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Fatigue in Patients with Cancers of the Breast or Prostate Undergoing Radical Radiotherapy

      Abstract

      To determine the prevalence, severity, and correlates of fatigue among patients with cancers of the prostate or breast receiving high dose radiotherapy with curative intent, a prospective, questionnaire-based study evaluated a convenience sample of 62 patients who were about to start a course of radiotherapy. Patients were assessed immediately prior to treatment, and again within a week of finishing. Fatigue was assessed using the Fatigue Severity Scale (FSS) and the Bidimensional Fatigue Scale (BFS). Quality of life was assessed using the European Organisation for Research and Treatment of Cancer 30-item Quality of Life Questionnaire (EORTC QLQc30). Psychological distress was assessed using the Hospital Anxiety and Depression Scale (HADS). Personality Traits were assessed using the Eysenck Personality Inventory (EPI). Fatigue severity increased significantly on 3 out of the 5 assessment instruments used. Radiotherapy was associated with a decline in global quality of life, role, cognitive and social functioning, and an increase in nausea/vomiting, pain, insomnia, diarrhea, and financial difficulty. At baseline, 39% of the variation in fatigue scores among the patients could be explained by a combination of measures of their global quality of life and physical functioning. A combination of fatigue and anxiety scores at baseline was able to predict 54% of the variation in fatigue scores at the completion of radiotherapy. These data indicate that fatigue is a significant problem for patients receiving radical radiotherapy, although its severity is relatively modest.

