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Clinically relevant fatigue in recurrence-free prostate cancer survivors
original articles
Annals of Oncology
Annals of Oncology 23: 65–72, 2012 doi:10.1093/annonc/mdr034 Published online 24 March 2011
Clinically relevant fatigue in recurrence-free prostate cancer survivors D. J. Storey1,2*, D. B. McLaren2, M. A. Atkinson2, I. Butcher3, S. Liggatt2, R. O’Dea2, J. F. Smyth1 & M. Sharpe1,4 1 Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh; 2Edinburgh Cancer Centre, Western General Hospital, Edinburgh; 3Centre for Population Health Sciences, Edinburgh; 4Psychological Medicine Research, University of Edinburgh, Edinburgh, UK
Background: Little is known about the prevalence and associations of clinically relevant fatigue (CRF) in recurrencefree prostate cancer survivors.
Patients and methods: Four hundred and sixteen recurrence-free prostate cancer survivors who were >1 year post-radiotherapy or radical prostatectomy were surveyed. The prevalence of CRF (defined as Brief Fatigue Inventory >3) was determined and compared with a noncancer control group. Other measures included the Hospital Anxiety and Depression Scale, International Prostate Symptom Score, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Relationships between these factors and CRF were explored in univariate and multivariate analyses. Results: Analyzable data were obtained from 91% (377/416) of patients. The prevalence of CRF was 29% (108/377) versus 16% (10/63) in the controls (P = 0.031). CRF was more common in post-radiotherapy than in postprostatectomy 33% (79/240) versus 22% (29/133), P = 0.024. However, when other factors (current depression, anxiety, urinary symptoms, medical comorbidities, pain and insomnia) were controlled for, previous treatment did not predict CRF. Current depression [Hospital Anxiety and Depression Scale ‡8 was by far the strongest association [odds ratio 9.9, 95% confidence interval 4.2–23.5)]. Conclusions: Almost one-third of recurrence-free prostate cancer survivors report CRF. Depression, anxiety, urinary symptoms, pain and insomnia measured at outcome are more strongly associated than type of cancer treatment previously received. Key words: cancer, fatigue, prostate, radiotherapy, surgery, survivor
introduction Prostate cancer is the commonest male cancer in western countries [1, 2]. In 90% of new cases where the cancer is clinically localized to the prostate gland, the most common treatment in the UK is external beam radiotherapy or radical prostatectomy. It is unclear which of these treatments provide best long-term disease control. Management decisions are therefore based mainly on cancer stage with consideration also given to the patient’s age, medical comorbidities and treatment preferences, which in turn will be influenced by anticipated adverse effects of treatment. Bowel dysfunction has been found to be more frequent after radiotherapy and incontinence and sexual difficulties after radical prostatectomy [3–6]. Fatigue is the most common symptom affecting cancer patients but is often underreported because patients regard it as inevitable and untreatable [7]. It is also a major factor determining of quality-of-life years after curative treatment of *Correspondence to: Dr D. J. Storey, Edinburgh Cancer Research UK Centre, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK. Tel: +44-131-777-3529; Fax: +44-131-777-3520; E mail: [email protected]
Hodgkin’s lymphoma, testicular and breast cancer [8–10]. While fatigue has been found to increase during radiotherapy for patients with prostate cancer [11–16], little is known about the long-term prevalence of fatigue and its associations with initial cancer treatment. In our clinical experience, many prostate cancer survivors complain of fatigue but it is unclear whether this fatigue is specifically associated with their prostate cancer and its treatment or simply age, depression, anxiety and the sleep disrupting effect of prostatic symptoms. Few of the studies that have compared quality of life after different treatments for prostate cancer have evaluated fatigue. Those that have done so reported only mean scores on qualityof-life fatigue subscales, which can be difficult to translate into meaningful information for clinicians and patients. It is important and more clinically useful to know the proportion of patients who report fatigue of a severity that interferes with function (clinically relevant fatigue, CRF). Only three previous studies of long-term fatigue after prostate cancer treatment have used fatigue-specific scales that allow CRF to be estimated: one, which examined 103 patients who had received radiotherapy 2 years previously found the prevalence of ‘severe
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Received 2 July 2010; revised 21 October 2010; revised 17 January 2011; accepted 24 January 2011
original articles
patients and methods This was a cross-sectional survey of recurrence-free prostate cancer survivors. Data were collected by self-report questionnaires and supplemented with clinical data from medical records. The study was approved by the local Research Ethics Committee. Edinburgh Cancer Centre is the sole provider for specialist cancer services to a geographically defined area of approximately 1.5 million people in South East of Scotland, UK. After radical prostatectomy or conformal hypofractionated radiotherapy (55 Gy in 20 fractions), patients are followed up for between 1 and 2 years in the outpatient clinic. Thereafter, they are routinely placed on a 6-monthly nurse-led postal follow-up system where patients complete and return a prostate symptombased questionnaire. This coincides with prostate-specific antigen (PSA) tests taken by their family doctor. If problems are identified, patients are invited to return to the outpatient clinic for further assessment. The sample size was based on the number of patients available for the study. The medical notes of all 905 postal follow-up patients were screened for eligibility. Patients were eligible for the study if they had localized (stage T1–T3, N0, M0) prostate cancer at the time of treatment; were treated >1 year previously; their PSA was controlled and there was no documented evidence of relapse. Since this was a clinical postal follow-up system, it was assumed that patients participating in it were able to understand English and did not have cognitive impairment. Patients were excluded if they were on ‘watch and wait’ or ‘active monitoring’; had received palliative primary androgen deprivation therapy alone or had another concurrent cancer diagnosis. Between August and November 2005, eligible patients from this system were sent a postal questionnaire. Patients were invited to complete and return it using the stamped addressed envelope provided. Those who did not reply within 1 month were mailed again. There were no ‘normal’ UK male Brief Fatigue Inventory (BFI) data to compare our findings to and there was the clinical impression that age, nocturia and consequent sleep disturbance may influence fatigue in prostate cancer patients. To test the specificity of the findings to cancer patients, we compared them with data collected from a sample of similarly aged men with urinary symptoms (63 men with benign prostatic hypertrophy consecutively recruited at Urology Clinics) who had completed the same questionnaire for another study.
66 | Storey et al.
Data collected from medical records included age and postcode (to assess Scottish Index of Multiple deprivation [20], ranging 1–5; most to least deprived), date and type of previous prostate cancer treatment. Other medical conditions may influence fatigue. Patients were asked to report these by ticking a box if they had heart or breathing problems, diabetes, a stroke, problems with their bones or joints that limited mobility and also an open-ended question where they could describe other medical conditions they thought relevant [6], Fatigue was measured using the BFI [21], a nine-item instrument consisting of three fatigue severity items relating to present, usual and worst level of fatigue and six items concerning the interference of fatigue with general activity, mood, walking ability, normal work, relations with other people and enjoyment of life over the last week. These items are each scored on an 11-point scale between 0 (‘no fatigue’/‘does not interfere’) and 10 (‘as bad as you can imagine’/‘completely interferes’). The global BFI score is the arithmetic mean of all nine items (range 0–10). CRF was defined as global BFI score of >3, based on National Comprehensive Cancer Network recommendations and previous publications [22, 23]. Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS), a self-rated 14-item scale relating to the last week [24]. Each item can be answered on a four-point scale (0–3) generating a total between 0 and 21 for both subscales. Recommended cut-off scores for clinically likely cases of anxiety (‡9) or depression (‡8) were applied [25]. Urinary symptoms were assessed using the International Prostate Symptom Score, a seven-item scale. Each item is rated on six points (0–5), giving a score of 0–35. Scores ‡8 represent moderate to severe symptoms [26]. Quality of life was assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire core 30 (EORTC QLQc30 version 3.0) [27]. To reduce questionnaire burden and avoid replication of themes, only the physical, role and social functioning, fatigue and other symptom subscales were used. Each item relates to the past week and is answered on a four-point scale, not at all, a little, quite a bit, very much. Two overall health and quality-of-life items are rated on a seven-point scale (1–7). Scores were transformed to a 0–100 scale [28]; higher scores represent a better level of functioning or a worse level of symptoms.
data analysis The mean score was used to impute European Organisation for Research and Treatment of Cancer (EORTC) items when >50% of the scale was completed [28]. To assess whether data were representative of the eligible sample, participants and nonparticipants were compared using Student’s t-tests and chi-square tests as appropriate. A similar approach was used for comparing the cancer group with controls. Univariate associations of CRF in the cancer group were examined using binary logistic regression for categorical variables and Student’s t-tests as appropriate for continuous variables. Independent associations of CRF were examined using multivariate binary logistic regression. No variable selection was used, and all relevant covariates were forced into the multivariate regression model. HADS depression question 8 ‘I feel as if I am slowed down’ may be construed as referring to fatigue. Hence, associations between CRF and depression were carried out both including and excluding this item [29]. The relationship between the different measures of fatigue (global BFI and EORTC QLQc30 Fatigue) was examined using the Spearman’s rank correlation coefficient. A P value of <0.05 was considered to indicate statistical significance. Data analysis used SAS/STAT software, Version 9.1.
results Of 416 eligible patients, 377 questionnaires were analyzable (91% participation rate), Figure 1. There were no statistically
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fatigue’ to be 18.7% [17]. Another, which examined 861 patients who had undergone radiotherapy, brachytherapy and radical prostatectomy found the prevalence of ‘clinical fatigue’ to be 23.6%, 19.8% and 12.7%, respectively [18]. The third study examined 521 hormone-naive patients who were a median of 23 months post-radical prostatectomy or radiotherapy and found 13.4% and 26.1% had ‘chronic fatigue’, respectively [19]. However, all these studies included patients with relapsed or metastatic disease, which may confound fatigue findings and only one included a control group [19]. We therefore aimed to: (i) determine the prevalence of CRF in recurrence-free survivors who had received treatment of localized prostate cancer >1 year ago; (ii) compare this to a noncancer control group; (iii) examine associations of CRF and (iv) determine whether type of previous anticancer treatment is independently associated with CRF. Our hypotheses, based on the previous literature, were that the prevalence of CRF in recurrence-free survivors would be higher in controls and that CRF would be associated with depression, anxiety, more severe urinary symptoms and having previously received radiotherapy.
