A 6-month prospective, assessor-blinded, randomized controlled trial will be conducted to compare an Exercise Group to a Control Group. Patients will be recruited through CancerCare Manitoba. Baseline and follow-up visits will be conducted at the Department of Physical Therapy at the University of Manitoba. The University of Manitoba Research Ethics Board has approved the study protocol (Ethics Reference # H2008:318), which is also in compliance with the Helsinki Declaration.
Participants
Inclusion criteria
Patients will be included in the study if they are men aged 50 years or older, diagnosed with adenocarcinoma prostate cancer, and will initiate and receive continuous ADT (luteinizing hormone releasing hormone agonist (LHRH) or combination of LHRH and anti-androgen) for at least 6 months after recruitment. Patients will be required to provide written informed consent to participate in the study.
Exclusion criteria
Patients will be excluded from the study if they have severe cardiac disease (New York Heart Association class III or greater), angina, pre-existing osteoporosis with T-score at or below −2.5, stable bone lesion, uncontrolled hypertension (blood pressure > 160/95 mm Hg), moderate to severe aortic stenosis, acute illness or fever, uncontrolled atrial or ventricular dysrhythmias, uncontrolled sinus tachycardia (> 120 beats per minute), third-degree atrio-ventricular heart block, active pericarditis or myocarditis, recent pulmonary embolism, deep vein thrombosis, uncontrolled diabetes, uncontrolled pain, cognitive impairment, history of falls due to balance impairment or lost of consciousness, or severe neuromusculoskeletal conditions that limit their ability to perform walking exercise (including ataxia, peripheral or sensory neuropathy, unstable bone lesion, severe arthritis, pathological lower limb fractures within 6 months, lower limb amputation).
Recruitment
A total of 20 patients will be recruited consecutively during office visits at the initial 3-month phase of the study at CancerCare Manitoba. The attending physician will screen the patients for inclusion criteria (men aged 50 or older, diagnosed with adenocarcinoma prostate cancer, will initiate and receive continuous ADT (LHRH or combination of LHRH and anti-androgen for at least 6 months). The physicians will be provided with an information sheet that provides brief information about study. If the patients meet the preliminary inclusion criteria, the physicians will provide a brief explanation about the study, and verbal consent to refer them to a clinical research nurse. The clinical research nurse will confirm that all inclusion and exclusion criteria are met, explain the study protocol, provide an information sheet for patients, and obtain written informed consent from the patients who would like to participate in the study. The clinical research nurse will provide the student research assistant (SRA) with the signed consent forms and contact information of the consented patients of the study.
Assessment sessions
Each participant will attend a total of three assessment sessions: one baseline, and two follow-up sessions at 3 and 6 months after ADT initiation at the Department of Physical Therapy. The Exercise Group will complete telephone survey between follow-up sessions.
Baseline assessment session
The SRA, who is trained in health sciences field, will contact the participants to schedule a baseline assessment in coordination with a clinical psychology research assistant (CPRA), who is trained to administer neuropsychological tests.
The baseline assessment will be administered by the CPRA first, followed by the SRA. The CPRA will collect the sociodemographic characteristics, and administer the primary (cognitive-psychosocial functions) and secondary outcome measures (health related quality of life (HRQOL)). The SRA will collect data on the physical activity variables.
The CPRA will be blinded to the group assignments of the participants. After the baseline assessment, the SRA will assign the participant the first available number from a randomly generated list consisting of “1” and “2”, that are generated by mixed randomization, [
38] using both simple randomization and permuted-block methods. Number “1” is designated as the Exercise Group that will receive instructions in setting up an individualized 6-month home-based walking exercise program in addition to their daily activities. Number “2” is designated as the Control Group that will be advised to perform daily activities as usual and follow the standard medical advice from their attending physician.
Follow-up sessions
The CPRA will schedule follow-up sessions for all participants at 3 and 6 months after ADT initiation. At 3 months, primary outcome (psychosocial functions) and secondary outcome variables (HRQOL) will be re-assessed. At 6 months, all primary (cognitive and psychosocial functions) and secondary (HRQOL) outcome measures will be re-assessed.
Exercise group protocol
The SRA will assess the baseline health and fitness of the participants of the Exercise Group using an exercise screening form that includes the revised Physical Activity Readiness Questionnaire (PAR-Q)[
40], and other screening questions for exercise contraindications and precautions. If any exercise contraindications (e.g. shortness of breath, severe headache, sudden onset of numbness or weakness) is present, the participant will be excluded from the study and referred to their family physician for investigation. If any exercise precautions (e.g. fever, severe cachexia, extreme fatigue, sickness or bone pain) is present, high-intensity or high-impact exercise will be avoided initially. If severe nausea or painful calf is present, the participants will be advised to consult their family physician for further investigation and clearance prior to beginning the exercise program.
The SRA will provide each participant of the Exercise Group with a pedometer and a take-home package that contains pedometer and exercise instructions and precautions, daily logs, general exercise tips, stretching instructions and self-addressed envelopes. The pedometer instructions and daily log instructions are same as per Control Group protocol.
