|Year : 2010 | Volume
| Issue : 4 | Page : 516-520
Fatigue in prostate cancer patients treated with external beam radiotherapy: A prospective 5-year long-term patient-reported evaluation
Department of Nursing, UmeŚ University, SE-901 87 UmeŚ, Sweden
|Date of Web Publication||24-Feb-2011|
Senior Lecturer, Department of Nursing, UMEŇ University, SE-901 87 UmeŚ
Source of Support: Swedish Cancer Society, Conflict of Interest: None
Background: Limited information is available regarding the long-term effect of external beam radiotherapy (EBRT) on fatigue in individuals with prostate cancer (PC).
Materials and Methods: Men with PC treated with EBRT from January 1992 to June 2003 were enrolled in a prospective study. The QLQ-C30 questionnaire was used to evaluate pre-treatment fatigue and up to 5 years post-treatment.
Results: 407 men with 5-year assessments were analyzed. Fatigue increased between pre-treatment (mean: 15.5; CI: 13.6-17.4) and 5-years post-treatment (mean: 22.8; CI: 20.5-25.1; P<0.001). Pre-treatment fatigue was absent in 206/407 (59%) patients and 5-year post-treatment was reported by 264/407 (66%). Sixteen of 407 patients (4%) reported severe fatigue after 5 years. Physical-, emotional-, cognitive function, and dyspnea were the factors that correlated most to higher level of fatigue 5-year post-treatment.
Conclusions: Fatigue is a common symptom among patients with PC. A large percentage of patients reported pre-treatment fatigue. Fatigue increased over time, with the highest level seen at the end of EBRT. Severe fatigue was reported by 4% 5-year post-treatment. More work is needed in order to identify which patients are most susceptible to developing fatigue especially during radiotherapy.
Keywords: Fatigue, prostate cancer, radiotherapy, patient-reported, quality of life
|How to cite this article:|
Fransson P. Fatigue in prostate cancer patients treated with external beam radiotherapy: A prospective 5-year long-term patient-reported evaluation. J Can Res Ther 2010;6:516-20
|How to cite this URL:|
Fransson P. Fatigue in prostate cancer patients treated with external beam radiotherapy: A prospective 5-year long-term patient-reported evaluation. J Can Res Ther [serial online] 2010 [cited 2016 May 26];6:516-20. Available from: http://www.cancerjournal.net/text.asp?2010/6/4/516/77076
| > Introduction|| |
The decision over the optimal treatment for the individual prostate cancer (PC) patient is a challenging one. PC patients have several treatment options (radical prostectomy, external beam radiotherapy, brachytherapy, and active surveillance are the most common) but there are still no clear guidelines to help them make a treatment decision.
Given this lack of guidelines, the patients need information pertaining to the side effects and quality of life (QoL) limitations that may be caused by the treatments. 
Treatment of PC is often associated with different levels and types of side effects, for example fatigue. Fatigue in cancer may be caused by the disease itself, or it may be caused by various treatments such as external beam radiotherapy (EBRT).  Fatigue is the most frequently reported long-term side effect in patients treated with radiotherapy,  even for localized carcinoma of the prostate;  and it also influences post-therapy QoL. 
The QLQ-C30 questionnaire is a core QoL instrument developed by the European Organisation for Research and Treatment of Cancer (EORTC) for use in clinical trials.  It is one of the most commonly used health-related QoL instruments.  Fatigue is included as a subscale with three items.
When the questionnaire was developed, few instruments evaluating fatigue were available. Due to the increasing interest in fatigue as an important symptom and side effect of cancer treatment, many other tools for assessment of fatigue are now available. In a recent study the QLQ-C30 fatigue scale did not detect differences over time, whereas two other fatigue-specific instruments did. 
Despite many studies evaluating treatment-related fatigue, there is still a lack of information regarding large prospective long-term evaluation of fatigue among PC patients undergoing EBRT.