      Keywords

      Introduction

      Fatigue may be defined as an unpleasant sensation of tiredness, weakness or lack of energy. It is increasingly being recognized as a troublesome complaint among patients with cancer, in particular among patients receiving anti-cancer therapies. In uncontrolled studies, the prevalence of fatigue among patients receiving radiotherapy has usually been reported to be in excess of 65%.
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      Self-care burden, stress appraisal, and mood among persons receiving radiotherapy.
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      Frequency and correlates of fatigue in lung cancer patients receiving radiation therapy implications for management.
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      A quantitative approach to the distress caused by symptoms in patients treated with radical radiotherapy.
      It has also been reported to be the most distressing side effect of radiotherapy treatment.
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      • Chang A.S
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      Self-care burden, stress appraisal, and mood among persons receiving radiotherapy.
      Some studies have reported a progressive increase in fatigue prevalence or severity as treatment progresses,
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      Emotional reactions to radiation treatment.
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      Frequency and correlates of fatigue in lung cancer patients receiving radiation therapy implications for management.
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      Assessment of malaise in cancer patients treated with radiotherapy.
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      Treatment-related fatigue and serum interleukin-1 levels in patients during external beam irradiation for prostate cancer.
      whereas others have suggested that fatigue severity waxes and wanes throughout treatment
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      Fatigue in patients receiving localized radiation.
      or reaches a peak and then flattens out.
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      Fatigue syndrome due to localized radiation.
      Haylock and Hart
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      Fatigue in patients receiving localized radiation.
      reported that fatigue severity improved over the weekend (when patients were not treated), whereas Greenberg et al.
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      Fatigue syndrome due to localized radiation.
      found no such pattern.
      Despite the growing body of literature in this area a number of simple questions about the prevalence, severity, and correlates of fatigue remain unanswered. Fatigue is a common complaint among the general population
      • David A
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      Tired, weak, or in need of rest fatigue among general practice attenders.
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      A population based study of fatigue and psychological distress.
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      Chronic fatigue syndrome in the community prevalence and associations.
      and this needs to be taken into account when reporting the prevalence of this symptom among cancer patients. If patients receiving radiotherapy are simply asked whether or not they have experienced fatigue in the last week,
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      Patients' descriptions of the experience of receiving radiation therapy.
      it is not entirely surprising that 93% of them respond in the affirmative. The more informative figure would be the excess level of fatigue experienced by these patients relative to patients not receiving treatment, or otherwise healthy adults.
      We have only been able to find three studies that have attempted to compare fatigue levels among patients receiving radiotherapy with fatigue levels in non-cancer groups. Irvine investigated a mixed group of cancer patients receiving radiotherapy (n = 55) or chemotherapy (n = 49) with a control group of healthy volunteers (n = 53). She found no differences between the cancer patients or the controls at baseline but did find that fatigue had increased significantly in the cancer patients by the last week of their treatment. However, the magnitude of the increase in fatigue was only 2.4 units (on a 27-point scale). It is unclear how clinically significant this statistically significant increase should be considered.
      Smets and co-workers have reported the development and subsequent use of the 20-item Multi-dimensional Fatigue Inventory (MFI-20). In the original validation study,
      • Smets E.M
      • Garssen B
      • Bonke B
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      The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue.
      it was reported that a heterogeneous group of cancer patients receiving radiotherapy (n = 111) reported no more “General Fatigue” than soldiers in training, junior doctors, psychology students, or medical students. Subsequent studies by the same group
      • Smets E
      • Visser M
      • Willems-Groot A
      • et al.
      Fatigue and radiotherapy (A) experience in patients undergoing treatment.
      • Smets E
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      • et al.
      Fatigue and radiotherapy (B) experience in patients 9 months following treatment.
      reported that “General Fatigue” did increase significantly after radiotherapy, but only by 0.7 points on a 20-point scale. Mean baseline fatigue scores in the patients were, however, significantly higher (by 1.1 points) than mean fatigue scores in a control group of non-cancer volunteers. These results suggest that either the General Fatigue sub-scale of the MFI-20 is not a very sensitive tool, or else the large number of uncontrolled studies in patients receiving radiotherapy have over-estimated the extent of this problem. Another possible explanation is the development of a “response shift”. That is, the tendency of patients to become used to increasing levels of fatigue (or indeed any other symptom) by re-setting their internal standards. Some evidence for the existence of such a “response shift” among cancer patients receiving radiotherapy has recently been presented.
      • Sprangers M.A.G
      • Dam F.S.A.M.V
      • Broersen J
      • et al.
      Revealing response shift in longitudinal research on fatigue the use of the thentest approach.
      The causes of fatigue in either health or disease are poorly understood. Among the general population, fatigue is strongly associated with psychological distress, particularly depression. A similar association has also been reported among cancer patients.
      • Bruera E
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      Association between asthenia and nutritional status, lean body mass, anemia, psychological status, and tumor mass in patients with advanced breast cancer.
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      Preliminary results of a study assessing asthenia and related psychological and biological phenomena in patients with advanced cancer.
      • Smets E.M
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      • de Haes J.C
      Application of the multidimensional fatigue inventory (MFI-20) in cancer patients receiving radiotherapy.
      • Stone P
      • Hardy J
      • Richards M
      • A'Hern R
      A study to investigate the prevalence, severity and correlates of fatigue among patients with cancer in comparison with a control group of volunteers without cancer.
      Individuals with certain personality types may be more susceptible to the development of chronic fatigue, or more likely to report such symptoms. Research into Chronic Fatigue Syndrome has suggested that the traits of emotionality,
      • Blakely A.A
      • Howard R.C
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      • et al.
      Psychiatric symptoms, personality and ways of coping in chronic fatigue syndrome.
      neuroticism
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      • Howard R.C
      • Sosich R.M
      • et al.
      Psychiatric symptoms, personality and ways of coping in chronic fatigue syndrome.
      • Magnusson A
      • Nias D
      • White P
      Is perfectionism associated with fatigue?.
      and perfectionism
      • Magnusson A
      • Nias D
      • White P
      Is perfectionism associated with fatigue?.
      are particularly associated with increased complaints of fatigue. Smets and co-workers
      • Smets E
      • Visser M
      • Willems-Groot A
      • et al.
      Fatigue and radiotherapy (A) experience in patients undergoing treatment.
      failed to find any correlation between the traits of either neuroticism or optimism and fatigue in patients receiving radiotherapy.
      If prolonged stress is proposed to contribute to the development of fatigue,
      • Aistars J
      Fatigue in the cancer patient a conceptual approach to a clinical problem.
      then one might expect fatigue to increase in positive relation to the severity of other symptoms. Blesch and co-workers
      • Blesch K.S
      • Paice J.A
      • Wickham R
      • et al.
      Correlates of fatigue in people with breast or lung cancer.
      investigated a mixed group of patients receiving chemotherapy or radiotherapy. They found that fatigue was significantly correlated with the severity of pain. Arathuzik
      • Arathuzik D
      Pain experience for metastatic breast cancer patients—unraveling the mystery.
      conducted a study into the pain experienced by patients with advanced breast cancer, and found that 74% of such patients felt that their pain caused them to feel fatigued. Other researchers have demonstrated an association between fatigue and nausea
      • Knobf M.T
      Physical and psychologic distress associated with adjuvant chemotherapy in women with breast cancer.
      or emotional upset
      • Peck A
      • Boland J
      Emotional reactions to radiation treatment.
      • Knobf M.T
      Physical and psychologic distress associated with adjuvant chemotherapy in women with breast cancer.
      • Nerenz D.R
      • Leventhal H
      • Love R.R
      Factors contributing to emotional distress during cancer chemotherapy.
      respectively. Smets and co-workers
      • Smets E
      • Visser M
      • Willems-Groot A
      • et al.
      Fatigue and radiotherapy (A) experience in patients undergoing treatment.
      reported that post-radiotherapy fatigue scores were significantly correlated with physical distress, functional disability, quality of sleep, psychological distress, and depression.
      The purpose of this study was to determine the prevalence, severity, and correlates of fatigue among patients receiving radiotherapy. In order to aid the interpretation of our results, fatigue was measured using an instrument that had been previously administered to a control group of elderly volunteers without cancer. The hypothesis that fatigue is due to the overall “stress” associated with treatment was tested by examining the extent and severity of other cancer-related symptoms. It was also hypothesized that fatigue would be related to the personality trait of neuroticism.

