The Effect of Exercise on Tumor Hypoxia in Men With Localized Prostate Cancer Undergoing Radical Prostatectomy.

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 one acute exercise bout on tumor hypoxia in patients with localized prostate cancer undergoing radical prostatectomy. The primary hypothesis is that exercise reduces tumor hypoxia and that the reduction is greater in patients performing one acute high intensity exercise bout compared to no training controls. The investigators have not been able to identify any prior or current randomized trials investigating exercise and tumor hypoxia, and believe that such research is warranted and would be of great importance. 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 one single acute High Intensity Interval Training bout or usual care and no training the day prior to radical prostatectomy. All patients will undergo assessment at inclusion (baseline) and the day prior to surgery. Assessment includes: anthropometrics; blood pressure; resting hearth rate; hip and waist circumference, ECG, quality of life by self-report questionnaires; fasting blood sample measuring PSA (prostate specific antigen), cholesterol, triglycerides, insulin, c-peptide, HbA1c, glucose and inflammatory markers. All patients will receive one dose of pimonidazole hydrochloride (500 mg per m2 body surface) in order to quantify tumor hypoxia by pathological analyses after removal of the prostate. Biological tissue from tumor (primary prostate biopsies) will also 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 one acute exercise bout on tumor hypoxia in patients with localized prostate cancer randomized to one single acute I) High Intensity Interval Training bout compared to (II) usual care and no training prior to radical prostatectomy. In addition to this the aim is to investigate the effect of one exercise bout on tumor vessel morphology and to investigate the effect of one acute exercise bout on intratumoral immune cell infiltration and to investigate the modulation of tumor-metabolism, -biology and signaling in patients randomized to either one acute High Intensity Interval Training bout compared to usual care and no training, the day prior to surgery. Moreover this study will explore the acute response in immune cells, hormones and cytokines in blood samples taken before, during and after a single exercise session, and will collect physiological (metabolic profile and metabolic inflammatory markers) and psycho-social (e.g. fatigue, emotional well-being, anxiety) information regarding patients randomized to either one acute High Intensity Interval Training bout compared to usual care and no training, the day prior to surgery.

Official Title
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The Effect of Exercise on Tumor Hypoxia 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 bout


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men with histologically verified localized prostate adenocarcinoma undergoing curative intended radical prostatectomy. Exclusion Criteria: Age: <18 years Any other known malignancy requiring active treatment Performance status > 1 Allergy to pimonidazole 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: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Intensity Interval Training bout<br>Patients randomized to this group will perform a wattmax test immediately followed by 4 intervals of high and low intensity based on percentage of wattmax. Immediately after the exercise bout is finished patients will receive one dose of pimonidazole hydrochloride (500 mg per m2 body surface) in order to quantify tumor hypoxia by pathological analyses after removal of the prostate by radical prostatectomy the following day. | Behavioral: High Intensity Interval Training bout<br>* Patients randomized to the HIIT bout will perform one single supervised High Intensity Interval Training bout consisting firstly of a wattmax test on a stationary bike, in order to set the training intensity. This is followed by 10 minutes at low intensity at approximately 30% of wattmax. Subsequently patients will perform 16 min with 4 cycles with High and Low intensity. HI intervals consisting of 1 min with 100% of wattmax followed by 3 min recovery with the intensity load of 30% of wattmax.<br>|
| No Intervention: Controls (usual care)<br>Patients randomized to the control group will not be doing any exercise, but will after approximately 35 min from baseline blood sampling receive one dose of pimonidazole hydrochloride (500 mg per m2 bodysurface) in order to quantify tumor hypoxia by pathological analyses after removal of the prostate by radical prostatectomy the following day. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor hypoxia | Quantification of tumor hypoxia will be assessed using pimonidazole staining | At prostatectomy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intratumoral immune cell infiltration | Intratumoral immune cell infiltration will be quantified using histological analyses | Primary prostate biopsies and until radical prostatectomy | 
| Tumor vessel morphology | Tumor vessel morphology will be evaluated using histological analyses | Primary prostate biopsies and until radical prostatectomy | 
| Tumor metabolism-, biology and signaling | Tumor samples will undergo proteomic analyses in order to uncover potential upregulated biomarkers | Primary prostate biopsies and until radical prostatectomy | 
| Changes in immune cells during an acute exercise bout | Changes in immune cells during an acute exercise bout will be measured in blood samples using flowcytometry | From start of exercise bout and until 60 minutes post exercise | 
| Changes in epinephrine concentration | Concentration of epinephrine will be measured in blood samples by radioimmunoassay analyses. | From start of exercise bout and until 60 minutes post exercise | 
| Changes in nor-epinephrine concentration | Concentration of nor-epinephrine will be measured in blood samples by radioimmunoassay analyses. | From start of exercise bout and until 60 minutes post exercise | 
| Changes in various interleukines | Concentration of various interleukines will be measured in blood samples by measured in blood samples by Enzyme-Linked Immunosorbent Assay (ELISA) analyses. | From start of exercise bout and until 60 minutes post exercise | 
| Changes in Tumor Necrosis Factor alpha (TNFa) concentration | Concentrations of TNFa will be measured in blood samples by Enzyme-Linked Immunosorbent Assay (ELISA) analyses. | From start of exercise bout and until 60 minutes post exercise | 
| Changes in Interferon Gamma (IFNγ) concentration | Concentrations of IFNγ will be measured in blood samples by Enzyme-Linked Immunosorbent Assay (ELISA) analyses. | From start of exercise bout and until 60 minutes post exercise | 
| Concentration of C-reactive Protein (CRP) | Concentration of CRP will be measured in fasting blood sample by standard laboratory methods. | Blood sampling on the day of radical prostatectomy | 
| Total plasma cholesterol concentration | Concentrations of total cholesterol will be measured in fasting blood samples by standard laboratory methods. | Blood sampling on the day of radical prostatectomy | 
| Plasma LDL-Cholesterol concentration | Concentrations of LDL- cholesterol will be measured in fasting blood samples by standard laboratory methods. | Blood sampling on the day of radical prostatectomy | 
| Plasma HDL-Cholesterol concentration | Concentrations of HDL- cholesterol will be measured in fasting blood samples by standard laboratory methods. | Blood sampling on the day of radical prostatectomy | 
| Plasma triglyceride concentrations | Concentrations of triglycerides will be measured in fasting blood samples by standard laboratory methods. | Blood sampling on the day of radical prostatectomy | 
| HbA1C concentration | Concentrations of HbA1C will be measured in fasting blood samples by standard laboratory methods. | Blood sampling on the day of radical prostatectomy | 
| Plasma Insulin concentration | Concentrations of insulin will be measured in fasting blood samples by standard laboratory methods. | Blood sampling on the day of radical prostatectomy | 
| Plasma Glucose concentration | Concentrations of glucose will be measured in fasting blood samples by standard laboratory methods. | Blood sampling on the day of radical prostatectomy | 
| Wattmax-test | The participants in the HIIT group 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 3 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. | At baseline assessment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prostate neoplasm, exercise, high intensity interval training, tumor hypoxia, immune cells