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ABSTRACT Androgen deprivation therapy (ADT) is the standard treatment for advanced prostate cancer, but its effect on cardiovascular and metabolic function in Asian patients is still

inconclusive. We prospectively assess the effects of ADT on 36 patients with advanced prostate cancer, with reference to another 24 prostate cancer patients not requiring ADT, for 2 years.

Patients’ anthropometric, metabolic and vascular parameters were assessed every six-monthly. The baseline parameters of the two groups were comparable. There was a significant negative

effect of the usage of ADT on the changes in BMI (p = 0.020), waist to hip ratio (p = 0.005), body fat percentage (p = 0.012), and high-density-lipoprotein (p = 0.012). ADT-patients were 4.9

times more likely to have metabolic syndrome at 24 months. (CI 0.889–27.193, p = 0.068). The Framingham risk score (p = 0.018) and pulse-wave-velocity (p = 0.024) for ADT-group were also

significantly higher than controls, which signified increase in cardiovascular risk. Although there was no statistically significant difference in ischemic cardiovascular events between two

groups, a trend for more events in ADT-group was observed. Therefore, Asian patients have increased cardiovascular and metabolic risks after being treated with ADT for two years. Appropriate

counselling and monitoring of associated complications with ADT are essential. SIMILAR CONTENT BEING VIEWED BY OTHERS TEMPORAL TRENDS IN CARDIOVASCULAR BURDEN AMONG PATIENTS WITH PROSTATE

CANCER RECEIVING ANDROGEN DEPRIVATION THERAPY: A POPULATION-BASED COHORT STUDY Article Open access 19 April 2023 CHANGES IN BODY COMPOSITION AND LIPID PROFILE IN PROSTATE CANCER PATIENTS

WITHOUT BONE METASTASES GIVEN DEGARELIX TREATMENT: THE BLADE PROSPECTIVE COHORT STUDY Article 15 March 2021 METABOLIC SYNDROME AND ITS PHARMACOLOGIC TREATMENT ARE ASSOCIATED WITH THE TIME TO

CASTRATION-RESISTANT PROSTATE CANCER Article 24 January 2022 INTRODUCTION Since the ground-breaking work of Charles Huggins on the role of androgen deprivation therapy (ADT) in prostate

cancer, it has become one of the key players in the management of prostate cancer (PCa), particularly in metastatic disease1. Even in castration resistant stage, ADT is still considered the

backbone therapy for most patients1. Currently, beside the traditional bilateral orchidectomy (surgical castration), there were also luterizing hormone releasing hormone agonist (LHRH

agonist) and antagonist (LHRH antagonist) available as options for medical castration1. The choice of treatment would be depend on the clinical conditions (need of rapid testosterone

suppression), financial implications, patient preference etc. With the advancements in clinical care, the overall survival of prostate cancer patients has prolonged2. But there is also

increasing concern about potential long-term side effects and even mortality related to ADT in patients with prostate cancer. In some early single-arm prospective studies, ADT were found to

be associated with increased body weight and body fat3, reduced insulin sensitivity and increased arterial stiffness4. These concerns were further supported by observational studies, which

showed that patients who received ADT had increased incidence of diabetes, myocardial infarction and even cardiac mortality5,6. Unfortunately these results were inconsistent. Some

prospective randomized clinical studies reported that ADT were not associated with increase in cardiovascular risk7. Despite these controversies, 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 disease8. Nevertheless, the evidence is still inconclusive even in latest meta-analyses9. The situation in Asia is also controversial, as information on ADT is scanty.

Large-scale prospective randomized studies on prostate cancer in Asia are lacking. Studies related to ADT were mainly observational or retrospective in nature. The earliest information was

from the J-Cap registry study, which showed that the incidence of cardiovascular events in ADT patients was similar to that of the general population10. Thereafter, several groups reported

investigations regarding this topic, with some showing increased cardiovascular risk in patients managed with ADT11,12, while others suggesting otherwise13,14,15. Therefore, there is a need

for further studies to assess the effect of ADT on prostate cancer patients, including the fundamental effect on body compositions, cardiovascular related metabolic changes and

cardiovascular risks. METHODS This was a prospective cohort study. The objective of this study is to assess the cardiovascular and metabolic effects of ADT in Chinese patients who were

diagnosed to have PCa. The study was approved by the institutional ethics committee (Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee)

