To Investigate the Effect of Multidisciplinary Care Approach on Cardiovascular Risk Modification in Prostate Cancer Patients Receiving Androgen Deprivation Therapy

Study Overview
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Brief Summary
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Prostate cancer is characterised by its slow progression nature, and even for metastatic disease, the 5-year survival is up to 30%. While ADT can effectively control disease, there is increasing evidence suggesting that it can also result in many adverse cardiovascular side effects on the patients, and these effects are particularly important due to the prolonged survival of these patients. There are suggestions that close cardiovascular (CV) monitoring will help to reduce cardiovascular risk and related morbidities. However, there is limited data to show the positive impact of these monitoring could reducing CV risk and morbidities. Moreover, information regarding the optimal follow-up approach and schedule is also lacking. Therefore, there is a need to have more information on the approach to monitoring the CV risk and the real-life impact of this monitoring on our patients. Patients diagnosed with prostate cancer and plan to receive ADT are invited to participate in this study to assess the potential benefit of multidisciplinary care approach to CV risk modification.

Detailed Description
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(i) Prostate Cancer (PCa) and androgen deprivation therapy (ADT) PCa is the most common cancer and the second leading cancer death in adult male globally. In Hong Kong, it is one of the most rapidly increasing cancer and is now the third most common cancer and the 4th leading cancer death in male. [1] Despite the increased usage of serum PSA for early cancer diagnosis, more than 50% of patients were diagnosed at stage III &amp;amp; IV, with lymph node +/- bone / visceral metastasis. Therefore, ADT is still commonly used in PCa patients, both as neo-adjuvant/ adjuvant to radiotherapy, [2] as well as backbone therapy for metastatic disease. [3] While the overall survival of PCa patients has been prolonged by ADT, there is also increasing concern about potential long-term side effects, in particular cardiovascular effect. (ii) ADT and cardiovascular risk Castration as the physiological basis of ADT has been shown to be associated with derangement of glucose and lipid metabolism, and subsequently a wide range of adverse events including cardiothrombotic disease, diabetes, metabolic syndrome and osteoporosis. [4-5] Plenty of studies have suggested that ADT could lead to increase in cardiovascular risk and metabolic complications in Caucasian population. As a result, a joint statement was issued by the American Urological Association, the American Society for Radiation Oncology and the American Heart Association to raise physicians' awareness about the potential association between ADT and cardiovascular disease. [6] However, evidence in Asian population was limited. (iii) ADT complications in local Chinese PCa patients In order to understand the effect of ADT in Chinese patients, we have performed various clinical and laboratory studies to assess the cardio-metabolic effect of ADT over the past 10 years and confirmed that ADT could lead to endothelial dysfunction, increased cardiovascular risk and also mortality in Asian population. [7] Retrospective studies: In retrospective studies comparing PCa patients with or without receiving ADT, we observed that ADT usage was associated with increased myocardial infarction, [8] new onset diabetes, [9] and fracture. [10] In another study based on the whole Hong Kong population, longer ADT exposure was associated with increased cardiovascular risk. [11] Prospective studies: In a prospective study, PCa patients who had received 2years of ADT had a significantly increased Framingham risk and arterial stiffness when compared to PCa patients with no ADT. [12] In another prospective multicentre study in Hong Kong, PCa patients receiving ADT had significantly more new-onset of hypertension, diabetes and hyperlipidaemia, as well as more new initiation of medications for these conditions. [13] These studies further supported our previous retrospective observations. Laboratory and Animal studies: In animal studies, we have shown that 6 months of ADT exposure would lead to an increase in endothelial dysfunction, which might be one of the mechanisms for increased thromboembolic events in patients with ADT. [14] In another cross-sectional study on human gut microbiome, we also observed a difference in the composition of gut microbiota in PCa patients receiving ADT, compared to those did not. The related functional pathway changes might be related to metabolic changes observed in ADT patients. [15] These studies provided evidence to support the mechanistic effect of ADT on cardio-metabolic changes in ADT-treated patients. With these evidences, the cardiovascular risk of ADT on local Chinese population is well established and it is time to consider how to improve the cardiovascular risk in these patients. (iv) Approach to improve cardiovascular risk in PCa patients received ADT While there are guidelines suggesting basic principles in assessing and monitoring patients receiving ADT, [6,16] most of the recommendations are based on low level evidence, [16,17] unfortunately. There is also limited prospective evidence to guide cardiovascular risk monitoring and treatment, hence it is difficult to standardize the monitoring and intervention for these patients. [18] In a recent study comparing the cardiovascular risk of luteinizing hormone releasing hormone (LHRH) agonist and antagonist, [19] the incorporation of cardiology monitoring &amp;amp; intervention seemed to improve the cardiovascular risk changes in patients receiving LHRH agonist. [19,20] This suggests that secondary cardiovascular risk prevention, such as statin usage, might help to reduce cardiovascular risk in patients. [20] However, the study protocol might not easily translate into daily clinical practice, in particular in real life situations due to various constraints. (v) Challenges in cardio-oncological care in current clinical practise Despite the recognition of the potential cardiovascular morbidities related to ADT, the current shortage of cardiologists in Hong Kong and other regions makes it difficult to cope with this increasing incidence of PCa patients. The long waiting time for cardiac consultation might result in delay in either cancer treatment or secondary cardiovascular risk prevention / modification, which will both affect the clinical outcomes of PCa patients. As a result, the involvement of other clinicians, family physicians and urologists/oncologists in a multidisciplinary approach may help to share out the workload. This will include the establishment of evidence-based simple practical guidelines for family physicians, urologists and oncologists to manage common cardiovascular risk factors and identify high-risk patients for cardiologist referral and assessment. This multi-disciplinary approach might help to balance the demand and manpower in the current health care system. Therefore, there is a need for prospective studies to understand the role of close cardiovascular assessment, monitoring and treatment on the cardiovascular risk of PCa patients receiving ADT. Information on the risk factors at baseline &amp;amp; follow-up, and also treatment / secondary prevention adopted, will help to provide evidence to fill the current knowledge gap and build practical guidelines for clinical usage. In the long run, the data will also help to estimate the medical resources required for future health care planning to cope with the medical needs of the rapidly increasing PCa population.

