Current Role of Diethylstilbestrol in the Management of Advanced Prostate Cancer

Home , Diethylstilbestrol, Fosfestrol, Orteronel

Current role of diethylstilbestrol in the management of advanced prostate cancer BJUIBJU INTERNATIONAL Pierre-Olivier Bosset , Laurence Albiges * * , Thomas Seisen , Thibault de la Motte Rouge * , V é ronique Ph é , Marc-Olivier Bitker and Morgan Roupr ê t Urology Academic Department of la Pitié -Salp ê tri è re Hospital, Assistance Publique- Hô pitaux de Paris, Faculté de M é decine Pierre et Marie Curie, University Paris VI, Paris , * Department of Medical Oncology, Centre de Lutte contre le Cancer (CLCC) , and * * Institut Gustave Roussy, Universit é Paris XI, Villejuif, France Accepted for publication 23 March 2012

The aim of this review was to describe the What ’s known on the subject? and What does the study add? most recent data from contemporary Diethylstilbestrol (DES) has been found to have anti-tumour properties and clinical clinical trials of diethylstilbestrol ( DES) to effectiveness in prostate cancer that is resistant to the fi rst-line hormonal therapy. better determine its current role in advanced prostate cancer treatment as new This review found that low-dose DES has anti-tumour effi cacy with limited hormonal therapies emerge. Relevant cardiovascular side effects and should be considered for secondary hormone clinical studies using 1 mg of DES in manoeuvres. castrate-resistant prostate cancer (CRPC) were identifi ed from the literature, clinical trial databases, websites and conference doses of DES. The 1-mg dose is associated KEYWORDS abstracts. The effi cacy and safety outcomes with a reduced toxicity, including fewer were summarized. DES in CRPC produced a thromboembolic and cardiovascular events. hormone-resistant prostate cancer , biological response (change in PSA level) Low-dose DES appears to be safe and diethylstilbestrol , progression , PSA , low and improved the median survival of effective for CRPC before initiating molecular weight heparin , androgen patients when used as a second-line chemotherapy. The cost/effi ciency ratio deprivation therapy hormone therapy after standard androgen may encourage physicians to consider DES deprivation with bicalutamide and LHRH as a therapy option before chemotherapy analogues. These fi ndings were for low in non-symptomatic CRPC.

INTRODUCTION in prostate cancer that is similar to higher complex causes a decrease in LH secretion, doses but with fewer cardiovascular side consequently decreasing androgen secretion Androgen deprivation therapy has been the effects [ 2 ] . Although DES was seldom used [ 4 ] . DES also increases the levels of sex standard approach for advanced prostate in the USA, it was an important option in hormone-binding globulin and pituitary cancer treatment. In the 1940s, the two the armamentarium of European doctors, prolactin secretion which decreases standard therapies were orchiectomy and especially after the failure of fi rst-line testosterone production in the testes [ 1,5 ] . diethylstilbestrol (DES). The Veterans hormonal therapy [ 3 ] . The objective of the DES can also suppress the function of Administration Cooperative Urological present review was to describe the most Leydig cells and inhibit the secretion of Research Group (VACURG) demonstrated recent data from contemporary clinical trials androgenic steroids. This effect decreases that orchiectomy and DES have an of DES to better determine its current role the secretion of testosterone, as shown by equivalent effi cacy; however, DES has an in advanced prostate cancer treatment as the in vitro work of Geisler et al. [ 6 ] . increased cardiovascular toxicity at a 5-mg new hormonal therapies emerge. dose in patients with metastatic prostate Recently, in CRPC, DES has been shown to cancer, which limits the its use [ 1 ] . The DIETHYLSTILBESTROL act as a telomerase activity inhibitor [ 7 ] . It is advent of GnRH agonists, which showed an well established that androgen receptors effi cacy similar to 3 mg of DES without the Diethylstilbestrol is a synthetic ethinyl play a crucial role in CRPC and recently, it cardiovascular toxicity, resulted in a decrease oestrogen. Its anti-tumour effi cacy is has been reported that DES exhibits a high in the use of DES. However, results from attributable to different actions on the binding affi nity for these receptors and further VACURG studies suggested that prostate cancer. First, the negative feedback could play a mediating role in the disease lower doses (1 mg daily) of DES had activity exerted on the hypothalamic – pituitary [ 8 ] .

