David Dearnaley, Academic Urology Unit, Royal Marsden Hospital, Sutton, Surrey, UK, SM2 SPT. e-mail: email@example.com
Study Type – Therapy (case series)
Level of Evidence 4
What's known on the subject? and What does the study add?
Diethylstilbestrol (DES) was the first hormone treatment used for prostate cancer and has also shown effectiveness in castration-resistant disease in small studies; however, concerns over thromboembolic toxicity have restricted its use in the past.
Over 200 elderly men with castration-resistant prostate cancer were treated with 1–3 mg of DES, given with 75 mg aspirin and breast bud irradiation. Almost 30% of men showed a significant PSA response and the median time to PSA progression was 4.6 months. Almost 20% of patients with pain had a significant analgesic benefit. The most important toxicity was thromboembolism in 10% of men. Overall the drug has an acceptable toxicity profile and offers a palliative benefit in frail elderly men who may not be fit for chemotherapy.
• To assess the efficacy and toxicity of diethylstilbestrol (DES) in the management of castration-resistant prostate cancer (CRPC).
PATIENTS AND METHODS
• A total of 231 patients with CRPC received treatment with DES at the Royal Marsden Hospital between August 1992 and August 2000.
• The median pre-treatment prostate-specific antigen (PSA) level was 221 ng/mL.
• DES was used at a dose of 1–3 mg daily, with aspirin 75 mg.
• The primary endpoint was PSA response rate.
• The PSA response rate (using PSA Working Group criteria) was 28.9%.
• The median time to PSA progression was 4.6 months.
• Of patients with bone pain, 18% had an improvement in their European Organisation for the Research and Treatment of Cancer pain score.
• Thromboembolic complications were seen in 9.9% of all patients.
• DES has significant activity in CRPC and can be of palliative benefit.
• DES has an acceptable toxicity profile in the management of patients with symptomatic CRPC when used at a dose of 1–3 mg, combined with aspirin and prophylactic breast bud radiotherapy.
European Organisation for the Research and Treatment of Cancer
European Cooperative Oncology Group
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.
PATIENTS AND METHODS
Patients receiving DES for CRPC between August 1992 and August 2000 were identified from a prospectively collected clinical database of patients treated for prostate cancer (n= 243). Patients with a lack of follow-up information were excluded from the analysis (n= 12) leaving 231 patients as the study cohort. For PSA response, a further six patients were excluded, as their date of last PSA result was before the date of administration of DES; therefore, only 225 patients were considered for analysis. Patients with good clinical and biochemical follow-up data on DES, but with an unknown date of death, were censored for the survival analysis (n= 10).
All patients had CRPC, defined as progressive disease (rising PSA, and/or evidence of progression on imaging) with a castrate testosterone. Baseline data, at the time of starting DES included patient age, type and duration of previous hormone therapy, number of previous hormonal treatments, pre-treatment PSA, clinical stage and WHO grade. European Cooperative Oncology Group (ECOG) performance status was recorded and pain at baseline was scored according to EORTC criteria . Haematological and biochemical variables measured included haemoglobin, alkaline phosphatase and albumin. When clinically indicated, an isotope bone scan was used to determine the presence or absence of metastatic disease.
During the time period of 1992–1996 DES was used as a ‘standard of care’ for patients with CRPC. Patients did not formally consent to enter into a clinical trial but were verbally informed of the intention to closely monitor their therapy, and data were prospectively recorded on proformas designed for the purpose in the Bob Champion Data Management Unit. The delay in reporting findings was as a result of the study not fulfilling present EU Directive guidelines. After review by the Royal Marsden Hospital/Institute of Cancer Research Committee for Clinical Research, it was agreed that the experience should be reported as a Service Evaluation (CCRSE No: 3462SE).
Between 1992 and 1996 patients received a daily dose of 3 mg DES. From 1997, after a protocol amendment, an initial daily dose of 1 mg was used, with titration up to a possible 3 mg. Aspirin at a dose of 75 mg daily was given to all patients with the exception of those who were already using warfarin for anti-coagulation for other indications (36 patients). All patients were offered radiotherapy to the breast buds before starting DES, to prevent painful breast enlargement. This was administered using a single fraction of 8 Gy with orthovoltage X-rays.
Patient assessment during treatment with DES was performed at ∼2-monthly intervals, and included history, physical examination and serum PSA measurement. Pain was scored according to EORTC criteria .