Official Title
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To Investigate the Effect of Multidisciplinary Care Approach on Cardiovascular Risk Modification in Prostate Cancer Patients Receiving Androgen Deprivation Therapy

Conditions
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Cardiovascular Risk, Prostate Cancer

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult men 18-80 years old With histological proven prostate cancer or clinically diagnosed to have prostate cancer, Planned for ADT for at least 1 year Exclusion Criteria: Subjects with established major atherosclerotic cardiovascular disease (ASCVD) as defined by a recent acute coronary syndrome within the past 12 months, a history of myocardial infarction other than the recent acute coronary syndrome event, a history of ischemic stroke, and symptomatic peripheral arterial disease (defined as history of claudication with ankle-brachial index &lt;0.85 or previous revascularization or amputation Prior neoadjuvant or adjuvant hormone therapy within 1 year before Refuse or unable to give written informed consent Participation in an investigational program with interventions outside of routine clinical practice

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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 |
| --- | --- |
| PCa receiving ADT<br>prostate cancer patients receiving androgen deprivation therapy | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change in Framingham Risk Score between baseline and 1-year after ADT. | The Framingham Risk Score is a gender-specific algorithm based on multiple cardiovascular risk factors including age, smoking status, blood pressure level, serum total cholesterol and HDL-cholesterol level for the estimation of the 10-year risk of developing cardiovascular disease. This remain a commonly used assessment for cardiovascular risk, including PCa patients treated with ADT internationally. | From enrollment to 1-year after ADT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of new-onset diabetes | Incidence of new-onset diabetes after ADT | From enrollment to 1-year after ADT | 
| Incidence of new-onset hypertension | Incidence of new-onset hypertension after ADT | From enrollment to 1-year after ADT | 
| Changes in fasting blood sugar | Changes in fasting blood sugar (serum level) | From enrollment to 1-year after ADT | 
| Changes in LDL-Cholesterol | Changes in LDL-Cholesterol (serum level) | From enrollment to 1-year after ADT | 
| Changes in HDL-cholesterol | Changes in HDL-cholesterol (serum level) | From enrollment to 1-year after ADT | 
| Changes in triglyceride | Changes in triglyceride (serum level) | From enrollment to 1-year after ADT | 
| Changes in HbA1c | Changes in HbA1c (serum level) | From enrollment to 1-year after ADT | 
| Incidence of additional medical therapies for optimization of cardiovascular risk | Number of additional cardiovascular medical therapies | From enrollment to 1-year after ADT | 
| Change in pulse wave velocity | Change in pulse wave velocity assessed by the Vascular Profiler-1000 machine (Omron, Kyoto, Japan) using the oscillometric cuff technique | From enrollment to 1-year after ADT | 
| Change in Quality of life | Change in Quality of life as assessed by EQ5D questionnaire (score) | From enrollment to 1-year after ADT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate Cancer, Androgen deprivation Therapy