Feasibility of aspirin and/or vitamin D3 for men with prostate cancer on active surveillance with Prolaris® testing.

Objectives: To test the feasibility of a randomised controlled trial (RCT) of aspirin and/or vitamin D3 in active surveillance (AS) low/favourable intermediate risk prostate cancer (PCa) patients with Prolaris® testing. Patients and Methods: Newly-diagnosed low/favourable intermediate risk PCa patients (PSA ≤ 15 ng/ml, International Society of Urological Pathology (ISUP) Grade Group ≤2, maximum biopsy core length <10 mm, clinical stage ≤cT2c) were recruited into a multi-centre randomised, double-blind, placebo-controlled study (ISRCTN91422391, NCT03103152). Participants were randomised to oral low dose (100 mg), standard dose (300 mg) aspirin or placebo and/or vitamin D3 (4000 IU) versus placebo in a 3 × 2 factorial RCT design with biopsy tissue Prolaris® testing. The primary endpoint was trial acceptance/entry rates. Secondary endpoints included feasibility of Prolaris® testing, 12-month disease re-assessment (imaging/biochemical/histological), and 12-month treatment adherence/safety. Disease progression was defined as any of the following (i) 50% increase in baseline PSA, (ii) new Prostate Imaging-Reporting and Data System (PI-RADS) 4/5 lesion(s) on multi-parametric MRI where no previous lesion, (iii) 33% volume increase in lesion size, or radiological upstaging to ≥T3, (iv) ISUP Grade Group upgrade or (v) 50% increase in maximum cancer core length. Results: Of 130 eligible patients, 104 (80%) accepted recruitment from seven sites over 12 months, of which 94 patients represented the per protocol population receiving treatment. Prolaris® testing was performed on 76/94 (81%) diagnostic biopsies. Twelve-month disease progression rate was 43.3%. Assessable 12-month treatment adherence in non-progressing patients to aspirin and vitamin D across all treatment arms was 91%. Two drug-attributable serious adverse events in 1 patient allocated to aspirin were identified. The study was not designed to determine differences between treatment arms. Conclusion: Recruitment of AS PCa patients into a multi-centre multi-arm placebo-controlled RCT of minimally-toxic adjunctive oral drug treatments with molecular biomarker profiling is acceptable and safe. A larger phase III study is needed to determine optimal agents, intervention efficacy, and outcome-associated biomarkers.

Treatment-related toxicity in men who received Intensity-modulated versus 3D-conformal radiotherapy after radical prostatectomy: A national population-based study.

BACKGROUND AND PURPOSE: In the post-prostatectomy setting the value of Intensity-modulated (IMRT) relative to 3D-conformal radiotherapy (3D-CRT) in reducing toxicity remains unclear. We compared genitourinary (GU) and gastrointestinal (GI) toxicity after post-prostatectomy IMRT or 3D-CRT. MATERIALS AND METHODS: A population-based study of all patients treated with post-prostatectomy 3D-CRT (n = 2422) and IMRT (n = 603) was conducted between January 1 2010 and December 31 2013 in the English National Health Service. We identified severe GI and GU toxicity using a validated coding-framework and compared IMRT and 3D-CRT using a competing-risks proportional hazards regression analysis. RESULTS: There was no difference in GI toxicity between patients who received IMRT and 3D-CRT (3D-CRT: 5.8 events/100 person-years; IMRT: 5.5 events/100 person-years; adjusted HR: 0.85, 95%CI: 0.63-1.13; p = 0.26). The GU toxicity rate was lower with IMRT but this effect was not statistically significant (3D-CRT: 5.4 events/100 person-years; IMRT: 3.8 events/100 person-years; adjusted HR: 0.76, 95%CI: 0.55-1.03; p = 0.08). CONCLUSIONS: The use of post-prostatectomy IMRT compared to 3D-CRT is not associated with a statistically significant reduction in rates of severe GU and GI toxicity, although there is some evidence that GU toxicity is lower with IMRT. We would caution against rapid transition to post-prostatectomy IMRT until further evidence is available supporting its superiority.

Robot-assisted radical prostatectomy vs laparoscopic and open retropubic radical prostatectomy: functional outcomes 18 months after diagnosis from a national cohort study in England.