The Exercise Group will follow a walking exercise program that comprises a progressive structured exercise protocol and progressive target daily step counts regimen. The structured exercise protocol will initially begin with a 10-minute walking session, 3 sessions per week. The Exercise Group participants will be instructed to perform a 5-minute warm-up period by walking slowly, followed by a 10-minute walking workout period, and then a 5-minute cool-down period by walking slowly and a stretching routine that is in the Exercise Group taken-home package. The SRA will also demonstrate to the participants how the stretches are to be done.
Participants will use the Borg Scale of Ratings of Perceived Exertion (RPE) [
41] to estimate their exercise intensity level during the workout and warm-up/cool-down periods. RPE is a reliable method in monitoring and regulating exercise intensity, with high correlation to oxygen uptake (r ≥ 0.83) [
42] and high internal consistency at different levels of velocities and heart rates (α > 0.90) [
43]. During the warm-up/cool-down periods, the participants will maintain an exertion level between 7.5 and 8 on (i.e. extremely light level of exertion). During the 10-minute walking workout session, the participants will gradually increase their walking speeds until they attain and maintain an RPE level between 9 and 13 (i.e. very light to light exertion) according to their baseline physical activity level (sedentary, moderately active, or active) as reported on their self-reported physical activity questionnaire. Sedentary individuals will start at RPE level of 9 (very light exertion), moderately active individuals will start at RPE level of 11 (light exertion), and active individuals will start at RPE level of 13 (somewhat hard exertion).
Each participant’s exercise level will be progressed every two week, first in frequency (1-day increment), then walking session (5-minute increment, and lastly RPE level. Based on the set progression protocol, the Exercise Group participants will be performing five walking exercise sessions per week, 30 minutes walking workout period per session, and will have attained RPE level of 15 (heavy exertion) by around 18 to 20 weeks. This level of exercise protocol will be maintained for the rest of the study period. The participants are instructed to record the date, start time, exercise duration and maximum RPE attained during each session in an exercise daily log.
The participants will also be encouraged to walk at their chosen pace at times outside their structured exercise protocol so as to achieve their assigned target daily step counts. The initial target will be set at 5000 steps for sedentary individuals, 6000 steps for moderately active individuals, and 7000 steps for active individuals. The target daily step counts will be progressed every two weeks (1000-steps increment) up to a maximum daily target of 10,000 steps. The participants will be counseled on the warning symptoms of impending cardiovascular events including chest pain or discomfort, shortness of breath, dizziness, severe headache, sudden onset of numbness or weakness, or painful calf suggestive of deep vein thrombosis. They will be strongly advised to discontinue the exercise program and report these symptoms to their attending physician and SRA immediately.
The SRA will call the Exercise Group participants every two weeks to monitor their safety, adherence, and progress using a short, structured phone survey. The results of the phone survey will be used to guide the adjustments/progression of the structured exercise and step counts protocols. In addition, the participants will return their pedometer and exercise daily logs every four weeks.
Data collection
At baseline session, the CRN will collect clinical data from the medical records of all consented patients that will include current cancer stage, time since diagnosis, treatment intent, testosterone level, prostate specific antigen level, Gleason score, comorbidity index. The SRA will collect sociodemographic data including age, marital status, ethnicity, living arrangement, education, work status, alcohol consumption and smoking history.
At baseline and 6-month follow-up visits, the primary outcome variable of
cognitive function including memory, attention and working memory, and executive function will be assessed by the CPRA using well-established neurocognitive tests. Additionally, each participant will complete a standardized “effort test” to ensure validity of the test results. A minimum of 6 months between tests is required to prevent practice or carry-over effects.
Memory will be assessed using: (1) the Brief Visuospatial Memory Test - Revised (BVMT-R) [
44] for non-verbal memory, and (2) the California Verbal Learning Test, 2
nd Edition (CVLT-II) [
45] for verbal memory.
Attention and working memory will be assessed using: (3) the Digit Span and Letter-Number Sequencing tasks from the Wechsler Adult Intelligence Scale – 3
rd Edition (WAIS-III). [
46]
Executive function will be assessed using: (4) the Stroop Color and Word Test [
47] for processing speed and inhibition, and (5) the Trail Making Test Parts A and B [
48] for visuomotor tracking and mental flexibility.
Test-taking effort of the neurocognitive tests will be confirmed using the (6) Word Memory Test (WMT) [
49].
At baseline and all follow-up sessions (3 and 6 months), the primary (psychosocial functions) and secondary outcome variables (HRQOL) will be assessed. Cognitive function of
self-reported memory function will be assessed using the Prospective Retrospective Memory Questionnaire (PRMQ) [
50,
51] for short and long-term memory.
Psychosocial function will be assessed using: (8) the Center for Epidemiological Studies Depression (CES-D) for
depression, [
52] (9) the Spielberger State-Trait Anxiety Inventory (STAI) [
53] for
anxiety, (10) the Rosenberg Self-Esteem Scale (SES) for
self-esteem. [
54,
55]
HRQOL will be assessed using (12) the Functional Assessment of Cancer Therapy Prostate Module (FACT-P) [
56] as a disease-specific global HRQOL instrument. Every four weeks, physical activity levels of both Control and Exercise groups will be monitored based on the completed pedometer daily logs returned by all participants.
Exercise group
Exercise adherence of the Exercise Group participants will be monitored using the exercise daily logs returned every four weeks, and phone surveys conducted by SRA every two weeks. The phone surveys will also be used to monitor exercise safety and progress.