Quality-of-life outcomes from the Prostate Adenocarcinoma: TransCutaneous Hormones (PATCH) trial evaluating luteinising hormone-releasing hormone agonists versus transdermal oestradiol for androgen suppression in advanced prostate cancer.

OBJECTIVES: To compare quality-of-life (QoL) outcomes at 6 months between men with advanced prostate cancer receiving either transdermal oestradiol (tE2) or luteinising hormone-releasing hormone agonists (LHRHa) for androgen-deprivation therapy (ADT). PATIENTS AND METHODS: Men with locally advanced or metastatic prostate cancer participating in an ongoing randomised, multicentre UK trial comparing tE2 versus LHRHa for ADT were enrolled into a QoL sub-study. tE2 was delivered via three or four transcutaneous patches containing oestradiol 100 µg/24 h. LHRHa was administered as per local practice. Patients completed questionnaires based on the European Organisation for Research and Treatment of Cancer quality of life questionnaire 30-item core (EORTC QLQ-C30) with prostate-specific module QLQ PR25. The primary outcome measure was global QoL score at 6 months, compared between randomised arms. RESULTS: In all, 727 men were enrolled between August 2007 and October 2015 (412 tE2, 315 LHRHa) with QoL questionnaires completed at both baseline and 6 months. Baseline clinical characteristics were similar between arms: median (interquartile range) age of 74 (68-79) years and PSA level of 44 (19-119) ng/mL, and 40% (294/727) had metastatic disease. At 6 months, patients on tE2 reported higher global QoL than those on LHRHa (mean difference +4.2, 95% confidence interval 1.2-7.1; P = 0.006), less fatigue, and improved physical function. Men in the tE2 arm were less likely to experience hot flushes (8% vs 46%), and report a lack of sexual interest (59% vs 74%) and sexual activity, but had higher rates of significant gynaecomastia (37% vs 5%). The higher incidence of hot flushes among LHRHa patients appear to account for both the reduced global QoL and increased fatigue in the LHRHa arm compared to the tE2 arm. CONCLUSION: Patients receiving tE2 for ADT had better 6-month self-reported QoL outcomes compared to those on LHRHa, but increased likelihood of gynaecomastia. The ongoing trial will evaluate clinical efficacy and longer term QoL. These findings are also potentially relevant for short-term neoadjuvant ADT.

Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09).

BACKGROUND: Luteinising-hormone-releasing-hormone agonists (LHRHa) to treat prostate cancer are associated with long-term toxic effects, including osteoporosis. Use of parenteral oestrogen could avoid the long-term complications associated with LHRHa and the thromboembolic complications associated with oral oestrogen. METHODS: In this multicentre, open-label, randomised, phase 2 trial, we enrolled men with locally advanced or metastatic prostate cancer scheduled to start indefinite hormone therapy. Randomisation was by minimisation, in a 2:1 ratio, to four self-administered oestrogen patches (100 µg per 24 h) changed twice weekly or LHRHa given according to local practice. After castrate testosterone concentrations were reached (1·7 nmol/L or lower) men received three oestrogen patches changed twice weekly. The primary outcome, cardiovascular morbidity and mortality, was analysed by modified intention to treat and by therapy at the time of the event to account for treatment crossover in cases of disease progression. This study is registered with ClinicalTrials.gov, number NCT00303784. FINDINGS: 85 patients were randomly assigned to receive LHRHa and 169 to receive oestrogen patches. All 85 patients started LHRHa, and 168 started oestrogen patches. At 3 months, 70 (93%) of 75 receiving LHRHa and 111 (92%) of 121 receiving oestrogen had achieved castrate testosterone concentrations. After a median follow-up of 19 months (IQR 12-31), 24 cardiovascular events were reported, six events in six (7·1%) men in the LHRHa group (95% CI 2·7-14·9) and 18 events in 17 (10·1%) men in the oestrogen-patch group (6·0-15·6). Nine (50%) of 18 events in the oestrogen group occurred after crossover to LHRHa. Mean 12-month changes in fasting glucose concentrations were 0·33 mmol/L (5·5%) in the LHRHa group and -0·16 mmol/L (-2·4%) in the oestrogen-patch group (p=0·004), and for fasting cholesterol were 0·20 mmol/L (4·1%) and -0·23 mmol/L (-3·3%), respectively (p<0·0001). Other adverse events reported by 6 months included gynaecomastia (15 [19%] of 78 patients in the LHRHa group vs 104 [75%] of 138 in the oestrogen-patch group), hot flushes (44 [56%] vs 35 [25%]), and dermatological problems (10 [13%] vs 58 [42%]). INTERPRETATION: Parenteral oestrogen could be a potential alternative to LHRHa in management of prostate cancer if efficacy is confirmed. On the basis of our findings, enrolment in the PATCH trial has been extended, with a primary outcome of progression-free survival. FUNDING: Cancer Research UK, MRC Clinical Trials Unit.

