- Top of page
- PATIENTS AND METHODS
- CONFLICT OF INTEREST
- Supporting Information
Prostate cancer is a major health problem accounting for >10 000 deaths each year in the UK . First-line treatment for advanced prostate cancer is androgen withdrawal, either by surgical castration or use of a Luteinising Hormone Releasing Hormone (LHRH) agonist. Whilst initial response rates of 90% are expected, progression to castration-resistant prostate cancer (CRPC) is inevitable after a median duration of response of 18–24 months . Systemic treatment options for CRPC include palliative chemotherapy such as docetaxel  and cabazitaxel , as well as radioisotope therapy including radium 223 . Further hormonal interventions include corticosteroids or oestrogens, and more recently the CYP-17 inhibitor abiraterone acetate  and the androgen receptor antagonist MDV3100 . The immunotherapy sipuleucel-T has also been shown to improve survival in CRPC . There has recently been renewed interest in the use of oestrogens as a systemic treatment for advanced prostate cancer in topical form .
Diethylstilbestrol (DES), which is a synthetic oestrogen, was the first endocrine treatment shown to suppress prostate cancer activity in pivotal studies conducted by Huggins et al. in the 1940s [10,11]. DES and orchidectomy were subsequently used as first-line treatment options over the next decades with reported efficacy [12,13]; however when DES was tested in a prospective randomized controlled trial setting, concerns were raised over increased mortality from cardiovascular and thromboembolic events .
In the VACURG I study, 188 (17%) deaths from cardiovascular disease occurred among 1103 patients taking DES at a dose of 5 mg, with no anticoagulation, compared with 129 (11.7%) deaths among 1101 patients taking placebo . The VACURG II study did not show a significantly increased cardiovascular risk using a dose of DES of 1 mg, and in a castration-sensitive population, this dose was shown to be of similar clinical efficacy to 5 mg, despite not consistently reducing testosterone to a castrate level [15–17]. The relative safety and efficacy of DES at 1 mg was subsequently confirmed in a European Organisation for the Research and Treatment of Cancer (EORTC) study .
The better toxicity profile associated with LHRH agonists and anti-androgens together with concerns over cardiovascular risks meant that use of DES as a first-line medical treatment was abandoned [19,20]. However, the drug has maintained a role in CRPC when used with LHRH agonists, at a lower dose of 1–3 mg, and with anticoagulation. There are small published studies suggesting that DES is efficacious in CRPC [21,22], even when compared with anti-androgens [23,24]. Use of the drug concomitantly with, or sequentially after a corticosteroid has recently been reported . It can be an important treatment option, particularly when palliative chemotherapy is inappropriate, for example, because of low performance status. Our unit has previously reported that DES at a dose of 3 mg has a 75% PSA response rate , where PSA response rate was defined as any fall in PSA level. The aim of the present study was to update this experience in a large relatively unselected cohort of patients with CRPC.
- Top of page
- PATIENTS AND METHODS
- CONFLICT OF INTEREST
- Supporting Information
In this large unselected cohort of patients with progressive CRPC, DES has been shown to have significant therapeutic activity. The majority of patients had advanced, symptomatic metastatic disease and 28.9% achieved a PSA decline of >50%, maintained for >4 weeks.
Small studies have previously reported that DES is an active drug in the treatment of advanced prostate cancer. Smith et al.  studied DES 1 mg daily in 21 patients with CRPC. A PSA response (>50% response) was seen in nine patients. In a series of 34 patients with CRPC who received DES 1 mg daily, hydrocortisone 40 mg daily and aspirin 75 mg daily, PSA response (>50% decline) was seen in 21 patients (61.8%) . In addition, 24 out of 29 symptomatic patients had improvement in their pain. Jazieh et al.  reported on 14 patients with progressive prostate cancer after orchidectomy. They were treated with DES at a dose of 3 mg in three divided doses per day, with routine anticoagulation with warfarin. Nine patients responded with a >75% decline in baseline PSA with a median duration of response of 8 months. In patients with symptomatic disease, 50% showed improvement of their symptoms .