BACKGROUND: Robot-assisted radical prostatectomy (RARP) has been rapidly adopted without robust evidence comparing its functional outcomes against laparoscopic radical prostatectomy (LRP) or open retropubic radical prostatectomy (ORP) approaches. This study compared patient-reported functional outcomes following RARP, LRP or ORP. METHODS: All men diagnosed with prostate cancer in England during April - October 2014 who underwent radical prostatectomy were identified from the National Prostate Cancer Audit and mailed a questionnaire 18 months after diagnosis. Group differences in patient-reported sexual, urinary, bowel and hormonal function (EPIC-26 domain scores) and generic health-related quality of life (HRQoL; EQ-5D-5L scores), with adjustment for patient and tumour characteristics, were estimated using linear regression. RESULTS: In all, 2219 men (77.0%) responded; 1310 (59.0%) had RARP, 487 (21.9%) LRP and 422 (19.0%) ORP. RARP was associated with slightly higher adjusted mean EPIC-26 sexual function scores compared with LRP (3·5 point difference; 95% CI: 1.1-5.9, P=0.004) or ORP (4.0 point difference; 95% CI: 1.5-6.5, P=0.002), which did not meet the threshold for a minimal clinically important difference (10-12 points). There were no significant differences in other EPIC-26 domain scores or HRQoL. CONCLUSIONS: It is unlikely that the rapid adoption of RARP in the English NHS has produced substantial improvements in functional outcomes for patients.

National Population-Based Study Comparing Treatment-Related Toxicity in Men Who Received Intensity Modulated Versus 3-Dimensional Conformal Radical Radiation Therapy for Prostate Cancer.

PURPOSE: To compare, in a national population-based study, severe genitourinary (GU) and gastrointestinal (GI) toxicity in patients with prostate cancer who were treated with radical intensity modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3D-CRT). METHODS AND MATERIALS: Patients treated with IMRT (n=6933) or 3D-CRT (n=16,289) between January 1, 2010 and December 31, 2013 in the English National Health Service were identified using cancer registry data, the National Radiotherapy Dataset, and Hospital Episodes Statistics, the administrative database of care episodes in National Health Service hospitals. We developed a coding system that identifies severe toxicity (at least grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events scoring system) according to the presence of a procedure and a corresponding diagnostic code in patients' Hospital Episodes Statistics records after radiation therapy. A competing risks regression analysis was used to estimate hazard ratios (HRs), comparing the incidence of severe GI and GU complications after IMRT and 3D-CRT, adjusting for patient, disease, and treatment characteristics. RESULTS: The use of IMRT, as opposed to 3D-CRT, increased from 3.1% in 2010 to 64.7% in 2013. Patients who received IMRT were less likely than those receiving 3D-CRT to experience severe GI toxicity (4.9 vs 6.5 per 100 person-years; adjusted HR 0.66; 95% confidence interval 0.61-0.72) but had similar levels of GU toxicity (2.3 vs 2.4 per 100 person-years; adjusted HR 0.94; 95% confidence interval 0.84-1.06). CONCLUSIONS: Prostate cancer patients who received radical radiation therapy using IMRT were less likely to experience severe GI toxicity, and they had similar GU toxicity compared with those who received 3D-CRT. These findings in an unselected "real-world" population support the use of IMRT, but further cost-effectiveness studies are urgently required.

Recovery of Baseline Erectile Function in Men Following Radical Prostatectomy for High-Risk Prostate Cancer: A Prospective Analysis Using Validated Measures.

INTRODUCTION: Recovery of baseline erectile function (EF) after robotic radical prostatectomy in men with high-risk prostate cancer is under-reported. Published studies have selectively reported on low-risk disease using non-validated and poorly defined thresholds for EF recovery. AIM: To assess return to baseline EF in men after robotic radical prostatectomy for high-risk prostate cancer. MATERIALS: Five hundred thirty-one men underwent robotic radical prostatectomy for high-risk prostate cancer from February 2010 through July 2014. Pre- and postoperative EF was prospectively assessed using the International Index of Erectile Dysfunction (IIEF-5) questionnaire. Multivariate logistic regression analysis determined the effect of age, preoperative function, comorbidities, body mass index, prostate-specific antigen level, cancer stage or grade, nerve-sparing status, adjuvant therapy, and continence on EF return (defined as postoperative return to baseline EF with or without use of phosphodiesterase type 5 inhibitors). Kaplan-Meier analysis and log-rank test were used to analyze return over time. Mann-Whitney U-test was used to compare IIEF-5 scores. MAIN OUTCOME MEASURES: Pre- and postoperative EF was assessed using the IIEF-5 Sexual Health Inventory for Men at 3 months, 6 months, 1 year, 2 years, 3 years, and 4 years postoperatively. RESULTS: Overall, return of EF was seen in 23.5% of patients at 18 months. This was significantly increased in men no older than 60 years (P = .024), with a preoperative IIEF-5 score of at least 22 (P = .042), and after undergoing neurovascular bundle preservation (34.9% of patients, P < .001). There was no significant change in IIEF-5 scores from 3 to 36 months in patients who were treated with phosphodiesterase type 5 inhibitors in the non-neurovascular bundle preservation group (P = .87), although there was significant improvement in those receiving second- or third-line therapies (P = .042). Other than preoperative hypertension (P = .03), none of the other comorbidities predicted return of EF. CONCLUSION: In this study, 23.5% of men recovered to baseline EF. Of those who underwent bilateral neurovascular bundle preservation robotic radical prostatectomy, 70% recovered baseline EF; however, this accounted for only 9.6% of all patients. Only 4% of men who underwent non-neurovascular bundle preservation had baseline recovery with phosphodiesterase type 5 inhibitors up to 36 months. There was significant improvement after use of second- or third-line therapies, indicating the need for earlier institution of these treatment modalities.