Trends in pathologic outcomes after introduction of active surveillance in the UK: implication for focal therapy.

BACKGROUND: We aimed to evaluate the trends in pathologic outcomes of clinically localized prostate cancer treated with radical prostatectomy prior to and after national guidelines placing active surveillance as the primary management in men with low-risk prostate cancer. Further, we examined whether there was a coincident change in the proportion of men potentially suitable for focal therapy. METHODS: All cancer foci in 195 whole mount radical prostatectomy samples during two periods (Period 1: 07/2001-10/2003, n = 100 and Period 2: 01/2007-11/2009, n = 95) were examined. Individual tumor volumes, Gleason grade, and extracapsular extension/positive surgical margins were evaluated. The index lesion was defined as the largest by volume. RESULTS: There was a statistically significant increase in the proportion of Gleason score ≥7 tumors (31-69%; P < 0.001) and pathologically non-organ confined disease (21-37%; P = 0.008), between period 1 and 2, respectively. The proportion of patients with unifocal prostate cancer potentially suitable for focal ablation was stable (14-13.7%; P = 0.9). Although there was a decrease in the proportion of patients potentially suitable for index lesion ablation (51-43%; P = 0.4) and unilateral prostate cancer potentially suitable for hemi-ablation (11-6.3%; P = 0.3), these differences were not statistically significant. CONCLUSION: The increasing use of active surveillance in the UK may be responsible for a trend towards higher grade and stage prostate cancer in whole mount specimens. Despite this, there remain a significant proportion of men who currently undergo radical surgery who may be suitable for focal therapy, if that included index lesion ablation.

Reproducibility of quantitative assessment of altered hepatic hemodynamics with dynamic contrast-enhanced ultrasound.

OBJECTIVES: The aim of this clinical study was to evaluate the reproducibility of quantitative assessment of altered hepatic hemodynamics with dynamic contrast-enhanced ultrasound. METHODS: Fifteen patients with colorectal liver metastases and 5 volunteers were studied. The hepatic artery proper and the portal vein were imaged simultaneously with dynamic contrast-enhanced ultrasound. The examination was repeated with 2 different contrast bolus volumes (1.2 and 2.4 mL), and time-intensity curves were formed from dynamic contrast-enhanced ultrasound image loops. The rise time, peak intensity, and wash-in slope were derived from hepatic artery and portal vein time-intensity curves. Inter-reader, intra-reader, and inter-scan agreement was assessed by 2 independent readers. Quantitative (intraclass correlation coefficients and coefficients of variation [CVs]) and qualitative (Landis and Koch classification) analyses were performed. RESULTS: Intra-reader and inter-reader agreement was "almost perfect" for the hepatic artery (CV, 10%-15% and 8%-9%, respectively), portal vein (CV, 5%-8% and 6%-12%), and hepatic artery/portal vein ratio (CV, 8%-14% and 10%-15%) measurements of 3 all studied parameters. In contrast, inter-scan agreement was only "slight" to "moderate" (CV, 25%-27%) and "fair" to "moderate" (CV, 19%-24%) for rise time and peak intensity measurements in the hepatic artery and portal vein, respectively. CONCLUSIONS: Quantitative assessment of altered hepatic hemodynamics with dynamic contrast-enhanced ultrasound is reproducible provided that measurements in the hepatic artery are normalized by those in the portal vein.

Survival of patients with bladder cancer from a UK hospital: a 10-year follow-up study.

