 21 Berger called this development of intensity the roller-coaster pattern. A recent study by Schwartz among 31 patients with breast cancer had a similar result. 27 Patients who did or did not exercise were asked to record the fatigue they experienced in a diary during 3 cycles of chemotherapy. The most common pattern was a rapid increase in the first 24 to 48 hours after chemotherapy, although several women demonstrated a chaotic pattern of fatigue, with erratic and wide swings.
In the side effects study by Greene et al, 86 patients with breast cancer recorded the incidence and severity of side effects 2 and 5 days after the administration of the first and second cycles of chemotherapy. 28 The authors used a self-care diary to collect patient-reported side effects for 3 chemotherapy regimens for breast cancer (Table 2). Fatigue was the most frequently reported side effect. The percentage of patients experiencing fatigue varied from 58% to 86% (Table 2), and the mean severity scores for those who experienced fatigue indicated mild to moderate severity. The incidences did not differ for the 3 drug regimens. Greene et al did not find a distinct clinical pattern of fatigue, although fatigue was significant for time. A reason for not finding any pattern may have been the choice of the measurement points, which may have been too close together in time to reveal any effect. If the purpose of the study were to describe the pattern of fatigue within 2 cycles of chemotherapy, they would probably have had to cover a longer and/or different period of time. The study also had several other limitations: a relatively small sample size was evaluated and subjects were not randomized into the treatment regimens.
Fatigue After Completion of Chemotherapy
Gaston-Johansson et al studied 127 patients with breast cancer who had undergone mastectomy, had completed chemotherapy, and were scheduled for autologous bone marrow/peripheral blood stem cell transplant. 29 The prevalence rate of fatigue was 91% as measured by the Fatigue Visual Analogue Scale (VAS). Participants reported low to moderate levels of fatigue. A limitation of this study was that no data were collected on the length of time between chemotherapy completion and the assessment of fatigue.
Mast studied fatigue in 109 survivors of breast cancer 1 to 6 years after treatment 30 and found that they experienced low to moderate fatigue. The authors did not report figures on the incidence of fatigue. Fatigue was measured by a single item in the revised version of the Symptom Distress Scale (SDS): a linear analogue self-assessment scale. The reliability and validity of this item as a measure have not been assessed. Other limitations of this study are the wide range of periods after treatment and that the pattern, consistency, and intensity of fatigue over time were not evaluated.
Lindley et al used the semantic version of the SDS in 86 patients with breast cancer who had survived for 2 to 5 years after the initiation of adjuvant cytotoxic and/or hormonal therapy. 31 Sixteen of these patients had undergone radiation therapy. The most commonly reported moderate to severe symptom was fatigue (31.4%), followed by insomnia (23.3%), worsening appearance (14.0%), and altered bowel function (11.6%). Berglund et al studied patients over an even wider range of periods after treatment for breast cancer. 32 They reported prevalence rates in patients with breast cancer who were free of recurrence 2 to 10 years after treatment. Sixty-eight percent of the patients who had received adjuvant chemotherapy perceived fatigue, compared with 76% of the postoperative radiotherapy patients. No significant differences were found between the two groups in the reported frequencies of fatigue. This self-made instrument, a symptom list with 32 items, was not tested for reliability or validity, making the results difficult to interpret.
Okuyama et al studied 134 disease-free patients with breast cancer 786 ± 463 (SD) days after surgery, and found a prevalence rate of fatigue of 56%. 33 Unlike Okuyama et al, Leddy did a comparative study, that found no significant differences in fatigue between women who had been treated for breast cancer within the past 10 years (n = 53) and healthy women (n = 89). 34 Fatigue was assessed using the Fatigue Experience Scale, which has been sufficiently tested for validity and reliability. In this study, the women treated for breast cancer were significantly older than the control group and the two sample sizes were unequal. The influence of these differences on the fatigue data is unclear.
Broeckel et al also compared two groups, 1 of 61 women who had completed an average of 471 days of adjuvant chemotherapy and 1 of 59 women with no history of cancer. 35 Results indicated that the former chemotherapy patients reported more severe fatigue as measured by the POMS-F than the noncancer comparison subjects. In addition, the former chemotherapy patients reported higher levels of current fatigue as measured by the Fatigue Symptom Inventory (FSI) and scored significantly higher on the general, physical, and mental subscales of the Multidimensional Fatigue Symptom Inventory (MFSI). A limitation of the study is that there was no control group of patients with other forms of breast cancer treatment besides adjuvant chemotherapy, which may have influenced the differences in fatigue.
