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Pilot study of a home-based aerobic exercise program for sedentary cancer survivors treated with hematopoietic stem cell transplantation
RW Wilson1, PB Jacobsen2 and KK Fields2
1 School of Physical Therapy, University of South Florida College of Medicine, Tampa, FL, USA; and 2H Lee Moftt Cancer Center and Research Institute, Tampa, FL, USA

Summary: We report a pilot study of a home-based aerobic exercise program in a group of 17 adult hematopoietic stem cell transplant (HSCT) recipients. Participants had received no cancer treatment for at least 6 months and reported leisure time physical activity less than 20 min per day and fewer than three times a week during the previous month. Following baseline assessments of aerobic tness, fatigue symptoms, and quality of life, participants were placed on home-based aerobic exercise programs consisting of 20 40 min of activity in the target heart rate zone (4060% predicted heart rate reserve) delivered in three to ve sessions per week for 12 weeks. Subjects were supplied with electronic heart rate monitors and we encouraged program adherence using weekly telephone contacts and exercise diaries. In all, 32 of the 42 qualied candidates consented (acceptance 76%). Of these, 17 kept appointments for baseline assessments, four did not complete the study (attrition 46%), and no exercise-related adverse events were reported. Scores on measures of aerobic tness, fatigue severity, and physical well-being improved (signed ranks test; Po0.05) during program participation. Our ndings suggest that individually prescribed, homebased aerobic exercise is an acceptable, safe, and potentially effective intervention for improving physical functioning and fatigue in sedentary HSCT recipients. Bone Marrow Transplantation (2005) 35, 721727. doi:10.1038/sj.bmt.1704815 Published online 7 February 2005 Keywords: exercise; fatigue; quality of life; rehabilitation

The association between hematopoietic stem cell transplantation (HSCT) and physical dysfunction in cancer survivors is well documented. Although a majority of patients report rewarding and productive lives following HSCT, a substantial proportion report problems with

Correspondence: Dr RW Wilson, School of Physical Therapy, University of South Florida College of Medicine, 12901 Bruce B Downs Blvd., MDC 77, Tampa, FL, USA 33612-4766; E-mail: rwilson@hsc.usf.edu Received 14 July 2004; accepted 26 October 2004 Published online 7 February 2005

fatigue, physical functioning (motor task performance), and physical-role participation (eg working, domestic chores, recreation).17 Data show that these problems persist well beyond the acute recovery period immediately following treatment. Fatigue symptoms and physical limitations have been found to be prevalent among cancer patients surviving 310 years following HSCT.812 Sedentary lifestyles may contribute to the physical symptoms and functional limitations experienced by HSCT recipients. Physical inactivity is known to be associated with an increased risk of obesity and decreased lean body mass, which can be expected to lower the anaerobic threshold in working muscle, produce symptoms of fatigue, diminish physical work capacity, and limit customary physical activities.13 Although previous studies have found that people diagnosed with cancer are willing to make positive lifestyle changes,1416 the limited data available suggest that cancer survivors are no more likely than others to engage in regular physical activity.1719 Results from intervention trials conducted with cancer patients have generally shown structured exercise to be effective for improving cardiorespiratory tness, physical functioning, and fatigue symptoms.2029 Most studies, including six randomized trials of aerobic exercise, involved early-stage breast cancer patients.20,24,2629 In the largest randomized trial published to date, Segal and co-workers26 compared the effects of supervised and unsupervised aerobic exercise programs on 99 early-stage breast cancer patients receiving adjuvant chemotherapy or radiotherapy. Following the exercise intervention, participants randomized to the unsupervised exercise arm demonstrated substantial improvements in physical functioning when compared to nonexercising controls. Their ndings suggest that a home-based exercise intervention may be at least as effective as a similar intervention delivered under supervised conditions. While there is strong evidence to suggest that aerobic exercise may be benecial to women with early-stage breast cancer, the effects of exercise on quality of life following HSCT are less well documented. Previous exercise intervention studies involving HSCT recipients have consisted of closely supervised programs, which continued no more than 6 weeks following hospitalization.2123,3032 Outcome measures in these studies consisted of an assortment of physiological and psychological variables rather than recognized measures of fatigue, physical functioning, or

