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A randomized, controlled trial of aerobic exercise for treatment-related fatigue in men receiving radical external beam radiotherapy for localized prostate carcinoma
Version of Record online: 22 JUN 2004
Copyright © 2004 American Cancer Society
Volume 101, Issue 3, pages 550–557, 1 August 2004
How to Cite
Windsor, P. M., Nicol, K. F. and Potter, J. (2004), A randomized, controlled trial of aerobic exercise for treatment-related fatigue in men receiving radical external beam radiotherapy for localized prostate carcinoma. Cancer, 101: 550–557. doi: 10.1002/cncr.20378
- Issue online: 19 JUL 2004
- Version of Record online: 22 JUN 2004
- Manuscript Accepted: 23 APR 2004
- Manuscript Revised: 12 APR 2004
- Manuscript Received: 21 NOV 2003
- aerobic activity;
- Brief Fatigue Inventory;
- prostate carcinoma;
- radiation fatigue
Advice to rest and take things easy if patients become fatigued during radiotherapy may be detrimental. Aerobic walking improves physical functioning and has been an intervention for chemotherapy-related fatigue. A prospective, randomized, controlled trial was performed to determine whether aerobic exercise would reduce the incidence of fatigue and prevent deterioration in physical functioning during radiotherapy for localized prostate carcinoma.
Sixty-six men were randomized before they received radical radiotherapy for localized prostate carcinoma, with 33 men randomized to an exercise group and 33 men randomized to a control group. Outcome measures were fatigue and distance walked in a modified shuttle test before and after radiotherapy.
There were no significant between group differences noted with regard to fatigue scores at baseline (P = 0.55) or after 4 weeks of radiotherapy (P = 0.18). Men in the control group had significant increases in fatigue scores from baseline to the end of radiotherapy (P = 0.013), with no significant increases observed in the exercise group (P = 0.203). A nonsignificant reduction (2.4%) in shuttle test distance at the end of radiotherapy was observed in the control group; however, in the exercise group, there was a significant increase (13.2%) in distance walked (P = 0.0003).
Men who followed advice to rest and take things easy if they became fatigued demonstrated a slight deterioration in physical functioning and a significant increase in fatigue at the end of radiotherapy. Home-based, moderate-intensity walking produced a significant improvement in physical functioning with no significant increase in fatigue. Improved physical functioning may be necessary to combat radiation fatigue. Cancer 2004. © 2004 American Cancer Society.
Fatigue in cancer patients is a common treatment and disease-related problem that is associated with psychologic distress, depression, anemia, pain, sleep disturbance, poor nutrition, and reduced functional capacity. In a patient survey administered in the U.K., only 14% of patients had been recommended any treatment for fatigue by any health care professional. The most common advice was to take rest and relaxation; only 4% of patients had been advised to exercise.1
During radiotherapy, fatigue may be cumulative,2 with up to 80% of patients experiencing fatigue during a course of radiotherapy and with fatigue becoming chronic in 30% of patients.3 Patients receiving radiotherapy who are told to rest and avoid physical effort may take that to mean that they must take time off work or curtail social activities. Inactivity actually may increase fatigue; anecdotally, walking, cycling, or swimming may be beneficial. Some patients have reported exercise as part of a strategy of self-care behaviors initiated in response to fatigue after chemotherapy or radiotherapy.4, 5 However, to our knowledge there is a lack of randomized, controlled trials regarding exercise.
Men with localized prostate carcinoma are unlikely to have any systemic effects; therefore, fatigue that develops during radiotherapy should be due to treatment. Exercise training at home (walking at 60–70% of peak heart rate) can improve functional capacity significantly in sedentary, middle-aged males.6 In the current study, the objectives were to determine whether an aerobic exercise intervention during a 4-week course of radiotherapy for localized prostate carcinoma would reduce the incidence of radiotherapy-related fatigue, prevent any deterioration in physical functioning, and be acceptable in terms of adherence to exercise.