Bower et al compared 1,957 survivors of breast cancer at an average of 3 years after initial breast cancer diagnosis with age-matched women (n = 1,953) from a general population, using the energy/fatigue scale of the RAND Health Survey. 36 The majority of survivors of breast cancer did not experience increased levels of fatigue relative to women in the general population. A strong methodological aspect of this study is the large sample size, although its value is limited by its cross-sectional design. Beisecker et al studied 21 patients with node-negative breast cancer who had undergone adjuvant chemotherapy; they made two assessments, one shortly after the completion of adjuvant chemotherapy and one 6 months later. 37 The prevalence rates of fatigue at these two moments were 95% and 83%, respectively. Although the researchers did not study the course of the severity of fatigue, the study found that fewer patients experienced fatigue at the second assessment moment. The research team had developed the interview protocol themselves, and its reliability and validity had not been demonstrated. The small sample size was justified by the researchers by their desire to limit the sample to node-negative patients with breast cancer.
These studies are difficult to compare because of the differences in the timing and number of measurements, instruments, populations, sample sizes, and treatments. In summary, high prevalence rates were found during as well as after the administration of adjuvant chemotherapy. The intensity of fatigue seems to have been stable throughout the treatment cycles, although the first two days after a chemotherapy treatment seem to be the worst period.
Factors Relating to Fatigue
The actual mechanisms that produce fatigue are unknown. 6,38 The most reasonable approach is to consider multiple factors. 39 Numerous factors have been found to influence fatigue, including demographic factors, disease/health factors, treatment factors, and symptoms. Tables 1 and 2 present specific details of the studies. Table 3 presents an overview of the factors relating to fatigue.
Mast and Jacobsen et al found no significant relationship between fatigue and age. 22,30 Woo et al found that younger women experienced significantly higher fatigue levels than older women. 40 They investigated the differences in fatigue for different treatment methods in 322 survivors of breast cancer, who had received their treatment within the last 18 months. Bower et al also found a negative association between fatigue and age. 36 The results showed that women in the group that was fatigued were slightly younger, had a lower annual income, and were less likely to be married or in a significant relationship than those in the nonfatigued group. This study did not find ethnicity, educational attainment and employment status to be associated with fatigue.
Mast, Jacobsen et al, and Okuyama et al found no relationship between fatigue and stage of disease. 22,30,33 Irrespective of the type of cancer treatment, concurrent illness was found to have a strongly positive relation with fatigue. 30,36 Bower et al specifically reported the correlation with chronic medical problems. 36 The relationship between the two variables is not surprising, because the most common symptom of illness is fatigue. 1 Blesch et al reported a positive relationship between the duration of illness and fatigue in patients with breast cancer. 41 Their results with respect to concurrent illness are corroborated by the findings by Gaston-Johansson et al and Berger and Higginbotham. 29,42 Gaston-Johansson et al undertook a correlational study of 127 women with breast cancer who had undergone mastectomy and had completed chemotherapy, 29 while Berger and Higginbotham undertook a pilot study of 14 women with breast cancer to examine the relationship between health status and fatigue. 42 Both teams found a negative association between fatigue and health status, with patients with a better health status experiencing less fatigue. Jacobsen et al found the same negative association before the start of treatment. 22 On the other hand, they found no relationship after the start of chemotherapy.
None of the biochemical factors, such as hemoglobin or white blood count, significantly influenced fatigue in the study by Blesch et al. 41 They mentioned that the nonsignificant findings might have been caused because biochemical factors were abstracted from the medical record and were often not collected concurrently with the person’s self-assessment of fatigue.
The study by Berger and Farr supports the idea that daytime inactivity is associated with higher cancer-related fatigue. 43 They studied the influence of daytime inactivity and nighttime restlessness in 72 patients with breast cancer during the first 3 chemotherapy cycles. Berger and Higginbotham found similar results in their pilot study 42: there was a positive relation between lower activity rates and fatigue. Both studies found fatigue to be positively related to nighttime restlessness.