Small cohort studies of i.v. oestrogens show varied results in CRPC , although these drugs are no longer routinely available in the UK. Subjective and objective responses are reported in a limited number of patients treated with diethylstilbestrol diphosphate [31,32] or fosfestrol [33,34], Patients with bulky soft tissue disease may be more likely to benefit from i.v. oestrogen therapy .
The present study is considerably larger than the aforementioned series reporting on oral and i.v. oestrogens. It is more representative of routine clinical practice, with a large proportion of elderly patients with advanced disease. This may explain the lower rate of PSA responses seen. When compared with other prospective series there is a high proportion of patients of performance status 2 or more, and this cohort have worse survival according to our multivariate analysis. Furthermore, this cohort of patients appears to be more heavily pre-treated. The study by Smith et al.  included 13 patients who had only one previous hormonal manipulation and eight patients with two or more previous hormone treatments. By contrast, the present study included one patient (0.5%) with one previous hormone treatment and 227 patients (98%) with two or more previous hormone treatments. This may also explain why there was no significant correlation between number of previous hormone treatments and PSA response in the present study, in contrast to the study by Smith et al.
The present study was designed before the PSA Working Group criteria for response were defined. If PSA levels had been measured at 4-week (rather than ∼2-month) intervals, it is likely that the observed PSA response rate would have been >28.9%. It is interesting that 36 patients (16%) showed a PSA response of between 25 and 50%, and 68 patients (32%) showed a PSA response of up to 25%. These figures concur with observed clinical practice where a substantial proportion of patients appear to achieve prolonged stabilization of PSA on DES, without necessarily achieving a substantial drop in PSA measurements.
The findings of the present study raise the issue of possible mechanisms of action of DES in the treatment of CRPC. In hormone-naïve patients, the main action of DES is via suppression of the hypothalamo-testicular axis. In this context 3 mg daily has been shown to reduce serum testosterone to castrate levels . Aggarwal et al.  have suggested DES induces changes in the adrenal androgens dehydroandrostenedione (DHEA) and its sulphate derivative DHEAS, which may relate to the mechanism of action in CRPC. Further studies have shown promotion of cell cycle arrest and induction of apoptosis by DES . Robertson et al.  showed that induction of apoptosis in hormone-insensitive prostate cancer cells, was independent of oestrogen receptor status . DES has also been shown to inhibit the bc-1 complex in the mitochondrial respiratory chain, thus disturbing cellular energy metabolism . Oestrogens have also been shown to inhibit tubulin polymerization  and directly inhibit DNA synthesis and angiogenesis .
The rate of cardiovascular toxicity in the present study was considerably lower than earlier studies, where anticoagulation was not used routinely and modern drugs for management of cardiovascular disease were not available. A 17% cardiovascular mortality was seen using 3 mg and 5 mg of DES in the VACURG studies . The EORTC trials 30761 and 30762 used DES at 3 mg and showed a thromboembolic rate of 9.6 and 17%, respectively with 2.7 and 16% of events, respectively, being lethal . Later studies also using DES at 3 mg show significant thromboembolic events. In the Leuprolide Study Group, 7/101 patients experienced a thromboembolic event. Chang et al.  report a grade III or worse cardiovascular toxicity in 33.3% of patients on DES compared with 17.6% on flutamide. Similarly, in a phase III study of goserelin vs DES at 3 mg, 16 cardiovascular adverse events occurred amongst 126 patients taking DES with no events in the goserelin arm .
Whilst cardiovascular morbidity is significantly reduced using low dose DES, it remains higher than after orchidectomy or LHRH agonist treatment. The EORTC 30805 study using DES at 1 mg showed that the cardiovascular mortality was 14.8%, almost twice the rate with orchidectomy alone (8.3%). This difference persisted in a subgroup with no history of cardiovascular disease ; however, in a smaller single-institution study, only 8/106 patients developed cardiovascular side effects over 12 months, of which only one was a thromboembolic event and there were no cardiovascular-related deaths .
