Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme.

BACKGROUND: Androgen suppression is a central component of prostate cancer management but causes substantial long-term toxicity. Transdermal administration of oestradiol (tE2) circumvents first-pass hepatic metabolism and, therefore, should avoid the cardiovascular toxicity seen with oral oestrogen and the oestrogen-depletion effects seen with luteinising hormone releasing hormone agonists (LHRHa). We present long-term cardiovascular follow-up data from the Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. METHODS: PATCH is a seamless phase 2/3, randomised, multicentre trial programme at 52 study sites in the UK. Men with locally advanced or metastatic prostate cancer were randomly allocated (1:2 from August, 2007 then 1:1 from February, 2011) to either LHRHa according to local practice or tE2 patches (four 100 µg patches per 24 h, changed twice weekly, reducing to three patches twice weekly if castrate at 4 weeks [defined as testosterone ≤1·7 nmol/L]). Randomisation was done using a computer-based minimisation algorithm and was stratified by several factors, including disease stage, age, smoking status, and family history of cardiac disease. The primary outcome of this analysis was cardiovascular morbidity and mortality. Cardiovascular events, including heart failure, acute coronary syndrome, thromboembolic stroke, and other thromboembolic events, were confirmed using predefined criteria and source data. Sudden or unexpected deaths were attributed to a cardiovascular category if a confirmatory post-mortem report was available and as other relevant events if no post-mortem report was available. PATCH is registered with the ISRCTN registry, ISRCTN70406718; the study is ongoing and adaptive. FINDINGS: Between Aug 14, 2007, and July 30, 2019, 1694 men were randomly allocated either LHRHa (n=790) or tE2 patches (n=904). Overall, median follow-up was 3·9 (IQR 2·4-7·0) years. Respective castration rates at 1 month and 3 months were 65% and 93% among patients assigned LHRHa and 83% and 93% among those allocated tE2. 157 events from 145 men met predefined cardiovascular criteria, with a further ten sudden deaths with no post-mortem report (total 167 events in 153 men). 26 (2%) of 1694 patients had fatal cardiovascular events, 15 (2%) of 790 assigned LHRHa and 11 (1%) of 904 allocated tE2. The time to first cardiovascular event did not differ between treatments (hazard ratio 1·11, 95% CI 0·80-1·53; p=0·54 [including sudden deaths without post-mortem report]; 1·20, 0·86-1·68; p=0·29 [confirmed group only]). 30 (34%) of 89 cardiovascular events in patients assigned tE2 occurred more than 3 months after tE2 was stopped or changed to LHRHa. The most frequent adverse events were gynaecomastia (all grades), with 279 (38%) events in 730 patients who received LHRHa versus 690 (86%) in 807 patients who received tE2 (p<0·0001) and hot flushes (all grades) in 628 (86%) of those who received LHRHa versus 280 (35%) who received tE2 (p<0·0001). INTERPRETATION: Long-term data comparing tE2 patches with LHRHa show no evidence of a difference between treatments in cardiovascular mortality or morbidity. Oestrogens administered transdermally should be reconsidered for androgen suppression in the management of prostate cancer. FUNDING: Cancer Research UK, and Medical Research Council Clinical Trials Unit at University College London.

Does intraprostatic inflammation have a role in the pathogenesis and progression of benign prostatic hyperplasia?

OBJECTIVE: To compare the incidence of acute and/or chronic intraprostatic inflammation (ACI) in men undergoing transurethral resection of the prostate (TURP) for urinary retention and lower urinary tract symptoms (LUTS), as recently a role was suggested for ACI in the pathogenesis and progression of BPH, and urinary retention is considered an endpoint in the natural history of this condition. PATIENTS AND METHODS: Details of TURPs done between January 2003 and December 2005 at one institution were obtained from the operating theatre database. Patients were divided by indication (retention/LUTS). Clinical data and histology reports were then reviewed and bivariate and logistic regression used to compare the pathological features between these groups. RESULTS: Of 406 patients, 374 had evaluable data; 70% of men with urinary retention had ACI, vs 45% of those with LUTS (P < 0.001). On logistic regression, the pathological factors associated with TURP for acute retention compared to that for LUTS were ACI, old age, and resection weight to a lesser degree. CONCLUSION: Inflammation appears to be important in the pathogenesis and progression of BPH. In this study, the risk of urinary retention due to BPH was significantly greater in men with ACI than in those without, and the association of TURP for retention with ACI was stronger than that with prostate weight. This finding might offer new avenues for the medical treatment of men with LUTS due to BPH.

Incidental acute prostatic inflammation is associated with a lower percentage of free prostate-specific antigen than other benign conditions of the prostate: a prospective screening study.

OBJECTIVE: To evaluate the performance of percentage free/total prostate-specific antigen (f/tPSA) as a screening tool for prostate cancer, and to assess the impact of prostatic inflammation on f/tPSA. PATIENTS AND METHODS: Men aged 50-65 years were invited for prostate cancer screening. Biopsies were taken from men with a tPSA of > or = 4 ng/mL, together with those with a tPSA of 1.1-3.99 ng/mL and a f/tPSA of < or = 20%. Histological evidence of prostate cancer, acute inflammation, chronic inflammation, and benign prostatic tissue were noted in biopsy cores, together with the associated f/tPSA values. RESULTS: The cancer detection rate was 4.3% (33/773). Evidence of inflammation was found in about half (87/175) of those biopsied. Men with acute inflammation (27/175, 15%) had significantly lower serum f/tPSA values (mean 13.4%) than those with chronic inflammation (mean 16.6%, P = 0.002) and benign prostatic tissue (mean 15.7%, P = 0.034), but were similar to men with prostate cancer (mean 15.3%, P = 0.315). CONCLUSIONS: In this prospectively screened cohort of men, there was a high incidence of asymptomatic inflammation on prostatic histology; f/tPSA values were significantly lower in men with acute inflammation. This might explain the variability of f/tPSA in improving specificity when used as a screening tool for prostate cancer, and might also reduce its effectiveness in differentiating tumours with more aggressive potential.

