Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial.

BACKGROUND: The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression. METHODS: We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7-10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60-68). Median follow-up was 4·9 years (IQR 3·0-6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81-1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58-1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3-4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020). INTERPRETATION: These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy. FUNDING: Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society.

Indications, results and safety profile of transperineal sector biopsies (TPSB) of the prostate: a single centre experience of 634 cases.

OBJECTIVE: To describe a protocol for transperineal sector biopsies (TPSB) of the prostate and present the clinical experience of this technique in a UK population. PATIENTS AND METHODS: A retrospective review of a single-centre experience of TPSB approach was undertaken that preferentially, but not exclusively, targeted the peripheral zone of the prostate with 24-38 cores using a 'sector plan'. Procedures were carried out under general anaesthetic in most patients. Between January 2007 and August 2011, 634 consecutive patients underwent TPSB for the following indications: prior negative transrectal biopsy (TRB; 174 men); primary biopsy in men at risk of sepsis (153); further evaluation after low-risk disease diagnosed based on a 12-core TRB (307). RESULTS: Prostate cancer was found in 36% of men after a negative TRB; 17% of these had disease solely in anterior sectors. As a primary diagnostic strategy, prostate cancer was diagnosed in 54% of men (median PSA level was 7.4 ng/mL). Of men with Gleason 3+3 disease on TRB, 29% were upgraded and went on to have radical treatment. Postoperative urinary retention occurred in 11 (1.7%) men, two secondary to clots. Per-urethral bleeding requiring hospital stay occurred in two men. There were no cases of urosepsis. CONCLUSIONS: TPSB of the prostate has a role in defining disease previously missed or under-diagnosed by TRB. The procedure has low morbidity.

Recent Advances in Systematic and Targeted Prostate Biopsies.

Prostate biopsy is the definitive investigation to diagnose prostate cancer. The ideal procedure would be one that offers fast and efficient results safely as an outpatient procedure. Historically, transrectal ultrasound (TRUS) biopsy is considered the gold standard but transrectal biopsy can under-sample the anterior and apical regions of the prostate and is associated with a risk of prostate biopsy-related sepsis, which may require intensive care admission. Transperineal (TP) biopsy addresses the inefficient sampling of TRUS biopsy but historically has been done under general anaesthetic, which makes it difficult to incorporate into timed diagnostic pathways such as the National Health Service (NHS) 2-week cancer pathway. TRUS biopsy has remained the mainstay of clinical diagnosis because of its simplicity; however, the recent development of simpler local anaesthetic transperineal techniques has transformed outpatient biopsy practice. These techniques practically eliminate prostate biopsy-related sepsis, have a shallow learning curve and offer effective sampling of all areas of the prostate in an outpatient setting. The effectiveness of TP biopsy has been enhanced by the introduction of multiparametric MRI prior to biopsy, the use of PSA density for risk stratification in equivocal cases and combined with more efficient targeted and systematic biopsies techniques, such as the Ginsburg Protocol, has improved the tolerability and diagnostic yield of local anaesthetic TP biopsies, reducing the risk of complications from the oversampling associated with transperineal template mapping biopsies. Areas where the literature remains unclear is the optimum number of cores needed to detect clinically significant disease (CSD) in patients with a definable lesion on MRI, in particular, whether there is a need for systematic biopsy in the face of equivocal MRI findings to ensure no CSD is missed. The Covid-19 pandemic has had a profound impact on prostate cancer referrals and prostate biopsy techniques within the UK; prior to the pandemic 65% of all prostate biopsies were TRUS, since the pandemic the proportions have reversed such that now over 65% of all prostate biopsies in the NHS are transperineal.

Systemic therapy for advancing or metastatic prostate cancer (STAMPEDE): a multi-arm, multistage randomized controlled trial.