OBJECTIVE: To compare 10-year overall (OS) and cancer-specific survival (CSS) of a cohort of consecutively presenting patients with bladder cancer of all pT categories from one UK institution. PATIENTS AND METHODS: Data were collected on 144 patients with newly diagnosed bladder tumours presenting from 1983 to 1985 followed up for 10 years. Histological variables were reviewed by one pathologist who had no knowledge of the clinical details. Bladder muscle was present in 95% of the transurethral resection specimens. Date and causes of death were ascertained through death certificates, primary care physicians and/or hospital case notes. Data were analysed using the Kaplan-Meier method and Cox model. RESULTS: There were 69 patients (48%) with pTa, 32 (22%) with pT1 and 43 (30%) with pT2/3/4 tumours. The 10-year OS was 54%, 34% and 16% and the CSS was 97%, 50% and 29%, respectively. There were only two cancer-related deaths in the pTa category whereas half the pT1 cases and half the muscle-invasive cases died within 5 and 2 years of diagnosis, respectively. CONCLUSIONS: This study compared the 10-year OS and CSS of a cohort of patients with bladder cancer from the UK, where such data are lacking, and showed marked differences. The CSS was higher in all pT categories compared with OS, especially within pTa cancers in which almost all patients died of competing causes. It is important to be aware of such a significant difference between the two survival measures and to use them appropriately in the right context.

Early hormonal data from a multicentre phase II trial using transdermal oestrogen patches as first-line hormonal therapy in patients with locally advanced or metastatic prostate cancer.

OBJECTIVE: To assess the hormonal effects of Fem7 (Merck, KGaA, Darmstadt, Germany) 100 microg transdermal oestrogen patches on men undergoing first-line androgen-deprivation therapy for prostate cancer. PATIENTS AND METHODS: PATCH is a multicentre, randomized, phase II trial for men with locally advanced or metastatic prostate cancer, comparing luteinizing hormone-releasing hormone agonist therapy with oestrogen patches. To assess the dosing schedule for the patches, as this was the first time that this brand of patch had been used in men, and to reassure patients and participating clinicians, the Independent Data Monitoring Committee agreed to early release of hormonal data from this study. RESULTS: Oestradiol, testosterone and prostate-specific antigen (PSA) levels are presented for the first group of 14 patients who received the patches (with 1 withdrawal) and for whom there were > or =12 weeks of follow-up by March 2007. After 12 weeks, testosterone levels (nmol/L) in eight of the 13 patients were <1.7, two were 1.7-2 and three were >2. The median (range) serum oestradiol levels was 442 (52.1-1542) pmol/L and all patients had a PSA response, with eight having a PSA level of <4 ng/mL. CONCLUSION: These results confirm that oestrogen patches produce castrate levels of testosterone and concomitant PSA responses. They also highlighted the potential differences between different brands of oestrogen patches, and the need to monitor hormonal response, toxicity and efficacy until more experience with oestrogen patches for this clinical indication is obtained. The number of patches recommended in the PATCH study has now been increased.

A Randomised Comparison Evaluating Changes in Bone Mineral Density in Advanced Prostate Cancer: Luteinising Hormone-releasing Hormone Agonists Versus Transdermal Oestradiol.

BACKGROUND: Luteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa. OBJECTIVE: To compare BMD change in men receiving either LHRHa or oestradiol patches (OP). DESIGN, SETTING, AND PARTICIPANTS: Men with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006-2011; 1:1, thereafter) were recruited into a BMD study (2006-2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr. INTERVENTIONS: LHRHa as per local practice, OP (FemSeven 100µg/24h patches). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance. RESULTS AND LIMITATIONS: A total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was -0.021g/cm(3) for patients randomised to the LHRHa arm (mean percentage change -1.4%) and +0.069g/cm(3) for the OP arm (+6.0%; p<0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa -3.0% and OP +7.9% (p<0.001). CONCLUSIONS: Transdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial. PATIENT SUMMARY: This study found that prostate cancer patients treated with transdermal oestradiol for hormonal therapy did not experience the loss in bone mineral density seen with luteinising hormone-releasing hormone agonists. Other clinical outcomes for this treatment approach are being evaluated in the ongoing PATCH trial. TRIAL REGISTRATION: ISRCTN70406718, PATCH trial (ClinicalTrials.gov NCT00303784).

Contemporary hormone therapy with LHRH agonists for prostate cancer: avoiding osteoporosis and fracture.

INTRODUCTION: Prostate cancer is a large clinical burden across Europe. It is, in fact, the most common cancer in males, accounting for more than 92,300 deaths annually throughout the continent. Prostate cancer is androgen-sensitive; thus an androgen deprivation therapy (ADT) is often used for treatment by reducing androgen to castrate levels. Several ADT agents have achieved benefits with effective palliation, but, unfortunately, severe adverse events are frequent. Contemporary ADT (Luteinising Hormone Releasing Hormone agonist - LHRHa injections) can result in side effects that include osteoporosis and fractures, compromising quality of life and survival. METHODS: In this review we analysed the associated bone toxicity consequent upon contemporary ADT and based on the literature and our own experience we present future perspectives that seek to mitigate this associated toxicity both by development of novel therapies and by better identification and prediction of fracture risk. RESULTS: Preliminary results indicate that parenteral oestrogen can mitigate associated osteoporotic risk and that CT scans could provide a more accurate indicator of overall bone quality and hence fracture risk. CONCLUSIONS: As healthcare costs increase globally, cheap and effective alternatives that achieve ADT, but mitigate or avoid such bone toxicities, will be needed. More so, innovative techniques to improve both the measurement and the extent of this toxicity, by assessing bone health and prediction of fracture risk, are also required.