MATERIALS AND METHODS
Consecutive, unselected men on the outpatient waiting list for radical conformal radiotherapy for localized prostate carcinoma were approached at their first planning visit and written informed consent was obtained at the second planning visit prior to radiotherapy (baseline). Exclusion criteria were physical frailty due to age and comorbidity, such as unstable or severe angina, recent myocardial infarction, or dementia. Patients with cardiac pacemakers were not suitable because this would interfere with signals to the heart-rate monitor.
The study employed a randomized, controlled design with an exercise group and a control (normal advice) group. To detect a reduction ≥ 50% in fatigue incidence in the exercise group, with a 1-sided 5% significance level and a power of 90%, 33 patients were needed in each group. Patients were randomized to trial group by telephone call to the Scottish Cancer Therapy Network randomization line before baseline tests were performed. Ethical approval was granted by the Tayside Local Research Ethics Committee (LREC).
The exercise intervention was home-based, moderate-intensity, continuous walking for 30 minutes on at least 3 days of each week of radiotherapy at a target heart rate of 60–70% calculated maximum heart rate (as a guide to the intensity of the activity). The duration of activity and the heart rate before and at completion of activity were recorded using a wrist-band heart-rate monitor (Polar Series 1 [Polar Electro Oy, Helsinki, Finland]). Patients in the control group were not discouraged from performing normal activities but were advised to rest and take things easy if they became fatigued.
Patients were treated prone, with the bladder empty, using a three-field, beam-directed radiotherapy technique with 6-megavolt photons. Patients who were treated during the period between December 2001 to January 2002 received our standard target dose of 50 grays (Gy) in 20 fractions over 4 weeks. From January 2002, dose escalation was initiated with the availability of 3-dimensional conformal radiotherapy; a target dose of 52 Gy in 20 fractions over 4 weeks was received by subsequent patients in the current study. The clinical target volume in all patients included the prostate and seminal vesicles, but not the pelvic lymph nodes.
Weight was recorded, and blood was taken for serum albumin, hemoglobin, and hematocrit levels at baseline, at the end of radiotherapy, and at follow-up 4 weeks after the end of radiotherapy. Patients in the exercise group were allowed to keep their heart-rate monitor, whereas patients in the control group were given an information leaflet on aerobic walking exercise after completion of the study.
The Brief Fatigue Inventory (BFI)7 (The University of Texas M. D. Anderson Cancer Center) was self-completed by all patients at baseline; after 5 fractions, 10 fractions, 15 fractions, and 20 fractions of radiotherapy; and at follow-up 4 weeks after the completion of treatment. The BFI is a 1-page questionnaire assessing 9 items, each measured on a 0–10 numeric rating scale, using single-word designations of fatigue severity levels and domains to make it easy to administer and understand.
At baseline and at the end of radiotherapy, the resting heart rate was recorded, a modified shuttle test was performed, and the heart rate was recorded at completion (exercise heart rate). The modified shuttle test8 uses external pacing and an incremental work protocol to evoke a symptom-limited exercise response. Participants walk back and forth on a 10-meter course at speeds dictated by an audio signal from a cassette recorder. Test endpoints are patient exhaustion or inability to maintain the speed set by the audio signal; patients are allowed to run. A validated questionnaire for the Scottish population, the Scottish Physical Activity Questionnaire (SPAQ), was administered at baseline to assess patient attitude toward activity and usual activity levels.9
All patients kept a patient-activity diary during radiotherapy detailing the frequency and duration of the walking intervention together with the heart rate achieved (exercise group) or the frequency and duration of everyday aerobic activity (control group). Patients were contacted weekly during radiotherapy. The exercise group was contacted by a physiotherapist to encourage adherence to the exercise program, and the control group was contacted by a nurse who asked general health questions and reinforced standard advice.
Matched (paired) Student t tests, matched sign-rank tests, and one-way analyses of variance ([ANOVAs] with 95% confidence intervals) were used to assess the significance of group differences in variables and pooled-variance Student t tests were used to assess between-group differences in mean values at each time point (Biomedical Statistical Package [BMDP] Statistical Software, University of California).