Since 1992, we have been conducting an ongoing prospective long-term QoL follow-up of patients with PC undergoing EBRT with a validated self-assessment questionnaire, Prostate Cancer Symptom Scale (PCSS), and the EORTC QLQ-C30 formula. ,
The main objectives of the study were to determine the frequency of, severity of, and changes in fatigue, as reported by the QLQ-C30 questionnaire, during EBRT and up to 5 years afterward. We also wanted to determine whether there was any predictor for increased fatigue during a course of EBRT for PC.
| > Materials and Methods|| |
During the period between 1 January 1992 and 1 June 2003, 625 patients with PC referred to the Department of Oncology at Umeå University Hospital for EBRT were offered the opportunity to participate in the ongoing prospective evaluation of side effects after EBRT.
All patients were given five fractions per week, with a daily dose of 2.0 Gy (to the isocenter point or a point close to the isocenter). The patients were treated with 3D-conformal technique with doses 61-78 Gy and were treated with 20 MV or 50 MV photons.
Fatigue and other cancer-specific symptoms were prospectively evaluated with patient-reported questionnaires up to 5-year post-radiotherapy. All patients were asked by an oncology nurse at the radiotherapy department to participate in the study before their first day of treatment. They were asked to complete the questionnaire on the same day and return it to the staff. The individuals were encouraged to evaluate their quality of life during the previous week.
All recruited patients were then mailed a questionnaire at four specific follow-up assessments: 3 months, 1 year, 3 years, and 5 years after finishing treatment. The questionnaires were returned by mail in a prepaid envelope. Reminders were sent to those not responding within 4 weeks.
The core EORTC QLQ-C30 was developed as an integrated system for assessing quality of life among cancer patients.  The questionnaire includes a total of 30 questions organized into five functional subscales (physical, role, emotional, cognitive, and social) and three symptom scales (nausea/vomiting, pain, and fatigue). It also includes a global health/QoL scale and six single additional symptom items (constipation, diarrhea, loss of appetite, sleep disturbance, dyspnea, and financial impact).
Each item is assessed on a four-point Likert scale: (1) "not at all"; (2) "a little"; (3) "quite a bit"; (4) "very much", with the exception of the global health status/QoL items whose responses range from (1) "very poor" to (7) "excellent." All calculations based on the EORTC QLQ-C30 questionnaire were performed after the scores were linearly transformed to a 0 to 100 scale to facilitate presentation and interpretation of the data according to the EORTC QLQ-C 30 scoring procedures.
Higher mean scores on the functional and global health/QoL subscales represent better functioning and better QoL, while higher mean scores on the three symptom scales and on the single items represent more symptoms.
The study was approved by the Ethics Committee of the Faculty of Medicine at Umeå University, Sweden.
Only those individuals with at least both baseline and 5 year follow-up completed questionnaires were included in the analysis.
The raw item data were summarized for all items at all follow-ups.
Mean values and 95% confidence intervals (CI) were calculated for all scales and all single items.
Comparisons between the start of EBRT and the 5-year follow-up were calculated using paired t-tests. Comparisons between the other follow-ups were calculated using the non-parametric Mann--Whitney test. To find the contributing factors to fatigue a linear regression analysis was performed using Enter method.
If two of three items from the scale had been answered the missing value was replaced with the average of the respondent's score on the other two items.
A scale change of 5-10 is considered to be small but clinically significant. A change of 10-20 is considered moderate, and a change above 20 is considered a large change in function or in the symptom. 
Reported P values are based on a two-sided hypothesis, with a P value of less than 0.05 considered to indicate statistical significance.
All analyses were performed using version 15.0 of the SPSS software package (SPSS Inc., Chicago, IL).
| > Results|| |
From January 1992 to June 2003, we invited a total of 625 consecutive PC patients treated with a course of EBRT to participate in the study.
The baseline (at the start of EBRT) questionnaire was completed by 554 men (89%). The remaining 71 patients did not answer this questionnaire, mainly because of logistic problems with delivering the baseline formula to the patients before the start of treatment, especially at the start of the study.
At the 5-year follow-up, 83 patients had died, and so 542 patients were eligible for analysis; of these, 455/542 (84%) completed the questionnaire. 48 (10%) of these 455 patients had not completed the baseline and were therefore excluded. The analyzed study cohort contains a total of 407 individuals with at least two completed questionnaires: the baseline and the 5-year assessment.
