PROstaTe Cancer - Exercise-STudy (PRO-TEST)

Study Overview
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Brief Summary
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Background and purpose: The purpose of this study is to investigate the effect of exercise on intratumoral natural killer (NK)-cell variability in patients with localized prostate cancer undergoing radical prostatectomy. The primary hypothesis is that exercise induces epinephrine-mediated intratumoral natural killer (NK)-cell infiltration in patients with localized prostate cancer, and that the infiltration is greater in patients performing High Intensity Interval Training compared to usual care controls. Currently there is a lack of randomized controlled trials examining different types of exercise in patients with localized prostate cancer. Moreover there is a need for studies including biological measurements to allow a full assessment of the effect of exercise on diverse biomarkers and mechanistic pathways, which may influence cancer survival. Subjects: Patients with histologically verified prostate adenocarcinoma scheduled for radical prostatectomy at Urologic Department, Rigshospitalet, Copenhagen, Denmark. Methods: In this randomized controlled pilot study 30 patients with localized prostate cancer undergoing radical prostatectomy will be included and randomized 2:1 to either High Intensity Interval Training (HIIT) exercise intervention or observational control receiving usual care from inclusion and until planned surgery (radical prostatectomy). All patients will undergo assessments at inclusion (baseline) and at follow-up after the exercise intervention period (maximum 8 weeks) 3-5 days prior to surgery. Assessments include: anthropometrics; blood pressure; resting hearth rate; cardiorespiratory fitness by cardiopulmonary exercise test (VO2 peak.); body composition by DXA scan; quality of life by self-report questionnaires; fasting blood sample measuring cholesterol, triglycerides, insulin, c-peptide, HbA1c, glucose, hormones and inflammatory markers. Biological tissue from tumor (primary prostate biopsies) will be retrieved from the respective local pathological departments and from the perioperative prostate specimen and sent to protocol analyses.

Detailed Description
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The purpose of this study is to investigate the effect of exercise on the variability of intratumoral Natural Killer (NK)-cell infiltration in tumor biopsies taken before and after an exercise intervention in patients randomized 2:1 to one of two study arms: I) High Intensity Interval Training (HIIT) (N=20) or II) usual care, prior to radical prostatectomy. In addition to this the investigators wish to investigate the effect of HIIT exercise on the infiltration of other immune cells into the tumor, tumor vessel morphology, modulation of tumor-metabolism, -biology and signaling. Finally the aim is to explore the effect of pre-operative HIIT exercise on physiological (e.g. cardiovascular fitness, body composition, metabolic profile and metabolic inflammatory markers) and psycho-social (e.g. fatigue, emotional well-being, anxiety) endpoints relative to usual care.

Official Title
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Effect of Different Exercise Regimens on Intratumoral Natural Killer (NK) Cell Variability in Men With Localized Prostate Cancer Undergoing Radical Prostatectomy - a Randomized Controlled Pilot Study

Conditions
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Prostate Cancer

Intervention / Treatment
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* Behavioral: High Intensity Interval Training
* Behavioral: Usual Care Observational Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically verified localized prostate cancer Eligible for curative radical prostatectomy Exclusion Criteria: Any other known malignancy requiring active treatment Performance status > 1 Ongoing treatment with beta blockers Physical disabilities precluding physical testing and/or exercise Inability to read and understand Danish