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general health status.33 The possibility that a home-based exercise program could impact quality of life outcomes for HSCT recipients beyond the acute recovery period following hospitalization has not, to our knowledge, been investigated with any degree of scientic rigor. This pilot study was conducted to explore the safety, feasibility, and potential efcacy of home-based aerobic exercise for cancer survivors treated with HSCT. Although limited by a small sample size and the absence of a comparison group, the study contributes to existing knowledge by examining the responses of sedentary HSCT recipients to a self-administered exercise program using standard outcome measures of aerobic tness, fatigue, and health-related quality of life.

Patients not excluded from participation based on this initial screening met with a member of the study staff who described the study, invited candidates to participate, answered any questions, obtained written consent, and scheduled an appointment for the baseline assessment. Consenting candidates were then discussed briey with their attending oncologist for the purpose of obtaining written medical clearance to participate. At the conclusion of this discussion, patients with known cardiovascular disease, hypothyroidism, signs of infection (T4381C), metastatic bone disease involving the lower extremities, cachexia (BMIo18 kg/m2), anemia (Hbo10 g/dl), neutropenia (ANCo1 109/l), and thrombocytopenia (platelets o30 109/l) were medically disqualied from participation. Patient recruitment, enrollment, and attrition are summarized in Figure 1.

Patients and methods Patients

Participants in this study were a convenience sample recruited from patients who met the eligibility criteria at the time of their outpatient appointments with the Moftt Cancer Center HSCT program staff. Patient eligibility was initially determined by a member of the research team based on a medical record review and discussion with clinic staff. To be eligible for the study, participants were required to (a) be 1865 years of age; (b) have no documented or observable psychiatric or neurological disorders that would interfere with study participation (eg, sensorimotor disturbances, dementia, or psychosis); (c) be capable of speaking and reading English at an eighth grade level; (d) have received blood stem cell or bone marrow transplantation at least 6 months prior to enrollment; (e) report leisure time physical activity less than 20 min per day and fewer than three times a week during the past month; and (f) be willing to travel to and from the study site. Patients who did not meet all the demographic, disease, or treatment eligibility characteristics listed above were excluded from participation.

Methods
Baseline assessments. Qualied candidates were scheduled for an appointment at the University of South Florida Clinical Exercise Physiology Laboratory to complete a packet of self-report questionnaires and a submaximal graded exercise test (GXT). Data obtained during the treadmill GXT were used to assess participants tness levels and physiological responses to exercise. We also collected data concerning anthropometric and demographic characteristics, quality of life, and fatigue using standardized measures that are in widespread use and/or validated for use with cancer patients in prior research (see Measures below). Exercise intervention. The aerobic exercise intervention used in the current study was designed to conform to precautions and considerations for exercise, following cancer diagnosis published by the American College of Sports Medicine.34 As part of the intervention instructions, participants received instructions concerning appropriate warm-up and cool down procedures. Values of 40 and 60%

103 HSCT recipients 29 geographically disqualified 24 non-sedentary 8 medically ineligible 10 refused 32 enrolled volunteers 42 eligible patients

8 medical disqualifications 7 pre-participation withdrawals

17 participants

1 recurrence of active disease 1 avascular necrosis

Figure 1
Patient recruitment, enrollment, and attrition.