The primary endpoint for this study was PSA response. This was defined according to the PSA Working Group criteria, as ‘a 50% or greater decrease in serum PSA confirmed on two separate measurements at least four weeks apart’. The proportion of patients experiencing a ≥80% decrease in serum PSA confirmed on two separate measurements at least 4 weeks apart was also recorded.
Secondary endpoints were time to PSA progression, pain response, thromboembolic events, toxicities necessitating cessation of DES and overall survival. Pain was assessed according to the EORTC pain score 3 months after starting DES . Thromboembolic events included occurrence of deep vein thrombosis, pulmonary embolism or non-haemorrhagic cerebrovascular accident during DES treatment.
Further study objectives were to identify predictors of PSA response including: albumin, haemoglobin, alkaline phosphatase, number of previous hormone treatments, duration of first hormone treatment, presence of proven metastatic disease, dose of DES and ECOG performance status.
Kaplan–Meier survival curves were used to calculate the median time to PSA progression and median overall survival. Time to PSA progression was defined according to the PSA Working Group criteria as ‘time from start of therapy to first PSA increase that is >25% and >2 ng/mL above the nadir, and which is confirmed by a second value 3 or more weeks later’[2,28]. Overall survival was measured from time of starting DES until death. Patients lost to follow-up were censored at the date of last follow-up.
The relationship between predictive factors and PSA response, overall survival and pain response was assessed using univariate and multivariate binary logistic regression models, reporting odds ratios (ORs) and 95% CIs. An unplanned analysis of the relationship between pain response and PSA response was conducted using Fisher's exact test.
The study group consisted of 231 patients. Patient characteristics are shown in Table 1. The mean age was 70 years and the median PSA level before treatment was 221 ng/mL. The median time from initial diagnosis of prostate cancer to start of DES was 3.4 years. Patients had received a median of 3 previous hormone treatments. Thirty patients had previously undergone an orchidectomy, 168 patients were treated with an LHRH analogue and short-course anti-androgen and 95 patients received LHRH analogue alone. This included LHRH analogue as a re-challenge in some patients who had initially received it as neoadjuvant treatment and subsequently at the point of disease relapse. Sixty patients were treated with bicalutamide, 93 with flutamide and 48 with cyproterone acetate. Eighty-three patients were treated with corticosteroid in the form of prednisolone or dexamethasone and 16 patients received other treatments including aminoglutethimide, ketoconazole and medroxyprogesterone acetate. The median duration of first hormone treatment was 1.8 years. A total of 109 patients were treated with a dose of 3 mg DES daily and after the protocol amendment in 1997, 122 patients were treated with a dose of 1 mg DES daily.
Table 1. Patient characteristics (N= 231)
DES treatment, n (%)
PSA level at baseline, ng/mL (N= 221)
255 (21 298.3)
1.7, 21 300
Bone metastases, n (%)
No. of previous hormone treatments, n (%)
Duration of first hormone treatment, years (N= 229)
Previous chemotherapy, n (%)
Performance Status at baseline, n (%)
WHO Grade, n (%)
Low grade, well differentiated
Moderate grade, moderately differentiated
High grade, poorly differentiated
Time from initial diagnosis to start of stilbestrol, years
Median (interquartile range)
Haemoglobin, n (%)
Alkaline Phosphatase, n (%)
Albumin, n (%)
In all, 80% of patients had documented bone metastases before treatment. At baseline 69% of patients required analgesia, of whom 31% received strong opiates. At baseline, 33% of patients had ECOG performance status 0 or 1, 50% performance status 2 and 15% performance status 3 (Table 1).
A PSA response of >50% was observed in 65/225 patients (28.9% [95% CI 23.1–35.3]). The PSA response was confirmed as >80% in 31 patients (13.8% [95% CI 9.6–19]). In all, 36 patients (16%) showed a PSA response of between 25 and 50%, and 68 patients (32%) showed a PSA response of up to 25%. The median time to PSA progression was 137 days (95% CI 120–153). The proportion of patients responding at 12 months and 24 months was 16.1% (95% CI 10.9–22.3) and 4.6% (95% CI 1.9–9.1) respectively. PSA progression is shown in Fig. 1A and Table 2. Kaplan–Meier curves for PSA progression stratified according to metastatic or non-metastatic status are shown in Fig. 1B.
Table 2. Proportion of patients with a ≥50% decrease in serum PSA with DES treatment
Confirmed on two separate measurements at least 4 weeks apart.