      Methods

      Patients

      The patients in this study comprised a convenience sample of outpatients (from the Royal Marsden Hospital, Surrey, UK) with limited stage (non-metastatic) carcinomas of the breast or prostate. All patients were about to start a course of radical radiotherapy (high-dose treatment with curative intent) as part of the primary therapy of their cancer. Subjects were only approached if the principal researcher judged them to have sufficient English language skills to be able to comprehend the questionnaires. Patients were assessed on two occasions, immediately prior to starting radiotherapy and within one week of finishing treatment. The protocol was approved by the relevant Scientific and Ethics Committees.

      Assessment Instruments

      After informed consent had been obtained, patients were asked to complete a number of questionnaires.

      The Fatigue Severity Scale (FSS)

      This scale has been used to assess fatigue in a number of chronic medical conditions
      • Krupp L.B
      • LaRocca N.G
      • Muir Nash J
      • Steinberg A.D
      The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus.
      • Krupp L.B
      • LaRocca N.G
      • Muir J
      • Steinberg A.D
      A study of fatigue in systemic lupus erythematosus.
      • Packer T.L
      • Martins I
      • Krefting L
      • Brouwer B
      Activity and post-polio fatigue.
      and in patients with advanced cancer.
      • Stone P
      • Hardy J
      • Broadley K
      • et al.
      Fatigue in advanced cancer a prospective, controlled, cross-sectional study.
      Subjects are asked to indicate their degree of agreement (on a 7-point scale) with nine statements pertaining to fatigue (e.g., I am easily fatigued). Thus, scores can range between 9 (indicating minimum fatigue) and 63 (indicating maximum fatigue). In a previous study of cancer related fatigue,
      • Stone P
      • Hardy J
      • Broadley K
      • et al.
      Fatigue in advanced cancer a prospective, controlled, cross-sectional study.
      it was reported that 95% of an elderly control population without cancer scored less than 42 on this scale. Thus “severe fatigue” in the cancer patients in this study was operationally defined as a score of 42 or greater on the FSS.