Annals of Oncology
original articles
Annals of Oncology
Figure 1. Derivation of sample.
Volume 23 | No. 1 | January 2012
these other factors were controlled for, treatment originally received was no longer associated with CRF and depression had the strongest independent association (OR 9.9, 95% CI 4.2–23.5, Table 3). This association remained even when the confounding fatigue item was excluded from the HADS score (OR 10.3 with minimal change in the ORs of the other variables). Although not our primary measure, the fatigue subscale scores from the EORTC are also presented to allow comparison with other data (Table 2). As expected, the BFI and EORTC fatigue scores were highly correlated (correlation coefficient 0.78, P < 0.001). On the EORTC fatigue score, the prostate cancer group had higher scores than the noncancer controls, though, in contrast to CRF, the difference was not statistically significant. However, in common with the CRF findings, the prostate cancer group who had radiotherapy had a higher fatigue score than those who had received radical prostatectomy [27.5 (95% CI 24.5–30.5) versus 20.8 (95% CI 17.2–24.3), P = 0.006].
discussion To our knowledge, this is the first study of CRF in recurrencefree prostate cancer survivors. The main findings were: (i) >1 year post-treatment, almost one-third of patients had CRF and this was more common than in a noncancer control group. (ii) While patients who underwent radiotherapy were more likely to have CRF than radical prostatectomy patients but this was no longer the case if other factors measured at follow-up (current depression, anxiety, moderate/severe urinary symptoms, medical comorbidities, pain and insomnia) were controlled for. (iii) Current depression was the strongest independent association of CRF (even when the confounding HADS fatigue item was removed). These findings suggest that the presence of CRF after treatment of prostate cancer may be more influenced by current medical and psychological comorbidities than the type of initial treatment received. CRF may be more common in prostate cancer survivors than in controls because of previous cancer treatment or because of currently associated psychological distress. However, the severity of anxiety and depression were similar in both groups. The cancer patients were slightly older but age was not associated with fatigue in this group and both the cancer patients and controls had similar proportions with medical comorbidities so these are unlikely explanations. Urinary symptoms are known to be associated with fatigue [30] but the cancer group had less severe urinary problems than controls. Interestingly, although the prevalence of CRF as measured on the BFI was higher in the prostate cancer survivors, the EORTC fatigue score was not statistically significantly greater. While this could be because the recommended BFI cut-off for CRF [21] is suboptimal, the EORTC does not adequately capture fatigue that interferes with function. It could also simply be a type 2 error reflecting the small size of the control group, so these results must be interpreted with caution. As hypothesized, CRF was more common in postradiotherapy than in post-radical prostatectomy but treatment type was not independently associated with CRF when other current symptom variables were included. Patient characteristics confound management decisions and
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significant demographic or clinical differences between participants and nonparticipants. The mean age was 72 years [standard deviation (SD) 6.1] and the median time since treatment was 56 months (range 13– 233). Two hundred and forty four (65%) had received radiotherapy and 133 (35%) had undergone radical prostatectomy (n = 18 also had post-operative radiotherapy). The radiotherapy group had more medical comorbidities than the radical prostatectomy group. Compared with the cancer group, controls were slightly younger (Tables 1 and 2). The prevalence of CRF in the prostate cancer group was 29% (108/377) compared with 16% (10/63) in the noncancer control group [odds ratio (OR) 2.16, 95% confidence interval (CI) 1.06–4.40, P = 0.031, Table 1]. As there was a statistically significant difference in age between the groups, the analysis was repeated while adjusting for age and the findings were largely unchanged (OR 2.27, 95% CI 1.08–4.76, P = 0.030). CRF was more common in patients who had received radiotherapy than in those who had undergone radical prostatectomy [33% (95% CI 27% to 39%) compared with 22% (95% CI 16% to 30%); P = 0.024]. Time since treatment was shorter for radiotherapy patients [mean 58 months (SD 31) versus 78 months (SD 33), P < 0.001] but there was no association between time since treatment and CRF (OR per month 1.002, 95% CI 0.995–1.008, P = 0.647). CRF was associated with current depression, anxiety, moderate/severe urinary symptoms, pain and insomnia (Table 3). Patients with CRF had significantly poorer global health-related quality of life (mean 53 [SD 20] versus 81 [14]), poorer physical function (61 [23] versus 89 [14]), poorer role function (57 [30] versus 93 [15]) and poorer social function (56 [30] versus 90 [18]) (all P < 0.0001). CRF was not associated with age or social deprivation category. To determine whether treatment received was independently associated with CRF, other potentially clinically relevant variables were entered into a multivariate logistic regression: these variables were current anxiety, depression, pain, urinary symptoms, insomnia, medical comorbidities and age. When
original articles
Annals of Oncology
Table 1. Age, social deprivation category and medical comorbidities at the time of survey for the noncancer control group and RFPC group according to treatment received RFPC group n = 377
Noncancer control group n = 63
82 52 52 30 22
(35) (22) (22) (13) (9)
67 23 19 18 4
(51) (18) (15) (14) (3)
28 14 7 7 5
86 63 35 22 96 3
(37) (27) (15) (10) (41) (1)
28 25 5 7 51 2
(21) (19) (4) (5) (39) (2)
29 (46) 5 (8) 6 (10) 2 (3) 13 (21) 0 (0)
63 (26) 96 (40) 83 (34) Mean (SD) 72.8 (5.6)
52 (39) 53 (40) 28 (21) Mean (SD) 70.6 (6.7)
(46) (23) (12) (12) (8)
25 (40) 23 (36) 15 (24) Mean (SD) 66.2 (6.7)
RFPC group versus control group Odds ratio P valuea (95% CI) 0.80 0.86 1.84 1.15 0.85
(0.46–1.38) (0.45–1.64) (0.80–4.21) (0.50–2.68) (0.31–2.30)
0.67 (0.39–1.17) 1.15 (0.66–1.99) 1.34 (0.72–2.50) Mean difference (95% CI) 5.8 (4.1–7.5)
0.646
0.342
<0.0001
a
Comparison using Student’s t-tests and chi-square tests as appropriate (statistically significant results are in bold). CI, confidence interval; RFPC, recurrence-free prostate cancer; SD, standard deviation; SIMD, Scottish index of multiple deprivation.
consequently, the treatment groups may have differed at baseline. Men who undergo radical prostatectomy have to be fit enough for a general anesthetic whereas those who get radiotherapy tend to be older have more medical comorbidities and therefore could be expected to have higher levels of CRF. Attempts were made to address these factors by including them in a multivariate analysis but prospective studies will be required to reliably determine whether treatment itself influences subsequent CRF. Radiotherapy patients received 3 months of neoadjuvant androgen deprivation therapy. Serum testosterone may have remained low for some men afterwards (possibly contributing to CRF), but the majority should have recovered by 1 year [31] so this is unlikely to have influenced CRF in the radiotherapy group. In common with previous findings, the strongest association with CRF was current depression [32]. This is not surprising given that fatigue is part of the syndrome of depression. However, only 40% of patients with CRF had depression according to our criteria and this dropped to 21% once the confounding HADS item was removed. Hence, CRF and depression are not equivalent. CRF was also associated with pain, but presumably, this was due to nonmalignant causes as these survivors were recurrence free. The combination of fatigue, pain and depression is a common symptom cluster [33] but interview-based proposed International Classification of Diseases-10 criteria for cancer-related fatigue [34] specifically exclude psychiatric diagnoses such as depression, so some of the patients with CRF in this study would not have satisfied those criteria.
68 | Storey et al.