and conducted according to the principles of the Helsinki Declaration on human experimentation. Adult Chinese patients with histological diagnosis of PCa whom decided for long term ADT

monotherapy were prospectively recruited for the study in our centre. ADT could be in the form of bilateral orchidectomy, luteinizing hormone-releasing hormone (LHRH) agonists or LHRH

antagonist. Maximal androgen blockage was not our usual practice, additional short course of androgen receptor blocker was only used as flare prevention in some patients receiving LHRH

agonist. Written informed consent was obtained from all subjects. Additional age-matched Chinese patients with the diagnosis of PCa, who did not receive ADT treatment or other active

treatment, were recruited as control arm. These patients were diagnosed to have localized disease and had undergone radical surgery or managed conservatively for their cancer. If the patient

was not able to provide consent or comply with the follow-up arrangement, or if based on clinical judgement that the life expectancy of the patient was limited, the patient would be

excluded from the study. STUDY PROTOCOL Written informed consent was obtained from all subjects. All patients then underwent a series of clinical, biochemical and vascular function

assessment at baseline, followed by 6-monthly assessment for two years to determine their metabolic and cardiovascular status. CLINICAL ASSESSMENT Anthropometric parameters including

patients’ height, body weight, BMI, waist and hip circumference were measured. Waist circumference was measured at the level of umbilicus. Hip circumference was defined as the maximum

circumference of the buttock. A skinfold caliper was used for the measurement of skinfold thickness for the estimation of the total amount of body fat. Four areas of the body, biceps (front

side of the mid-upper arm), triceps (back side of the mid-upper arm), shoulder blade (just below the subscapular) and supra-iliac (just above the iliac crest) were measured. The sum of the

four measurements was then used to estimate the body fat percentage using the Durnin and Womersley formula16. All the above measurements were performed when the patient stood relaxingly in a

warm examination room with privacy. Blood pressure and pulse were measured twice with 5-min interval by an automated machine after resting for 5 min. During each follow-up, besides

repeating these measurements, cardiovascular events of the patients were recorded. LABORATORY Blood samples were collected from patients after overnight fasting for the measurements of sugar

level, total triglycerides (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and complete blood picture (including

haemoglobin level). Testosterone level was also measured to confirm the castration in patients receiving ADT. VASCULAR FUNCTION ASSESSMENT In this study, the central and peripheral arterial

conditions were assessed by brachial-ankle pulse wave velocity (baPWV) and Ankle brachial index (ABI), respectively. Brachial-ankle pulse wave velocity is an approach to assess central

arterial stiffness, which is well-recognized to be associated with cardiovascular disease17,18. The system involved four separate cuffs applied to the four limbs and automatic measurement of

the blood pressure and pulse wave in the limbs. Combined with the information on body height, it will provide the baPWV of the measured individual. The faster the baPWV, the stiffer the

central blood vessel, and higher cardiovascular risk. Ankle brachial index (ABI) is an index for the assessment of vascular occlusion due to peripheral vascular disease. It is defined as the

ratio of the blood pressure of the lower limb, as measured at the ankle, to the blood pressure of the upper limb, as measured at the upper arm (brachial artery). The lower the ratio, i.e.

greater difference between the upper and lower limb, the more severe arterial occlusion by peripheral arterial disease. In this study, both baPWV and ABI were assessed by the Vascular

Profiler-1000 machine (Omron, Kyoto, Japan) using the oscillometric cuff technique. Patient was asked to rest in supine position in a quiet and warm environment for at least 10 min. The 4

measuring cuffs would be applied to both arms and ankles, respectively. The machine would then automatically measure the baPWV and ABI. After inputting the height of the patient, baPWV was

calculated automatically between the ankle and brachial pulse waveform for both sides. The average of the two sides’ readings would be used for the assessment of baPWV of the subjects in our

study. OVERALL ASSESSMENT As many parameters were measured in our study, we used the Framingham Risk Score as the primary endpoint to assess the overall cardiovascular risk of the patients

during the study period. 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 disease19. We also applied the National Cholesterol Education Program