      Bidimensional Fatigue Scale (BFS)

      This scale
      • Chalder T
      • Berelowitz G
      • Pawlikowska T
      • et al.
      Development of a Fatigue Scale.
      has been used to measure fatigue in large community
      • Pawlikowska T
      • Chalder T
      • Hirsch S
      • et al.
      A population based study of fatigue and psychological distress.
      • Lawrie S
      • Pelosi A
      Chronic fatigue syndrome in the community prevalence and associations.
      and primary care
      • David A
      • Pelosi A
      • McDonald E
      • et al.
      Tired, weak, or in need of rest fatigue among general practice attenders.
      studies. The scale consists of 11 items, 7 of which form a physical fatigue subscale (BFS-P) and 4 of which form a mental fatigue subscale (BFS-M). A combined score for the total scale can also be constructed (BFS-T). Each of the 11 items can be scored on a four-point (0–3) scale, thus the BFS-T can range between 0 (minimum fatigue) and 33 (maximum fatigue).

      The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ core 30)

      This is a well-validated 30-item quality-of-life questionnaire
      • Aaronson N.K
      • Ahmedzai S
      • Bergman B
      • et al.
      The European Organization for Research and Treatment of Cancer QLQ-C30 a quality-of-life instrument for use in international clinical trials in oncology.
      specifically designed for use in cancer patients. It consists of 5 functional scales (physical, role, cognitive, emotional, and social functioning), 3 symptom scales (fatigue, pain and nausea/vomiting), a two-item global quality of life scale, and a number of single items assessing additional symptoms commonly reported by cancer patients (dyspnea, loss of appetite, insomnia, constipation, diarrhea, and financial difficulties). Subjects are asked to rate each item on a four-point scale (e.g., During the past week: “Have you had pain?” Not at all, A little, Quite a bit, Very much). Scores are then transformed onto a 0 - 100 scale; a higher score represents a higher (i.e. “better”) level of functioning, or a higher (i.e. “worse”) level of symptoms.

      The Hospital Anxiety and Depression Scale (HADS)

      This is a 14-item screening tool.
      • Zigmond A.S
      • Snaith R.P
      The hospital anxiety and depression scale.
      It consists of separate scales for anxiety (HADA) and depression (HADD). The scale was developed for use among hospital inpatients and its effectiveness is relatively unaffected by the presence of concurrent physical illness. It has been previously validated in patients with advanced cancer.
      • Hopwood P
      • Howell A
      • Maguire P
      Screening for psychiatric morbidity in patients with advanced breast cancer validation of two self-report questionnaires.
      Scores on each subscale can range between 0 (no symptoms of depression/anxiety) to 21 (numerous and severe symptoms). When the scale is used as a screening tool in medically sick populations a cut-off score of 11 or greater on either subscale is taken to indicate a “probable case” of anxiety or depression.
      • Snaith R
      • Zigmond A
      One of the questions on the depression subscale (Item 8: “I feel as if I am slowed down”) may be construed as referring to fatigue and so to reduce confounding, this item was excluded from the analysis when correlations were sought with the FSS. This approach has previously been reported.
      • Smets E.M
      • Garssen B
      • Cull A
      • de Haes J.C
      Application of the multidimensional fatigue inventory (MFI-20) in cancer patients receiving radiotherapy.
      • Stone P
      • Hardy J
      • Broadley K
      • et al.
      Fatigue in advanced cancer a prospective, controlled, cross-sectional study.

      Eysenck Personality Inventory

      The Eysenck Personality Inventory (EPI)
      • Eysenck H
      • Eysenck S
      contains 57 items and measures two major dimensions of personality, Extroversion (E) and Neuroticism (N).

      Statistical Methods

      Measurement scales could typically only take a defined number of discrete values; non-parametric methods of analysis were therefore employed—for example, correlation was assessed using the Spearman Rank Correlation Coefficient (Rs) and the Mann Whitney test was used for comparing groups. The calculation of Spearman's Rank correlation included a correction for ties.
      • Zar J
      Simple linear correlation.
      Multiple regression analysis was used to identify subsets of factors that were independently predictive of fatigue. Analysis was undertaken using the MINITAB program (Minitab Inc., Pennsylvania USA).