This trial is reported as recommended by the Consolidated Standards of Reporting Trials statement,10 and patients were recruited between December 2001 and December 2002. Eleven men (14.3% of those who were eligible) refused participation (Fig. 1). Sixty-six men with a mean age 68.8 years (range, 52–82 years) were randomized: Nineteen of 66 patients (28.8%) were receiving adjuvant hormone therapy for high-risk tumors, including 10 of 33 patients in the control group and 9 of 33 patients in the exercise group (P = 0.786; chi-square test). Nine of 66 patients were receiving β-blockers, including 2 of 33 patients in the control group and 7 of 33 patients in the exercise group (P = 0.073; chi-square test). One patient who was randomized to the exercise group withdrew before the initiation of radiotherapy. Data from 65 patients who completed the study were analyzed.
There were no significant between-group differences with regard to age, weight, hemoglobin levels, hematocrit levels, and albumin levels at baseline and at the end of radiotherapy (Table 1). Within-group comparisons demonstrated a significant decrease in hemoglobin levels (control group, P < 0.0001; exercise group, P = 0.0001), hematocrit levels (control group, P < 0.0001; exercise group, P = 0.0005), and albumin levels (P < 0.0001 for both groups) from baseline to the end of radiotherapy. There were no significant decreases in weight noted during radiotherapy in the control group (P = 0.9), and weight loss in the exercise group did not achieve statistical significance (P = 0.06).
|Parameter||Control group (n = 33 men)||Exercise group (n = 32 men)||P value|
|Baseline||14.45 ± 0.18||14.93 ± 0.17||0.055|
|End||13.88 ± 0.19||14.45 ± 0.2||0.039|
|Baseline||0.437 ± 0.006||0.450 ± 0.005||0.079|
|End||0.42 ± 0.006||0.435 ± 0.006||0.085|
|Baseline||42.4 ± 0.39||43.1 ± 0.33||0.178|
|End||41.1 ± 0.45||41.8 ± 0.39||0.278|
|Baseline||82.9 ± 1.76||81.6 ± 2.57||0.67|
|End||82.8 ± 1.8||80.5 ± 2.7b||0.46|
|Age (yrs)||69.3 ± 1.3||68.3 ± 0.9||0.553|
The majority of patients had early-stage tumors; 51 of 65 patients had tumors that were classified as T1 or T2. There were no significant between-group differences with regard to tumor stage (P = 0.37; chi-square test) or Gleason sum score (P = 0.92; chi-square test). A target dose of 50 Gy was received by 12 patients, including 5 patients in the control group and 7 patients in the exercise group; and 53 patients received a target dose of 52 Gy, including 28 patients in the control group and 25 patients in the exercise group (P = 0.48; chi-square test).
Mean BFI sum scores for the control group and the exercise group did not differ significantly at baseline (P = 0.55) or after 4 weeks of radiotherapy (P = 0.18) (Fig. 2A,B). Similarly, at Week 8 (4 weeks after the end of radiotherapy), there was no significant difference in mean BFI sum scores between the control group and the exercise group (P = 0.197).
In the control group, there was a significant increase in fatigue scores at the end of radiotherapy compared with baseline (P = 0.013), and there was no significant difference in fatigue scores for the exercise group (P = 0.203). At the follow-up visit 4 weeks after the end of radiotherapy, increased mean fatigue scores in the control group, compared with baseline scores, nearly reached significance (P = 0.053), but there was no significant difference noted for the exercise group (P = 0.132) (Fig. 3A,B).
There was a significant increase in mean BFI sum scores at the end of radiotherapy compared with baseline for the 53 patients who received a dose of 52 Gy (P = 0.0017). Among the 12 patients who received a dose of 50 Gy, there was no significant difference noted with regard to fatigue scores from baseline to the end of radiotherapy (P = 0.477).