Jacobsen et al concluded that fatigue was not influenced by the type of surgery (lumpectomy or mastectomy), 22 nor did they find an association between fatigue and chemotherapy regimens. Patients in this study received doxorubicin, AC, CAF, or doxorubicin, cyclophosphamide, and methotrexate. Data provided by Mast suggest that chemotherapy, with or without radiation therapy, is associated with long-term fatigue. 30 Bower et al found similar results. 36 They reported that women in the fatigued group were more likely to have been treated with a combination of chemotherapy and radiation therapy or with chemotherapy alone than those in the nonfatigued group. The latter group was more likely to have been treated with radiation alone or with surgery alone. This finding is corroborated by the results obtained by Okuyama et al, 33 who found no correlation between fatigue and radiation therapy. On the other hand, fatigue was not correlated with past intravenous chemotherapy in this study. The studies by Mast, Bower et al, and Okuyama et al found no relationship between fatigue and hormonal treatment. 30,33,36
A combination of treatments seems to increase the levels of fatigue, as was found in a study by Woo et al. 40 They concluded that women who received combination therapy (combination of radiation, chemotherapy, and hormone therapy) experienced significantly more fatigue than those who received radiation alone. Woo et al commented that this difference may have been affected by the disease stage and the treatment, because combination therapy is primarily used for women with advanced stages of breast cancer. Andrykowski et al did not find a relationship between fatigue and the type of treatment in the breast cancer group. 44
The influence of time on fatigue has not been thoroughly examined, although different periods of time after treatment or diagnosis have been studied. Andrykowski et al found that time since treatment completion did not appear to explain fatigue, and Mast did not find a relationship between fatigue and time since treatment either. 30 The number of years since the initial diagnosis did not affect fatigue in the study by Bower et al, 36 and fatigue was not influenced by the number of days since operation in the study by Okuyama et al. 33
Berger and Higginbotham found a correlation between greater levels of fatigue and more symptoms of distress. 42 Most other studies have examined single associations between particular symptoms and fatigue. All found a positive relationship between pain and fatigue. 22,29,36,41 Not unexpectedly, they also found a positive association between sleeping problems and fatigue. 22,33,35,36,42,43 Like pain and sleeping problems, depression was found to correlate with fatigue in a number of studies. 29,33,36,44 The relationship between these two variables is not unexpected, because one of the symptoms of depression is fatigue and chronic fatigue might be one of the causal factors of depression. Broeckel et al reported that pain and psychological distress are likely causes of sleep disturbance. 35 This would imply that the variables pain, sleep problems, and depression are interrelated.
Other positive relations between psychological symptoms and fatigue were found in the studies by Broeckel et al, Mast, and Jacobsen et al. 22,30,35 Broeckel et al reported a relationship between fatigue and the variables anxiety, mood disorder, and use of catastrophizing as a coping strategy. 35 This coping strategy is characterized by negative self-statements and negative thoughts and ideas about the future. Mast reported a positive relationship with illness uncertainty, and Jacobsen et al found a similar relationship with emotional upset. 22,30 Jacobsen et al also mentioned positive correlations between fatigue and some physical symptoms such as nausea, mouth sores, muscle weakness, change in taste, chills, and vomiting. 22
Okuyama et al found a positive association between fatigue and dyspnea, 33 which they assumed might have been caused by the delayed effect of cancer treatment or by fear of recurrence, because there is evidence that dyspnea is associated with psychological status in a healthy population.
Andrykowski et al found that fatigue was positively correlated with body mass because women who were heavier experienced greater fatigue. 44 Weight gain caused by chemotherapy-induced hyperphagia is the most popular theory. Other mechanisms that could explain weight gain are a reduction in physical activity, metabolic rate, or thermogenesis. 45
Results on the influence of menopausal symptoms have not been unequivocal. Some researchers found that fatigue was significantly more severe among patients with more menopausal symptoms such as hot flushes and night sweats. 35,36 Broeckel et al suggested that two mechanisms could contribute to increased fatigue in menopausal subjects. 35 The increase in nighttime vasomotor symptoms and the menopausal symptoms could intensify depressive symptoms, including fatigue. On the other hand, Jacobsen et al found no association between fatigue and menopausal status. 22
The relation between two symptoms is difficult to define, because it is often not clear which symptom is the cause and which is the effect. Besides, some symptoms are inextricably linked.
Discussion and Conclusions
Fatigue is one of the most common and problematic side effects of breast cancer treatment. High and fluctuating prevalence rates of fatigue have been found not only during but also after the administration of adjuvant chemotherapy.
In contrast with the common perception that more chemotherapy treatments lead to greater fatigue, studies reported on in the literature found the intensity of fatigue to be stable throughout the treatment cycles. Patients becoming accustomed to fatigue might cause this. In other words, the standard for determining the level of fatigue might be changing, a shift in the internal norm. This process of changing one’s internal standard is called response shift. 46
After the treatment with adjuvant chemotherapy has ended, patients with breast cancer still experience fatigue, but because everyone experiences fatigue on a daily basis, it is unknown whether this fatigue can be regarded as normal fatigue.
There is clearly a fluctuating intensity of fatigue within two cycles of chemotherapy treatment. The first two days after the administration of the chemotherapy treatment seem to be the worst. Practitioners should inform patients with cancer about this potential pattern of fatigue to help them, for example, make appropriate plans for daily activities.
