Diethylstilbestrol in castration‐resistant prostate cancer

Abstract

E 7 2 7What ' s known on the subject? and What does the study add? Diethylstilbestrol (DES) was the fi rst 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 signifi cant PSA response and the median time to PSA progression was 4.6 months. Almost 20% of patients with pain had a signifi cant analgesic benefi t. The most important toxicity was thromboembolism in 10% of men. Overall the drug has an acceptable toxicity profi le and offers a palliative benefi t in frail elderly men who may not be fi t for chemotherapy. OBJECTIVE• To assess the effi cacy 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 prostatespecifi c 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. RESULTS• 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. CONCLUSIONS• DES has signifi cant activity in CRPC and can be of palliative benefi t.• DES has an acceptable toxicity profi le 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. KEYWORDS

Antitumour activity of abiraterone and diethylstilboestrol when administered sequentially to men with castration-resistant prostate cancer

“…Furthermore, we assessed abiraterone activity using PSA endpoints, which are commonly used activity endpoints, but not robust surrogates of overall survival(Fleming et al , 2006). Of note, the median time on DES in our pre-chemotherapy cohort was considerably longer than previously reported (Wilkins et al , 2012). It is likely that patients with a good response to prior hormonal manipulations and no clinical indication for cytotoxic chemotherapy were positively selected in the Phase II trials of abiraterone pre-chemotherapy.…”

“…Several mechanisms have been proposed to explain DES activity, including reduction of luteinizing hormone, testosterone and androgenic steroid levels (Bosset et al , 2012), inhibition of telomerase activity (Geier et al , 2010); direct binding of the androgen receptor (AR) (Wang et al , 2010) and suppression of β -tubulin isotypes (Montgomery et al , 2005). High-dose (5 mg daily) DES was associated with cardiovascular toxicity (Malkowicz, 2001), but low-dose DES 1 mg daily had a more acceptable therapeutic ratio, with reported activity including ⩾50% PSA declines in 23–43% of patients (Smith et al , 1998; Manikandan et al , 2005; Clemons et al , 2011; Wilkins et al , 2012) and time to PSA progression of 4–4.6 months (Clemons et al , 2011; Wilkins et al , 2012). Combined with dexamethasone, DES treatment resulted in ⩾50% PSA declines in 64–68% of patients in a small randomised study (Shamash et al , 2011), but venothromboembolic events occurred in 22% of patients in the combination arm.…”

Oral ethinylestradiol in castration‐resistant prostate cancer: A 10‐year experience

“…In contrast, it is also true that the development of new significant treatment strategies for CRPC might limit the use of an old therapy, such estrogens. The interest in estrogens, in particular for CRPC cases, is based on: (i) estrogens represent a different way of achieving castration, and it is possible that the beneficial effect of estrogens is also based on a direct cytotoxic effect on PC cells; (ii) discovery of new estrogen receptors in PC tissue that can be upregulated by first‐line castration therapies; and (iii) clinical trials, in particular using DES, showing a high rate of PSA response in CRPC …”

Diethylstilbestrol for the treatment of patients with castration-resistant prostate cancer: Retrospective analysis of a single institution experience

“…The accepted first-line treatment for advanced prostate cancer is surgical or chemical castration, using LH-RH partial agonists or antagonists or a combination of an LH-RH analog with an anti-androgen (3). With this treatment, ~80% of men experience symptomatic improvement and a reduction in prostate-specific antigen (PSA) serum levels.…”