Ligand activation of the androgen receptor downregulates E-cadherin-mediated cell adhesion and promotes apoptosis of prostatic cancer cells.

Androgen independence is the major cause of endocrine therapy failure in advanced prostate cancer (PC). To examine the effects of human androgen receptor (AR) expression on growth of human PC cells, transfection of full-length AR cDNA in an androgen-insensitive human prostatic adenocarcinoma cell line (DU145) was performed. Transcriptional activity of AR was confirmed by the MMTV luciferase assay and AR expression was assessed by reverse transcriptase polymerase chain reaction, Western blotting, and immunocytochemistry. Two stable transfectant cell lines expressing functional AR were established and passaged over 60 times. Under standard culture conditions, AR expression in transfected cells was predominantly cytoplasmic. Exposure to dihydrotestosterone (DHT; 60 pM-10 nM) resulted in a rapid (maximal at 30 minutes) translocation of AR to the nucleus. Treatment with DHT (5 nM) caused a significant reduction in cell-cell adhesion and aggregation accompanied by a decrease in E-cadherin expression. This was associated with up to 40% inhibition of proliferation and approximately two-fold increase in apoptosis. These results suggest that gene transfer-mediated AR expression in DU145 cells confers sensitivity to DHT, modulates cell-cell adhesion through E-cadherin, and suppresses cell growth by inhibiting proliferation and promoting apoptosis. This provides amodelfor studies ofAR-regulated cell signalling and identification of novel androgen-regulated genes in PC.

MUC1 mucin and trefoil factor 1 protein expression in renal cell carcinoma: correlation with prognosis.

This study examines the coexpression of MUC1 mucin and trefoil factor 1 (TFF1) and their relationship to progression of renal cell carcinoma (RCC). Immunohistochemistry was performed on tumor and adjacent normal tissue from clear-cell RCC (n = 60) and tissues from normal controls (n = 5) using a set of well-characterized monoclonal antibodies recognizing different epitopes of MUC1 and TFF1. Results of immunohistochemistry were compared with clinical parameters, including tumor grade, tumor size, presence of metastasis, and progression-free survival of patients after surgery. In normal tissue, MUC1 and TFF1 were absent from the normal proximal tubular epithelium but were identified in distal and collecting tubular epithelium. In RCC, increased MUC1 expression positively correlated to tumor progression. MUC1 recognized by HMFG1 was associated with large tumor size (P < .05), distant metastasis (P < .05), and invasion of large veins (P < .05). Expression of the under-glycosylated form of MUC1 recognized by SM3 was found to correlate to time to progression (recurrence, metastasis, or death of patient; P < .001). Expression of TFF1 did not significantly correlate with any prognostic parameters. However, there was a significant correlation (P < .01) between TFF1 and MUC1 expression (HMFG2 epitope) in RCCs. These results are consistent with the following conclusions: (1) MUC1 may be an independent prognostic marker in RCC; (2) TFF1 is frequently coexpressed with MUC1 and may act synergistically; and (3) RCC may originate from distal tubular epithelium.

TFF1 is membrane-associated in breast carcinoma cell line MCF-7.

Trefoil factor family (TFF) domain peptides, products of mucin-secreting epithelial cells, are thought to influence mucosal integrity. Molecular studies revealed that mammalian TFFs lack transmembrane domains. Using immunocytochemistry and FACS analysis we demonstrated the association of TFF1 with the cell membrane in MCF-7 (a breast adenocarcinoma cell line), and tested the hypothesis that glycosylphosphatidylinositol (GPI) linkage is the mechanism for this association. Cleavage of GPI anchorage using phospholipase C did not affect TFF1 binding to the cell membrane. Our results demonstrate for the first time that TFF1 is associated with the cell membrane of MCF-7 cells and is not linked via a GPI anchor.

TFF2 (trefoil family factor2) inhibits apoptosis in breast and colorectal cancer cell lines.