Evaluating variation in use of definitive therapy and risk-adjusted prostate cancer mortality in England and the USA.

OBJECTIVES: Prostate cancer mortality (PCM) in the USA is among the lowest in the world, whereas PCM in England is among the highest in Europe. This paper aims to assess the association of variation in use of definitive therapy on risk-adjusted PCM in England as compared with the USA. DESIGN: Observational study. SETTING: Cancer registry data from England and the USA. PARTICIPANTS: Men diagnosed with non-metastatic prostate cancer (PCa) in England and the USA between 2004 and 2008. OUTCOME MEASURES: Competing-risks survival analyses to estimate subhazard ratios (SHR) of PCM adjusted for age, ethnicity, year of diagnosis, Gleason score (GS) and clinical tumour (cT) stage. RESULTS: 222,163 men were eligible for inclusion. Compared with American patients, English patients were more likely to present at an older age (70-79 years: England 44.2%, USA 29.3%, p<0.001), with higher tumour stage (cT3-T4: England 25.1%, USA 8.6%, p<0.001) and higher GS (GS 8-10: England 20.7%, USA 11.2%, p<0.001). They were also less likely to receive definitive therapy (England 38%, USA 77%, p<0.001). English patients were more likely to die of PCa (SHR=1.9, 95% CI 1.7 to 2.0, p<0.001). However, this difference was no longer statistically significant when also adjusted for use of definitive therapy (SHR=1.0, 95% CI 1.0 to 1.1, p=0.3). CONCLUSIONS: Risk-adjusted PCM is significantly higher in England compared with the USA. This difference may be explained by less frequent use of definitive therapy in England.

Robotic radical prostatectomy as the initial step in multimodal therapy for men with high-risk localised prostate cancer: initial experience of 160 men.

OBJECTIVES: • To report the outcome of robotic-assisted laparoscopic radical prostatectomy (RALP) for men with localised high-risk prostate cancer at diagnosis. • Although commonly managed by radiotherapy (RT) with prolonged androgen-deprivation therapy (ADT), we hypothesize that initiation of multimodal therapy with RALP is oncologically efficacious and may allow many men to avoid ADT. PATIENTS AND METHODS: • Between December 2003 and September 2010, 1480 men underwent RALP of whom 160 fulfilled the National Comprehensive Control Network criteria for high-risk disease (prostate-specific antigen (PSA) > 20 ng/mL and/or clinical stage, cT ≥ 3 and/or biopsy Gleason score ≥ 8). • Biochemical recurrence (postoperative PSA ≥ 0.2) was used to assess outcome after RALP monotherapy. • Treatment failure was defined as either a rising PSA level after salvage RT or the initiation of ADT. RESULTS: • The mean age ± standard deviation was 63.1 ± 6.3 years. Median PSA level was 9.95 ng/mL (interquartile range 6.0-21.4). • Analysis of prostatectomy specimen showed Gleason 8-10 cancers in 65 (41%), and extracapsular disease, pT ≥ 3, in 96 (60%) of which seminal vesicle invasion was evident in 36 (23%). Downgrading by prostatectomy occurred in 64 (40% of total group) and five (3%) were downstaged to pT2 disease. By contrast, any upgrading occurred in 29 (18% of total group) and upstaging occurred in 68 (43%). The overall positive surgical margin rate was 38%, correlating with stage pT2 (15%) or pT3 (53%). • With median follow-up of 26.2 months (interquartile range 5.5-37.3), two non-cancer-related deaths have occurred (overall survival 98.8%; cancer-specific survival 100%), and biochemical recurrence has occurred in 53 men (33%). RALP surgery has served as monotherapy (n= 117, 73%), or has been followed by salvage RT (n= 24, 15%) and/or ADT (n= 43, 27%). Overall 2-year and 3-year treatment failure was 31 and 41%, respectively. • Serum PSA level was the only independent predictor of overall treatment failure (hazard ratio [HR] 1.02, P= 0.001) although a strong trend was observed for both clinical stage (HR 1.22, P= 0.058) and the number of positive biopsy cores on transrectal biopsy (HR 1.06, P= 0.057). CONCLUSIONS: • RALP incorporating the use of postoperative RT is a good multimodal management strategy for men with this aggressive variant of prostate cancer. • At median follow-up in excess of 2 years, we found low rates of treatment failure enabling a high proportion of men to remain free of ADT.

