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.

Is routine digital rectal examination required for the followup of prostate cancer?

PURPOSE: With more men being diagnosed and radically treated for prostate cancer there is an increasing number of patients requiring followup. A proportion of radically treated patients have recurrence and require early salvage treatment. Traditionally followup involved physical examination, urinalysis, imaging and biopsy. Since the development of the prostate specific antigen assay, followup has largely consisted of digital rectal examination and prostate specific antigen determination. Although digital rectal examination is routinely used, its efficacy for detecting recurrent cancer in the absence of biochemical evidence of disease progression was questioned in recent studies. MATERIALS AND METHODS: We performed a literature search using the key words digital rectal examination, per rectal examination, radical prostatectomy and radical radiotherapy, and cross-referenced all results. RESULTS: The literature that supports digital rectal examination as part of patient followup after radical prostatectomy is based on case studies and it is less applicable with more sensitive prostate specific antigen assays. In almost 5,000 patients after prostatectomy a prostate specific antigen increase reliably preceded disease recurrence, making digital rectal examination superfluous to requirements. No published literature supports repeat digital rectal examination after radical radiotherapy. CONCLUSIONS: Prostate specific antigen allows the early detection of disease recurrence. Although digital rectal examination is widely used to follow patients, contemporary studies consistently show that disease progression does not occur in the absence of increasing prostate specific antigen. This suggests that remote followup of patients with prostate specific antigen alone is a safe practice, although caution should be exercised in those with higher grade tumors, which may not produce significant amounts of prostate specific antigen.