The baseline characteristics of the 407 eligible men are presented in [Table 1].
Mean dose to the prostate was 73.7 Gy (63.7-78.0 Gy); 98 patients were treated with the conformal technique at doses of 60-71 Gy, while 116 received 74 Gy, 64 received 76 Gy, and 129 received 78 Gy.
Changes occurring between the baseline and the 5-year assessment
Pre-treatment fatigue was absent in 59% (n=206) of 407 patients, while 66% (n=264) of 407 patients had fatigue 5 years after treatment. Pre-treatment severe fatigue, defined as ≥77.78 on the fatigue scale, was reported by 7 of 407 patients (2%). Severe fatigue 5-year post-treatment was reported by 16 of 407 patients (4%).
[Figure 1] shows the mean values for the fatigue score over time between baseline and up to 5 years post-treatment. A significant increase in fatigue was seen between the baseline (mean: 15.5; CI: 13.6-17.4) and 5 year post-treatment (mean: 22.8; CI: 20.5-25.1; P<0.001) but also between the baseline and all the other follow-ups [Figure 1].
|Figure 1: Mean values and 95% confidence intervals of fatigue score. Higher scores indicate more severe fatigue. The scale ranges from 0 to 100. P values represent comparisons between baseline and the specific follow-ups|
Click here to view
Global health/QoL was lower 5 year post-treatment among those with fatigue (mean 65.4; CI 63.1-67.8) in comparison with those with no fatigue (mean 85.4; CI 82.4-88.4; P<0.001).
Changes occurring when stratifying into actual treatment groups
A stratification into three actual treatment groups were performed; (1) no previously or ongoing hormonal treatment (NHT; n=203), (2) ongoing hormonal treatment but no skeletal metastasis (HT; n=167), and (3) ongoing hormonal treatment and skeletal metastasis (HT+; n=37).
At 5 year HT reported the lowest degree of fatigue (mean 20.3; CI: 16.6-23.6) compared with NHT (mean 22.4; CI: 19.2-25.7), and HT+ (mean 37.1; CI: 28.0-46.3; P=0.001).
Clinical significant change
When comparing baseline with the 5-year follow-up, 108/407 (26%) reported no clinically significant change in fatigue score (0-5 on the 0 to 100 graded scale), 64/407 (16%) reported a moderate increase (10-20 on the scale), and 98/407 (24%) reported a large clinically significant increase (>20 on the scale). However, 44/407 (9%) reported a moderate decrease in fatigue score, and 36/407 (9%) reported a large decrease.
Linear regression analysis
The results of the linear regression at the 5-year follow-up are described in [Table 2]. Nine factors contributed uniquely to fatigue. Physical function, emotional function, cognitive, and dyspnea contributed the most, followed by global health/quality of life, insomnia, diarrhea, appetite loss, and financial difficulties.
Missing case analysis
To verify the results, we compared the baseline profiles of the 218 non-responders (including those 83 who had died between the baseline and 5 year assessment and those who did not complete the baseline assessment) and the 407 included responders of the 5 year follow-up. Mean age did not significantly differed between responders (66.0 years, CI 65.4-66.6) and non-responders (66.7 years, CI 65.8-67.6, P=0.141).
Fatigue was higher in the non-responders (mean 24.4, CI 20.8-28.1) than in the responders (mean 15.5, CI 13.6-17.4; P<0.001). Physical function was worse in the non-responders (mean 86.7, CI 83.7-89.6) than in responders (mean 92.5, CI 90.9-94.1; P=0.002).
| > Discussion|| |
This is one of the first studies with a large sample of men with prostate cancer specifically aimed at investigating fatigue during radiotherapy and over long-term follow-up. The first goal of this study was to determine the frequency of, severity of, and changes in fatigue during treatment and up to 5 years afterward. At start of treatment, a significant number of patients (59%) reported some level of fatigue, as compared to 66% 5 years later. In the whole sample, 4% of the patients reported severe fatigue 5 years post-treatment, while 2% reported severe fatigue pre-treatment.