We also found that patients with CRF had much worse physical, role and social functioning and poorer health-related quality of life. The difference in scores between those with and without CRF far exceeded the 20 points described as a ‘large’ clinically significant difference [35] illustrating the major impact of CRF on the life of patients. The heterogeneity of fatigue scales used, various populations studied and the differing criteria used to define fatigue make it difficult to compare these findings with previous studies. Only three have specifically examined fatigue in prostate cancer patients post-treatment using fatigue-specific measures. The first was a cross-sectional survey, which examined 103 men who had received radiotherapy with a median of 2.1 years previously [17]. Using a cut-off of ‡7 on the single item of ‘worst fatigue’ from the BFI, the prevalence of ‘severe fatigue’ was 18.7% (applying the same criteria to our sample similarly found 18.9%). However, several factors may have confounded this finding: the majority of patients had also undergone radical prostatectomy; the patients had mixed cancer stages, disease recurrence and 29% were receiving androgen suppression (which is associated with fatigue [29]). Another cross-sectional survey compared the ‘psychological functioning’ of 861 men who had radiotherapy, radical prostatectomy or brachytherapy [18]. Fatigue was measured using the Multidimensional Fatigue Inventory and the prevalence of ‘clinical fatigue’ was 18.5% overall and 23.6%, 19.8% and 12.7%, respectively, for radiotherapy, brachytherapy and radical prostatectomy groups. This study also found that patients who had received radiotherapy were more likely to have ‘clinical fatigue’ (and
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Deprivation category (SIMD), n (%) 1 149 (40) 2 75 (20) 3 71 (19) 4 48 (13) 5 26 (7) Comorbidities, n (%) Cardiac problems 114 (31) Respiratory problems 88 (24) Diabetes 40 (11) Cerebrovascular accident 29 (8) Musculoskeletal problems 147 (40) Neurological problems 5 (1) Total comorbidities None 115 (31) One 149 (40) Two or more 111 (30) Mean (SD) Age at time of survey (years) 72.0 (6.1)
RFPC cancer group by previous treatment received Radiotherapy Radical prostatectomy n = 244 n = 133
original articles
Annals of Oncology
Table 2. Fatigue, anxiety, depression, urinary symptoms and quality-of-life measures for the noncancer control group and RFPC group according to treatment received
EORTC QLQc30 Global health-related QLa Physical functiona Role functiona Cognitive functiona Social functiona Dyspneab Constipationb Fatigueb
RFPC cancer group by previous treatment received Radiotherapy, Radical prostatectomy n = 244 n = 133
Noncancer control group n = 63
108 (29)
79 (33)
29 (22)
10 (16)
2.16 (1.06–4.40)
0.031
50 (13) 52 (14) 27 (7)
34 (14) 39 (16) 23 (10)
16 (12) 13 (10) 4 (3)
8 (13) 5 (8) 4 (6)
1.06 (0.48–2.35) 1.87 (0.72–4.87) 1.14 (0.39–3.39)
0.891 0.196 0.808
139 (37)
99 (41)
40 (30)
43 (69)
0.27 (0.15–0.49)
<0.0001
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean difference (95% CI)
71 78 79 78 78 22 13 28
77 86 89 81 83 15 12 21
80 89 91 80 86 15 8 21
26.8 27.8 27.9 21.0 26.4 4.2 4.7 3.8
73 81 83 79 80 20 13 25
(20) (21) (26) (19) (27) (28) (23) (23)
(21) (22) (28) (20) (29) (29) (22) (24)
(19) (18) (22) (16) (24) (24) (25) (21)
(15) (15) (18) (16) (22) (19) (16) (15)
RFPC group versus control group Odds ratio P valuec (95% CI)
(212.0 to 21.5) (213.2 to 22.3) (214.7 to 21.1) (25.8 to 3.8) (213.5 to 0.6) (22.9 to 11.3) (21.3 to 10.7) (22.1 to 9.6)
0.012 0.005 0.022 0.687
0.207
a
Higher scores = better function. Higher scores = worse symptoms. c Comparison using Student’s t-tests and chi-square tests as appropriate (statistically significant results in bold). BFI, Brief Fatigue Inventory; CI, confidence interval; EORTC QLQc30, European Organization for Research and Treatment of Cancer Quality of Life core 30; HADS, Hospital Anxiety and Depression Scale; IPSS, International Prostate Symptom Score; QL, quality of life; RFPC, recurrence-free prostate cancer; SD, standard deviation. b
depression) than those who had other treatments. However, they did not include a control group. Although they studied a good-sized sample, only 56% of those eligible participated and this included patients who had relapsed local or metastatic cancer. A third study published recently examined 521 hormone-naive patients who were a median of 23 months postradical prostatectomy or radiotherapy found 13.4% and 26.1% had ‘chronic fatigue’, respectively, compared with 16.8% in the general Norwegian population (measured using the Fatigue Questionnaire and duration ‡6 months). None of these differences were statistically significant however [19]. In common with our findings, this study also found fatigue was associated with pain, post-treatment comorbidity and urinary dysfunction as well as high neuroticism (depression was not assessed) and intestinal dysfunction. However, current disease status was not assessed and given some patients either had PSA ‡20 and other high-risk features pretreatment; it is likely many patients were not recurrence free. One study that solely examined predictors of fatigue was a secondary multivariate analysis of prospectively collected data from 149 patients who underwent radiotherapy/brachytherapy (grouped together), radical prostatectomy or watchful waiting. It found that treatment did not predict fatigue at follow-up [36]. However, there were several shortcomings: fatigue was not measured using a fatigue-specific instrument (SF-36); disease stage was not described and the time post-treatment was not
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clear as the follow-up data were reported as ‘6–12 months after prostate biopsy’, which can predate treatment by several months. Several studies have compared different prostate cancer treatments using quality-of-life measures but few have reported findings on fatigue. Of those that have one examined patients up to 5 years post-treatment and found that radiotherapy patients had lower vitality (measured by the SF-36) than radical prostatectomy patients [5] whereas others found no difference at 2 and 5 years [3, 4]. Another study reported no difference in EORTC fatigue subscale scores between patients who were a median of 10 years post-radiotherapy or watchful waiting [27 patients in each group, both of which had EORTC fatigue scores of approximately 28 which is comparable to our data (range 0–100 where higher scores represent a worse fatigue)]. However, 69% still had cancer, which may have confounded fatigue findings [37]. Studies that compared patient with control data have reported similar fatigue/vitality scores irrespective of type of treatment received [6, 38, 39]. A crosssectional study of 249 patients who were >2 years postradiotherapy reported EORTC fatigue scores similar to those of people >70 years of age in the general German population (mean 29.5 versus 27.8 which is comparable with our data). However, 34% had relapsed disease, which as with other studies may have confounded fatigue findings [40]. Finally, a study of 78 patients found EORTC fatigue scores transiently increased during radiotherapy but had returned to
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Clinically relevant fatigue (BFI global fatigue >3), n (%) HADS, n (%) Anxiety ‡9 Depression ‡8 Depression ‡8 (with fatigue item removed) Moderate/severe urinary symptoms (IPSS >7), n (%)
RFPC group, n = 377
original articles
Annals of Oncology
Table 3. Univariate and multivariate analysis showing associations with CRF Variable
Total, n
CRF n = 108 n %
None/mild fatigue n = 265 n %
Univariate analysis Multivariate analysisa OR P-value OR P-value (95% CI) (Wald chi-square) (95% CI) (Wald chi-square)
133 240
29 79
27 73
104 161
39 61
1 1.8 (1.1–2.9)
Urinary symptoms (IPSS) None/mild Moderate/severe
235 137
41 67
38 62
194 70
74 27
1 4.5 (2.8–7.3)
Comorbidities None One Two or more
114 148 110
14 43 50
13 40 47
100 105 60
38 40 23
1 2.9 (1.5–5.6) 6.0 (3.0–11.7)
HADS anxiety ‡9 No Yes
323 50
73 35
68 32
250 15
94 6
1 8.0 (4.1–15.4)
HADS depression ‡8 No Yes
321 52
65 43
60 40
256 9
97 3
1 18.8 (8.7–40.6)
HADS depression ‡8 (with fatigue item removed) No 346 85 79 Yes 27 23 21
261 4
99 2
1 17.7 (5.9–52.5)
Pain None To some extent
233 139
40 68
37 63
193 71
73 27
1 4.6 (2.9–7.4)
Insomnia None To some extent
192 178
29 79
27 73
163 99
62 37
1 4.5 (2.7–7.3)
373
72 (SD 6.4)
Age (years) Mean Per 10 years
0.024 (5.1)
0.1662 (1.9) 1 1.6 (0.8–3.0)
<0.0001 (38.9)
<0.0092 (6.8) 1 2.2 (1.2–4.1)
<0.0001 (27.4)
0.0584 (5.7) 1 2.4 (1.1–5.3) 2.6 (1.1–6.1)
<0.0001 (38.3)
0.0448 (4.0) 1 2.3 (1.0–5.3)
<0.0001 (56.1)
<0.0001 (26.8) 1 9.9 (4.2– 23.5)
<0.0001 (26.7) See text
<0.0001 (39.7)
See text
0.0051 (7.9) 1 2.4 (1.3–4.4)
<0.0001 (35.5)
0.0028 (9.0) 1 2.6 (1.4–4.7)
0.599 (0.3)
0.6488 (0.2)
72 (SD 6.0) 0.9 (0.6–1.3)
0.9 (0.6–1.5)
Statistically significant results in bold. CRF n = 107 and none/mild n = 264. CRF, clinically relevant fatigue; HADS, Hospital Anxiety and Depression Scale; IPSS, International Prostate Symptom Score; OR, odds ratio; SD, standard deviation. a
pretreatment levels 2 years later. However,this study did not include a control group [16]. Fatigue is also a problem for survivors treated for other cancers [8–10]. We are however, only aware of one study that has specifically addressed fatigue in recurrence-free survivors using the same fatigue measure as our study. This study examined 1933 breast cancer patients who were 4.6 years postsurgery [41] and the prevalence of moderate/severe fatigue (BFI single item ‘worst fatigue’ ‡4) was higher (66% compared with 45% in our sample after applying the same criteria). Our study had several limitations: first, in common with all cross-sectional studies, we can only offer a ‘snap shot’; prospective studies are required to fully understand the
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incidence and trajectory of CRF after differing prostate cancer treatments. Second, the comparison with treatment outcomes is potentially confounded by patient characteristics, as treatments were not randomly allocated. Third, the associations of CRF with treatment were historical whereas the other associations were current; this limits the inferences that can be made regarding CRF development post-treatment (e.g. CRF could have occurred via depression or vice versa). Fourth, the use of standard cut-off score for continuous variables (such as global fatigue and HADS anxiety and depression), while making the results more clinically meaningful, reduces the statistical power for finding associations [42]. Fifth, HADS cut-off scores are not the same as an interview-defined case
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Previous treatment Radical prostatectomy Radiotherapy
Annals of Oncology
definition of depression or anxiety. Sixth, asking patients about their other medical conditions relied heavily on the patient’s interpretation of the questions and recall and understanding of their medical history.