The median treatment duration was 4.6 months. The median follow-up was 16.3 months. All patients have since died and the date of death was known precisely for 220 patients (95%) and the remaining 11 (5%) were censored at the time of last known contact.
Median overall survival was 9.3 months (281 [95% CI 236–326] days), overall survival is shown in Fig. 1B. Kaplan–Meier survival curves, stratified according to metastatic or non-metastatic status, are shown in Fig. 1D. Patients in this study were treated at least 10 years ago; it should be noted that more recent data sets show better survival than in the past.
A total of 210 patients with pain before treatment with DES were assessable for pain response. Pain scores were assessed for the first time ∼3 months after starting DES with a median time between baseline and follow-up for pain scores of 95 days. A total of 37 patients (18% [95% CI 13–23]) had an improvement in their pain score, 83 patients (39% [95% CI 33–46]) had a deterioration in their pain score, and 90 patients (43% [95% CI 36–50]) had no change in their pain score.
A total of 23 patients (9.9%) developed thromboembolic complications as shown in Table 3. Of these, 11 patients had deep vein thromboses, six patients had pulmonary emboli with one of these having an additional superficial femoral thrombosis, four patients had cerebrovascular accidents, of which two were non-haemorrhagic and two were of an uncertain nature. Two patients were diagnosed with transient ischaemic attacks. No patient died as a result of thromboembolic complications. Management of thromboembolic complications with respect to use of DES is shown in Table 4.
Table 3. Thromboembolic events whilst taking or within 8 weeks of cessation of DES
No. of patients (%)
Deep vein thrombosis
Transient ischaemic attack
Table 4. DES treatment after thromboembolic events
No. of patients (%)
DES stopped completely
DES restarted after warfarin
DES continued, patient given warfarin
DES stopped before thromboembolic event
The main toxicities requiring cessation of DES were thromboembolism (11 patients) and nausea (nine patients). Other toxicities for which DES was stopped included lymphoedema (two patients), deranged liver function tests (two patients) and lethargy (two patients). One patient stopped DES because of reflux symptoms, another because of chest pain with no evidence of ischaemic damage and a further patient stopped the drug because of pulmonary oedema. These toxicities, together with toxicities requiring a dose reduction from 3 to 1 mg, are shown in Table 5A and B.
Table 5. Toxicities that required (a) cessation of DES and (b) dose reduction of DES to 1 mg
Number stopping DES
Lower limb oedema
Deranged liver function tests
Possible transient ischaemic attacks
Congestive cardiac failure
PREDICTORS OF PSA RESPONSE
Predictors of PSA response, pain response and survival were analysed in a total of 225 patients. Univariate analysis of PSA response showed that the presence of metastatic disease was the only significant variable, where presence of metastatic disease compared with absence of metastatic disease was less likely to give a PSA response (P= 0.045). As there was only one significant variable and owing to incomplete data for the variables, a multivariate analysis was not performed. For pain response, a univariate analysis showed haemoglobin of 11–12.5 g/dL to be the only significant variable hence multivariate analysis was not performed. Fisher's exact test showed no evidence of a relationship between pain response and PSA response as shown in Table 6 (P= 0.315, unplanned analysis).
Table 6. PSA response stratified by pain response
Pain response (EORTC score)
No change/worse, n (%)
Improved, n (%)
A number of factors were significant predictors of survival in univariate analysis. These included albumin >30 g/L, haemoglobin >12.5 g/dL, alkaline phosphatase <133 IU/L, the absence of metastatic disease, longer duration of first hormone treatment, DES dose of 1 mg and ECOG performance status of 2 or better. In a multivariate analysis, a performance status of 2 or worse, or albumin <30 g/L were poor prognostic factors. Results from univariate and multivariate analyses are shown in Table 7 and Supplementary Tables S1–3.
Table 7. Overall survival multivariable model
Alkaline phosphatase (IU/L):
No. of previous hormone treatments
Proven metastatic disease
Duration of first hormone treatment, years
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 .
This work was undertaken in The Royal Marsden NHS Foundation Trust who received a proportion of its funding from the NHS Executive; the views expressed in this publication are those of the authors and not necessarily those of the NHS Executive. This work was supported by the Institute of Cancer Research, the Bob Champion Cancer Trust and Cancer Research UK Section of Radiotherapy [CUK] grant number C46/A2131. We acknowledge NHS funding to the NIHR Biomedical Research Centre.