Fatigue is a common symptom that occurs after radiotherapy. 
The pre-treatment prevalence of any level of fatigue in our sample is similar to previous reports of 57-60%. , However, Goedendorp et al.  reported a higher prevalence of severe pre-treatment fatigue among prostate cancer patients, 14%, in comparison with 2% in our sample.
The significant increase of fatigue during the acute phase in our study is similar to that reported in the literature. ,, The highest level of fatigue in our population was reported at the end of RT, which corresponds well with the previously-reported information from other studies showing a peak of fatigue at weeks 4 to 6. , However, our "end of RT" follow-up took place during the last treatment week, which in our sample ranged from 6 to 8 weeks after initiation of RT.
It should be remembered that 24% reported a large clinically significant increase (>20) and 9% reported a large clinically significant decrease of fatigue score between the baseline and the 5-year follow-up.
Several factors such as physical, cognitive, and emotional function, global health/quality of life, dyspnea, insomnia, appetite loss, diarrhea, and financial difficulties contributed significantly to fatigue at the 5-year assessment. Low physical function was one of the factors that showed the highest correlation with high level of fatigue. This findings was also supported by Goedendorp and co-workers  and also confirmed in other studies of fatigue in cancer patients. ,
Previous studies have reported that fatigue has an impact on QoL. ,, In the present study, QoL was lower in those with fatigue. This was evident from the very start of EBRT up to the 5-year follow-up.
Stone et al.  reported increased fatigue severity in 66% of patients receiving 3 months of first-line hormone therapy. In our sample, fatigue was absent in 41% of patients pre-treatment and in 34% of patients post-treatment, a difference of 7%. The study by Stone et al.  reported on a sample of men receiving hormone therapy, while the present study included both patients with and patients without hormonal treatment. However, we found differences between patients receiving hormonal treatment and those without hormonal treatment.
The relatively small increase of pre-treatment fatigue (59%; defined as any level of fatigue more than "0" on scale) to 66% 5 years post-treatment in our sample may also be due to the instrument used to evaluate fatigue (QLQ-C30). This instrument is mainly designed to evaluate overall quality of life in a population of cancer patients. The reason it was used in the present study is that at the time the study was designed, there were only a limited number of fatigue-specific instruments available.
The fatigue component of the QLQ-C30 questionnaire only includes three items, each answered on a four-point scale. This gives a rather limited range of possible values for the fatigue score, resulting in limited possibilities to detect small changes in fatigue.
The missing case analysis showed that the non-responders had more fatigue and a worse physical function which may limit the findings of the study. The patients included in the study were treated at the same department in the northern part of Sweden which may also limit the generalizing of the findings to other PC populations. However, the strength of this study is the prospective long-term assessment with a large sample followed at multiple assessments with the same evaluation method.
Other frequently-described instruments such as the Functional Assessment of Cancer Therapy Fatigue Scale (FACT-F), the Lee Fatigue Scale (LFS), the Piper Fatigue Scale (PFS), and Profile of Mood States (POMS), which are specifically aimed at evaluating fatigue, use a greater number of items to detect the prevalence and severity of fatigue. In a study by Stone et al., the EORTC QLQ-C30 failed to detect variations in fatigue over time that were revealed by two fatigue-specific instruments.  Knobel et al. found some issues with evaluating fatigue with the EORTC QLQ-C30 in palliative care patients, and recommended the use of a fatigue-specific instrument instead. 
| > Conclusions|| |
Fatigue is a common symptom among patients with prostate cancer. A high percentage of patients reported pre-treatment fatigue. Fatigue increased over time, with the highest level of fatigue seen at the end of EBRT. Severe fatigue was reported by 4% 5 years post-treatment. Physical-, emotional-, cognitive function, and dyspnea were the factors that correlated most to higher level of fatigue. This analysis showed no dramatic increase of fatigue during long-term follow up 5 years after radiotherapy. However, more work is needed in order to identify which patients are most susceptible to developing fatigue especially during radiotherapy.
| > Acknowledgments|| |
This investigation was supported by grants from the Swedish Cancer Society.
