Bladder Cancer and exeRcise Training During intraVesical thErapy (BRAVE)

Feasibility and Preliminary Efficacy of High-Intensity Interval Training in Bladder Cancer Patients Receiving Intravesical Therapy: A Randomized Controlled Trial

Bladder cancer is the fifth most common cancer in Canada and has the eighth highest cancer mortality rate. The treatment for the most frequent type of bladder cancer is surgically removing the tumour followed by six weeks of medication placed within the bladder. There are physical and psychosocial challenges from bladder cancer and its treatment that may affect how patients feel and function, and consequently their quality of life. Moreover, bladder cancer patients are at a high risk of their bladder cancer coming back and getting worse. Exercise is a low-cost intervention that may lower the chances of bladder cancer coming back or getting worse, manage side effects related to treatment, help patients feel better, and improve quality of life. To date, however, no study has examined if it is safe or even possible for bladder cancer patients to exercise when they are receiving drugs placed into their bladder. The Bladder cancer and exeRcise trAining during intraVesical thErapy (BRAVE) Trial will be the first study to test the safety, feasibility, and efficacy of exercise in bladder cancer patients during this drug therapy. The investigators will ask some patients to do a supervised exercise program during their drug treatment while other patients will be asked not to exercise. The investigators will compare the 2 groups on how they fare with their bladder cancer treatment. This study will provide information on whether exercise may help patients feel better, function better, and possibly even lower their chances of the disease coming back or getting worse.

Non-muscle invasive bladder cancer, Exercise, High-intensity interval training, Randomized Controlled Trial

Participants and investigators will not be blinded to group assignment given the nature of the intervention. Outcome assessors will be blinded to group assignment for the clinical outcomes of tumour recurrence and progression.

The exercise intervention will consist of 36 high-volume high-intensity interval sessions over a 12-week period. The exercise frequency will be three times per week during the 6 weeks of intravesical therapy and the 6 weeks of recovery (total 12 weeks) prior to a surveillance cystoscopy.

Patients randomized to the control group will be asked not to initiate any exercise program or to increase their exercise level from baseline during the 12-week study. After the post-intervention assessments and 3-month cystoscopy, patients in the control group will be offered a 4-week supervised exercise program at the Behavioural Medicine Fitness Centre, University of Alberta.

The intervention will be performed on a treadmill and will include a warm-up and cool-down at 50-60% and 40% of the VO2peak respectively, for up to five minutes. The HIIT protocol will be 4x4, which consists of four bouts of four minutes at a workload corresponding to vigorous intensity (75-95% of the baseline and 6-week VO2peak) alternating with three minutes of recovery intervals at 40% of the VO2peak. The exercise session will last 35 minutes and include 16 minutes of high intensity exercise.

VO2 peak will be directly measured by the modified Bruce treadmill protocol exercise test, using a metabolic measurement system system (Parvo Medics TrueOne® 2400; Sandy, UT, USA).VO2peak will be defined as the highest oxygen-uptake value recorded during the test and will be expressed as relative to body mass (i.e., ml O2·kg-1·min-1).

30-second chair stand Scores are compared with normative data based on sex and age, with "normal" defined as the middle 50% of the population. Those scoring above this range would be considered above average for their age and those below the range as below average

Arm curl Scores are compared with normative data based on sex and age, with "normal" defined as the middle 50% of the population. Those scoring above this range would be considered above average for their age and those below the range as below average

Chair sit-and-reach Scores are compared with normative data based on sex and age, with "normal" defined as the middle 50% of the population. Those scoring above this range would be considered above average for their age and those below the range as below average

Back Scratch Scores are compared with normative data based on sex and age, with "normal" defined as the middle 50% of the population. Those scoring above this range would be considered above average for their age and those below the range as below average

8-foot up-and-go Scores are compared with normative data based on sex and age, with "normal" defined as the middle 50% of the population. Those scoring above this range would be considered above average for their age and those below the range as below average

6-minute walk test Scores are compared with normative data based on sex and age, with "normal" defined as the middle 50% of the population. Those scoring above this range would be considered above average for their age and those below the range as below average

Assessment of health-related quality of life (HRQoL) using the European Organization for Research and Treatment of Cancer (EORTC) core 30-item questionnaire (QLQ-C30) version 3.0. The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / quality of life scale, and six single items. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.

At baseline, 3-month (post-exercise intervention/prior to the 3-month surveillance cystoscopy), and at one-year follow-up

European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for non-muscle invasive bladder cancer core 24-item (EORTC QLQ NMIBC C24). EORTC QLQ NMIBC C24 is composed of scales assessing urinary symptoms, bowel symptoms, sexual, and side effects of intravesical treatment (fever, malaise, convenience of and worry due to repeated cystoscopies). All of the scales a range in score from 0 to 100. A high scale score represents a higher response level.