Variability of detrusor overactivity on repeated filling cystometry in men with urge symptoms: comparison with spinal cord injury patients.

OBJECTIVE: To investigate the variation in urodynamic variables during repeated filling cystometry and the impact that the variability had on the observed incidence of detrusor overactivity, to evaluate the correlation of detrusor overactivity with the symptoms of urge in men with lower urinary tract symptoms (LUTS), and to compare the variability of detrusor overactivity in men with LUTS to that in men with spinal cord injury (SCI). PATIENTS AND METHODS: Sixty men with LUTS and 35 with neurogenic bladders after SCI were assessed. Investigations included the International Prostate Symptom Score (IPSS), Madsen-Iversen Symptom Score (MSS), uroflowmetry, filling cystometry and pressure-flow, in three successive studies. RESULTS: In men with LUTS, a significant decrease in the number and pressure of involuntary detrusor contractions (IDCs) in consecutive cystometries resulted in a reduction of observed detrusor overactivity from 72% to 63% and 48%, in the three studies. Urgency scores were significantly lower in men who became 'stable' than in those who remained 'unstable' throughout the three studies. In men with SCI, cystometric variables and detrusor overactivity remained consistent over sequential studies. CONCLUSION: Urodynamic detrusor overactivity is affected by repeated cystometry. In men with LUTS, two populations with detrusor overactivity were identified; one group adapted to repeated filling while another had persistent IDCs and greater urgency scores. The latter group had bladder behaviour similar to that of men with neurogenic bladders secondary to SCI. These findings might be important in explaining the cause of symptoms, initiating further investigation, and predicting the outcome of therapy.

Serum prostate-specific antigen to predict the presence of bladder outlet obstruction in men with urinary symptoms.

OBJECTIVE: To determine whether prostate specific antigen (PSA) level can usefully predict or exclude bladder outlet obstruction (BOO), in men with lower urinary tract symptoms (LUTS). PATIENTS AND METHODS: A cohort of men from 1996 to 1999 who had LUTS caused by BPH was evaluated by serum PSA and pressure-flow urodynamic studies, and a blinded comparison made. The settings were teaching hospitals in London, UK and L'Aquila, Italy. Men (302) were referred by primary-care practitioners with LUTS and a PSA of < 10 ng/mL. Regression analysis was used to predict the extent of BOO, and create likelihood ratios and predictive values for BOO according to the PSA value. RESULTS: PSA was significantly associated with BOO (P < 0.001; r2 0.07), with significant likelihood ratios altering the probability of BOO. If the PSA was > 4 ng/mL, mild or definite BOO was likely (89%), whereas if the PSA was <2 ng/mL, there was about a one-third chance each of no, mild and definite BOO. CONCLUSION: High PSA levels in patients with LUTS are significantly associated with BOO; low PSA levels mean that definite BOO is unlikely.

Role of i.v. urography in patients with haematuria.

OBJECTIVE: Traditionally, patients presenting with haematuria undergo a series of investigations, including urine cytology, cystoscopy, i.v. urography (IVU) and renal tract ultrasound (US). Studies have suggested that the omission of IVU as a routine investigation for painless haematuria does not dramatically reduce the detection rate of malignant conditions. In this large retrospective study we evaluated the impact of the omission of IVU on the diagnosis of renal tract malignancies and other non-malignant but significant conditions. MATERIAL AND METHODS: A retrospective analysis of all patients attending our haematuria clinic between January 2000 and August 2002 was carried out. The diagnostic yields of IVU and a US scan were compared and the significance of abnormalities missed by either modality was assessed with regard to the overall management of patients. Diagnoses were divided into those that were significant and potentially harmful [e.g. tumour, pelvi-ureteric junction (PUJ) obstruction, hydronephrosis] and those that were insignificant and harmless (e.g. simple cyst, non-obstructing calculus). Liddell's exact test for matched pairs was used to test for statistical significance and to give the relative risk of a positive result. RESULTS: A total of 1211 patients were included in the study. When cytology, cystoscopy and US were normal, IVU did not detect any additional malignant pathology. Performing IVU instead of a US scan would have resulted in 74 non-malignant conditions remaining undiagnosed. Similarly, US alone would have missed 64 non-malignant lesions. Six non-malignant but significant conditions, including PUJ obstruction (n = 5) and benign ureteric stricture with hydronephrosis (n = 1), were missed by US but detected by IVU. CONCLUSION: In this cohort of retrospectively studied patients attending a haematuria clinic, IVU could safely have been omitted without decreasing the overall detection of malignant pathologies. Nevertheless, significant non-malignant pathologies would have remained undiagnosed. The authors suggest that US combined with a MAG III renogram could be considered as a first-line investigation instead of IVU. This is likely to result in maximum detection of malignant and non-malignant conditions, while reducing the radiation exposure to the patient.