1 moved away 1 withdrew

13 completed study

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(moderate intensity) of age-predicted heart rate reserve (0.40.6 {(220age)resting HR} resting heart rate) provided the lower and upper limits for target heart rate zones used during home-based aerobic exercise training. Participants were supplied with digital heart rate monitors (Polar Model a1; Polar Electro Inc.) and instructed to exercise at least three times per week for 20 continuous minutes within their specied heart rate training zone. Patients were allowed to select a preferred mode of exercise (ie walking, cycling, swimming, exercise tapes). Exercise diaries and weekly telephone contact. To promote and document adherence to the intervention, participants were asked to record the following information for each exercise session in a diary: date, resting heart rate, time spent in the prescribed exercise intensity zone, and subjective exercise response. Diary contents were reviewed during weekly telephone contacts to validate delivery of the prescribed exercise program and adjust the duration and intensity of exercise sessions to suit individual responses. Adherence rates were determined by computing a simple ratio of the number of exercise sessions performed to the number prescribed (see Measures). Post-intervention assessments. To assess participants responses to the exercise intervention, nal assessment sessions were scheduled 12 weeks following the baseline assessment. This interval was judged to be sufcient to observe exercise-related changes in tness and quality of life outcomes in the intervention group based on results of previous exercise intervention studies.34,35 At the conclusion of the study, participants were offered $75.00 as compensation for their time and expenses incurred traveling to and from the study site.

that would have made it advisable to temporarily discontinue exercising (eg sprains, falls, muscle cramps, fever, or dizziness), as well as conditions that placed participants at increased risk for dehydration or electrolyte imbalance (eg episodes of vomiting or diarrhea). Health-related quality of life. The Medical Outcomes Study 36-Item Short Form (SF-36) is a widely used selfreport measure designed to assess perceived health and functioning whose construct validity and internal reliability of the SF-36 have been established in a number of clinical populations, including cancer patients.36,37 The SF-36 is multidimensional, containing eight subscales assessing various dimensions of health and well-being: Physical Functioning (PF), Role-Physical (RP) (problems in role functioning attributed to physical problems); Bodily Pain (BP); General Health (GH); Vitality (VT); Social Functioning (SF); Mental Health (MH); and Role-Emotional (RE) (problems in role functioning attributed to emotional problems). Scales comprise different numbers of items using a Likert-type rating format. Raw scores were converted to a standard metric (0100), with higher scores being indicative of a better health state. To allow comparisons with healthy people, standard scores were then transformed into T-scores (mean 50; standard deviation 10) using US population norms derived from the Medical Outcomes Study.37 The test manual distributed by the Medical Outcomes Trust also includes instructions for computing two health summary scores, the Mental Component Score and Physical Component Score.37 Fatigue. The Fatigue Symptom Inventory (FSI) assesses the duration and severity of fatigue as well as its perceived interference with quality of life.38 Duration was assessed as the number of days in the past week (07) that respondents felt fatigued. Severity was measured on an 11-point scale (0 not at all fatigued to 10 as fatigued as I could be) that assessed most fatigue experienced in the past week. Perceived interference was measured on separate 11-point scales (0 no interference to 10 extreme interference) that assess the degree to which fatigue in the past week was judged to interfere with general level of activity, ability to bathe and dress, normal work activity, ability to concentrate, relations with others, enjoyment of life, and mood. Individual item scores were summed to produce an overall fatigue interference score ranging from 0 to 77. Previous research has demonstrated the reliability and validity of the FSI with cancer patients.39,40 Aerobic tness. Aerobic tness, the ability to sustain submaximal physical activity, was assessed by measuring oxygen utilization at the ventilatory threshold of lactate production (VT). VT is widely used as a measure of aerobic tness and has demonstrated reliability and validity in previous studies of healthy subjects and patient populations.4143 To determine VT, respired gases were collected during a progressive, submaximal treadmill exercise test (Stanford protocol) (Franklin et al,44 p 98). Gas exchange variables were recorded continuously, averaged at 20-s intervals, and analyzed using open-circuit spirometry and an automated metabolic cart (MAX-1 Oxygen Uptake
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Measures
Anthropometric characteristics. Height and weight measured at the baseline and post-intervention assessments were used to calculate body mass index (wt (kg)/ht (m2)). Feasibility. Feasibility of the self-administered aerobic exercise program was assessed by calculating: (1) the percentage of eligible patients who agree to participate (acceptability); (2) the percentage of eligible patients enrolled who actually completed the study (attrition); and (3) the percentage of prescribed exercise performed by study participants (adherence; number of sessions performed/number of sessions prescribed). Although participants were free to exercise as many times each week as they wished, no more than three sessions in any week were included in the adherence calculations. Safety. In order to document any potential safety issues or adverse events possibly related to exercise training following HSCT, participants were asked to review a checklist of possible symptoms or events that could be attributed to exercise training during the weekly telephone follow-up sessions. The list included all medical conditions identied in the exclusionary criteria for the study, possible symptoms of overtraining (eg insomnia on exercise days, elevated resting heart rate), adverse events or symptoms