At baseline, 3-month (post-exercise intervention/prior to the 3-month surveillance cystoscopy), and at one-year follow-up

Fear of cancer recurrence/progression will be assessed by the Fear of Cancer Recurrence Inventory Minimum: 0 Maximum:168 Higher score= higher levels of fear of cancer recurrence/progression

At baseline, 3-month (post-exercise intervention/prior to the 3-month surveillance cystoscopy), and at one-year follow-up

Anxiety will be assessed using the 10-item State-trait Anxiety Inventory. Minimum: 20 Maximum: 80 Higher score= worse anxiety

At baseline, 3-month (post-exercise intervention/prior to the 3-month surveillance cystoscopy), and at one-year follow-up

Depression will be assessed using the Epidemiologic Studies Depression Scale (CES-D) questionnaire. Minimum: 0 Maximum: 30 (cut off point: 10) Higher score= worse depression

At baseline, 3-month (post-exercise intervention/prior to the 3-month surveillance cystoscopy), and at one-year follow-up

Perceived stress will be assessed using the Perceived Stress Scale (PSS) questionnaire. questionnaire. Minimum: 0 Maximum: 56 Higher score=worse perceived stress

At baseline, 3-month (post-exercise intervention/prior to the 3-month surveillance cystoscopy), and at one-year follow-up

Fatigue will be assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire Minimum: 0 Maximum: 52 Higher score=worse fatigue

At baseline, 3-month (post-exercise intervention/prior to the 3-month surveillance cystoscopy), and at one-year follow-up

Self-esteem using the Rosenberg self-esteem scale Minimum: 10 Maximum: 40 Higher score= better self-esteem

At baseline, 3-month (post-exercise intervention/prior to the 3-month surveillance cystoscopy), and at one-year follow-up

Sleep quality will be assessed by the Insomnia Severity Index (ISI) Minimum: 0 Maximum: 28 Higher score= worse insomnia

At baseline, 3-month (post-exercise intervention/prior to the 3-month surveillance cystoscopy), and at one-year follow-up

Social cognitive predictors of exercise adherence: motivation, perceived benefits, enjoyment, support from others, self-efficacy, and barriers

At baseline, 3-month (post-exercise intervention/prior to the 3-month surveillance cystoscopy), and at one-year follow-up

3-month (post-exercise intervention/prior to the 3-month surveillance cystoscopy) and one-year follow-up

Intravesical therapy adherence will be tracked by medical records of attendance and self-report drug retention time

Incidence of Adverse events related to the High-Intensity Interval Training during Intravesical Therapy

To evaluate the safety of the program, any adverse events during the physical assessments (baseline, post- intravesical therapy, and post-intervention) and during the exercise sessions will be recorded.

Recruitment rate of non-muscle invasive bladder cancer patients to a high-intensity interval training during Intravesical Therapy

The recruitment rate will be the number of non-muscle invasive bladder cancer patients enrolled in the study divided by the number of eligible patients.

Adherence to the program will be measured by the number of exercise sessions completed without dose modifications. Reasons for not completing the exercise session or for dose adjustments will be recorded.

Follow-up assessment rate of non-muscle invasive bladder cancer patients to a high-intensity interval program during Intravesical Therapy

The follow-up assessment rate will be determined by the number of participants who do not complete the post-intervention or follow-up assessments for any reason.

Inclusion Criteria: Eligible participants will include men and women that (1) are ≥ 18 years old, (2) have a confirmed diagnosis of non-muscle invasive bladder cancer (clinical stage cis, Ta or T1), and (3) are scheduled to receive induction intravesical therapy with chemotherapy (e.g., Gemcitabine or Mitomycin) or immunotherapy (e.g., BCG) agents. Exclusion Criteria: Exclusion criteria for participants include: (1) not being medically cleared to participate in the exercise intervention by their treating urologist and a certified exercise physiologist using the Physical Activity Readiness Questionnaire for Everyone (PAR-Q+), (2) having contraindications for cardiopulmonary stress and/or physical fitness tests, (3) already exercising according to the Godin Leisure-Time Exercise Questionnaire (GLTEQ), (4) not having the ability to read and comprehend English, and (5) not willing to be randomized to a supervised exercise training program or usual care (no exercise) for 12 weeks.

Arthuso FZ, Fairey AS, Boule NG, Courneya KS. Bladder cancer and exeRcise trAining during intraVesical thErapy-the BRAVE trial: a study protocol for a prospective, single-centre, phase II randomised controlled trial. BMJ Open. 2021 Sep 24;11(9):e055782. doi: 10.1136/bmjopen-2021-055782.