      Results

      A total of 69 patients entered the study, 35 patients with prostate cancer and 34 patients with breast cancer. Follow-up (post-radiotherapy) FSS scores were available on 64/69 (93%) of the patients. The median age of the patients was 63 years (41–79) and more than 90% were white. Patients with prostate cancer received a median total radiation dose of 64 Gy. Treatment was administered in daily fractions (Monday to Friday) for a period of approximately six weeks. Patients with breast cancer received a median total radiation dose of 50 Gy plus an electron boost of 11.1 Gy; 12 of these patients also received radiotherapy to local lymph nodes at a median dose of 50 Gy.
      All of the patients with prostate cancer had been receiving androgen suppression therapy (goserelin) for at least three months prior to starting radiotherapy. A large proportion of the patients with breast cancer (30/34) were also taking hormone therapy (tamoxifen). A total of 14/34 of the breast cancer patients had received adjuvant chemotherapy a median of 30.5 days (0–84 days) prior to starting radiotherapy.

      Changes Occurring after Radiotherapy

      The changes occurring after radiotherapy are summarized in Table 1.
      Table 1Changes Occurring After Radiotherapy
      Pre-radiotherapyPost-radiotherapyNP
      Measures of Subjective Fatigue
      FSS26.5 (9–63)
      Range in parentheses.
      29 (9–59)64ns
      E-Fatigue22 (0–89)33 (0–100)62<0.01
      BFS-Mental8 (0–13)7 (5–15)65ns
      BFS-Physical13 (0–22)14 (7–27)65<0.001
      BFS-Total21 (0–31)22 (12–39)65<0.001
      Measures of Psychological Distress
      HADA5 (0–17)5 (0–20)62ns
      HADD2 (0–12)3 (0–12)65<0.05
      HADD-81 (0–10)1 (0–10)64<0.05
      HADT7 (0–29)8.5 (0–28)62ns
      HADT-86 (0–26)7 (0–26)61ns
      Measures of Functional Abilities and Global Quality of Life
      E-PhysicalF100 (40–100)80 (40–100)63ns
      E-RoleF100 (17–100)67 (0–100)640.001
      E-EmotionalF83 (0–100)75 (0–100)63ns
      E-CognitiveF83 (33–100)83 (0–100)63<0.01
      E-SocialF83 (17–100)83 (0–100)640.001
      E-QoL75 (0–100)67 (0–100)64<0.05
      Measures of the Severity of Other Symptoms
      E-NV0 (0–67)0 (0–83)64<0.05
      E-Pain0 (0–100)17 (0–100)62<0.01
      E-Dyspnea0 (0–100)33 (0–100)64ns
      E-Insomnia33 (0–100)33 (0–100)64<0.05
      E-Anorexia0 (0–100)0 (0–100)63ns
      E-Constipation0 (0–100)0 (0–100)64ns
      E-Diarrhea0 (0–67)0 (0–67)64<0.01
      E-Finance0 (0–100)0 (0–100)63<0.05
      Measures of Personality Traits
      EPI-Extroversion11 (2–18)N/A62N/A
      EPI- Neuroticism7 (1–21)N/A62N/A
      FSS = Fatigue Severity Scale; BFS = Bi-dimensional Fatigue Scale; E-Fatigue = EORTC QLQc30 Fatigue sub-scale; E-PhysicalF = EORTC QLQe30 Physical Functioning sub-scale; HADA = Hospital Anxiety and Depression Anxiety sub-scale; HADT-8 = Hospital Anxiety and Depression Total score (without item 8); EPI = Eysenck Personality Inventory.
      a Range in parentheses.

      Subjective fatigue

      There was a significant (P < 0.01) increase in subjective fatigue on 3 out of the 5 assessment instruments used. However, there was no significant increase in the primary measure of fatigue (the FSS) and the magnitude of the increase in the other scales was relatively modest.
      Using the operational definition of “severe fatigue” previously described (i.e., a score of 42 or greater on the FSS); the prevalence of such fatigue in the patients at baseline was 12/64 (19%), showing a non-significant increase to 18/64 (28%) at the end of radiotherapy (McNemar's test).

      Measures of psychological distress

      Using the established cut-offs on the HADS (i.e., 11 or greater on either sub-scale), 16% (10/62) of patients were probable cases of anxiety and 8% (5/65) were probable cases of depression at baseline. There was a small but significant (P < 0.05) change in depression scores after radiotherapy, but no change in either the anxiety or the total scores on the HADS.