It is clear that anticoagulation reduces the cardiovascular toxicity of DES, but the specific choice of drug is less obvious as no prospective randomized studies have been conducted. Fixed low-dose warfarin at 1 mg does not reduce the thromboembolic toxicity associated with DES , but a fixed dose of 2 mg of warfarin used by Oh et al.  gave a rate of thromboembolism of 9% , which is a similar rate to that using aspirin. Furthermore, Jazieh et al.  used full anticoagulation with warfarin in 14 patients treated with DES at 3 mg per day and no cardiovascular or thrombotic events were reported.
Aspirin at a dose of 75 mg has been shown to give a rate of thromboembolic events that varies from 0 to 12% [22,23,49,50]. The thromboembolic risk of 9.9% in the present study is similar to the rate of 12.6% seen in a recently published study also using DES at 1 mg with aspirin at 75 mg . In both studies DES was continued with full anticoagulation after the majority of thromboembolic events, and there were no toxic deaths. A modest risk of thromboembolism, which would prevent the use of DES in the primary treatment of hormone-naïve patients, may be acceptable in the context of patients with symptomatic CRPC, who have few other treatment options and a poor life expectancy from their cancer.
The present study was designed in the early 1990s and has a number of limitations. First, imaging assessment of measurable disease was not routinely performed. Second, the prospective recording of side effects did not use standardized instruments such as the common toxicity criteria. The frequency and severity of gastrointestinal toxicity, gynaecomastia and other non-thromboembolic toxicities that did not require cessation of DES cannot therefore be accurately described. Third, the monitoring of PSA at ∼ 2-monthly intervals may have influenced the PSA response rate and the progression-free survival rate.
The systemic treatment of CRPC has evolved significantly since the present study was performed. After the results of the TAX 327 trial , docetaxel plus prednisolone is a standard treatment for patients with symptomatic CRPC. In that trial, a 45–48% PSA response was seen using docetaxel with prednisolone, but 12–14% of patients had a Karnofsky performance status of 70 or less in the TAX 327 trial. This compares with 65% of patients having an ECOG performance status of 2 or worse in the present study on DES, suggesting that these patients had more advanced disease. More recently the novel microtubule-binding agent cabazitaxel showed a higher PSA response rate of 39.2% vs 17.8% with mitoxantrone (P < 0.001) . All patients had ECOG performance status 0–2, with >90% of patients having performance status 0 or 1 at baseline.
A phase III study of the CYP-17 inhibitor abiraterone acetate plus prednisolone vs placebo plus prednisolone showed improved overall survival and PSA response rates of 29 vs 6%, respectively, in a cohort of patients pre-treated with chemotherapy [6,51]. Again, patients had better performance status than in the present study, with only 10% of patients having ECOG performance status 2 or worse. MDV3100, a novel androgen receptor antagonist has also shown improved overall survival in a phase III setting . Other exciting developments include the immunotherapy sipuleucel-T, which has extended median overall survival by 4.1 months in a phase III placebo-controlled trial . Finally, radium 223 has recently been shown to improve overall survival and reduce skeletal-related events in the ALSYMPCA trial .
Despite the risk of cardiovascular complications, DES is an active drug in CRPC. The precise mechanism of action of DES in CRPC is unknown but may be related to suppression of adrenal androgens, reduced bioavailability of testosterone owing to elevation of sex hormone-binding globulin, changes in intratumoural hormone levels or possibly non-hormonal mechanisms, including antimitotic, pro-apoptotic or anti-angiogenic effects . A recently published National Cancer Research Network trial addressing whether DES should be started with dexamethasone or deferred until after dexamethasone supported sequential use of DES . When available, newer hormonal options such as abiraterone acetate or MDV 3100 will become preferable to earlier use of DES but presently DES remains a reasonable palliative option for patients with symptomatic CRPC not fit for chemotherapy. The role of topical oestrogens, as first-line therapy, is currently being evaluated in the Medical Research Council PATCH trial .