A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol

Abstract

Background:The role of further hormone therapy in castration-resistant prostate cancer (CRPC) remains unclear. We performed a multi-centre randomised phase III study comparing the use of Dexamethasone, Aspirin, and immediate addition of Diethylstilbestrol (DAiS) vs Dexamethasone, Aspirin, and deferred (until disease progression) addition of Diethylstilbestrol (DAdS).Methods:From 2001 to 2008, 270 men with chemotherapy-naive CRPC were randomly assigned, in a 1 : 1 ratio, to receive either DAiS or DAdS. They were stratified for performance status, presence of bone metastases, and previous normalisation of prostate-specific antigen (PSA) to androgen deprivation. The study end points were the proportion of patients achieving a 50% PSA response, progression-free survival (PFS), overall survival, and quality of life. Intention-to-treat analysis was carried out. The effect of treatment was studied first by Kaplan–Meier curves and log-rank test, and finally through multivariable stratified Cox's proportional hazards model adjusting for the effects of possible baseline prognostic factors. Quality of life was analysed using multivariate analysis of variance.Results:At study entry, the median age was 76 years (inter-quartile range: 70–80 years), the median PSA was 79 ng ml−1, and 76% of the cohort had metastatic disease. The response rates for DAiS (68%) and DAdS (64%) were not significantly different (P=0.49). Similar to the response rate, neither the PFS (median=8.1 months for both arms) nor the overall survival (19.4 vs 18.8 months) differed significantly between the DAiS and DAdS groups (P>0.20). However, the response rate for the DAiS (68%) was significantly higher than the response rate of DA (before adding Diethylstilbestrol) (50%) (P=0.002). Similarly, the median time to progression for DAiS (8.6 months) was significantly longer than that of DA (4.5 months) (P<0.001). Multivariable analysis showed that patients with previous haemoglobin ⩾11 g dl−1 decreased the risk of death significantly (hazard ratio: 0.44, 95% CI: 0.25–0.77). Patients treated with previous anti-androgens alone had more than 5 times more risk of death compared with patients treated with gonadorelin analogues throughout their castration-sensitive phase. Treatment sequencing did not affect the quality of life but pre-treatment performance status did. The incidence of veno–thromboembolic events was 22% (n=28) in DAiS and 11% (n=14) in the DA arm (P=0.02). Painful gynaecomastia occurred in only 1% on DA, whereas in 40% on DAiS (P=0.001).Conclusion:Dexamethasone and immediate Diethylstilbestrol resulted in neither higher PSA response rate nor higher PFS compared with Dexamethasone with deferred Diethylstilbestrol. There was no suggestion of significantly improved overall survival or quality of life. Given the significantly higher toxicity of Diethylstilbestrol, deferring Diethylstilbestrol until failure of Dexamethasone is the preferred strategy when using these agents in CRPC.

A Randomised Phase 2 Trial of Dexamethasone Versus Prednisolone in Castration-resistant Prostate Cancer

“…Phase 2 studies of low-dose, daily dexamethasone have reported somewhat higher PSA response rates of 50-60%, with median time to PSA progression from 7 mo to 8 mo [4,11]. The two largest studies, including a combined total of 237 patients treated with dexamethasone as a single agent, both reported PSA response rates of around 50% [4,12]. The published activity data for low-dose, daily dexamethasone in CRPC are summarised in Table 1.…”

“…In these trials, the PSA response rate to prednisolone has ranged from 16% to 24%, and the median time to PSA progression has ranged from 2 mo to 6 mo [6][7][8][9][10]. The published activity data for prednisolone in CRPC are summarised in Table 1 [3,4,[6][7][8][9][10][11][12][13][14][15][16][17].…”

Debating controversies in the management of advanced prostate cancer

“…Men were randomised to receive dexamethasone and aspirin with either the immediate or deferred (at progression) addition of DES. 5 The results of the study showed that there were no significant advantages in using both drugs in combination as initial therapy in terms of PSA response rate, progression-free survival (8.1 months in both arms), overall survival or quality of life. In view of the fact that the potential toxicity of DES is higher than that of dexamethasone, the authors have concluded that a preferred strategy could be to defer DES until failure of dexamethasone when using these agents in CRPC.…”

A Prospective Audit of Intermittent Anti-Androgen verses Pituitary Blockade Suggests a Bipolar Androgen Type Strategy May Be Safe in Untreated Prostate Cancer

“…Second-line endocrine treatment was mainly LHRH agonist in the iAAm group followed by Stilboestrol plus or minus Dexamethasone [14][15][16] followed by chemotherapy with CL56, a 2-week treatment with oral Chlorambucil and Lomustine repeated 8 weekly [17]. This had been shown to produce equivalent survival to Docetaxel with the added advantage that when given without continued androgen suppression, patients often responded a second time to previous endocrine treatments that they had initially failed and were considered to have progressed to hormone-refractory disease [17][18][19].…”