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

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.

The long-term risks of adjuvant carboplatin treatment for stage I seminoma of the testis.

BACKGROUND: The use of adjuvant carboplatin in the management of stage I seminoma of the testis has been limited by the lack of long-term data. In this study, we address this issue for the first time. PATIENTS AND METHODS: Data on 199 patients treated with single-agent carboplatin for stage I seminoma of the testis were prospectively collected. Overall mortality, deaths from circulatory disease and the incidence of second cancers were compared with expected values derived from the UK general population. RESULTS: The median follow-up for the cohort was 9.0 years (range 0.1-20.1). There has been no excess in overall mortality [standardised mortality ratio (SMR) 0.89; 95% CI 0.36-1.83], death from circulatory diseases (SMR 1.44; 95% CI 0.39-3.69) or the incidence of second nontestis cancers (standardised incidence ratio 0.96; 95% CI 0.26-2.45) in this group of patients. These findings also applied to specific follow-up periods of >5 or 10 years. Specifically, neither haematological nor solid nontestis tumours occurred in excess. There was an increase in the long-term development of contralateral testis cancers. CONCLUSIONS: This study addresses some of the concerns surrounding the long-term safety of single-agent carboplatin. It also helps in planning long-term follow-up for patients receiving this form of treatment.

Population and social structure in a Bedfordshire parish: The Cardington listing of inhabitants, 1782.

Abstract This paper describes some of the main social and demographic characteristics of a Bedfordshire parish in the second half of the eighteenth century. It is based on an analysis of the 'Listing of Inhabitants' of Cardington in 1782, and on the use of the parish registers. The listing does not allow an analysis of the entire population of the parish. Its most serious deficiency is the failure to give sufficient detail for the upper social strata of the parish population, viz. the residents of 'farm tenements' and a small number of other properties likewise poorly documented. In the main, the data given in the article refer only to the residents of 'cottage tenements'. They represent the majority of the parish population, but omit the small group at the top of village society. For the 'cottage tenement' population a number of conclusions are drawn. Within this population there was an overall excess of females over males, but the excess was slight, and the number and proportion of males and females in each age-group balanced quite closely. 43-44% of the population of known age were less than 15 years old, and almost half the population were aged between 16 and 60 years. An analysis of marital status tentatively suggests that adult celibacy was rare. The average number of residents per 'cottage' household was only a little higher than the average size of family, confirming that only a small proportion of households contained more than one family. Household and family size may have been larger among craftsmen than labourers, with the households and families of the former containing more resident offspring than those of the latter. About one in every three marriages was either a broken marriage or are-marriage. A reconstitution of certain 'cottage tenement' families tentatively suggests an average of over five baptisms per family. Yet there were only two resident offspring per family in 1782. The difference may be explained by the high level of infant and child mortality, with one-third of all baptised children failing to reach the age of 15 years, and by the high degree of population mobility, albeit over short distances.