We have recently demonstrated that human TFF2 inhibits apoptosis in the non-TFF2 expressing breast adenocarcinoma cell line MCF-7. In this study we examined the impact of TFF2 and an anti-TFF2 antibody (hSP3) on the survival of other human adenocarcinoma cell lines; TFF2-positive (LS174T and SW480) and TFF2-negative (MCF-7 and T47D). Addition of TFF2 protected the (TFF2-) lines but had no effect on those constitutively expressing TFF2. Blocking with hSP3 significantly increased apoptosis in the (TFF2+) cell lines with minimal effect on the (TFF2-) cells. Our results show that the cytoprotective effect of TFF2 seen in MCF-7 cells is not cell line-specific and can be abrogated by inhibition of its expression.

Anatomically versus biologically unifocal prostate cancer: a pathological evaluation in the context of focal therapy.

OBJECTIVES: Since tumor focality in prostate cancer continues to be considered a major limitation for focal prostate therapy, in this study we attempted to compare the pathological features and the proportion of patients with anatomically unifocal versus biologically unifocal tumors (i.e. multifocal prostate cancer in which the secondary nonindex elements are small, low grade and clinically insignificant) who were suitable for focal therapy. METHODS: Ninety-five consecutive whole mount laparoscopic radical prostatectomy samples underwent pathological assessment (from January 2007 to November 2009). Tumor focality, laterality, Gleason score and volume of individual foci, total tumor volume, pathological stage and surgical margin status were assessed. The index lesion was defined as the largest by volume. Patients suitable for focal ablation were defined as having tumors that were unifocal, organ confined, with a Gleason score (GS) up to 7 prostate cancer, or multifocal, organ confined, GS up to 7 prostate cancer, with one large index lesion and the remaining foci demonstrating features of clinically insignificant disease (total tumor volume of all secondary foci ≤0.5 cm(3) with GS ≤ 6). RESULTS: Patients with biologically unifocal cancer had significantly lower total tumor volume (3.26 versus 7.28 cm(3); p < 0.001), index lesion volume (2.9 versus 7.16 cm(3); p < 0.001), rates of seminal vesicle invasion (4% versus 34%; p < 0.001), rates of positive surgical margins (22.4% versus 52.1%; p < 0.001) and rates of 4+3 GS tumors (10.2% versus 29.1%; p = 0.018). The proportion of patients suitable for focal therapy was higher in the biologically unifocal versus anatomically unifocal cancer group, although without reaching statistical significance (65.3% versus 45.8%; p = 0.11). CONCLUSIONS: Patients with biologically unifocal tumors have better pathological outcome than those with anatomically unifocal disease. At present the assumption that multifocality should a priori exclude patients from any organ-preserving prostate cancer treatment is only theoretical and needs to be validated by future clinical trials since there are a large proportion of patients with multifocal disease apparently suitable for focal prostate therapy.

Margin status after laparoscopic radical prostatectomy and the index lesion: implications for preoperative evaluation of tumor focality in prostate cancer.

PURPOSE: The objective of this study was to evaluate the impact of tumor focality on positive surgical margins (PSM) after laparoscopic radical prostatectomy. PATIENTS AND METHODS: Ninety-five consecutive whole-mount laparoscopic radical prostatectomy samples (January 2007 to November 2009) were evaluated for tumor focality, laterality, Gleason score, and volume of individual foci, total tumor volume, pathologic stage, and surgical margin status. RESULTS: Thirty-nine percent, 36%, and 25% were in low, intermediate, and high D'Amico risk categories. Thirty-three percent (31/95) had PSM. Overall, 269 tumor foci were identified. The incidence of PSM within lesions ≤ 0.5 cc and ≤ 0.2 cc was 1.2% (2/160) and 0% (0/132), respectively. Among the 71 multifocal cases, 19 (27%) exhibited PSM. In 13 of these, the index lesion appeared at the inked surface (mean volume 5.4 cc, range 0.63-26.9 cc) compared with 6 in which both index and satellite foci appeared at the inked margins. Mean volume of these satellite foci was 1.06 cc (range 0.22-2 cc); three had Gleason score 6 and three had Gleason score 7 (3+4). CONCLUSIONS: PSM is usually attributed to the index lesion and lesions larger than commonly used thresholds for clinically significant lesion volumes. Because such lesions might be detected by multiparametric magnetic resonance imaging (MRI) or template mapping biopsies, the information from these staging modalities could be used intraoperatively to reduce PSM.