On the SPAQ, 29 of 33 patients in the control group and 26 of 32 patients in the exercise group claimed that they regularly were physically active and had been for at least the past 6 months; others currently were not regularly physically active. There were no differences noted with regard to activity level by trial group (P = 0.73; chi-square test), by tumor stage (P = 0.577; chi-square test), or by use of hormone therapy (P = 0.219; chi-square test). The mean sum BFI scores were lower in patients who regularly were physically active compared with patients who regularly were not physically active at baseline (P = 0.055), at the end of 4 weeks of radiotherapy (P = 0.043), and at follow-up 4 weeks after radiotherapy (P = 0.065).
Everyday aerobic activity in the week prior to baseline for the control group was 10.9 ± 6.8 hours compared with 13.9 ± 7.7 hours for the exercise group (P = 0.15; ANOVA). No differences were observed with regard to resting or exercise heart-rate values between the groups at baseline or at the end of the course of radiotherapy (Table 2).
|Parameter||Control group (n = 33 men)||Exercise group (n = 32 men)||P value (Student t test)|
|Resting heart rate|
|Baseline||70.7 ± 1.7||66.4 ± 2.1||0.11|
|After 20 fractions||70.7 ± 1.6||68.2 ± 2.0||0.33|
|P value (Student t test)||0.87||0.179||—|
|Exercise heart rate|
|Baseline||103.9 ± 2.4||110.7 ± 3.3||0.101|
|After 20 fractions||105.6 ± 2.9||104.4 ± 3.0b||0.766|
|P value (Student t test)||0.457||0.11||—|
The mean shuttle-test distance for the control group at baseline was 479.1 ± 19.8 meters compared with 467.6 ± 23.2 meters at the end of radiotherapy (P = 0.49); for the exercise group, it was 511.6 ± 31.2 meters compared with 579.1 ± 27 meters, respectively (P = 0.0003). The shuttle-test distance did not differ significantly between groups at baseline (P = 0.38) but did differ at the end of radiotherapy (p = 0.0025) (Fig. 4).
The control group showed a small, nonsignificant decline in hours of reported aerobic activity per week during radiotherapy (Fig. 5A). All patients in the exercise group recorded at least 1.5 hours of aerobic exercise at the recommended percentage maximum heart rate per week throughout radiotherapy. The increase in hours of prescribed exercise during radiotherapy did not achieve statistical significance (Week 1 compared with Week 5: P = 0.056) (Fig. 5B).
Studies of conformal radiotherapy for prostate carcinoma have shown that fatigue increases significantly by the end of treatment, followed by improvement 1 month after the end of radiotherapy, but not to pretreatment levels.11, 12 In the current study, patients in the control group who followed normal advice also demonstrated a significant increase in fatigue from baseline to the end of radiotherapy, and their fatigue decreased at 4 weeks after radiotherapy but still did not reach baseline levels. Patients in the exercise group had no significant changes in fatigue over time.
Patients with fatigue were more likely to report poor quality of physical well-being.12 Self-reported physical activity status (assessed by the SPAQ) in this study demonstrated that physically active patients had lower fatigue levels at all stages before, during, and after radiotherapy.
There is no “gold-standard” instrument for the measurement of fatigue. Fatigue is measured as a single construct on the BFI, which we believe was a valid and more practical measure for this study compared with more complex, multidimensional scales. The sum score or arithmetic mean of the nine questions on the BFI can be used as a global fatigue score. It may be argued that the BFI7 does not capture cognitive, affective, and somatic components of fatigue; however, fatigue in patients with localized prostate carcinoma is not due to depression or sleep disturbances.3
A recent review of interventions for fatigue in cancer patients suggested that it would be better to encourage patients to maintain normal activity levels during treatment.13 In the current study, there was no difference with regard to baseline physical functioning between groups assessed by the SPAQ and the modified shuttle-walk test. There was a nonsignificant deterioration (2.4%) in physical functioning in the control group; patients generally were active physically and continued normal activity, only resting and taking things easy if they felt tired. The majority of patients in the control group regularly were physically active and maintained their level of activity during radiotherapy; however, despite this, they had significantly increased fatigue scores at the completion of radiotherapy. Patients in the exercise group, which had no significant increases in fatigue, had a significant increase (13.2%) in distance walked at the end of 4 weeks of radiotherapy, suggesting that an actual improvement in physical functioning is needed to prevent radiation fatigue.