      Measures of quality of life

      There were a number of significant changes in domains assessed by the EORTC questionnaire. Role functioning (P = 0.001), cognitive functioning (P < 0.01), social functioning (P = 0.001) and global quality of life (P < 0.05) all decreased, while nausea/vomiting (P < 0.05), pain (P < 0.01), insomnia (P < 0.05), diarrhea (P < 0.01) and financial difficulties (P < 0.05) all increased.

      Correlates of Fatigue at the Baseline Assessment

      Fatigue severity at baseline was significantly correlated with a number of the study variables (Table 2). As one would expect, the FSS was strongly correlated with the other measures of fatigue (Rs > 0.5, P < 0.001). The next strongest association (Rs > 0.5, P < 0.001) was between the FSS and the scores on the HADS (even after removal of the potentially confounding item 8). Fatigue was inversely associated with global quality of life (Rs = −0.57, P < 0.001), and with emotional (Rs = −0.43, P < 0.001), cognitive (Rs = −0.41, P < 0.01), physical (Rs = −0.28, P < 0.05) and social functioning (Rs = −0.27, P < 0.05). There was also an association between fatigue and nausea/vomiting (Rs = 0.27, P < 0.05), pain (Rs = 0.37, P < 0.01), dyspnea (Rs = 0.35, P < 0.01), insomnia (Rs = 0.36, P < 0.01) and diarrhea (Rs = 0.27, P < 0.05), and with the personality trait of extroversion (Rs = 0.43, P < 0.001).
      Table 2Correlates of Fatigue at the Baseline Assessment
      NRs95% confidence intervalP
      Other Measures of Subjective Fatigue
      E-Fatigue610.730.58 to 0.83<0.001
      BFS-Mental640.550.34 to 0.70<0.001
      BFS-Physical640.710.55 to 0.81<0.001
      BFS-Total640.710.56 to 0.82<0.001
      Measures of Psychological Distress
      HADA610.500.28 to 0.67<0.001
      HADD640.750.61 to 0.84<0.001
      HADD-8630.630.45 to 0.76<0.001
      HADT610.640.45 to 0.77<0.001
      HADT-8600.580.37 to 0.73<0.001
      Measures of Functional Abilities and Global Quality of Life
      E-PhysicalF62−0.28−0.50 to −0.02<0.05
      E-RoleF63−0.25−0.47 to 0.01ns
      E-EmotionalF62−0.43−0.62 to −0.19<0.001
      E-CognitiveF62−0.41−0.60 to −0.17<0.01
      E-SocialF63−0.27−0.49 to −0.01<0.05
      E-QoL63−0.57−0.72 to −0.37<0.001
      Measures of the Severity of Other Symptoms
      E-NV630.270.01 to 0.49<0.05
      E-Pain610.370.12 to 0.57<0.01
      E-Dyspnea630.350.11 to 0.56<0.01
      E-Insomnia630.360.12 to 0.56<0.01
      E-Anorexia620.12−0.14 to 0.36ns
      E-Constipation630.15−0.11 to 0.39ns
      E-Diarrhea630.270.01 to 0.49<0.05
      E-Finance620.25−0.01 to 0.48ns
      Measures of Personality Traits
      EPI-Neuroticism550.04−0.23 to 0.31ns
      EPI-Extroversion550.430.17 to 0.630.001
      FSS = Fatigue Severity Scale; BFS = Bi-dimensional Fatigue Scale; E-Fatigue = EORTC QLQc30 Fatigue sub-scale; E-PhysicalF = EORTC QLQc30 Physical Functioning sub-scale; HADA = Hospital Anxiety and Depression Anxiety sub-scale; HADT-8 = Hospital Anxiety and Depression Total score (without item 8); EPI = Eysenck Personality Inventory.

