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.

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.

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.

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.

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.

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.

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.

Focal therapy for prostate cancer: opportunities and uncertainties.

Prostate cancer is the most common cancer and the second most common cause of cancer-related death in men. Screening with prostate specific antigen (PSA) has led to a clinical and pathological stage migration such that currently most men diagnosed with prostate cancer have clinically localized disease potentially offering opportunity for curative intervention. On the other hand, the benefit of radical therapy in terms of reducing overall mortality in PSA-screened populations has been controversial with concerns being raised about over-diagnosis and over-treatment. Treatment of prostate cancer is associated with risk and complications that negatively affect the quality of life of men with localized disease. Recently, a new treatment paradigm has been proposed which is called focal therapy, defined as an individualized treatment by which only known disease is targeted and ablated while preserving normal tissue. This review will attempt to describe the opportunities and uncertainties behind this proposed paradigm shift.

Tumor focality in prostate cancer: implications for focal therapy.

In recent years, there has been a growing interest in focal treatment for prostate cancer. Although widely used for the treatment of tumors of the breast and kidney, focal treatment for prostate cancer remains a controversial area. Criticism of focal prostate therapy has been based on the fact that prostate cancer is a multifocal disease. Until now, little attention has been paid to distinguishing between men with unifocal and those with multifocal disease because such information has little clinical relevance when treatment is aimed at the whole gland irrespective of the volume or number of cancers in the prostate. In this Review, we summarize existing knowledge and examine the issue of prostate cancer focality in the context of focal treatment.