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Intensity Interval Training<br>The HIIT-group will receive usual care plus a supervised aerobic High Intensity Interval Training program consisting of 4 weekly sessions of approximately 35 minutes. | Behavioral: High Intensity Interval Training<br>* Supervised aerobic High Intensity Interval Training program consisting of 4 weekly sessions of approximately 35 minutes. Patients will perform a test of maximum cardio-respiratory (VO2 peak test). Using the patient's individual wattmax, a personalized exercise program will be prescribed. After a light warm-up, patients will perform 25 min of aerobic high intensity interval training on a stationary bicycle, intervals will consist of cycles of HI intervals with 120% of wattmax for 1 min followed by recovery for 3 min at 30% of wattmax. Each session will be supervised by trained instructors to ensure proper technique, and progression in training load.<br>|
| Active Comparator: Usual Care Observational Control<br>Patients randomized to usual care control will receive the standard patient care program as provided by the Department of Urology, Rigshospitalet. | Behavioral: Usual Care Observational Control<br>* The reference group will receive the standard patient care program as provided by the Department of Urology, Rigshospitalet.This includes information regarding smoking cessation and alcohol reduction and a physiotherapist consultation regarding pelvic floor exercises. This group is allowed to exercise on their own initiative or participate in any standard care hospital- or municipality-based exercise program. This will be monitored by self-report.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variability in intratumoral Natural Killer (NK)-cell infiltration | Natural killer (NK)-cell infiltration will be quantified using histological analyses. | Primary prostate biopsies and up to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor vessel morphology | Tumor vessel morphology will be evaluated using histological analyses. | Primary prostate biopsies and up to 8 weeks | 
| Tumor-metabolism, - biology and signaling | Tumor samples will undergo proteomic analyzes in order to uncover potential upregulated biomarkers. | Primary prostate biopsies and up to 8 weeks | 
| Changes in immune cells | Quantification of immune cells will be measured in blood samples by flowcytometry analyses. | Baseline and up to 8 weeks | 
| Changes in epinephrine concentration | Concentrations of epinephrine will be measured in blood samples by radioimmunoassay analyses. | Baseline and up to 8 weeks | 
| Changes in nor-epinephrine concentration | Concentrations of nor-epinephrine will be measured in blood samples by radioimmunoassay analyses. | Baseline and up to 8 weeks | 
| Changes in IL-1 concentration | Concentrations of IL-1 (Interleukin 1) will be measured in blood samples by Enzyme-Linked Immunosorbent Assay (ELISA) analyses. | Baseline and up to 8 weeks | 
| Changes in IL- 2 concentration | Concentrations of IL-2 (Interleukin 2) will be measured in fasting blood samples by Enzyme-Linked Immunosorbent Assay (ELISA) analyses. | Baseline and up to 8 weeks | 
| Changes in IL- 6 concentration | Concentrations of IL-6 (Interleukin 6) will be measured in fasting blood samples by Enzyme-Linked Immunosorbent Assay (ELISA) analyses. | Baseline and up to 8 weeks | 
| Changes in IL- 8 concentration | Concentrations of IL-8 (Interleukin 8) will be measured in fasting blood samples by Enzyme-Linked Immunosorbent Assay (ELISA) analyses. | Baseline and up to 8 weeks | 
| Changes in IL- 10 concentration | Concentrations of IL-10 (Interleukin 10) will be measured in fasting blood samples by Enzyme-Linked Immunosorbent Assay (ELISA) analyses. | Baseline and up to 8 weeks | 
| Changes in IL- 15R alpha complex concentration | Concentrations of IL- 15Rα (IL- 15 receptor alpha) complex will be measured in blood samples by Enzyme-Linked Immunosorbent Assay (ELISA) analyses. | Baseline and up to 8 weeks | 
| Changes in Tumor Necrosis Factor alpha (TNFa) concentration | Concentrations of TNFa will be measured in blood samples by Enzyme-Linked Immunosorbent Assay (ELISA) analyses. | Baseline and up to 8 weeks | 
| Changes in Interferon Gamma (IFNγ) concentration | Concentrations of IFNγ will be measured in blood samples by Enzyme-Linked Immunosorbent Assay (ELISA) analyses. | Baseline and up to 8 weeks | 
| Changes in Plasma Total-Cholesterol concentrations | Concentrations of total cholesterol will be measured in fasting blood samples by standard laboratory methods. | Baseline and up to 8 weeks | 
| Changes in Plasma LDL-Cholesterol concentrations | Concentrations of LDL-cholesterol will be measured in fasting blood samples by standard laboratory methods | Baseline and up to 8 weeks | 
| Changes in Plasma HDL-Cholesterol concentrations | Concentrations of HDL-cholesterol will be measured in fasting blood samples by standard laboratory methods | Baseline and up to 8 weeks | 
| Changes in Plasma Triglyceride concentrations | Concentrations of triglycerides will be measured in fasting blood samples by standard laboratory methods | Baseline to and up to 8 weeks | 
| Changes in HbA1C (fasting blood samples) | Concentrations of HbA1C will be measured in fasting blood samples by standard laboratory methods | Baseline and up to 8 weeks | 
| Changes in insulin | Concentrations of Insulin will be measured in fasting blood samples by standard laboratory methods | Baseline and up to 8 weeks | 
| Change in body composition | Body weight and anthropometrics (height, waist and hip circumference) will be assessed using standard procedures. Resting heart rate and blood pressure (Microlife, BPA100) will be determined in a supine position. Body composition (fat mass, bone mass and fat-free mass) and bone mineral density are analyzed by whole-body dual-energy X-ray absorptiometry (DXA) scan (Lunar, Lunar Corporation Madison, Wisconsin, USA). Transverse scans at 1 cm intervals are made from head to toe measuring the absorption of x-ray beams at two different energy levels as these are sent through the body. Since the different chemical compounds in the body absorb the intensity of the X-rays differently, the scan allows for a valid determination of bone mass, fat mass and fat-free/bone-free mass | Baseline and up to 8 weeks | 
| Change in VO2peak | The participants will undergo a maximal graded exercise test on a bicycle ergometer for evaluation of cardiovascular function and determination of the peak oxygen uptake (VO2peak). The test starts with a 5 min warm up at 70 watt (the watts may have to be adjusted to the individual fitness level). Warm up is immediately followed by a 20 watt increase every 1 min until exhaustion. Ventilation and expired gases will be measured during the test via an indirect calorimetric system, and heart rate will be assessed simultaneously. | Baseline and up to 8 weeks | 
| Change in wattmax | The participants will undergo a maximal graded exercise test on a bicycle ergometer for evaluation of cardiovascular function and determination of the maximum watt (wattmax). The test starts with a 5 min warm up at 70 watt (the watts may have to be adjusted to the individual fitness level). Warm up is immediately followed by a 20 watt increase every 1 min until exhaustion. The maximum watt will be calculated. | Baseline and up to 8 weeks | 
| Changes in patient-reported Quality of Life - FACT | Patient reported quality of life is measured by Functional Assessment of Cancer Treatment (FACT) | Baseline and up to 8 weeks | 
| Changes in Sleep Quality | Patient reported sleep quality is measured by the Pittsburgh Sleep Quality Index (PSQI) questionaire. | Baseline up to 8 weeks | 
| Changes in Anxiety and Depression | Patient reported Anxiety and Depression is measured by the Hospital Anxiety and Depression Scale (HADS). | Baseline up to 8 weeks | 
| Changes in Physical Activity level | Patient reported physical activity is measured by the International Physical Activity Questionaire (IPAQ) - short form. | Baseline up to 8 weeks | 
| T-cell infiltration | T-cell infiltration will be quantified using histological analyses. | Primary prostate biopsies from baseline and up to 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate cancer, Localized, Exercise, Physical activity, Natural killer cells, Immune cells