anti-androgen and castration (i.e. TABLE 1 Recent major studies on the use of DES in hormone-resistant prostate cancer testosterone < 50 ng/dL) treatments. Mean (range) Mean % time to ADVERSE EVENTS FROM LOW DOSES No. of PSA progression, OF DES Study, year patients Therapy response months Orlando et al. , 2000 [ 14 ] 38 DES 1 mg 79 (66-92) 7 The dose escalation sought by Huggins [ 23 ] Rosenbaum and Carducci, 2003 [ 15 ] 18/35 DES 1 mg/2 mg 66 7.5 (2 – 36) in 1941 was related to the cardiovascular Aspirin 100 mg toxicity of DES. Because the VACURG results Smith et al. , 1998 [ 12 ] 21 DES 1 – 2 mg 43 (22 – 64) – showed a 36% increase in mortality in the Clemons et al. , 2011 [ 13 ] 58 DES 1 mg 38.8 6.7 (4.8 – 15.2) 5-mg arm, he was looking for the ideal dose Shamash et al. , 2010 [ 3 ] 145 DES 1 mg 67.5 – that would demonstrate effi cacy while limiting its cardiovascular toxicity [ 2 ] . Hypercoagulability has been linked to the increased synthesis of the coagulation METHODS OF DOSE EFFICACY IN of 30 months (95% CI, 21.9 – 68.7) [ 13 ] . factors I, II, VII, IX and X resulting from the HORMONE-RESISTANT PROSTATE Despite the number of previous hormonal administration of oestrogen [ 24 ] ; the CANCER manipulations, DES seemed to induce a increased synthesis of these coagulation biological response. Of the 34 patients factors would lead to a hypocoagulability, Historically, DES was administered at a dose who failed the androgen deprivation decreasing the plasminogen activator and of 5 mg [ 9 ] . At this dose, the effectiveness therapy, 56% biologically responded to cardiovascular effects. of DES was obvious but not without 1 mg of DES, and similar results were many side effects (e.g. gynaecomastia, observed with DES as second- and third-line At a 3-mg dose of DES, a 9.6% rate of cardiovascular risk). A 1 – 3-mg DES dose in therapies [ 12 ] . thromboembolic events was found in the CRPC has been shown to provide the best European Organisation for the Research and relationship between effectiveness and side In addition to the pre-chemotherapy results, Treatment of Cancer (EORTC) trial, protocol effects [ 10,11 ] . Major studies that used three out of nine patients treated after 30761, vs 2.7% in the other arm, which 1 – 3 mg of DES are listed in Table 1 undergoing docetaxel treatment had a PSA included cyproterone acetate and [ 3,12 – 15 ] . Chang et al. [ 16 ] reported a 62% response of > 50%. This fi nding shows the medroxyprogesterone acetate [ 25 ] . The decrease of PSA with 3 mg/day DES in 48 effectiveness of DES in a different setting of results were similar in EORTC protocol patients. These results were consistent with prostate cancer [ 13 ] . The successful use of 30762, which included a thromboembolic earlier reports by Prout et al. [ 10 ] and Kent DES after chemotherapy had already been event incidence of 17%, 16% of which were et al. [ 11 ] . shown by Serrate et al. [ 19 ] . In this trial, a lethal. In the present study, the risk PSA decrease of > 50% was observed in fi ve increased with age, a weight > 75 kg and a Nevertheless, toxicity, including cardiac of 20 patients. These data should have history of cardiovascular disease [ 26 ] . More toxicity, remained with the 1-mg DES encouraged physicians to consider DES as a recent studies using 3 mg of DES have treatments for prostate cancer. The test dose potential option after chemotherapy. A DES reported similar results. In a phase III of 1 mg/day of DES showed a promising re-challenge could be a therapeutic option. comparison of 3 mg of DES vs goserelin, 16 effect on PSA in a phase 1 – 2 trial [ 12 ] . Nine In this situation, the mean (range) duration cardiovascular events occurred in the DES of 21 (43%) patients had a PSA response, of treatment in four patients was 62.6 arm, which included 126 patients [ 27 ] . which was defi ned as a > 50% decline from weeks (44.1 – 92) [ 13 ] . Overall, there was an 8 – 12.6% incidence of baseline at the end of the phase II trial. cardiovascular events observed in the These results were identical after one or While DES was widely considered an old contemporary studies that used 3 mg of more hormonal manipulations, and the treatment, the present literature review has DES [ 1 ] . 2-year survival was 63% in a study by Klotz shown its effi cacy in locally advanced or et al. [ 14 ] . The median PSA dropped from metastatic prostate cancer. Although DES The fi nal analysis of EORTC protocol 30805, 95.4 μ mol/L (baseline) to 1.5 μ mol/L after 3 has not been used widely in the USA, it has which compared orchiectomy plus months of treatment with 1 mg of DES. DES remained a therapeutic option, and cyproterone acetate and low-dose DES use in their study was associated with meanwhile new hormone treatments are (1 mg daily) in patients with metastatic warfarin in CRPC [ 17 ] . Of the 108 patients emerging (e.g. abiraterone, MDV3100, disease, evaluated the clinical effi cacy and treated with 1 mg of DES for advanced orteronel) [ 20 – 22 ] . The development of toxicity of low-dose DES in a multicentre, prostate cancer (pT3, N0/1), 70 patients had these new hormones and looking at the prospective, randomized trial [ 26 ] . In the a signifi cant PSA response with a median of effectiveness of the old hormones blur the DES arm, 14.8% (16/108) of patients 21 months of treatment [ 18 ] . More recently, defi nition of hormone-resistant prostate reported thromboembolic events vs 8.3% 38.8% of patients (n = 49) treated with cancer. In 2012, CRPC is commonly defi ned (9/108) in the orchiectomy-only arm. This 1 mg daily before chemotherapy had a PSA as a clinical (weight loss, increased pain), population had no known cardiovascular response, defi ned as a > 50% decline from biological (new increase in PSA level) or history. Only two of 63 patients reported a baseline, with a median time to progression radiological progression despite deep vein thrombosis that was confi rmed by

a Doppler in the most recent study [ 13 ] . TABLE 2 Thromboembolic events with low-dose DES These results were obtained by adding 2 mg of warfarin to the diethylstilbestrol for 15 Percentage of patients with cardiovascular risk. Six patients Study, year thromboembolic events Previous treatment were previously treated with warfarin for Smith et al. , 1998 [ 12 ] 5 (1/21 patients) Aspirin 75 mg other indications. Clemons et al. , 2011 [ 13 ] 3.1 (2/63 patients) Warfarin 2 mg (25% patients) Bishop et al. , 1996 [ 18 ] 7.5 (8/106 patients) Nothing Similar results were found in the recent Robinson et al. , 1995 [ 26 ] 14.8 (16/108 patients) Nothing literature, with thromboembolic Manikandan et al. , 2005 [ 28 ] 7.5 (2/26 patients) Aspirin 75 mg complication rates of 5 – 8% [ 12,28 ] . Consequently, DES was combined with 75 mg of aspirin ( Table 2 [ 12,13,18,26,28 ] ). This increased risk of thromboembolic complications was investigated with CONCLUSION (diethylstilbestrol) signifi cantly decreases androgen deprivation. DES with aspirin plasma estrogen and androgen levels resulted in a rate of cardiovascular events In summary, low-dose DES remains a but does not infl uence in vivo (e.g. stroke, deep vein thrombosis) almost feasible, inexpensive and effective option for aromatization in postmenopausal breast identical to that of any androgen blockade. CRPC treatment before chemotherapy. cancer patients . J Steroid Biochem Mol The latter was estimated to be > 40% when Thromboembolic events occur in < 5% of all Biol 2005 ; 96 : 415 – 22 compared with a bilateral orchiectomy and patients receiving DES, therefore, it should 7 Geier R , Adler S , Rashid G , Klein A . should be considered in the therapeutic still be considered for the treatment of The synthetic estrogen diethylstilbestrol decision [ 29 ] . 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