1. The use of long-term transdermal estrogen for castration therapy for prostate cancer showed no difference in cardiovascular events versus current standard of care.
2. Gynecomastia was significantly more common in the transdermal estrogen group than standard of care group.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Prostate cancer, an ongoing major cause of morbidity and mortality worldwide, is usually treated with a combination of androgen suppression and radiotherapy in metastatic disease. Traditionally, androgen suppression was achieved with luteinizing hormone-releasing hormone agonists (LHRHAs), as exogenous estrogen administration was found to cause an increase in cardiovascular thromboembolic events. Exogenous estrogen administration, however, has many benefits, including avoiding the deleterious effects of estrogen depletion cause by LHRHA therapy. It is thought that a transdermal application of exogenous estrogen would bypass hepatic first-pass metabolism, thereby avoiding the increased risk of thromboembolic events. This phase 2/3, randomized trial, an offshoot of the PATCH trial, sought to compare the effects of long-term transdermal estradiol versus LHRHA therapy on cardiovascular events in individuals with locally advanced or metastatic prostate cancer. Overall, after a follow-up of 36 months, no major differences in cardiovascular events were seen between the LHRHA and estrogen groups. Time to first cardiovascular event between groups also did not differ significantly, and cardiovascular events over time remained stable in both groups. Finally, no evidence was found that increasing levels of estradiol patch use were associated with an increased risk for cardiovascular event. Gynecomastia was more common in the transdermal estrogen group, while hot flushes were more common among those receiving LHRHA. A notable strength of this study is its relatively lengthy follow-up time. It is important to point out, however, that this study was not blinded; additionally, one could argue that their median follow-up time of 3.9 years might not be sufficient to detect long-term thromboembolic events. The authors, however, intend to continue follow-up as their PATCH trial continues.
Relevant Reading: Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09)
In-Depth [randomized controlled trial]: This phase 2/3, randomized, multicenter trial took place at 52 sites in the United Kingdom and recruited a total of 1694 patients with locally advanced or metastatic prostate cancer. Patients were randomized to either receive exogenous transdermal estradiol or LHRHA therapy (n1=904, n2=790, respectively). The primary outcome was to determine the proportion of patients experienced cardiovascular events or sudden/unexpected deaths. By three months, both groups had comparable levels of testosterone levels below the desired value of 1.7nmol/L: 93% amongst LHRHA and 93% amongst estradiol groups. A total of 157 eligible cardiovascular events occurred. No baseline factors besides current or former smoking status was related to cardiovascular events. Rates of cardiovascular events were similar between groups (7% of patients in LHRHA vs 8% in estradiol groups experienced a cardiovascular endpoint event, including sudden death with no post-mortem explanation). At 36 months, the cardiovascular event rate in the LHRHA group was 7.2% (95% CI = 5.4-9.6) and in the estradiol group 8.0% (95% CI 6.2-10.4), with an absolute difference between rates of 0.8%. Rates of cardiovascular events also remained constant; at 12 months, rates were 2.8% (95% CI= 1.8-4.2) for LHRHA vs. 2.8% for estradiol (95% CI = 1.9-4.2%).
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