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System; Physio-Dyne Instrument Corp., Quogue, NY, USA). A 35 min warm-up and cool down period of selfpaced walking accompanied each test. The exercise test was terminated if any of the following situations occurred: (a) a subject complained of excessive fatigue, dyspnea, or discomfort; (b) Borg RPE (620 scale) score X16; (c) respiratory exchange ratio (RER) X1.00; heart rate increased to 85% of the subjects age-predicted maximum; or (d) oxygen uptake failed to increase during two successive increments. Each participants VT was determined using two different methods: v-slope and ventilatory equivalents.42 If VT estimates differed by 45%, the lower value was used to calculate oxygen utilization.

Statistics
Prior to conducting the main analysis, descriptive and exploratory analyses were conducted for all baseline measures. Scores for most variables were negatively skewed, resulting in a decision to use nonparametric (Wilcoxons signed-rank) tests for paired comparisons between the baseline and post-intervention conditions.

informed consent documents (acceptability 32/42 76%). Reasons given for refusal to participate included a lack of interest in exercise, symptoms of fatigue, and pain. Of the 32 volunteers who enrolled in the study, eight were subsequently determined to be medically ineligible by their oncologists and seven chose to withdraw prior to the baseline assessment. Of these, one cited driving distance to the testing cite as the reason for withdrawal. The remaining six did not keep appointments for baseline testing and did not return telephone calls requesting them to reschedule. Two participants became medically ineligible after beginning the study, one for recurrence of metastatic disease and one for avascular necrosis associated with corticosteroid therapy for chronic graft-versus-host disease. Two others chose not to complete the study (attrition 11/24 46%). One of these participants moved away to be closer to family and the other could not be reached to schedule an appointment for the post-intervention assessment. Adherence. Nine of 13 subjects completing the study returned completed exercise diaries. These patients generally exercised by walking. Of 324 exercise sessions assigned, participants reported completing 273 (84%) at the prescribed intensity and duration. Safety. No adverse reactions or events attributable to exercise were noted among the 17 participants who began the study.

Results Physical activity, anthropometric, and clinical characteristics

Descriptive data for the 17 subjects who contributed baseline data to the study are summarized in Table 1. Of the 103 patients initially screened for participation, 24 stated that they exercised at least three times per week for at least 20 min per session (sedentarism 79/103 77%). In all, 14 participants were classied as overweight using WHO and NIH guidelines (BMI 425 kg/m2] with seven exceeding threshold values for obesity (430 kg/m2).45,46 Three of the four patients treated with allogeneic transplantation received ongoing immunosuppressive therapy, including cyclosporine and corticosteroids, during their participation in the study.

Potential efcacy
Aerobic tness. Aerobic tness at baseline was poor. Oxygen utilization at VT (9 ml/kg/min or approximately 2.5 METs) was well below the average value of 15.0 16.5 ml/kg/min (4.254.75 METs) expected for adults ages 46 years and over,47,48 but demonstrated statistical and clinical improvement (415%) following 12 weeks of exercise intervention (Table 2). Fatigue. Although participants reported only modest levels of fatigue at entry into the study, symptom severity improved signicantly (signed ranks test; Po0.05) following 12 weeks of home-based exercise. Fatigue symptom duration and interference scores showed no changes from baseline levels (Table 2). Health-related quality of life. Reported levels of physical functioning and physical role functioning were substantially (40.5 s.d.) lower than US norms at baseline (Table 2). Statistically signicant (Po0.05) improvements were observed for the SF-36 Physical Functioning and Physical Role Functioning subscales.