acknowledgements We would like to thank Dr Grahame Howard and our Surgical Urology colleagues at the Western General Hospital, Edinburgh for their support and contribution to the clinical infrastructure that enabled this study to occur. We are also grateful to Professor Gordon Murray for his helpful comments on the analysis.
funding This work was supported by the Melville Trust for the Care and Cure of Cancer, the Prostate Research Campaign UK and the Charon Charity Fund.
disclosure The authors declare no conflict of interest.
references 1. SEER. Cancer Statistics Review http://seer.cancer.gov/csr/1975_2005/ index.html (12 October 2010, date last accessed). 2. Cancer Research UK. UK Cancer Incidence Statistics for Common Cancers http:// info.cancerresearchuk.org/cancerstats/incidence/commoncancers/ (12 October 2010, date last accessed). 3. Potosky AL, Davis WW, Hoffman RM et al. Five-year outcomes after prostatectomy or radiotherapy for prostate cancer: the prostate cancer outcomes study. J Natl Cancer Inst 2004; 96(18): 1358–1367. 4. Potosky AL, Legler J, Albertsen PC et al. Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the Prostate Cancer Outcomes Study. J Natl Cancer Inst 2000; 92(19): 1582–1592. 5. Bacon CG, Giovannucci E, Testa M, Kawachi I. The impact of cancer treatment on quality of life outcomes for patients with localized prostate cancer. J Urol 2001; 166(5): 1804–1810. 6. Lilleby W, Fossa SD, Waehre HR, Olsen DR. Long-term morbidity and quality of life in patients with localized prostate cancer undergoing definitive radiotherapy or radical prostatectomy. Int J Radiat Oncol Biol Phys 1999; 43: 735–743.
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7. Stone P, Richardson A, Ream E et al. Cancer-related fatigue: inevitable, unimportant and untreatable? Results of a multi-centre patient survey. Cancer Fatigue Forum. Ann Oncol 2000; 11: 971–975. 8. Fossa SD, Dahl AA, Loge JH. Fatigue, anxiety, and depression in long-term survivors of testicular cancer. J Clin Oncol 2003; 21: 1249–1254. 9. Bower JE, Ganz PA, Desmond KA et al. Fatigue in breast cancer survivors: occurrence, correlates, and impact on quality of life. J Clin Oncol 2000; 18: 743–753. 10. Hjermstad MJ, Oldervoll L, Fossa SD et al. Quality of life in long-term Hodgkin’s disease survivors with chronic fatigue. Eur J Cancer 2006; 42: 327–333. 11. Monga U, Kerrigan AJ, Thornby J, Monga TN. Prospective study of fatigue in localized prostate cancer patients undergoing radiotherapy. Radiat Oncol Investig 1999; 7: 178–185. 12. Greenberg DB, Gray JL, Mannix CM et al. Treatment-related fatigue and serum interleukin-1 levels in patients during external beam irradiation for prostate cancer. J Pain Symptom Manage 1993; 8: 196–200. 13. Geinitz H, Zimmermann F, Thamm R et al. Fatigue, quality of life and treatmentrelated toxicity during conformal radiation therapy (CRT) of patients with prostate cancer. Int J Radiat Oncol Biol Phys 2003; 57: S441–S442. 14. Windsor PM, Nicol KF, Potter J. A randomized, controlled trial of aerobic exercise for treatment-related fatigue in men receiving radical external beam radiotherapy for localized prostate carcinoma. Cancer 2004; 101: 550–557. 15. Rodrigues G, Bezjak A, Osoba D et al. The relationship of changes in EORTC QLQ-C30 scores to ratings on the Subjective Significance Questionnaire in men with localized prostate cancer. Qual Life Res 2004; 13(7): 1235–1246. 16. Geinitz H, Thamm R, Scholz C et al. Longitudinal analysis of quality of life in patients receiving conformal radiation therapy for prostate cancer. Strahlenther Onkol 2010; 186: 46–52. 17. Vordermark D, Schwab M, Flentje M et al. Chronic fatigue after radiotherapy for carcinoma of the prostate: correlation with anorectal and genitourinary function. Radiother Oncol 2002; 62: 293–297. 18. Hervouet S, Savard J, Simard S et al. Psychological functioning associated with prostate cancer: cross-sectional comparison of patients treated with radiotherapy, brachytherapy, or surgery. J Pain Symptom Manage 2005; 30: 474–484. 19. Kyrdalen AE, Dahl AA, Hernes E et al. Fatigue in hormone-naive prostate cancer patients treated with radical prostatectomy or definitive radiotherapy. Prostate Cancer Prostatic Dis 2010; 13: 144–150. 20. SIMD. Scottish Index of Multiple Deprivation 2004; http://www.scotland.gov.uk/ Publications/2004/06/19421/38085 (12 October 2010, date last accessed). 21. Mendoza TR, Wang XS, Cleeland CS et al. The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer 1999; 85: 1186–1196. 22. NCCN. Clinical Practice Guidelines in Oncology: Cancer Related Fatigue v. 1. 2009; http://www.nccn.org/professionals/physician_gls/PDF/fatigue.pdf. In Edition 2009 (12 October 2010, date last accessed). 23. Shafqat A, Einhorn LH, Hanna N et al. Screening studies for fatigue and laboratory correlates in cancer patients undergoing treatment. Ann Oncol 2005; 16: 1545–1550. 24. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67(6): 361–370. 25. Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J Psychosom Res 2002; 52: 69–77. 26. Fossa SD, Woehre H, Kurth KH et al. Influence of urological morbidity on quality of life in patients with prostate cancer. Eur Urol 1997; 31 (Suppl 3): 3–8. 27. Aaronson NK, 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. J Natl Cancer Inst 1993; 85(5): 365–376. 28. Fayers P, Aaronson N, Bjordal K et al. EORTC QLQ-C30 Scoring Manual. Brussels, Belgium: EORTC 2001. 29. Stone P, Hardy J, Huddart R et al. Fatigue in patients with prostate cancer receiving hormone therapy. Eur J Cancer 2000; 36: 1134–1141.
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clinical implications This is the first study to examine long-term CRF in recurrence-free prostate cancer survivors. We found CRF affected approximately one-third of patients. It was however not independently predicted by the type of cancer treatment previously received but was strongly associated with current depression. There is therefore no strong evidence to suggest that the development of CRF in the longer term should be a major consideration when choosing prostate cancer treatment. However, robust prospective studies are required to investigate this further. It appears factors such as depression, anxiety, pain, insomnia and urinary symptoms post-treatment may be more important. The management of CRF in long-term recurrence-free prostate cancer survivors should therefore be focused on optimizing identification and management of these associated conditions, the treatment of which may improve CRF.
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37. Fransson P, Damber J-E, Widmark A. Health-related quality of life 10 years after external beam radiotherapy or watchful waiting in patients with localized prostate cancer. Scand J Urol Nephrol 2009; 43: 119–126. 38. Brandeis JM, Litwin MS, Burnison CM, Reiter RE. Quality of life outcomes after brachytherapy for early stage prostate cancer. J Urol 2000; 163(3): 851–857. 39. Penson DF, Feng Z, Kuniyuki A et al. General quality of life 2 years following treatment for prostate cancer: what influences outcomes? Results from the prostate cancer outcomes study. J Clin Oncol 2003; 21: 1147–1154. 40. Geinitz H, Zimmermann FB, Thamm R et al. Late rectal symptoms and quality of life after conformal radiation therapy for prostate cancer. Radiother Oncol 2006; 79: 341–347. 41. Kim SH, Son BH, Hwang SY et al. Fatigue and depression in disease-free breast cancer survivors: prevalence, correlates, and association with quality of life. J Pain Symptom Manage 2008; 35: 644–655. 42. Altman DG, Royston P. The cost of dichotomising continuous variables. BMJ 2006; 332(7549): 1080.
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30. Jakobsson L, Loven L, Hallberg IR. Micturition problems in relation to quality of life in men with prostate cancer or benign prostatic hyperplasia: comparison with men from the general population. Cancer Nurs 2004; 27(3): 218–229. 31. Nejat RJ, Rashid HH, Bagiella E et al. A prospective analysis of time to normalization of serum testosterone after withdrawal of androgen deprivation therapy. J Urol 2000; 164: 1891–1894. 32. Storey DJ, Waters RA, Hibberd CJ et al. Clinically relevant fatigue in cancer outpatients: the Edinburgh Cancer Centre symptom study. Ann Oncol 2007; 18(11): 1861–1869. 33. Aktas A, Walsh D, Rybicki L. Symptom clusters: myth or reality? Palliat Med 2010; 24: 373–385. 34. Cella D, Peterman A, Passik S et al. Progress toward guidelines for the management of fatigue. Oncology 1998; 12: 369–377. 35. Osoba D, Rodrigues G, Myles J et al. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 1998; 16(1): 139–144. 36. Maliski SL, Kwan L, Orecklin JR et al. Predictors of fatigue after treatment for prostate cancer. Urology 2005; 65: 101–108.