(NCEP)/Adult Treatment Panel III (ATPIII) guidelines to assess whether the patients had increased risk of developing metabolic syndromes after ADT treatment20. STATISTICAL ANALYSIS All data

were reported as mean ± SD unless otherwise specified. Student’s t test and Fisher’s exact test were used for the comparison between ADT and control groups. Two-way mixed ANOVA was performed

to evaluate if any change in the outcome variables is the result of the interaction between usage of ADT and time. All tests were two-sided, with significance set at 5%. Statistical

analyses were performed by SPSS (Chicago, IL). TAKE HOME MESSAGE Androgen deprivation therapy in advanced prostate cancer in Chinese are associated with increased cardiovascular and

metabolic risks. Appropriate counselling and monitoring of these complications are essential. RESULTS From July 2011 to January 2016, 36 patients with prostate cancer managed with primary

ADT alone were recruited to the study. Amongst them, 20 patients had metastatic disease and the other 16 patients were diagnosed with locally advanced disease. The number of patients chose

bilateral orchidectomy, LHRH agonist and LHRH antagonist as the initial ADT were 18, 11 and 7, respectively (Table 1). The choice of medical or surgical castration depended on patient

preference and also financial implication, as the cost of medical castration was not reimbursed. Moreover, LHRH antagonist was only available in 2013 in our area and was mainly used in

patients with high volume metastasis (for rapid testosterone suppression) and increased cardiovascular risk. Due to the frequent injection schedule (monthly) and higher cost for LHRH

antagonist (degarelix), some patients initially started on LHRH antagonist changed to use 3-monthly LHRH agonist during their course of treatment. Another 24 patients with localized prostate

cancer were also recruited as control for the study. Eighteen of them had radical prostatectomy performed while the other six were under watchful waiting or active surveillance. The average

time between diagnosis and recruitment for the ADT arm and the control arm was 5.5 and 38.5 months, respectively. The baseline characteristics and blood parameters of the patients were

listed in Tables 2 and 3. The mean age of the whole group was 74.1 (range 52 to 90) years old, and there was no significant difference between the two groups. Most of the patients had

baseline cardiovascular and metabolic diseases. The most common ones were hypertension, hyperlipidaemia and diabetes. About 10% of patients in each arm had a history of cerebrovascular

diseases. Four patients (11.1%) in the ADT arm had a history of ischemic heart disease. However, there was no significant difference between the two groups for these medical problems.

Similarly, there was no difference in the smoking status between the two groups. The baseline body weight, body height, body mass index (BMI), waist circumference, hip circumference,

waist-hip ratio and body fat composition between the two groups were also similar. Fourteen patients (38.89%) in the ADT arm and seven patients (29.17%) in the control arm had metabolic

syndrome (p = 0.439). The baseline Framingham risk score for the ADT group and control group were 0.42 and 0.40 respectively (p = 0.720). For vascular assessment, the baseline ankle-brachial

index (ABI) for ADT and control group were 1.03 and 1.13 (p = 0.008). The baseline pulse wave velocity (PWV) for ADT and control group were 1766 cm/s and 1779 cm/s (p = 0.889). There were

two patients in the ADT group who withdrew from the study due to personal reasons. Ten ADT patients and one control patient died before 24 months. The causes of death in the ADT group

included progression of prostate cancer (6, 16.67%), right cerebellar haemorrhage (1, 2.78%), sepsis (2, 5.56%), and brain stem glioma (1, 2.78%). One patient in the control arm died of

ischemic stroke. In summary, there were 24 ADT patients and 23 control patients who completed the 2-year assessment for analysis. (Fig. 1). There was a significant interaction between usage

of ADT and time in explaining BMI (F1, 44 = 5.87, p = 0.020), waist to hip ratio (F1, 45 = 5.99, p = 0.018) and body fat percentage (F1, 44 = 6.92, p = 0.012) (Table 3). The BMI for ADT

group and control group changed from baseline 23.75 ± 3.08 and 23.15 ± 2.83 to 24.37 ± 2.97 and 22.90 ± 2.87, respectively. The waist to hip ratio for ADT group and control group changed

from baseline 0.96 ± 0.06 and 0.95 ± 0.06 to 0.98 ± 0.06 and 0.93 ± 0.07 respectively. The body fat percentage for ADT group and control group changed from baseline 29.89 ± 5.49 and 28.32 ± 

3.60 to 32.44 ± 3.65 and 28.12 ± 3.17 respectively. These changes suggested patients who received ADT had increased risk of central obesity. There was a statistically significant interaction

between usage of ADT and time in explaining high density lipoprotein (HDL) (Table 3). The HDL for ADT group and control group changed from baseline 1.53 ± 0.41 and 1.54 ± 0.39 to 1.26 ± 

