TACkLE Study - Tackling Adverse Chemotherapy-associated Late Effects

Study Overview
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Brief Summary
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Testicular cancer (TC) is a rare disease, which mostly affects young men aged 15-35 years. Their life expectancy has greatly improved due to the introduction of platinum-containing chemotherapy for disseminated TC in the late 1970s. Given the good prognosis of TC nowadays, prevention or early detection of late adverse effects of TC treatment has become increasingly important. Current literature suggests that TC treatment, and specifically exposure to platinum agents, is associated with increased risk of cardiovascular morbidity and mortality. The precise role of treatment components like platinum in the pathogenesis of cardiometabolic changes and cardiovascular disease (CVD) warrants further investigation, since it is not known if CVD develops through direct platinum-induced damage of the vascular wall or by mediation through development of cardiometabolic riskfactors. The aim of this study is to identify risk factors for development for CVD after treatment for TC. A more profound insight into pathophysiologic mechanisms and identification of risk factors for CVDs is needed to facilitate development of preventive strategies and to optimize survivorship care.

Detailed Description
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Design: The investigators will perform a multicenter case-cohort study. Patients treated for TC who developed cardiac disease ((either myocardial infarction, proven coronary artery disease (grade ≥2) or congestive heart failure (grade ≥2)) will be invited by their (former) treating oncologist to participate in this study (cases). Furthermore, in each hospital a random sample of 15% of the total population treated for TC will be invited (the subcohort). The investigators will collect detailed diagnostic- and treatment data on TC and on (risk factors for) CVD for all cases as well as for all subcohort members. All cases and subcohort members will be approached to complete a questionnaire and to donate a blood sample for DNA analysis, after written informed consent. Patients who were younger than 40 years at TC diagnosis and younger than 75 years at moment of study contact will be asked to participate in the cardiometabolic risk inventory sub study. For this, participants have to undergo a basic study assessment consisting of physical examination, venapuncture and handing in a morning urine sample. This assessment can be performed at the participating hospital, their general practitioner or during a home visit by a member of the investigators research team. Additional (non-invasive) cardiovascular function measurements (IMT and AGEs) are only performed in the UMCG.

Official Title
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A Case-cohort Study to Identify Risk Factors for Cardiovascular Disease in Testicular Cancer Survivors

Conditions
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Testicular Cancer

Intervention / Treatment
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* Other: Vena punction


Participation Criteria
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Eligibility Criteria
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All participating patients have to meet the following criteria: Alive TC diagnosis between 01-01-1976 to 31-12-2007 TC treatment center: UMCG, NKI/AVL, Erasmus MC, UMCN, LUMC Younger than 50 years of age at TC diagnosis Written informed consent Cases have to fulfill, beside the aforementioned criteria, the following criteria: Diagnosed with either myocardial infarction (MI), proven coronary artery disease (CAD) (CTCAE-4 grade 2 or higher) or congestive heart failure (CHF) (CTCAE-4 grade 2 or higher). No medical history of CVD before diagnosis of TC In order to be eligible to participate in the cardiometabolic risk inventory study (and to be invited to a study assessment), a subject must meet, next to the criteria mentioned in 1), the following inclusion criteria: Younger than 40 years of age at TC diagnosis Younger than 75 years of age at moment of inclusion Exclusion criteria: A potential subject who meets any of the following criteria will be excluded from participation in this study: Mental disorder (no informed consent available) Presence of active malignant disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cases<br>Patients who developed cardiovascular disease after testicular cancer treatment | Other: Vena punction<br>* Once 90 ml<br>|
| Subcohort members<br>A random selection out of the total cohort of testicular cancer patients per participating hospital | Other: Vena punction<br>* Once 90 ml<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characteristics of disease (i.e. stage/IGCCCG prognosis group) and treatment (chemotherapy/radiotherapy) | To evaluate the independent and joint effects of disease- and treatment characteristics of TC patients on cardiovascular disease risk. | 4 years | 
| Cardiovascular risk factors | To evaluate the effect of cardiometabolic risk factors (presence of metabolic syndrome, smoking behaviour, obesity, hypertension, dyslipidemia, diabetes mellitus, family history, physical activity) on cardiovascular disease risk in TC patients. | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarkers for endothelial activation, hemostatic activity and inflammatory activity after TC treatment and relation with CVD | To determine endothelial activation, hemostatic activity and inflammatory activity (represented by circulating biochemical markers) years after treatment for TC and its relationship between development of (components of) the metabolic syndrome and development of cardiovascular diseases. | 4 years | 
| Hypogonadism after TC treatment and relation with CVD | To evaluate the presence of hypogonadism in TC survivors and to investigate the association between hypogonadism and presence of (components of) the metabolic syndrome and development of cardiovascular disease. | 4 years | 
| DNA and telomere length analysis and association with (riskfactors for) CVD | To investigate the presence of candidate single nucleotide polymorphisms in genomic DNA and telomere length and its association with presence of (components of) the metabolic syndrome and development of cardiovascular disease. | 4 years | 
| Quality of life | To investigate the impact of cardiovascular disease on Quality of Life (QoL) in TC survivors. | 4 years | 
| Circulating platinum levels | In patients treated with platinum-containing chemotherapy: to evaluate circulating platinum levels in TC survivors and to investigate the relationship between circulating platinum levels and presence of (components of) the metabolic syndrome and development of cardiovascular disease. | 4 years | 
| Intima media thickness | Patients visiting the UMCG for the study visit: to evaluate thickness of the intima media of the carotid artery as a marker for subclinical damage in TC survivors, and to investigate the relationship between abnormal intima media thickness and presence of (components of) the metabolic syndrome and development of cardiovascular disease. | 4 years | 
| Arterial stiffness | Patients visiting the UMCG for the study visit: to assess the elasticity of the arterial wall of the carotid artery in TC survivors, and to investigate the relationship between abnormal arterial stiffness and presence of (components of) the metabolic syndrome and development of cardiovascular disease. | 4 years | 
| Skin auto fluorescence (SAF) as measure for Advanced Glycation End products (AGEs) | Patients visiting the UMCG for the study visit: to assess levels of AGEs with help of the SAF in TC survivors and to to investigate the relationship between SAF and presence of (components of) the metabolic syndrome and development of cardiovascular disease. | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Survivor, Cardiovascular disease, Risk factors, Testicular cancer