| > References|| |
|1.||Sanda MG, Dunn RL, Michalski J, Sandler HM, Northouse L, Hembroff L, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008;358:1250-61. |
|2.||Monga U, Kerrigan AJ, Thornby J, Monga TN, Zimmermann KP. Longitudinal study of quality of life in patients with localized prostate cancer undergoing radiotherapy. J Rehabil Res Dev 2005;42:391-9. |
|3.||Miaskowski C, Paul SM, Cooper BA, Lee K, Dodd M, West C, et al. Trajectories of fatigue in men with prostate cancer before, during, and after radiation therapy. J Pain Symptom Manage 2008;35:632-43. |
|4.||Walker BL, Nail LM, Larsen L, Magill J, Schwartz A. Concerns, affect, and cognitive disruption following completion of radiation treatment for localized breast or prostate cancer. Oncol Nurs Forum 1996;23:1181-7. |
|5.||Fosså SD, Woehre H, Kurth KH, Hetherington J, Bakke H, Rustad DA, et al. Influence of urological morbidity on quality of life in patients with prostate cancer. Eur Urol 1997;31:3-8. |
|6.||Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, 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;85:365-76. |
|7.||Kaasa S, Loge JH. Quality-of-life assessment in palliative care. Lancet Oncol 2002;3:175-82. |
|8.||Stone P, Hardy J, Huddart R, A'Hern R, Richards M. Fatigue in patients with prostate cancer receiving hormone therapy. Eur J Cancer 2000;36:1134-41. |
|9.||Fransson P, Damber JE, Tomic R, Modig H, Nyberg G, Widmark A. Quality of life and symptoms in a randomized trial of radiotherapy versus deferred treatment of localized prostate carcinoma. Cancer 2001;92:3111-9. |
|10.||Fransson P, Damber JE, 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;43:119-26. |
|11.||Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 1998;16:139-44. |
|12.||Monga U, Kerrigan AJ, Thornby J, Monga TN. Prospective study of fatigue in localized prostate cancer patients undergoing radiotherapy. Radiat Oncol Investig 1999;7:178-85. |
|13.||Hickok JT, Roscoe JA, Morrow GR, Mustian K, Okunieff P, Bole CW. Frequency, severity, clinical course, and correlates of fatigue in 372 patients during 5 weeks of radiotherapy for cancer. Cancer 2005;104:1772-8. |
|14.||Danjoux C, Gardner S, Fitch M. Prospective evaluation of fatigue during a course of curative radiotherapy for localised prostate cancer. Support Care Cancer 2007;15:1169-76. |
|15.||Goedendorp MM, Gielissen MF, Verhagen CA, Peters ME, Bleijenberg G. Severe fatigue and related factors in cancer patients before the initiation of treatment. Br J Cancer 2008;99:1408-14. |
|16.||Stone P, Richards M, A'Hern R, Hardy J. Fatigue in patients with cancers of the breast or prostate undergoing radical radiotherapy. J Pain Symptom Manage 2001;22:1007-15. |
|17.||Greenberg DB, Sawicka J, Eisenthal S, Ross D. Fatigue syndrome due to localized radiation. J Pain Symptom Manage 1992;7:38-45. |
|18.||Bruera E, Schmitz B, Pither J, Neumann CM, Hanson J. The frequency and correlates of dyspnea in patients with advanced cancer. J Pain Symptom Manage 2000;19:357-62. |
|19.||Truong PT, Berthelet E, Lee JC, Petersen R, Lim JT, Gaul CA, et al. Prospective evaluation of the prevalence and severity of fatigue in patients with prostate cancer undergoing radical external beam radiotherapy and neoadjuvant hormone therapy. Can J Urol 2006;13:3139-46. |
|20.||Rodrigues G, Bezjak A, Osoba D, Catton P, Tsuji D, Taylor 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;13:1235-46. |
|21.||Knobel H, Loge JH, Brenne E, Fayers P, Hjermstad MJ, Kaasa S. The validity of EORTC QLQ-C30 fatigue scale in advanced cancer patients and cancer survivors. Palliat Med 2003;17:664-72. |
[Table 1], [Table 2]
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