Testosterone, Cognition, Ageing, and Cancer

Study Overview
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Brief Summary
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The primary aim of the study is - in a prospective controlled design - to examine whether treatment-induced decreases in testosterone acts as a mechanism of cancer-related cognitive impairment (CRCI) in testicular and prostate cancer patients. Secondary aims are 1) to explore whether decreases in testosterone interacts with increasing age to cause more severe CRCI in older patients, 2) to explore underlying neurophysiological (brain morphology) mechanisms of CRCI, and 3) to evaluate selected genetic variants as possible moderators of CRCI.

Detailed Description
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The study will include three groups with a total of 120 participants: A) Forty testicular cancer patients will be included and examined 1) shortly after orchiectomy and prior to any further treatment and 2) at 6 months' follow- up. B) Forty prostate cancer patients will be included and examined at two time-points: 1) prior to initiation of medical castration and radiotherapy and 2) at 6 months' follow- up. C) Forty age- and education-matched healthy controls will be included and assessed at a similar time-interval, i.e., at an initial examination and at a 6 month follow-up. Measures include a battery of neuropsychological/ cognitive tests, questionnaires, blood samples, and Magnetic Resonance Imaging (MRI). Primary hypothesis Treatment-induced decreases in testosterone will be associated with decline in global cognitive functioning from baseline to 6 months' follow- up in both testicular and prostate cancer patients. Secondary hypotheses Treatment-induced decreases in testosterone will be associated with decline in individual cognitive domains (i.e., processing speed, attention, verbal fluency, executive functioning, working memory, verbal learning and memory, visuospatial learning and memory, and visuospatial ability) from baseline to 6 months' follow- up in both testicular and prostate cancer patients. Decline in cognitive functioning from baseline to 6 months' follow- up in both testicular and prostate cancer patients will correspond to changes in grey matter as measured by T1-weighted MRI. Decline in cognitive functioning from baseline to 6 months' follow- up in both testicular and prostate cancer patients will correspond to changes in brain white matter as measured with diffusion-weighted MRI. Treatment-induced decreases in testosterone will be more strongly associated with decline in cognitive functioning in prostate cancer patients compared with testicular cancer patients due to more advanced age in the former group. Treatment-induced decreases in testosterone will be more strongly associated with decline in cognitive functioning in both testicular and prostate cancer patients carrying the the Apolipoprotein E (APOE) ε4 allele, the Val catechol-O-methyltranferase (COMT) allele, the Val/Val Brain- derived neurotrophic factor (BDNF) genotype, and a short polymorphic CAG repeat length of the Androgen Receptor (AR) gene. Treatment-induced decreases in testosterone will be associated with increases in neurobehavioral symptoms (i.e., apathy, executive dysfunction, and disinhibition) from baseline to 6 months' follow- up in both testicular and prostate cancer patients. Treatment-induced decreases in testosterone will be associated with decreases in health-related quality of life from baseline to 6 months' follow- up in both testicular and prostate cancer patients. Treatment-induced decreases in testosterone will be associated with decreases in perceived cognitive functioning from baseline to 6 months' follow- up in both testicular and prostate cancer patients.

Official Title
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Testosterone, Cognition, Ageing, and Cancer - A Controlled, Prospective Study About the Association Between Testosterone and the Prevalence and Severity of Cancer Related Cognitive Impairment in Testicular and Prostate Cancer Patients.

Conditions
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Cancer-related Cognitive Impairment

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of testicular cancer Confirmed diagnosis of prostate cancer and prescription of medical castration and radiotherapy Exclusion Criteria: Previous cancer disease Previous central nervous system disease Brain metastases Severe psychiatric disease (e.g., schizophrenia, major depressive disorder) Insufficient Danish proficiency for neuropsychological testing