Annals of Oncology
Annals of Oncology
Annals of Oncology 23: 65–72, 2012 doi:10.1093/annonc/mdr034 Published online 24 March 2011
Clinically relevant fatigue in recurrence-free prostate cancer survivors D. J. Storey1,2*, D. B. McLaren2, M. A. Atkinson2, I. Butcher3, S. Liggatt2, R. O’Dea2, J. F. Smyth1 & M. Sharpe1,4 1 Edinburgh Cancer Research UK Centre, University of Edinburgh, Edinburgh; 2Edinburgh Cancer Centre, Western General Hospital, Edinburgh; 3Centre for Population Health Sciences, Edinburgh; 4Psychological Medicine Research, University of Edinburgh, Edinburgh, UK
Background: Little is known about the prevalence and associations of clinically relevant fatigue (CRF) in recurrencefree prostate cancer survivors.
Patients and methods: Four hundred and sixteen recurrence-free prostate cancer survivors who were >1 year post-radiotherapy or radical prostatectomy were surveyed. The prevalence of CRF (defined as Brief Fatigue Inventory >3) was determined and compared with a noncancer control group. Other measures included the Hospital Anxiety and Depression Scale, International Prostate Symptom Score, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Relationships between these factors and CRF were explored in univariate and multivariate analyses. Results: Analyzable data were obtained from 91% (377/416) of patients. The prevalence of CRF was 29% (108/377) versus 16% (10/63) in the controls (P = 0.031). CRF was more common in post-radiotherapy than in postprostatectomy 33% (79/240) versus 22% (29/133), P = 0.024. However, when other factors (current depression, anxiety, urinary symptoms, medical comorbidities, pain and insomnia) were controlled for, previous treatment did not predict CRF. Current depression [Hospital Anxiety and Depression Scale ‡8 was by far the strongest association [odds ratio 9.9, 95% confidence interval 4.2–23.5)]. Conclusions: Almost one-third of recurrence-free prostate cancer survivors report CRF. Depression, anxiety, urinary symptoms, pain and insomnia measured at outcome are more strongly associated than type of cancer treatment previously received. Key words: cancer, fatigue, prostate, radiotherapy, surgery, survivor
introduction Prostate cancer is the commonest male cancer in western countries [1, 2]. In 90% of new cases where the cancer is clinically localized to the prostate gland, the most common treatment in the UK is external beam radiotherapy or radical prostatectomy. It is unclear which of these treatments provide best long-term disease control. Management decisions are therefore based mainly on cancer stage with consideration also given to the patient’s age, medical comorbidities and treatment preferences, which in turn will be influenced by anticipated adverse effects of treatment. Bowel dysfunction has been found to be more frequent after radiotherapy and incontinence and sexual difficulties after radical prostatectomy [3–6]. Fatigue is the most common symptom affecting cancer patients but is often underreported because patients regard it as inevitable and untreatable [7]. It is also a major factor determining of quality-of-life years after curative treatment of *Correspondence to: Dr D. J. Storey, Edinburgh Cancer Research UK Centre, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK. Tel: +44-131-777-3529; Fax: +44-131-777-3520; E mail: [email protected]
Hodgkin’s lymphoma, testicular and breast cancer [8–10]. While fatigue has been found to increase during radiotherapy for patients with prostate cancer [11–16], little is known about the long-term prevalence of fatigue and its associations with initial cancer treatment. In our clinical experience, many prostate cancer survivors complain of fatigue but it is unclear whether this fatigue is specifically associated with their prostate cancer and its treatment or simply age, depression, anxiety and the sleep disrupting effect of prostatic symptoms. Few of the studies that have compared quality of life after different treatments for prostate cancer have evaluated fatigue. Those that have done so reported only mean scores on qualityof-life fatigue subscales, which can be difficult to translate into meaningful information for clinicians and patients. It is important and more clinically useful to know the proportion of patients who report fatigue of a severity that interferes with function (clinically relevant fatigue, CRF). Only three previous studies of long-term fatigue after prostate cancer treatment have used fatigue-specific scales that allow CRF to be estimated: one, which examined 103 patients who had received radiotherapy 2 years previously found the prevalence of ‘severe
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Received 2 July 2010; revised 21 October 2010; revised 17 January 2011; accepted 24 January 2011
original articles
patients and methods This was a cross-sectional survey of recurrence-free prostate cancer survivors. Data were collected by self-report questionnaires and supplemented with clinical data from medical records. The study was approved by the local Research Ethics Committee. Edinburgh Cancer Centre is the sole provider for specialist cancer services to a geographically defined area of approximately 1.5 million people in South East of Scotland, UK. After radical prostatectomy or conformal hypofractionated radiotherapy (55 Gy in 20 fractions), patients are followed up for between 1 and 2 years in the outpatient clinic. Thereafter, they are routinely placed on a 6-monthly nurse-led postal follow-up system where patients complete and return a prostate symptombased questionnaire. This coincides with prostate-specific antigen (PSA) tests taken by their family doctor. If problems are identified, patients are invited to return to the outpatient clinic for further assessment. The sample size was based on the number of patients available for the study. The medical notes of all 905 postal follow-up patients were screened for eligibility. Patients were eligible for the study if they had localized (stage T1–T3, N0, M0) prostate cancer at the time of treatment; were treated >1 year previously; their PSA was controlled and there was no documented evidence of relapse. Since this was a clinical postal follow-up system, it was assumed that patients participating in it were able to understand English and did not have cognitive impairment. Patients were excluded if they were on ‘watch and wait’ or ‘active monitoring’; had received palliative primary androgen deprivation therapy alone or had another concurrent cancer diagnosis. Between August and November 2005, eligible patients from this system were sent a postal questionnaire. Patients were invited to complete and return it using the stamped addressed envelope provided. Those who did not reply within 1 month were mailed again. There were no ‘normal’ UK male Brief Fatigue Inventory (BFI) data to compare our findings to and there was the clinical impression that age, nocturia and consequent sleep disturbance may influence fatigue in prostate cancer patients. To test the specificity of the findings to cancer patients, we compared them with data collected from a sample of similarly aged men with urinary symptoms (63 men with benign prostatic hypertrophy consecutively recruited at Urology Clinics) who had completed the same questionnaire for another study.
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Data collected from medical records included age and postcode (to assess Scottish Index of Multiple deprivation [20], ranging 1–5; most to least deprived), date and type of previous prostate cancer treatment. Other medical conditions may influence fatigue. Patients were asked to report these by ticking a box if they had heart or breathing problems, diabetes, a stroke, problems with their bones or joints that limited mobility and also an open-ended question where they could describe other medical conditions they thought relevant [6], Fatigue was measured using the BFI [21], a nine-item instrument consisting of three fatigue severity items relating to present, usual and worst level of fatigue and six items concerning the interference of fatigue with general activity, mood, walking ability, normal work, relations with other people and enjoyment of life over the last week. These items are each scored on an 11-point scale between 0 (‘no fatigue’/‘does not interfere’) and 10 (‘as bad as you can imagine’/‘completely interferes’). The global BFI score is the arithmetic mean of all nine items (range 0–10). CRF was defined as global BFI score of >3, based on National Comprehensive Cancer Network recommendations and previous publications [22, 23]. Anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS), a self-rated 14-item scale relating to the last week [24]. Each item can be answered on a four-point scale (0–3) generating a total between 0 and 21 for both subscales. Recommended cut-off scores for clinically likely cases of anxiety (‡9) or depression (‡8) were applied [25]. Urinary symptoms were assessed using the International Prostate Symptom Score, a seven-item scale. Each item is rated on six points (0–5), giving a score of 0–35. Scores ‡8 represent moderate to severe symptoms [26]. Quality of life was assessed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire core 30 (EORTC QLQc30 version 3.0) [27]. To reduce questionnaire burden and avoid replication of themes, only the physical, role and social functioning, fatigue and other symptom subscales were used. Each item relates to the past week and is answered on a four-point scale, not at all, a little, quite a bit, very much. Two overall health and quality-of-life items are rated on a seven-point scale (1–7). Scores were transformed to a 0–100 scale [28]; higher scores represent a better level of functioning or a worse level of symptoms.
data analysis The mean score was used to impute European Organisation for Research and Treatment of Cancer (EORTC) items when >50% of the scale was completed [28]. To assess whether data were representative of the eligible sample, participants and nonparticipants were compared using Student’s t-tests and chi-square tests as appropriate. A similar approach was used for comparing the cancer group with controls. Univariate associations of CRF in the cancer group were examined using binary logistic regression for categorical variables and Student’s t-tests as appropriate for continuous variables. Independent associations of CRF were examined using multivariate binary logistic regression. No variable selection was used, and all relevant covariates were forced into the multivariate regression model. HADS depression question 8 ‘I feel as if I am slowed down’ may be construed as referring to fatigue. Hence, associations between CRF and depression were carried out both including and excluding this item [29]. The relationship between the different measures of fatigue (global BFI and EORTC QLQc30 Fatigue) was examined using the Spearman’s rank correlation coefficient. A P value of <0.05 was considered to indicate statistical significance. Data analysis used SAS/STAT software, Version 9.1.
results Of 416 eligible patients, 377 questionnaires were analyzable (91% participation rate), Figure 1. There were no statistically
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fatigue’ to be 18.7% [17]. Another, which examined 861 patients who had undergone radiotherapy, brachytherapy and radical prostatectomy found the prevalence of ‘clinical fatigue’ to be 23.6%, 19.8% and 12.7%, respectively [18]. The third study examined 521 hormone-naive patients who were a median of 23 months post-radical prostatectomy or radiotherapy and found 13.4% and 26.1% had ‘chronic fatigue’, respectively [19]. However, all these studies included patients with relapsed or metastatic disease, which may confound fatigue findings and only one included a control group [19]. We therefore aimed to: (i) determine the prevalence of CRF in recurrence-free survivors who had received treatment of localized prostate cancer >1 year ago; (ii) compare this to a noncancer control group; (iii) examine associations of CRF and (iv) determine whether type of previous anticancer treatment is independently associated with CRF. Our hypotheses, based on the previous literature, were that the prevalence of CRF in recurrence-free survivors would be higher in controls and that CRF would be associated with depression, anxiety, more severe urinary symptoms and having previously received radiotherapy.