The thermo-expandable metallic stent for managing benign prostatic hyperplasia: a systematic review.

OBJECTIVES: To systematically review published reports of the safety, effectiveness and durability of a self-expanding metallic prostatic stent (Memokath, Engineers & Doctors A/S Ltd., Denmark) in patients with benign prostatic hyperplasia (BPH) who are unfit for surgery. METHODS: We systematically searched the Medline and Embase databases from 1992. The reference lists of included studies and the bibliographies of review articles were also searched. We contacted the manufacturer of Memokath for additional information. The primary outcomes were treatment failure (stent removal, replacement or repositioning) and urological symptom scores. Secondary outcomes were urodynamic indices and minor complications. Two reviewers independently assessed the methodological quality of the studies and extracted data. Data were synthesized using narrative techniques. RESULTS: In all, 14 case series described the use of the Memokath stent in 839 men with BPH. All patients were at high operative risk. Most studies were of poor quality with an inadequate follow-up. Treatment failure rates were 0-48% but the duration of follow-up was often unclear. Five studies reported International Prostate Symptom Scores and found reductions of 11-19 points after stent insertion. All seven studies that reported on maximum urinary flow rates found that these increased, and the four that described residual urine volumes found that these decreased. Minor complications were inconsistently reported. CONCLUSIONS: The Memokath stent can provide an effective treatment for BPH in men at high operative risk; it also appears to be safe, but inadequate follow-up does not allow firm conclusions on stent durability.

The effect of neoadjuvant androgen suppression on prostate cancer-related outcomes after high-intensity focused ultrasound therapy.

OBJECTIVE: To explore the effect of neoadjuvant androgen suppression (AS) compared to no AS on cancer-related outcomes after radical high-intensity focused ultrasound (HIFU) therapy for men with presumed organ-confined prostate cancer. PATIENTS AND METHODS: Between January 1999 and January 2005, 250 patients underwent HIFU for presumed localized adenocarcinoma of the prostate; 154 had received neoadjuvant hormonal therapy and 96 had not. The primary outcome measure was treatment failure, as defined by the presence of prostate cancer on the biopsy taken 6 months after HIFU. Multiple logistic regression was used to examine relationships between the use of HIFU with and with no neoadjuvant AS and treatment failure. RESULTS: The treatment failure rate was slightly lower in patients receiving neoadjuvant AS (31% vs 34%), but this was not statistically significant (P = 0.119). CONCLUSION: In this unrandomized comparison between neoadjuvant or no AS before HIFU for men with presumed organ-confined prostate cancer, there appeared to be little if any benefit associated with the previous administration of AS.

To what extent does the prostate-specific antigen nadir predict subsequent treatment failure after transrectal high-intensity focused ultrasound therapy for presumed localized adenocarcinoma of the prostate?

OBJECTIVE: To explore the association between the prostate-specific antigen (PSA) nadir after transrectal high-intensity focused ultrasound (HIFU) therapy for organ-confined prostate cancer and subsequent treatment failure, as defined by the presence of residual disease at biopsy 6 months after treatment. PATIENTS AND METHODS: Between January 1999 and January 2005, 115 patients in a Japanese hospital were treated using a transrectal HIFU system (Sonablate, Focus Surgery, IN, USA) for presumed localized adenocarcinoma of the prostate. All treatments were primary and none of the patients had received hormone therapy. The PSA level was measured at 2-monthly intervals and all patients had a transrectal prostate biopsy taken at 6 months. Multiple logistic regression was used to examine the relationship between PSA nadir and treatment failure, as defined by the presence of disease at biopsy. RESULTS: The PSA nadir was strongly associated with treatment failure (P < 0.001). Patients with a PSA nadir of 0.0-0.2 ng/mL had a treatment failure rate of only 11% (four of 36), compared to 46% (17 of 37) in patients with a PSA nadir of 0.21-1.00 ng/mL and 48% (20 of 42) with a PSA nadir of >1.0 ng/mL. In addition, the PSA nadir was strongly associated with both preoperative PSA level and residual prostate volume. CONCLUSION: There is a clear and intuitive association between the PSA nadir and the risk of treatment failure after HIFU. These data can be used to predict the risk of residual disease in patients with prostate cancer undergoing HIFU therapy. They can also be used to inform where the target PSA nadir should be set for this novel therapy.