0.32 and 1.60 ± 0.43, respectively. On the other hand, there was no significant difference between the two groups in 24-month change in total cholesterol (F1, 43 = 0.07, p = 0.791),

triglyceride (F1, 43 = 0.18, p = 0.673), low density lipoprotein (LDL) (F1, 43 = 0.08, p = 0.779), fasting blood glucose (F1, 43 < 0.01, p = 0.989) and glycosylated haemoglobin level

(HbA1C) (F1, 32 = 0.49, p = 0.491). Meanwhile, patients in the ADT arm were 4.918 times more likely to have metabolic syndrome at 24 months compared to control group after adjusting for the

baseline (CI 0.889, 27.193, p = 0.068). The Framingham risk score for ADT group and control group changed from baseline of 41.74% ± 20.94% and 39.79% ± 19.86% to 47.24% ± 22.86% and 37.67% ±

 19.93% respectively (Fig. 2a). The results showed that the change in Framingham risk score was significantly different for the two groups (F1, 43 = 6.04, p = 0.018). Vascular assessment

showed that there was a significant interaction between usage of ADT and time in explaining pulse wave velocity (PWV) (F1, 41 = 5.51, p = 0.024). The PWV for ADT group and control group

changed from baseline 17.66 ± 4.30 and 17.79 ± 2.70 to 20.52 ± 6.34 and 18.21 ± 3.75, respectively (Fig. 2b). There was no significant difference between the two groups in 24-month change in

systolic blood pressure (F1, 45 = 2.03, p = 0.161), diastolic blood pressure (F1, 45 = 2.17, p = 0.148) and ankle-brachial index (ABI) (F1, 42 = 0.28, p = 0.602). There were three (8.33%)

patients in the ADT group and one (4.17%) patient in the control group who developed ischemic stroke during the 2 year follow-up. Another 3 (8.33%) patients in the ADT group had new onset

ischemic heart disease diagnosed during the study period. However, there was no statistically significant difference in ischemic cardiovascular events between the two groups (p = 0.330).

DISCUSSION In this prospective comparative study, prostate cancer patients who received ADT had a significant increase in body weight, body fat and central obesity than those without ADT.

They also had increased chance of developing metabolic syndrome, higher Framingham risk score and increased pulse wave velocity at the end of 2-year follow-up. All these information points

towards that ADT would increase cardiovascular risk and metabolic syndrome. It also led to increase in arterial stiffness and atherosclerosis. Despite publications on multiple studies and

meta-analyses, the effect of ADT on patients was still controversial. In general, meta-analysis of observational studies supported a positive relationship between increased cardiovascular

risk and ADT, while the results from randomized studies were negative9. Hu et al. proposed that the reason for the conflicting outcomes might be related to the study designs9. For

observational studies, there may be problems related to confounding factors, treatment adherence and outcome reporting bias. Similarly for randomized studies, underpower of studies,

inadequate follow-up period, and selection bias, etc. might contribute to the negative findings. Nevertheless, there is a general consensus that there is an association between ADT usage and

cardiovascular risk21. While most of the observational studies on Caucasian population indicated that ADT would increase the cardiovascular risk of patients9,22, the results for Asians

suggested otherwise. In several observational studies based on national insurance databases in different populations, the results did not show an increased cardiovascular risk in Asian

patients receiving ADT13,14,15. The reason for this discrepancy was uncertain. It might be related to the study sample size, racial difference in response to ADT, the overall lower baseline

cardiovascular risk of Asian population, and underdiagnosis of cardiovascular events, etc. Nevertheless, this observation reminded us to be cautious in applying findings from Caucasian

studies to Asian population. Therefore, we performed this study to try to bridge the current knowledge gap, the insufficient information about the effect of ADT on Asian population. We

planned to overcome some of the pitfalls in previous studies, such as no control arm and short follow-up period3,4. While it would be unethical to randomize patients for ADT or not, we

included a comparable control arm with prostate cancer patients who did not require ADT. We also included physical, blood and vascular assessments for our patients, with follow-up for up to

two years, which was much longer than similar studies3,4. While we could continue for even longer follow-up, the dropout rate for ADT arm would be high due to the nature of underlying

disease. Six patients in the ADT group developed ischemic cardiovascular events, compared to only one patient in the control group. However, due to the small sample size, this was not