Annals of Oncology
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Annals of Oncology
Figure 1. Derivation of sample.
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these other factors were controlled for, treatment originally received was no longer associated with CRF and depression had the strongest independent association (OR 9.9, 95% CI 4.2–23.5, Table 3). This association remained even when the confounding fatigue item was excluded from the HADS score (OR 10.3 with minimal change in the ORs of the other variables). Although not our primary measure, the fatigue subscale scores from the EORTC are also presented to allow comparison with other data (Table 2). As expected, the BFI and EORTC fatigue scores were highly correlated (correlation coefficient 0.78, P < 0.001). On the EORTC fatigue score, the prostate cancer group had higher scores than the noncancer controls, though, in contrast to CRF, the difference was not statistically significant. However, in common with the CRF findings, the prostate cancer group who had radiotherapy had a higher fatigue score than those who had received radical prostatectomy [27.5 (95% CI 24.5–30.5) versus 20.8 (95% CI 17.2–24.3), P = 0.006].
discussion To our knowledge, this is the first study of CRF in recurrencefree prostate cancer survivors. The main findings were: (i) >1 year post-treatment, almost one-third of patients had CRF and this was more common than in a noncancer control group. (ii) While patients who underwent radiotherapy were more likely to have CRF than radical prostatectomy patients but this was no longer the case if other factors measured at follow-up (current depression, anxiety, moderate/severe urinary symptoms, medical comorbidities, pain and insomnia) were controlled for. (iii) Current depression was the strongest independent association of CRF (even when the confounding HADS fatigue item was removed). These findings suggest that the presence of CRF after treatment of prostate cancer may be more influenced by current medical and psychological comorbidities than the type of initial treatment received. CRF may be more common in prostate cancer survivors than in controls because of previous cancer treatment or because of currently associated psychological distress. However, the severity of anxiety and depression were similar in both groups. The cancer patients were slightly older but age was not associated with fatigue in this group and both the cancer patients and controls had similar proportions with medical comorbidities so these are unlikely explanations. Urinary symptoms are known to be associated with fatigue [30] but the cancer group had less severe urinary problems than controls. Interestingly, although the prevalence of CRF as measured on the BFI was higher in the prostate cancer survivors, the EORTC fatigue score was not statistically significantly greater. While this could be because the recommended BFI cut-off for CRF [21] is suboptimal, the EORTC does not adequately capture fatigue that interferes with function. It could also simply be a type 2 error reflecting the small size of the control group, so these results must be interpreted with caution. As hypothesized, CRF was more common in postradiotherapy than in post-radical prostatectomy but treatment type was not independently associated with CRF when other current symptom variables were included. Patient characteristics confound management decisions and
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significant demographic or clinical differences between participants and nonparticipants. The mean age was 72 years [standard deviation (SD) 6.1] and the median time since treatment was 56 months (range 13– 233). Two hundred and forty four (65%) had received radiotherapy and 133 (35%) had undergone radical prostatectomy (n = 18 also had post-operative radiotherapy). The radiotherapy group had more medical comorbidities than the radical prostatectomy group. Compared with the cancer group, controls were slightly younger (Tables 1 and 2). The prevalence of CRF in the prostate cancer group was 29% (108/377) compared with 16% (10/63) in the noncancer control group [odds ratio (OR) 2.16, 95% confidence interval (CI) 1.06–4.40, P = 0.031, Table 1]. As there was a statistically significant difference in age between the groups, the analysis was repeated while adjusting for age and the findings were largely unchanged (OR 2.27, 95% CI 1.08–4.76, P = 0.030). CRF was more common in patients who had received radiotherapy than in those who had undergone radical prostatectomy [33% (95% CI 27% to 39%) compared with 22% (95% CI 16% to 30%); P = 0.024]. Time since treatment was shorter for radiotherapy patients [mean 58 months (SD 31) versus 78 months (SD 33), P < 0.001] but there was no association between time since treatment and CRF (OR per month 1.002, 95% CI 0.995–1.008, P = 0.647). CRF was associated with current depression, anxiety, moderate/severe urinary symptoms, pain and insomnia (Table 3). Patients with CRF had significantly poorer global health-related quality of life (mean 53 [SD 20] versus 81 [14]), poorer physical function (61 [23] versus 89 [14]), poorer role function (57 [30] versus 93 [15]) and poorer social function (56 [30] versus 90 [18]) (all P < 0.0001). CRF was not associated with age or social deprivation category. To determine whether treatment received was independently associated with CRF, other potentially clinically relevant variables were entered into a multivariate logistic regression: these variables were current anxiety, depression, pain, urinary symptoms, insomnia, medical comorbidities and age. When
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Annals of Oncology
Table 1. Age, social deprivation category and medical comorbidities at the time of survey for the noncancer control group and RFPC group according to treatment received RFPC group n = 377
Noncancer control group n = 63
82 52 52 30 22
(35) (22) (22) (13) (9)
67 23 19 18 4
(51) (18) (15) (14) (3)
28 14 7 7 5
86 63 35 22 96 3
(37) (27) (15) (10) (41) (1)
28 25 5 7 51 2
(21) (19) (4) (5) (39) (2)
29 (46) 5 (8) 6 (10) 2 (3) 13 (21) 0 (0)
63 (26) 96 (40) 83 (34) Mean (SD) 72.8 (5.6)
52 (39) 53 (40) 28 (21) Mean (SD) 70.6 (6.7)
(46) (23) (12) (12) (8)
25 (40) 23 (36) 15 (24) Mean (SD) 66.2 (6.7)
RFPC group versus control group Odds ratio P valuea (95% CI) 0.80 0.86 1.84 1.15 0.85
(0.46–1.38) (0.45–1.64) (0.80–4.21) (0.50–2.68) (0.31–2.30)
0.67 (0.39–1.17) 1.15 (0.66–1.99) 1.34 (0.72–2.50) Mean difference (95% CI) 5.8 (4.1–7.5)
0.646
0.342
<0.0001
a
Comparison using Student’s t-tests and chi-square tests as appropriate (statistically significant results are in bold). CI, confidence interval; RFPC, recurrence-free prostate cancer; SD, standard deviation; SIMD, Scottish index of multiple deprivation.
consequently, the treatment groups may have differed at baseline. Men who undergo radical prostatectomy have to be fit enough for a general anesthetic whereas those who get radiotherapy tend to be older have more medical comorbidities and therefore could be expected to have higher levels of CRF. Attempts were made to address these factors by including them in a multivariate analysis but prospective studies will be required to reliably determine whether treatment itself influences subsequent CRF. Radiotherapy patients received 3 months of neoadjuvant androgen deprivation therapy. Serum testosterone may have remained low for some men afterwards (possibly contributing to CRF), but the majority should have recovered by 1 year [31] so this is unlikely to have influenced CRF in the radiotherapy group. In common with previous findings, the strongest association with CRF was current depression [32]. This is not surprising given that fatigue is part of the syndrome of depression. However, only 40% of patients with CRF had depression according to our criteria and this dropped to 21% once the confounding HADS item was removed. Hence, CRF and depression are not equivalent. CRF was also associated with pain, but presumably, this was due to nonmalignant causes as these survivors were recurrence free. The combination of fatigue, pain and depression is a common symptom cluster [33] but interview-based proposed International Classification of Diseases-10 criteria for cancer-related fatigue [34] specifically exclude psychiatric diagnoses such as depression, so some of the patients with CRF in this study would not have satisfied those criteria.
