Effect of androgen deprivation therapy on cardiovascular function in Chinese patients with advanced prostate cancer: a prospective cohort study

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.

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 investigational stage, and further studies are needed to assess their roles in clinical management, and also whether they could replace ADT as the primary therapy for patients.

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Eliza Grace
Managing Editor
Endocrinology and Metabolism: Open Access