      Multivariate Analyses

      Two multivariate analyses were undertaken (Table 3, Table 4). In the first analysis, the FSS at baseline was taken as the dependent variable and the other baseline data (with the exception of the other fatigue measures) were entered into the analysis as independent variables. On this analysis, 39% of the variation in fatigue scores could be explained by the combination of the EORTC global quality of life subscale (E-QL) and the EORTC physical functioning subscale (E-PF).
      Table 3Predictors of FSS at Baseline
      PredictorsVariance Explained TotalAdditional Variance Explained by Variable
      Quality of life (E-QL)32%32%
      Physical functioning (E-PF)39%7%
      Baseline variables included in the analysis: 1) All EORTC QLQc30 sub-scales with the exception of E - Fatigue; 2) HADA, HADD-8 and HADT-8; 3) EPI-E, EPI-N.
      Table 4Predictors of FSS After Radiotherapy
      PredictorsVariance Explained TotalAdditional Variance Explained by Variable
      Baseline Fatigue (FSS)45%45%
      Baseline anxiety (HAD-A)54%9%
      Baseline variables included in the analysis: 1) FSS; 2) BFS-M, BFS-P, BFS-T; 3) All EORTC QLQc30 sub-scales; 4) HADA, HADD-8 and HADT-8; 5) EPI-E, EPI-N.
      A second multivariate analysis was then undertaken in order to determine which of the study variables at baseline were independently predictive of fatigue at the completion of therapy. On this analysis, 54% of the variation in final fatigue scores could be predicted by the baseline fatigue score (as measured using the FSS) and the anxiety score (HAD-A).