statistically significant. Nevertheless, our data suggested that there was a negative effect of ADT on cardiovascular risk and metabolic parameters in our population. Development and

progression of atherosclerosis is believed to be one of the underlying mechanisms related to the increase in cardiovascular risk in patients receiving ADT23. In a previous Caucasian study,

the usage of ADT was shown to result in significant increase in pulse wave velocity after 3 months of therapy, which is a recognized indicator for major vessels stiffness, and in turn

atherosclerotic changes4,24,25. However, in a report from Japanese group, there was no significant overall increase in pulse wave velocity after six months of ADT26. Our results provided the

longest prospective data, up to two years, on the effect of ADT on pulse wave velocity, which further support the initial findings from Caucasian studies. The difference in the results

between our study and Oka et al. could be due to study duration, assessment method, or patients’ background. Again, further studies to investigate this area are needed in order to have a

better understanding of the situation. The relative small sample size and single centre experience might limit the generalizability of our findings to other populations. As we aimed to have

longer follow-up for our patients, we recruited mainly patients with relatively good performance status in the study. Unfortunately, despite careful selection, only roughly two-thirds of the

patients with ADT could survive to the end of the two-year follow-up. Moreover, the repeated assessments had also made some patients hesitate to participate in our study. All these

contributed to the slow recruitment rate of the study. In addition, some patients have used LHRH antagonist for treatment, which might have potential cardiovascular protective effect27, and

hence might affecting the overall incidence of cardiovascular events. Therefore, the small sample size of our study might not be able to detect any significant difference in clinical

cardiovascular events, including assessing the effect of different ADT approaches on the outcomes. Despite these, our results had showed convincing evidence of the metabolic and

cardiovascular effects of ADT in our patients. Currently, there are other studies in Asia that are trying to provide more information about the effect of ADT in prostate cancer patients. For

example, the real-life evaluation of the effect of ADT in prostate cancer patients in Asia (READT Asia Study) (Clinical trials registration NCT03703778) is a multi-nation prospective study

to assess the effect of ADT in prostate cancer patients. The initial result showed that there was a high prevalence of cardiovascular risk factors in Asian prostate cancer patients28.

Hopefully the study will provide more information on the effects of ADT in Asian patients. Nevertheless, the result of our study would support the incorporation of additional measures in

managing patients treated with ADT to minimize the potential metabolic and cardiovascular harm to patients. The recommended ABCDE approach should be introduced to all patients29. These

include awareness of the condition and patient education on diet, smoking and exercise, careful monitoring of blood pressure, blood sugar and lipid level for patients, appropriate patient

referral to cardiological assessment and usage of pharmacological agents, including aspirin, for high risk patients. For patients with high cardiovascular risk, the usage of LHRH antagonist

had shown to have less cardiovascular complications when compared to LHRH agonist27,30. All these measures would help to improve the overall standard of care and survival of patients.

Currently, there are also studies exploring the use of novel alternate treatments for managing advanced prostate cancer31,32. However, most of the these treatments are still in

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* SH Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong Chi-fai Ng, Peter K. F. Chiu, Chi-hang Yee, Becky S. Y. Lau, Steven C. H. Leung & 

Jeremy Y. C. Teoh Authors * Chi-fai Ng View author publications You can also search for this author inPubMed Google Scholar * Peter K. F. Chiu View author publications You can also search

for this author inPubMed Google Scholar * Chi-hang Yee View author publications You can also search for this author inPubMed Google Scholar * Becky S. Y. Lau View author publications You can

also search for this author inPubMed Google Scholar * Steven C. H. Leung View author publications You can also search for this author inPubMed Google Scholar * Jeremy Y. C. Teoh View author

publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS C.F.N., P.K.F.C., C.H.Y. and J.Y.C.T. were responsible for the clinical care and acquisition of data

of patients. B.S.Y.L. was responsible for data acquisition and S.C.H.L. was responsible for statistical analysis. C.F.N. conceived of the study, and participated in its design and

coordination and helped to draft the manuscript. All authors read and approved the final manuscript. CORRESPONDING AUTHOR Correspondence to Chi-fai Ng. ETHICS DECLARATIONS COMPETING

INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER'S NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and

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permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Ng, Cf., Chiu, P.K.F., Yee, Ch. _et al._ Effect of androgen deprivation therapy on cardiovascular function in Chinese patients with advanced

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