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Testicular cancer patients<br>Forty testicular cancer patients included after orchiectomy but prior to any further treatment. | |
| Prostate cancer patients<br>Forty prostate cancer patients included prior to medical castration and radiotherapy. | |
| Healthy controls<br>Forty age- and education-matched healthy controls (20 matched to testicular cancer patients, 20 matched to prostate cancer patients). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global cognitive functioning | Changes in global cognitive composite score as measured with neuropsychological tests specified under Secondary Outcome Measures. | Baseline and 6 months' follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visuospatial ability | Changes in visuospatial ability as measured with WAIS-IV Matrix Reasoning. | Baseline and 6 months' follow-up | 
| Visuospatial ability | Changes in visuospatial ability as measured with WAIS-IV Figure Weights. | Baseline and 6 months' follow-up | 
| Visuospatial ability | Changes in visuospatial ability as measured with WAIS-IV Visual Puzzles. | Baseline and 6 months' follow-up | 
| Visuospatial ability | Changes in visuospatial ability as measured with WAIS-IV Block Design. | Baseline and 6 months' follow-up | 
| Processing speed | Changes in processing speed as measured with Trail Making Test A. | Baseline and 6 months' follow-up | 
| Processing speed | Changes in processing speed as measured with WAIS-IV Coding. | Baseline and 6 months' follow-up | 
| Attention | Changes in attention as measured with WAIS-IV Digit Span Forwards. | Baseline and 6 months' follow-up | 
| Executive functioning | Changes in executive functioning as measured with Trail Making Test B. | Baseline and 6 months' follow-up | 
| Executive functioning | Changes in executive functioning as measured with Wisconsin Card Sorting Test. | Baseline and 6 months' follow-up | 
| Working memory | Changes in working memory as measured with WAIS-IV Digit Span Sequencing. | Baseline and 6 months' follow-up | 
| Working memory | Changes in working memory as measured with WAIS-IV Digit Span Backwards. | Baseline and 6 months' follow-up | 
| Verbal fluency | Changes in verbal fluency as measured with Controlled Oral Word Association Test. | Baseline and 6 months' follow-up | 
| Verbal learning and memory | Changes in verbal learning and memory as measured with Hopkins Verbal Learning Test-Revised. | Baseline and 6 months' follow-up | 
| Visuospatial learning and memory | Changes in visuospatial learning and memory as measured with WMS-III Visual Memory. | Baseline and 6 months' follow-up | 
| Testosterone levels | Changes in testosterone levels as measured with liquid chromatography tandem mass spectrometry (LC-MS/MS). | Baseline and 6 months' follow-up | 
| Brain grey matter | Changes in grey matter as measured with T1-weighted MRI. | Baseline and 6 months' follow-up | 
| Brain white matter | Changes in brain white matter as measured with diffusion-weighted MRI. | Baseline and 6 months' follow-up | 
| Moderator: APOE genotype | Genotype of the APOE gene obtained by TaqMan-genotyping the appropriate single nucleotide polymorphisms. | Baseline | 
| Moderator: COMT genotype | Genotype of the COMT gene obtained by TaqMan-genotyping the appropriate single nucleotide polymorphism. | Baseline | 
| Moderator: BDNF genotype | Genotype of the BDNF gene obtained by TaqMan-genotyping the appropriate single nucleotide polymorphism. | Baseline | 
| Moderator: CAG repeat length of the AR gene | CAG repeat lenght of the AR gene obtained by TaqMan-genotyping the appropriate single nucleotide polymorphism. | Baseline | 
| Neurobehavioral symptoms (i.e., apathy, executive dysfunction, and disinhibition) | Changes in neurobehavioral symptoms as measured with The Frontal Systems Behavior Scale (FrsBe). | Baseline and 6 months' follow-up | 
| Perceived cognitive functioning | Changes in perceived cognitive functioning as measured with The Patient Assessment of Own Functioning Inventory (POAFI). | Baseline and 6 months' follow-up | 
| Health-related quality of life | Changes in health-related quality of life as measured with The European Organization for Research and Treatment of Cancer, Quality of Life questionnaire for cancer patients (EORTC QLQ-C30). | Baseline and 6 months' follow-up | 
| Health-related quality of life - Prostate Cancer | Changes in disease specific health-related quality of life as measured with The European Organization for Research and Treatment of Cancer, Quality of Life Prostate Cancer Module (EORTC QLQ-PR25). | Baseline and 6 months' follow-up | 
| Health-related quality of life - Testicular Cancer | Changes in disease specific health-related quality of life as measured with The European Organization for Research and Treatment of Cancer, Quality of Life Testicular Cancer Module (EORTC QLQ-TC25). | Baseline and 6 months' follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer-related Cognitive Impairment, Cognitive Dysfunction, Cognition Disorders, Neurocognitive Disorder, Testosterone, Endocrinology, Testicular Cancer, Prostate Cancer