Androgen deprivation treatment in prostate cancerBMJ 2013; 346 doi: https://doi.org/10.1136/bmj.e8555 (Published 09 January 2013) Cite this as: BMJ 2013;346:e8555
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The recent therapeutics review on androgen deprivation therapy (ADT, i.e. castration) in prostate cancer  is timely as several promising new treatments have been reported over the past year or so, although their effectiveness and timing in treatment pathways remain to be fully elucidated. Additionally, awareness of the many side-effects of castration with contemporary therapy (Luteinising Hormone Releasing Hormone Agonists (LHRHa) is increasing as indications for ADT expand, it is prescribed ever earlier in the natural history of the disease and men survive for increasingly long periods. These side-effects are due not only to endogenous testosterone suppression (resulting in loss of libido and sarcopenic obesity) but also suppression of endogenous oestrogen (as oestrogen production requires testosterone as a substrate) which can lead to osteoporosis and higher fracture risk, adverse lipid changes, hot flushes and potentially cognitive impairment .
Missing from this recent paper however, was a discussion about the gradual re-emergence of oestrogen to the ADT armamentarium. Oral oestrogen was an effective and low-cost option for ADT in the 1950’s and up to the 1980’s but was then abandoned as randomized trials showed that it was associated with increased cardiovascular toxicity and thromboembolism  and LHRHa were introduced. It is now apparent that the route of administration of oestrogen is pivotal to development of this toxicity; taken orally, entero-hepatic first pass exposes the liver to high levels of oestrogen resulting in up-regulation of pro-coagulant proteins and a hypercoaguable state which in turn increases the risk of thromboembolism and cardiovascular events . This appears to be mitigated by giving oestrogen parenterally e.g. intramuscular  or transdermally . Moreover, exogenous oestrogen not only suppresses testosterone but also replaces the endogenous oestrogen lost with LHRHa, and thereby has the potential to achieve the same therapeutic effect but with reduced side-effects, without the need for additional agents.
More evidence in favour of parenteral oestrogen therapy has recently been published with cardiovascular data from the first stage of the PATCH (Prostate Adenocacinoma Trans Cutaneous Hormones) study; a phase II randomized clinical trial comparing transdermal oestrogen patches with LHRHa in locally advanced and metastatic prostate cancer. In a cohort of 254 men (randomized 2:1 to patches or LHRHa) with a median follow-up of 19 months, the rate of cardiovascular events was similar in the two trial arms . Castration rates were also similar. PATCH has since progressed to the second stage of the phase II study, assessing progression-free survival as the primary outcome measure with a non-inferiority design. Current recruitment exceeds 650 of the planned 730 men required for statistical analysis and to inform the decision to proceed to a confirmatory phase III study.
In summary, parenteral oestrogen seems to avoid the thromboembolic and cardiovascular toxicities associated with oral administration, and has the potential to both suppress testosterone to castrate levels and reduce or eliminate some of the serious toxicities of contemporary castration which result in significant morbidity and mortality (including osteoporosis with the increased risk of fracture, cognitive impairment and hot flushes), all in one single therapy. Furthermore, parenteral oestrogen is inexpensive. Thus, if efficacy is confirmed, this could be an important alternative to LHRHa in the management of prostate cancer.
1. Thomas, B.C. and D.E. Neal, Androgen deprivation treatment in prostate cancer. BMJ, 2013. 346: e8555
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Competing interests: No competing interests
Thomas and Neal provide a timely piece about androgen deprivation treatment in prostate cancer (1). In reference to an observational study from 2007, they say “Androgen deprivation treatment significantly increases the risk of a cardiovascular event, from 19% for men not receiving this treatment to 24% for men who are” (2). According to the latest guidance concerning matching language to evidence, this statement would be better worded in terms of correlation or association not causation (3).
Moreover, based on evidence better suited to establishing causation, i.e., randomized controlled trials, androgen deprivation therapy is no longer thought to increase cardiovascular morbidity and mortality (4,5) although the possibility that it might do so in some specific sub-group is difficult to eliminate completely (5). The effects of androgen deprivation therapy on cardiovascular disease are confusing because the initial observations of higher risk in men given androgen deprivation therapy have not been borne out in randomized controlled trials; nevertheless it is important to provide both sides of the argument.
(1) Thomas BC, Neal DE. Androgen deprivation treatment in prostate cancer. BMJ 2013; 346:e8555.
(2) Saigal CS, Gore JL, Krupski TL, Hanley J, Schonlau M, Litwin MS. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer 2007; 110:1493-1500.
(3) Editors HG. Statement on matching language to the type of evidence used in describing outcomes data. Heart 2012.
(4) Nguyen PL, Je Y, Schutz FA, Hoffman KE, Hu JC, Parekh A et al. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA 2011; 306(21):2359-2366.
(5) Zumsteg ZS, Zelefsky MJ. Short-term androgen deprivation therapy for patients with intermediate-risk prostate cancer undergoing dose-escalated radiotherapy: the standard of care? Lancet Oncol 2012; 13(6):e259-e269.
Competing interests: No competing interests