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We also found that patients with CRF had much worse physical, role and social functioning and poorer health-related quality of life. The difference in scores between those with and without CRF far exceeded the 20 points described as a ‘large’ clinically significant difference [35] illustrating the major impact of CRF on the life of patients. The heterogeneity of fatigue scales used, various populations studied and the differing criteria used to define fatigue make it difficult to compare these findings with previous studies. Only three have specifically examined fatigue in prostate cancer patients post-treatment using fatigue-specific measures. The first was a cross-sectional survey, which examined 103 men who had received radiotherapy with a median of 2.1 years previously [17]. Using a cut-off of ‡7 on the single item of ‘worst fatigue’ from the BFI, the prevalence of ‘severe fatigue’ was 18.7% (applying the same criteria to our sample similarly found 18.9%). However, several factors may have confounded this finding: the majority of patients had also undergone radical prostatectomy; the patients had mixed cancer stages, disease recurrence and 29% were receiving androgen suppression (which is associated with fatigue [29]). Another cross-sectional survey compared the ‘psychological functioning’ of 861 men who had radiotherapy, radical prostatectomy or brachytherapy [18]. Fatigue was measured using the Multidimensional Fatigue Inventory and the prevalence of ‘clinical fatigue’ was 18.5% overall and 23.6%, 19.8% and 12.7%, respectively, for radiotherapy, brachytherapy and radical prostatectomy groups. This study also found that patients who had received radiotherapy were more likely to have ‘clinical fatigue’ (and
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Deprivation category (SIMD), n (%) 1 149 (40) 2 75 (20) 3 71 (19) 4 48 (13) 5 26 (7) Comorbidities, n (%) Cardiac problems 114 (31) Respiratory problems 88 (24) Diabetes 40 (11) Cerebrovascular accident 29 (8) Musculoskeletal problems 147 (40) Neurological problems 5 (1) Total comorbidities None 115 (31) One 149 (40) Two or more 111 (30) Mean (SD) Age at time of survey (years) 72.0 (6.1)
RFPC cancer group by previous treatment received Radiotherapy Radical prostatectomy n = 244 n = 133
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Annals of Oncology
Table 2. Fatigue, anxiety, depression, urinary symptoms and quality-of-life measures for the noncancer control group and RFPC group according to treatment received
EORTC QLQc30 Global health-related QLa Physical functiona Role functiona Cognitive functiona Social functiona Dyspneab Constipationb Fatigueb
RFPC cancer group by previous treatment received Radiotherapy, Radical prostatectomy n = 244 n = 133
Noncancer control group n = 63
108 (29)
79 (33)
29 (22)
10 (16)
2.16 (1.06–4.40)
0.031
50 (13) 52 (14) 27 (7)
34 (14) 39 (16) 23 (10)
16 (12) 13 (10) 4 (3)
8 (13) 5 (8) 4 (6)
1.06 (0.48–2.35) 1.87 (0.72–4.87) 1.14 (0.39–3.39)
0.891 0.196 0.808
139 (37)
99 (41)
40 (30)
43 (69)
0.27 (0.15–0.49)
<0.0001
Mean (SD)
Mean (SD)
Mean (SD)
Mean (SD)
Mean difference (95% CI)
71 78 79 78 78 22 13 28
77 86 89 81 83 15 12 21
80 89 91 80 86 15 8 21
26.8 27.8 27.9 21.0 26.4 4.2 4.7 3.8
73 81 83 79 80 20 13 25
(20) (21) (26) (19) (27) (28) (23) (23)
(21) (22) (28) (20) (29) (29) (22) (24)
(19) (18) (22) (16) (24) (24) (25) (21)
(15) (15) (18) (16) (22) (19) (16) (15)
RFPC group versus control group Odds ratio P valuec (95% CI)
(212.0 to 21.5) (213.2 to 22.3) (214.7 to 21.1) (25.8 to 3.8) (213.5 to 0.6) (22.9 to 11.3) (21.3 to 10.7) (22.1 to 9.6)
0.012 0.005 0.022 0.687
0.207
a
Higher scores = better function. Higher scores = worse symptoms. c Comparison using Student’s t-tests and chi-square tests as appropriate (statistically significant results in bold). BFI, Brief Fatigue Inventory; CI, confidence interval; EORTC QLQc30, European Organization for Research and Treatment of Cancer Quality of Life core 30; HADS, Hospital Anxiety and Depression Scale; IPSS, International Prostate Symptom Score; QL, quality of life; RFPC, recurrence-free prostate cancer; SD, standard deviation. b
depression) than those who had other treatments. However, they did not include a control group. Although they studied a good-sized sample, only 56% of those eligible participated and this included patients who had relapsed local or metastatic cancer. A third study published recently examined 521 hormone-naive patients who were a median of 23 months postradical prostatectomy or radiotherapy found 13.4% and 26.1% had ‘chronic fatigue’, respectively, compared with 16.8% in the general Norwegian population (measured using the Fatigue Questionnaire and duration ‡6 months). None of these differences were statistically significant however [19]. In common with our findings, this study also found fatigue was associated with pain, post-treatment comorbidity and urinary dysfunction as well as high neuroticism (depression was not assessed) and intestinal dysfunction. However, current disease status was not assessed and given some patients either had PSA ‡20 and other high-risk features pretreatment; it is likely many patients were not recurrence free. One study that solely examined predictors of fatigue was a secondary multivariate analysis of prospectively collected data from 149 patients who underwent radiotherapy/brachytherapy (grouped together), radical prostatectomy or watchful waiting. It found that treatment did not predict fatigue at follow-up [36]. However, there were several shortcomings: fatigue was not measured using a fatigue-specific instrument (SF-36); disease stage was not described and the time post-treatment was not
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clear as the follow-up data were reported as ‘6–12 months after prostate biopsy’, which can predate treatment by several months. Several studies have compared different prostate cancer treatments using quality-of-life measures but few have reported findings on fatigue. Of those that have one examined patients up to 5 years post-treatment and found that radiotherapy patients had lower vitality (measured by the SF-36) than radical prostatectomy patients [5] whereas others found no difference at 2 and 5 years [3, 4]. Another study reported no difference in EORTC fatigue subscale scores between patients who were a median of 10 years post-radiotherapy or watchful waiting [27 patients in each group, both of which had EORTC fatigue scores of approximately 28 which is comparable to our data (range 0–100 where higher scores represent a worse fatigue)]. However, 69% still had cancer, which may have confounded fatigue findings [37]. Studies that compared patient with control data have reported similar fatigue/vitality scores irrespective of type of treatment received [6, 38, 39]. A crosssectional study of 249 patients who were >2 years postradiotherapy reported EORTC fatigue scores similar to those of people >70 years of age in the general German population (mean 29.5 versus 27.8 which is comparable with our data). However, 34% had relapsed disease, which as with other studies may have confounded fatigue findings [40]. Finally, a study of 78 patients found EORTC fatigue scores transiently increased during radiotherapy but had returned to
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Clinically relevant fatigue (BFI global fatigue >3), n (%) HADS, n (%) Anxiety ‡9 Depression ‡8 Depression ‡8 (with fatigue item removed) Moderate/severe urinary symptoms (IPSS >7), n (%)
RFPC group, n = 377
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Table 3. Univariate and multivariate analysis showing associations with CRF Variable
Total, n
CRF n = 108 n %
None/mild fatigue n = 265 n %
Univariate analysis Multivariate analysisa OR P-value OR P-value (95% CI) (Wald chi-square) (95% CI) (Wald chi-square)
133 240
29 79
27 73
104 161
39 61
1 1.8 (1.1–2.9)
Urinary symptoms (IPSS) None/mild Moderate/severe
235 137
41 67
38 62
194 70
74 27
1 4.5 (2.8–7.3)
Comorbidities None One Two or more
114 148 110
14 43 50
13 40 47
100 105 60
38 40 23
1 2.9 (1.5–5.6) 6.0 (3.0–11.7)
HADS anxiety ‡9 No Yes
323 50
73 35
68 32
250 15
94 6
1 8.0 (4.1–15.4)
HADS depression ‡8 No Yes
321 52
65 43
60 40
256 9
97 3
1 18.8 (8.7–40.6)
HADS depression ‡8 (with fatigue item removed) No 346 85 79 Yes 27 23 21
261 4
99 2
1 17.7 (5.9–52.5)
Pain None To some extent
233 139
40 68
37 63
193 71
73 27
1 4.6 (2.9–7.4)
Insomnia None To some extent
192 178
29 79
27 73
163 99
62 37
1 4.5 (2.7–7.3)
373
72 (SD 6.4)
Age (years) Mean Per 10 years
0.024 (5.1)
0.1662 (1.9) 1 1.6 (0.8–3.0)
<0.0001 (38.9)
<0.0092 (6.8) 1 2.2 (1.2–4.1)
<0.0001 (27.4)
0.0584 (5.7) 1 2.4 (1.1–5.3) 2.6 (1.1–6.1)
<0.0001 (38.3)
0.0448 (4.0) 1 2.3 (1.0–5.3)
<0.0001 (56.1)
<0.0001 (26.8) 1 9.9 (4.2– 23.5)
<0.0001 (26.7) See text
<0.0001 (39.7)
See text
0.0051 (7.9) 1 2.4 (1.3–4.4)
<0.0001 (35.5)
0.0028 (9.0) 1 2.6 (1.4–4.7)
0.599 (0.3)
0.6488 (0.2)
72 (SD 6.0) 0.9 (0.6–1.3)
0.9 (0.6–1.5)
Statistically significant results in bold. CRF n = 107 and none/mild n = 264. CRF, clinically relevant fatigue; HADS, Hospital Anxiety and Depression Scale; IPSS, International Prostate Symptom Score; OR, odds ratio; SD, standard deviation. a
pretreatment levels 2 years later. However,this study did not include a control group [16]. Fatigue is also a problem for survivors treated for other cancers [8–10]. We are however, only aware of one study that has specifically addressed fatigue in recurrence-free survivors using the same fatigue measure as our study. This study examined 1933 breast cancer patients who were 4.6 years postsurgery [41] and the prevalence of moderate/severe fatigue (BFI single item ‘worst fatigue’ ‡4) was higher (66% compared with 45% in our sample after applying the same criteria). Our study had several limitations: first, in common with all cross-sectional studies, we can only offer a ‘snap shot’; prospective studies are required to fully understand the
70 | Storey et al.