      Discussion

      This study failed to demonstrate a significant increase in FSS scores (the pre-selected primary end-point) among patients receiving radical radiotherapy. Although three of the other measures of fatigue did show significant increases, the magnitude of the changes was relatively modest. Although these results are in keeping with previously published research in this area, they still require some further explanation. After all, if the increase in median fatigue scores is so small, then why are clinicians often left with the impression that radiotherapy is such a fatiguing treatment? An insight into why this may occur can be found by looking more closely at the changes in fatigue severity experienced by individual patients participating in this study. The Physical fatigue subscale of the BFS only showed a small but significant one-point median increase after radiotherapy and this might lead one to believe that relatively few patients were affected by fatigue. However, despite the median score only increasing by one point, 44/64 (69%) patients reported that their physical fatigue got worse after therapy (Figure 1) and only 13/64 (20%) patients reported that their fatigue improved. Moreover, of those patients whose fatigue worsened, 12/44 (27%) reported an increase of 7 points or greater (scale scores can range between 0 to 21).
      Figure thumbnail gr1
      Fig. 1Change in BFS-P after radiotherapy. Each patient is represented by a separate bar on the chart. The length of the bar represents the magnitude of the change in fatigue scores between the pre- and the post-radiotherapy assessments. Positive changes represent patients whose fatigue scores increased (i.e., they experienced more fatigue).
      The most important predictor of fatigue levels after radiotherapy was the baseline fatigue level prior to starting treatment. On multivariate analysis, this was found to be significantly related to baseline global quality of life and physical functioning. Fatigue has been widely reported to have an adverse effect on quality of life.
      • Stone P
      • Hardy J
      • Broadley K
      • et al.
      Fatigue in advanced cancer a prospective, controlled, cross-sectional study.
      • Visser M.R.M
      • Smets E.M.A
      Fatigue, depression and quality of life in cancer patients how are they related?.
      • Hurny C
      • Bernhard J
      • Joss R
      • et al.
      “Fatigue and malaise” as a quality-of-life indicator in small-cell lung cancer patients. The Swiss Group for Clinical Cancer Research (SAKK).
      • Ferrell B.R
      • Grant M
      • Dean G.E
      • et al.
      “Bone tired” the experience of fatigue and its impact on quality of life.
      Although not surprising, this result does underline the importance that patients themselves attach to this symptom. The association between fatigue and impaired physical functioning could be explained in a number of ways. Patients who feel exhausted probably reduce their physical activity in order to minimize their discomfort. Indeed, reduced activity is one of the ways in which individuals gauge the severity of their fatigue. Another possibility is that reduced activity may itself contribute to the development of fatigue via the mechanism of deconditioning.
      • Winningham M.L
      • Nail L.M
      • Burke M.B
      • et al.
      Fatigue and the cancer experience the state of the knowledge.
      In support of this hypothesis, Mock and colleagues have reported that a brisk 30-minute walk five times per week is effective in reducing radiotherapy-related fatigue in patients with early stage breast cancer.
      • Mock V
      • Dow K.H
      • Meares C.J
      • et al.
      Effects of exercise on fatigue, physical functioning, and emotional distress during radiation therapy for breast cancer.
      Our hypothesis that cancer-related fatigue may be associated with the overall “stress” experienced by cancer patients was supported by the significant association between fatigue severity and psychological distress, nausea/vomiting, pain, dyspnea, insomnia, and diarrhea. The strongest of these associations was between fatigue severity and depression (even after removal of the potentially confounding item 8 of the HADD). This is not a new finding. Previous studies have also reported a strong link between fatigue and depression.
      • Bruera E
      • Brenneis C
      • Michaud M
      • et al.
      Association between asthenia and nutritional status, lean body mass, anemia, psychological status, and tumor mass in patients with advanced breast cancer.
      • Morant R
      • Stiefel F
      • Berchtold W
      • et al.
      Preliminary results of a study assessing asthenia and related psychological and biological phenomena in patients with advanced cancer.
      • Smets E.M
      • Garssen B
      • Cull A
      • de Haes J.C
      Application of the multidimensional fatigue inventory (MFI-20) in cancer patients receiving radiotherapy.
      • Stone P
      • Hardy J
      • Richards M
      • A'Hern R
      A study to investigate the prevalence, severity and correlates of fatigue among patients with cancer in comparison with a control group of volunteers without cancer.
      However, the nature of the association is complex and cannot simply be attributed to cause and effect. One way to explore the nature of the association between fatigue and depression is to determine how each symptom varies over time. Visser and Smets
      • Visser M.R.M
      • Smets E.M.A
      Fatigue, depression and quality of life in cancer patients how are they related?.
      have previously reported that whereas fatigue tends to increase after radiotherapy treatment, depression tends to decrease. In contrast, our study found that small but significant increases in depression scores were associated with small increases in fatigue scores. The nature of the association between these two symptoms is clearly in need of further investigation.
      Our hypothesis that cancer-related fatigue may be associated with a “neurotic” personality was not supported by this study. However, rather surprisingly we did find a significant association between fatigue severity and the personality trait of “extroversion”. Such an association has not been previously reported. It may be that individuals with an “extrovert” personality are more likely to report fatigue symptoms, or that they are more likely to perceive that fatigue is interfering with their activities of daily living. The association is certainly intriguing and is deserving of further investigation.
      There were a number of limitations to this study. The Fatigue Severity Scale has previously shown itself to be a reliable and valid measure of fatigue in patients with cancer.
      • Stone P
      • Hardy J
      • Richards M
      • A'Hern R
      A study to investigate the prevalence, severity and correlates of fatigue among patients with cancer in comparison with a control group of volunteers without cancer.
      • Stone P
      • Hardy J
      • Broadley K
      • et al.
      Fatigue in advanced cancer a prospective, controlled, cross-sectional study.
      However, on this occasion it did not detect any significant changes in fatigue severity among a population in whom increases in this symptom were expected. This may have been because the FSS was less sensitive to change than either the E-Fatigue scale or the BFS. Although the change in FSS score did not reach statistical significance, the trend was at least in the right direction. This suggests that with a slightly larger sample size the modest increases in fatigue that was detected by the E-Fatigue and the BFS would also have been detected by the FSS.
      Another drawback was that many of the patients had already received treatment with hormone therapy, chemotherapy, or surgery prior to entry into the study. It is possible that some of the changes that were detected after radiotherapy were simply due to the delayed effects of these other treatments. In order to minimize this risk, patients were only included in the study if they had completed chemotherapy at least one month before starting radiotherapy. Although it would have been preferable to only study patients in whom radiotherapy was the sole treatment, this would not have been very practical given the current vogue for combined therapies.
      In conclusion, this study has suggested that although radiotherapy is associated with significant increases in fatigue severity (on 3 out of the 5 assessment instruments used), the magnitude of this increase is relatively modest. Nonetheless, fatigue was found to have a significant correlation with quality of life and for some patients the increase in fatigue severity was substantial. Further work is needed in order to identify which patients are most susceptible to developing fatigue and to evaluate strategies to prevent or treat this debilitating symptom.

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