Feasibility
Acceptance and attrition. In all, 32 of the 42 qualied candidates identied during the initial screening signed
Table 1

Demographic and clinical characteristics (N 17)

Mean (s.d.) 48.9 (10.4) years 29.7 (5.0) kg/m2 16.9 (8.3) months 12.8 (1.2) g/dl 11 females, six males 13 autologous PBSCT 4 allogeneic BMT 8 multiple myeloma 6 breast CA 2 ALL 1 large B-cell lymphoma 12 caucasian 3 hispanic 1 African american 1 middle eastern

Characteristic Age BMI Time since transplant Hemoglobin Gender Transplant type Primary cancer

Discussion
This pilot study represents a preliminary effort to assess the feasibility of a self-administered aerobic exercise program for cancer survivors treated with HSCT. It is also the rst study to simultaneously assess the impact of aerobic exercise on cardiorespiratory tness, fatigue, and quality

Ethnicity/cultural preference

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Table 2

Means and s.d.s for aerobic tness, fatigue symptoms, and quality of life measures
Pre-intervention Mean (s.d.) Post-intervention Mean (s.d.) 10.4 (1.5) Wilcoxons Z 2.40 P-value 0.02

Oxygen utilization at VT (ml/kg/min) Fatigue (FSI) Severity Duration Interference SF-36 Summary Scores Physical component Mental component SF-36 Subscale Scores Physical functioning Rolephysical Roleemotional Vitality/fatigue Mental health Social functioning Bodily pain General health

9.0 (2.0)

3.9 (1.7) 2.9 (1.7) 15.3 (10.4)

3.3 (2.0) 2.0 (2.0) 10.8 (12.1)

1.99 1.70 1.89

0.05 0.09 0.06

41.4 (8.9) 52.5 (8.3)

45.2 (7.0) 52.6 (8.1)

1.78 0.11

0.08 0.92

41.3 43.5 48.7 48.5 51.7 47.9 47.1 43.7

(9.3) (7.1) (7.6) (8.1) (10.9) (8.6) (11.0) (11.2)

45.8 47.5 50.2 48.8 53.5 48.7 49.2 45.9

(8.4) (6.4) (6.8) (8.9) (8.8) (10.8) (6.8) (10.7)

2.06 2.32 0.32 0.05 1.14 0.42 0.92 1.13

0.04 0.02 0.75 0.96 0.26 0.67 0.36 0.26

of life beyond the acute recovery period immediately following HSCT. We found generally high levels of overall HRQoL, but with limitations in physical well-being consistent with previous HSCT studies.24,6 The mechanisms underlying this pattern of ndings are unclear. Previous investigators have attributed these physical deciencies to adverse physiological effects related to HSCT treatment (eg anemia, sarcopenia). Our patients reports of impaired physical functioning and role participation were accompanied by poor aerobic tness. Rates of sedentarism and obesity in our sample are somewhat higher than those previously reported for cancer survivors and undiagnosed adults of comparable age and gender.13,1619,49 These ndings suggest that physical inactivity and other modiable lifestyle factors may contribute to the physical impairments and functional limitations reported by HSCT recipients. Although limited sample size and absence of a comparison condition in the present study limit the conclusions that may be drawn concerning efcacy, our results contribute to a growing body of evidence, indicating that these decits may be reversible. We observed simultaneous improvements in physical functioning, role participation, and aerobic tness that are similar in magnitude to results from previous exercise trials conducted with cancer survivors.20,26 Given these ndings, it is tempting to conclude that improvements in physical wellbeing are mediated by improvements in physical tness. Several mechanisms (biological, psychological, social interaction) have been proposed to account for the benecial association between exercise training and quality of life observed among cancer patients,5052 but actual evidence in support of these potential mechanisms is quite limited. Formal mediational analyses of intervention effectiveness have been conducted in only one study, a controlled trial of exercise training for breast cancer survivors.20 We did not conduct a mediational analysis in the present study because the small sample size produced unacceptably low subject to variable ratios. Consequently, no empirical evidence exists to support the theory that positive changes in physical well-

