BERKELEY, CA (UroToday.com) - Over the years, there has been increasing use of hormonal therapy across a wide population of men at different ages and through different stages of prostate cancer. Before the development of gonadotropin-releasing hormone antagonists, androgen deprivation was achieved either by surgical castration (SC) or regular gonadotropin-releasing hormone agonist (GnRHa) injections. It has been shown in a meta-analysis that SC and GnRHa have equivalent clinical efficacies. Given that both SC and GnRHa reduce serum testosterone to a castration level, one may expect them to share similar safety profiles. Our study, however, suggested that their cardiovascular safety profiles might differ.
In our study, we investigated the risk of cardiovascular thrombotic events after SC versus GnRHa in Chinese men with prostate cancer. The primary outcome was any new onset of cardiovascular thrombotic events after SC or GnRHa, which was defined as any new event of acute myocardial infarction or ischemic stroke. A total of 684 patients were included, including 387 patients in the SC group and 297 patients in the GnRHa group. There was increased risk of new cardiovascular thrombotic events in the SC group when compared to the GnRHa group upon Kaplan-Meier analysis (P=0.014). SC remained as a significant risk factor of cardiovascular thrombotic events (hazard ratio 1.648, 95% confidence interval 1.05-2.59, P=0.031) upon multivariate Cox regression analysis. This would be an important aspect to consider while deciding on the mode of hormonal therapy, as the development of any cardiovascular thrombotic events would be detrimental.
There are two postulations on why SC may impose greater cardiovascular risk than GnRHa. Firstly, the risk of cardiovascular thrombotic events may be related to the degree of testosterone suppression. It has been previously shown that SC could reduce testosterone to a lower level than GnRHa. This difference in serum testosterone level may not be as important in terms of prostate cancer control, but this may possibly explain the increased cardiovascular thrombotic risk after SC when compared to GnRHa. Secondly, the cardiovascular risk may be related to the level of follicle-stimulating hormone (FSH). For patients receiving GnRHa, there would be a FSH surge at the first few weeks of treatment, which would then decrease rapidly and remain suppressed. On the contrary, SC would lead to a negative feedback to the hypothalamic-pituitary-gonadal axis, causing an elevated FSH level up to +300% from baseline. Such postulation was supported by a recent pooled analysis showing lower cardiovascular risk in men treated with gonadotropin-releasing hormone antagonists than those treated with GnRHa; the median FSH level was lower in patients receiving gonadotropin-releasing hormone antagonists (-88.5% from baseline) than those receiving GnRHa (-54.8% from baseline). We believe that a higher FSH level may be one of the mechanisms explaining the increased cardiovascular thrombotic risk as shown by our study. Future studies will be necessary to confirm these postulations.
- Seidenfeld J, Samson DJ, Hasselblad V, Aronson N, Albertsen PC et al. Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Annals of Internal Medicine 2000; 132: 566-77.
- Zaitsu M, Yamanoi M, Mikami K, Takeshima Y, Okamoto N, et al. Surgical castration in hormone-refractory metastatic prostate cancer patients can be an alternative for medical castration. Adv Urol. 2012; 2012: 979154.
- Koutsilieris M, Tolis G. Long-term follow-up of patients with advanced prostatic carcinoma treated with either buserelin (HOE 766) or orchiectomy: classification of variables associated with disease outcome. Prostate. 1985; 7: 31-9.
- Albertsen PC, Klotz L, Tombal B, Grady J, Olesen TK, et al. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol. 2014; 65: 565-73.
Jeremy Y.C. Teoh, MBBS, MRCSEd and Anthony C.F. Ng, FRCSEd (Urol), FHKAM (Surgery) as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Division of Urology, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong