BERKELEY, CA (UroToday.com) - DES was the first medical endocrine treatment used in prostate cancer [1] but was associated with significant cardiovascular mortality.[2] The improved therapeutic index of other hormone treatments, especially LHRH analogues, means use of DES is now confined to CRPC. Several novel agents have recently shown efficacy in CRPC in phase 3 randomised controlled trials.[3, 4, 5, 6, 7] DES has never been formally tested in this setting and a randomised controlled trial in CRPC is unlikely; this prospective cohort study is the largest series to report efficacy and toxicity of the drug, to date.[8]
The unselected cohort of over 200 men treated with DES included many elderly frail patients who would have been excluded from randomised controlled trials due to poor performance status (67% of patients ECOG performance status 2 or worse). Despite this, a PSA response of 28.9% was seen. Clinical and biochemical assessments were only carried out 2 monthly rather than 4 weekly (as in modern studies), hence PSA response may have been underestimated. Furthermore, 48% of men experienced a PSA decline that did not meet PSA working-group criteria, which suggests that a proportion of patients treated with DES experience PSA stabilisation, rather than a substantial drop in the biomarker.
The median survival after starting DES was 9.3 months which was comparable to survival outcomes in other studies conducted at a similar time.[9] Patients in this study were treated over 10 years ago when chemotherapy and other novel agents were unavailable for CRPC. Multivariate analysis showed a performance status of 2 or worse and low albumin (<30g/L) to be statistically significant factors predicting poor survival.
Whilst a pain response of 18% is encouraging, there was no significant correlation between a PSA response and analgesic benefit. This suggests that PSA may not be a precise surrogate marker for palliative benefit and highlights the need to directly assess quality of life and other palliative endpoints in patients receiving DES. The lack of formal evaluation of quality of life is a limitation of this study. In addition non-thromboembolic toxicity was only assessed according to whether the drug needed to be stopped, rather than by using standardised instruments such as Common Toxicity Criteria.
A pragmatic policy of using aspirin 75mg was adopted; some recent evidence suggests this was reasonable,[10] but no substantive studies are available to judge efficacy as compared with low dose warfarin or full anticoagulation. The observed rate of thromboembolism of approximately 10% is comparable with other recent studies of DES.[11] There were no fatal events from thromboembolism, and of these, 26% (6/23) of patients were able to continue DES once anticoagulated. It could be anticipated that this cohort of men with a pelvic malignancy and potentially poor performance status and mobility would have a baseline risk of thromboembolism prior to DES that is considerably higher than the age adjusted estimate of 0.5%.[12]
A significant proportion of patients with CRPC are symptomatic and too frail for palliative chemotherapy. This study suggests that in such patients, the modest risk of thromboembolism may be acceptable in view of the therapeutic activity of DES. However, as novel agents with fewer side effects become increasingly available, they will supersede DES as early palliative treatment options for CRPC and it would be valuable to gain evidence to determine the efficacy of DES following these agents.
References:
- Huggins, C. H., C. Studies on prostate cancer. I. The Effect of Castration, Of Estrogen and of Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate. Cancer Research 1, 293-297 (1941).
- Blackard, C. E., Doe, R. P., Mellinger, G. T. & Byar, D. P. Incidence of cardiovascular disease and death in patients receiving diethylstilbestrol for carcinoma of the prostate. Cancer 26, 249-256 (1970).
- de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364, 1995-2005 (2011).
- de Bono, J. S. et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376, 1147-1154 (2010).
- Parker C, H. D., O'Sullivan JM, Fossa SD, Chodacki A, Demkow T, Logue JP, Seke M, Widmark A, Johannessen DC, Nilsson S, Hoskin P, Solberg A, James ND, Syndikus I, Cross A, O'Bryan-Tear CG, Garcia-Vargas JE, Sartor AO. Overall survival benefit and safety profile of radium-223 chloride, a first-in-class alpha-pharmaceutical: Results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases. J Clin Oncol 30, 2012 (suppl 5; abstr 8) (2012).
- Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367, 1187-1197 (2012).
- Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363, 411-422 (2010).
- Wilkins, A. et al. Diethylstilbestrol in castration-resistant prostate cancer. BJU Int (2012).
- Fossa, S. D. et al. Prognostic factors in hormone-resistant progressing cancer of the prostate. Ann Oncol 3, 361-366 (1992).
- Brighton, T. A. et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 367, 1979-1987 (2012).
- Shamash, J. et al. A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol. Br J Cancer 104, 620-628 (2011).
- White, R. H. The epidemiology of venous thromboembolism. Circulation 107, I4-8 (2003).
Written by:
Anna Wilkins as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Academic Urology Unit, Royal Marsden Hospital, Sutton, UK
Diethylstilbestrol in castration-resistant prostate cancer - Abstract
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