The mechanisms of fatigue development are still poorly understood. The present literature study tried to identify factors relating to fatigue in patients with breast cancer, but found, for instance, that the relationship between fatigue and age does not seem to be unequivocal. Whereas some studies found no evidence of a relation between the two factors, some found a significant negative correlation, with younger women appearing to be more fatigued. Woo et al commented that this negative association might be caused by the more aggressive therapy that may have been given to younger women compared with those aged over 60 years. 40 Another reason they suggested may be that more of the younger women had jobs and had the responsibility of caring for their families and young children, giving them fewer opportunities to save energy.
The relationships between fatigue and poorer health status and between fatigue and concurrent illness are unequivocally positive. These relationships are not unexpected, because the most common symptom of illness is fatigue. 1 By contrast, stage of disease and hormonal treatment did not appear to explain fatigue.
It is obvious that fatigue is associated with various physical and psychological symptoms. More specifically, research has shown that pain, sleeping problems, and depression are positively related to fatigue. It is not unlikely that these variables are interrelated. For instance, Broeckel et al reported that pain and psychological distress are likely causes of sleep disturbance. 35 Contradictory results have been found with respect to the influence of menopausal symptoms. Lower levels of activity seem to show a positive relationship with fatigue, whereas some factors, such as change in weight, biochemical factors, the effect of certain coping strategies, and social support, have not been thoroughly studied, or even studied at all, so there is a clear need for further research.
The outcomes of the studies suggest that several of the symptoms are interrelated in a network of symptoms. This could explain why the results often fail to prove clearly whether it is the physical and/or psychological symptoms that cause fatigue or vice versa.
Studies examining the unusual character of fatigue in patients with cancer have been virtually lacking, although the NCCN definition of cancer-related fatigue suggests that fatigue in patients with cancer is of a specific and unusual nature. Only the study by Schwartz assessed the specific character of fatigue in patients with cancer patients. 27
Comparisons between the various studies are hampered by a number of aspects, the most obvious of which is the use of many different measuring instruments for fatigue and side effects: more than 10 different instruments were used for fatigue and as many for side effects. This raises questions about the validity of these comparisons. The differences in the answering options/categories, the use of unidimensional or multidimensional measures of fatigue and the reliability and validity of the instruments must be considered. Three of the fatigue studies used only unidimensional instruments, which means that the value of their findings is very limited. Some studies used combinations of different instruments and assessed data at different points in time. Patients were sometimes flooded with questionnaires, which might lead to them becoming tired of filling in questionnaires and hence affect the value of their answers. Other factors that may impede comparisons between the studies include the lack of a uniform definition of fatigue, the use of insufficiently valid and reliable instruments to measure fatigue, the lack of uniformity in measurement points, and the variety of research designs used in the studies.
Some studies collected data during chemotherapy, whereas others collected data after the completion of chemotherapy. Few studies have so far addressed the effect of chemotherapy on fatigue during as well as after the administration of chemotherapy. A few studies had cross-sectional designs, whereas others had longitudinal designs. Research with a longitudinal design can address the development of fatigue over time, while studies with a cross-sectional design, which involve the collection of data only at one point in time, cannot.
It should be noted that women might already have experienced fatigue before starting any treatment. Authors often suggest that fatigue did not occur in their population before surgery. A study by Cimprich, however, provides evidence to the contrary. 47 She studied 74 newly diagnosed patients with breast cancer, gathering data 11 days before primary surgery, and found that 77% of the patients in the sample reported fatigue (ranging from mild to moderate levels). Longitudinal research that starts before surgery is needed. Fatigue as a sequela of surgery in patients with cancer has rarely been examined, perhaps because it is difficult to separate the consequences of surgery and anesthesia from those of subsequent treatment. 48 Patients with cancer have often not fully recovered from surgery when adjuvant therapy is started. 7
An additional problem is the small sample size used in some of the studies, which makes it difficult to draw firm conclusions.
Because everyone experiences fatigue on a daily basis, it is difficult to distinguish between cancer-related fatigue and normal fatigue. A possible solution to this problem would be to study patients with cancer as well as healthy subjects. Most studies included in the present literature review did not use control groups. Another difficulty in measuring fatigue is its subjectivity. A person who objectively suffers a high level of fatigue may be less bothered by it than someone suffering less fatigue. Everyone copes with fatigue in a different way, and this variation in coping with fatigue has hardly been studied. Besides, most studies fail to distinguish whether the fatigue experienced affected daily functioning.
That breast cancer is a leading type of cancer among women and that fatigue is recognized as having a great effect on the quality of life means that further research is needed. Ongoing studies are expected to tell us more about fatigue and the related factors and to provide more information about possible treatments of this complex problem.
Further research, involving larger and more homogeneous samples, must be done. The use of healthy control subjects for comparison in a study with a longitudinal design would be advisable, while the typical characteristics of cancer-related fatigue must also be taken into account.
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