being reported by exercising HSCT recipients are mediated by physiological training effects. The current lack of understanding of the mechanisms operating between exercise and quality of life following HSCT warrants future research. Previous studies have documented that cancer-related fatigue is a prevalent and persistent problem among HSCT recipients.2,8,11,40 The modest levels of fatigue reported by participants in the present study are inconsistent with these ndings. The participants in our study were not receiving active cancer treatment and were rigorously screened for physical conditions known to contribute to physical fatigue (eg anemia, fever). This recruiting strategy may have excluded more symptomatic HSCT recipients represented in previous studies. To our knowledge, this was the rst exercise study involving HSCT recipients to use a multidimensional fatigue scale as an outcome measure. We found that fatigue severity improved signicantly over 12 weeks of individually prescribed, self-directed aerobic training. It is also important to note that other fatigue symptoms (duration and intrusion) did not worsen during exercise participation. Indeed, there were marginal improvements in duration and intrusion. These ndings are supported by results from previous trials demonstrating improvements in fatigue symptoms in response to exercise interventions in other populations of cancer survivors, and challenge the belief that aerobic exercise depletes energy reserves.20,25,26 Exercise adherence rates (84%) observed in our study fell well within the range of values reported in studies of cancer patients exercising under supervised conditions (7298%)20,26 and compare favorably with results obtained from the only previous study using a selfadministered exercise intervention (72%).26 These results should be interpreted cautiously since only nine of 13 participants (69%) who completed the present study returned completed exercise diaries. To decrease burden on participants and improve return rates in future work, consideration should be given to limiting the amount of data collected in the diary. Automated data entry and
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retrieval systems (eg e-mail reminders, PDAs) could provide novel alternatives to paper records and allow opportunities for continuous monitoring of responses. The acceptance rate in our study was somewhat higher than in other reports, but this advantage was offset by a higher rate of attrition. This was primarily due to the large number of recruits who provided informed consent but withdrew from the study before the initial assessment. The reason for this pattern is unclear, but may reect a conict between a desire for social acceptance (ie approval from family members and health-care staff) and low motivational readiness to modify lifestyle. Poor self-efcacy, or lack of condence in ones ability to participate in a positive lifestyle change, may have also been a factor. Pinto and coworkers53 found that overweight and obese women demonstrated signicantly lower exercise self-efcacy than other breast cancer survivors. The majority of participants in our study were overweight or obese, and breast cancer survivors comprised a substantial portion of our sample. This suggests that subject retention in future work with HSCT recipients may be improved by adding strategies aimed at improving exercise self-efcacy and behavior change. Participants in this study included four patients who received allogeneic stem cell transplantation. Treatmentrelated complications, particularly chronic graft-versushost disease and its attendant corticosteroid treatment, could be expected to result in muscle weakness, fatigue, and functional decits in this group.32 However, the small sample size in the current study precludes meaningful statistical comparisons of these traits between allogeneic and autologous transplant recipients. In the future, it might be useful to include sufcient numbers of both allograft and autograft recipients in randomized clinical trials (and stratify random assignment by type of transplant) so as to be able to address the issue of the relative benet and appropriateness of exercise for both groups of patients. An extended follow-up period of 612 months might also enable investigators to determine whether the benets of exercise interventions observed in the current study persist over the longer term. In summary, this work furnishes preliminary evidence supporting the safety and feasibility of an intervention (home-based aerobic exercise training) in a form that may be easily exported and disseminated in a variety of oncology settings. Results of this pilot study should be used to plan and develop denitive clinical trials aimed at demonstrating that home-based aerobic exercise training is effective for improving fatigue symptoms and quality of life for cancer survivors treated with hematopoietic stem cell therapy.

Acknowledgements
The authors gratefully acknowledge Zoe Swain and Iryna Watson for their assistance with recruitment and data collection.

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