In one other reported randomized trial of a walking exercise intervention for radiation fatigue in women who received 6 weeks of radiotherapy for early-stage breast carcinoma, women who exercised demonstrated a trend toward improved physical and psychosocial functioning. Physical functioning was assessed before and midway through radiotherapy using distance covered in a 12-minute walk, which increased by 4% in women who exercised and decreased by 5% in the control group.14
In patients with cancer who were rendered disease-free after completing radiotherapy 9 months earlier, the most significant predictor of fatigue was the degree of postradiotherapy functional disability.15 Advice to rest and reduce levels of activity leads to muscular deconditioning and loss of performance, requiring a higher degree of effort for patients to perform normal daily activities. A significant decline in neuromuscular efficiency was noted in men with prostate carcinoma who were evaluated before and after 8 weeks of radiotherapy,16 possibly due to a systemic effect of radiotherapy that resulted in subtle injury to muscular structures.
Radiation fatigue has not been correlated with weight loss, hematocrit level, or albumin level.17 In another study, patients with prostate carcinoma had higher fatigue levels before, during, and after radiotherapy if their hemoglobin level was < 12 g/dL.18 Although patients in the current study were not anemic, significant reductions in hemoglobin and hematocrit levels as well as albumin levels (a measure of nutritional status) were noted in both groups after only 4 weeks of radiotherapy, suggesting that localized radiotherapy does have a systemic effect on the patient. It was presumed that weight loss in the exercise group was due to aerobic walking.
Patients with early-stage prostate carcinoma have a high level of interest in life-style changes19 and are a receptive population for targeting an exercise intervention, which, if continued after radiotherapy, may have long-term general health benefits in this population of older men. In the current study, 85.7% of eligible patients agreed to participate, and 32 of 33 patients adhered to prescribed aerobic walking exercise. In a different study, moderate-intensity, brisk walking for 30 minutes on 5 or 6 days per week during therapy for breast carcinoma was never initiated by 22% of patients, and 13% of patients had dropped out before the end of a 6-month program.20 Drop-out rates are lower for self-directed, home-based exercise compared with the rates for supervised classes.21 Prompting by weekly contact with a physiotherapist, the use of a daily exercise diary, and providing a heart-rate monitor encouraged motivation; and it has been demonstrated that the lower intensity, home-based exercise used in the current study improves adherence. The body of evidence suggests that exercise programs for patients undergoing cancer therapies should become routine, similar to the widespread adoption of exercise in cardiac rehabilitation.
It has been suggested that there is a significant correlation between fatigue and bowel or urinary side effects of radiotherapy.22 It is known that exercise reduces depression, and patients with increased negative affect have more severe self-reported side effects. Patients who are receiving radiotherapy for prostate carcinoma report less severe fatigue if they are randomized to an intervention that provides information concerning side effects, although they may experience no improvement in bowel or urinary problems.23 Fatigue, physical functioning, and emotional functioning were reported to be independent predictive parameters for quality of life in patients with prostate carcinoma who were treated at least 1 year previously, whereas urinary or bowel symptoms were not significant.24
The treatment regimes used in this study employed a smaller number of larger fractions (2.5 Gy escalated to 2.6 Gy per fraction) compared with “standard” regimes of 72–80 Gy in 2-Gy fractions. It has been suggested that, due to the low α/β value for prostate tumors, hypofractionated regimes are equivalent to standard fractionation in terms of tumor control, with reduced acute morbidity.25, 26 The current study was not powered to determine the influence of radiation dose on fatigue, although there was a suggestion that the lower dose of 50 Gy did not result in increased fatigue scores.
It was noted that patients in the exercise group appeared to report less severe radiation proctitis and lower urinary tract symptoms. Prospective data regarding the incidence and severity of side effects will be the focus of a future multivariate analysis to assess correlations between trial group, symptom severity, and fatigue score.