incidence and trajectory of CRF after differing prostate cancer treatments. Second, the comparison with treatment outcomes is potentially confounded by patient characteristics, as treatments were not randomly allocated. Third, the associations of CRF with treatment were historical whereas the other associations were current; this limits the inferences that can be made regarding CRF development post-treatment (e.g. CRF could have occurred via depression or vice versa). Fourth, the use of standard cut-off score for continuous variables (such as global fatigue and HADS anxiety and depression), while making the results more clinically meaningful, reduces the statistical power for finding associations [42]. Fifth, HADS cut-off scores are not the same as an interview-defined case
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Previous treatment Radical prostatectomy Radiotherapy
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definition of depression or anxiety. Sixth, asking patients about their other medical conditions relied heavily on the patient’s interpretation of the questions and recall and understanding of their medical history.
acknowledgements We would like to thank Dr Grahame Howard and our Surgical Urology colleagues at the Western General Hospital, Edinburgh for their support and contribution to the clinical infrastructure that enabled this study to occur. We are also grateful to Professor Gordon Murray for his helpful comments on the analysis.
funding This work was supported by the Melville Trust for the Care and Cure of Cancer, the Prostate Research Campaign UK and the Charon Charity Fund.
disclosure The authors declare no conflict of interest.
references 1. SEER. Cancer Statistics Review http://seer.cancer.gov/csr/1975_2005/ index.html (12 October 2010, date last accessed). 2. Cancer Research UK. UK Cancer Incidence Statistics for Common Cancers http:// info.cancerresearchuk.org/cancerstats/incidence/commoncancers/ (12 October 2010, date last accessed). 3. Potosky AL, Davis WW, Hoffman RM et al. Five-year outcomes after prostatectomy or radiotherapy for prostate cancer: the prostate cancer outcomes study. J Natl Cancer Inst 2004; 96(18): 1358–1367. 4. Potosky AL, Legler J, Albertsen PC et al. Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the Prostate Cancer Outcomes Study. J Natl Cancer Inst 2000; 92(19): 1582–1592. 5. Bacon CG, Giovannucci E, Testa M, Kawachi I. The impact of cancer treatment on quality of life outcomes for patients with localized prostate cancer. J Urol 2001; 166(5): 1804–1810. 6. Lilleby W, Fossa SD, Waehre HR, Olsen DR. Long-term morbidity and quality of life in patients with localized prostate cancer undergoing definitive radiotherapy or radical prostatectomy. Int J Radiat Oncol Biol Phys 1999; 43: 735–743.
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7. Stone P, Richardson A, Ream E et al. Cancer-related fatigue: inevitable, unimportant and untreatable? Results of a multi-centre patient survey. Cancer Fatigue Forum. Ann Oncol 2000; 11: 971–975. 8. Fossa SD, Dahl AA, Loge JH. Fatigue, anxiety, and depression in long-term survivors of testicular cancer. J Clin Oncol 2003; 21: 1249–1254. 9. Bower JE, Ganz PA, Desmond KA et al. Fatigue in breast cancer survivors: occurrence, correlates, and impact on quality of life. J Clin Oncol 2000; 18: 743–753. 10. Hjermstad MJ, Oldervoll L, Fossa SD et al. Quality of life in long-term Hodgkin’s disease survivors with chronic fatigue. Eur J Cancer 2006; 42: 327–333. 11. Monga U, Kerrigan AJ, Thornby J, Monga TN. Prospective study of fatigue in localized prostate cancer patients undergoing radiotherapy. Radiat Oncol Investig 1999; 7: 178–185. 12. Greenberg DB, Gray JL, Mannix CM et al. Treatment-related fatigue and serum interleukin-1 levels in patients during external beam irradiation for prostate cancer. J Pain Symptom Manage 1993; 8: 196–200. 13. Geinitz H, Zimmermann F, Thamm R et al. Fatigue, quality of life and treatmentrelated toxicity during conformal radiation therapy (CRT) of patients with prostate cancer. Int J Radiat Oncol Biol Phys 2003; 57: S441–S442. 14. Windsor PM, Nicol KF, Potter J. A randomized, controlled trial of aerobic exercise for treatment-related fatigue in men receiving radical external beam radiotherapy for localized prostate carcinoma. Cancer 2004; 101: 550–557. 15. Rodrigues G, Bezjak A, Osoba D et al. The relationship of changes in EORTC QLQ-C30 scores to ratings on the Subjective Significance Questionnaire in men with localized prostate cancer. Qual Life Res 2004; 13(7): 1235–1246. 16. Geinitz H, Thamm R, Scholz C et al. Longitudinal analysis of quality of life in patients receiving conformal radiation therapy for prostate cancer. Strahlenther Onkol 2010; 186: 46–52. 17. Vordermark D, Schwab M, Flentje M et al. Chronic fatigue after radiotherapy for carcinoma of the prostate: correlation with anorectal and genitourinary function. Radiother Oncol 2002; 62: 293–297. 18. Hervouet S, Savard J, Simard S et al. Psychological functioning associated with prostate cancer: cross-sectional comparison of patients treated with radiotherapy, brachytherapy, or surgery. J Pain Symptom Manage 2005; 30: 474–484. 19. Kyrdalen AE, Dahl AA, Hernes E et al. Fatigue in hormone-naive prostate cancer patients treated with radical prostatectomy or definitive radiotherapy. Prostate Cancer Prostatic Dis 2010; 13: 144–150. 20. SIMD. Scottish Index of Multiple Deprivation 2004; http://www.scotland.gov.uk/ Publications/2004/06/19421/38085 (12 October 2010, date last accessed). 21. Mendoza TR, Wang XS, Cleeland CS et al. The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer 1999; 85: 1186–1196. 22. NCCN. Clinical Practice Guidelines in Oncology: Cancer Related Fatigue v. 1. 2009; http://www.nccn.org/professionals/physician_gls/PDF/fatigue.pdf. In Edition 2009 (12 October 2010, date last accessed). 23. Shafqat A, Einhorn LH, Hanna N et al. Screening studies for fatigue and laboratory correlates in cancer patients undergoing treatment. Ann Oncol 2005; 16: 1545–1550. 24. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67(6): 361–370. 25. Bjelland I, Dahl AA, Haug TT, Neckelmann D. The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J Psychosom Res 2002; 52: 69–77. 26. Fossa SD, Woehre H, Kurth KH et al. Influence of urological morbidity on quality of life in patients with prostate cancer. Eur Urol 1997; 31 (Suppl 3): 3–8. 27. Aaronson NK, 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. J Natl Cancer Inst 1993; 85(5): 365–376. 28. Fayers P, Aaronson N, Bjordal K et al. EORTC QLQ-C30 Scoring Manual. Brussels, Belgium: EORTC 2001. 29. Stone P, Hardy J, Huddart R et al. Fatigue in patients with prostate cancer receiving hormone therapy. Eur J Cancer 2000; 36: 1134–1141.
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clinical implications This is the first study to examine long-term CRF in recurrence-free prostate cancer survivors. We found CRF affected approximately one-third of patients. It was however not independently predicted by the type of cancer treatment previously received but was strongly associated with current depression. There is therefore no strong evidence to suggest that the development of CRF in the longer term should be a major consideration when choosing prostate cancer treatment. However, robust prospective studies are required to investigate this further. It appears factors such as depression, anxiety, pain, insomnia and urinary symptoms post-treatment may be more important. The management of CRF in long-term recurrence-free prostate cancer survivors should therefore be focused on optimizing identification and management of these associated conditions, the treatment of which may improve CRF.
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37. Fransson P, Damber J-E, Widmark A. Health-related quality of life 10 years after external beam radiotherapy or watchful waiting in patients with localized prostate cancer. Scand J Urol Nephrol 2009; 43: 119–126. 38. Brandeis JM, Litwin MS, Burnison CM, Reiter RE. Quality of life outcomes after brachytherapy for early stage prostate cancer. J Urol 2000; 163(3): 851–857. 39. Penson DF, Feng Z, Kuniyuki A et al. General quality of life 2 years following treatment for prostate cancer: what influences outcomes? Results from the prostate cancer outcomes study. J Clin Oncol 2003; 21: 1147–1154. 40. Geinitz H, Zimmermann FB, Thamm R et al. Late rectal symptoms and quality of life after conformal radiation therapy for prostate cancer. Radiother Oncol 2006; 79: 341–347. 41. Kim SH, Son BH, Hwang SY et al. Fatigue and depression in disease-free breast cancer survivors: prevalence, correlates, and association with quality of life. J Pain Symptom Manage 2008; 35: 644–655. 42. Altman DG, Royston P. The cost of dichotomising continuous variables. BMJ 2006; 332(7549): 1080.
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30. Jakobsson L, Loven L, Hallberg IR. Micturition problems in relation to quality of life in men with prostate cancer or benign prostatic hyperplasia: comparison with men from the general population. Cancer Nurs 2004; 27(3): 218–229. 31. Nejat RJ, Rashid HH, Bagiella E et al. A prospective analysis of time to normalization of serum testosterone after withdrawal of androgen deprivation therapy. J Urol 2000; 164: 1891–1894. 32. Storey DJ, Waters RA, Hibberd CJ et al. Clinically relevant fatigue in cancer outpatients: the Edinburgh Cancer Centre symptom study. Ann Oncol 2007; 18(11): 1861–1869. 33. Aktas A, Walsh D, Rybicki L. Symptom clusters: myth or reality? Palliat Med 2010; 24: 373–385. 34. Cella D, Peterman A, Passik S et al. Progress toward guidelines for the management of fatigue. Oncology 1998; 12: 369–377. 35. Osoba D, Rodrigues G, Myles J et al. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 1998; 16(1): 139–144. 36. Maliski SL, Kwan L, Orecklin JR et al. Predictors of fatigue after treatment for prostate cancer. Urology 2005; 65: 101–108.
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