There is a need to improve the outcomes for men with high-risk localised, nodal or metastatic prostate cancer, or with aggressively relapsing disease after initial therapy for local disease. This group of men is currently managed with long-term hormone therapy. Thus we aim to evaluate the toxicity and efficacy of three different systemic therapies (docetaxel, zoledronic acid and celecoxib) used alone or combined at the initiation of hormone manipulation for high-risk prostate cancer. A novel statistical design (multi-arm, multistage method) simultaneously tests multiple distinct strategies in parallel against a single control arm. The trial has several 'stages', from initial confirmation of safety to a phase III assessment of survival, with a series of intervening activity stages. This method provides a means of assessing several agents more quickly and efficiently, and allows inactive treatments to be dropped from further study at an early stage. STAMPEDE has been designed to address in parallel the activity and efficacy of these agents for this patient group. It is a flagship randomized clinical trial for academic research into prostate cancer in the UK. More than 500 patients have been recruited on schedule, confirming the acceptability of this complex trial design to patients and clinicians. The trial targets a population of approximately 3000 patients. STAMPEDE is a major new trial with a novel design applicable to the synchronous testing of several agents. It is hoped that the results will improve outcomes for patients with high-risk prostate cancer. The design could be applicable to the study of new therapies in other cancer types. Continued efforts are required by the urological cancer community to maintain the excellent recruitment shown to date.

The Use of Transperineal Sector Biopsy as A First-Line Biopsy Strategy: A Multi-Institutional Analysis of Clinical Outcomes and Complications.

PURPOSE: Systematic transrectal ultrasound biopsies have been the first-line biopsy strategy in men with suspected prostate cancer for over 30 years. Transperineal biopsy is an alternative approach but has been predominately reserved as a repeat biopsy strategy and not widely used as a first-line approach. This study evaluates the diagnostic and clinical outcomes of transperineal sector biopsy (TPSB) as a first-line biopsy strategy in the diagnosis and management of prostate cancer. MATERIALS AND METHODS: A multi-institutional review of 402 consecutive patients who underwent primary transperineal sector biopsy. All patients had no prior history of prostate biopsy. TPSB was carried out as a day-case procedure under general or regional anaesthesia. The cancer detection rate, location and complications for all cases were evaluated. RESULTS: Prostate cancer was identified in 249 patients (61.9%) and was comparably sited across anterior, middle and posterior sectors. The disease was clinically significant (Gleason 3+4 or > 4mm maximum cancer length) in 187 patients (47%). Post biopsy urinary retention occurred in 6 patients (1.5%). Hematuria requiring overnight hospital admission occurred in 4 patients (1.0%). There were no cases of urosepsis. CONCLUSIONS: As a primary diagnostic strategy, TPSB is a safe and effective technique with high cancer detection rates. It also offers an attractive compromise to more extensive transperineal protocols, which can be more time-consuming and associated with higher morbidity. .

Structured and Modular Training Pathway for Robot-assisted Radical Prostatectomy (RARP): Validation of the RARP Assessment Score and Learning Curve Assessment.

BACKGROUND: Use of robot-assisted radical prostatectomy (RARP) for prostate cancer is increasing. Structured surgical training and objective assessment are critical for outcomes. OBJECTIVE: To develop and validate a modular training and assessment pathway via Healthcare Failure Mode and Effect Analysis (HFMEA) for trainees undertaking RARP and evaluate learning curves (LCs) for procedural steps. DESIGN, SETTING, AND PARTICIPANTS: This multi-institutional (Europe, Australia, and United States) observational prospective study used HFMEA to identify the high-risk steps of RARP. A specialist focus group enabled validation. Fifteen trainees who underwent European Association of Urology robotic surgery curriculum training performed RARP and were assessed by mentors using the tool developed. Results produced LCs for each step. A plateau above score 4 indicated competence. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used a modular training and assessment tool (RARP Assessment Score) to evaluate technical skills. LCs were constructed. Multivariable Kruskal-Wallis, Mann-Whitney U, and κ coefficient analyses were used. RESULTS AND LIMITATIONS: Five surgeons were observed for 42 console hours to map steps of RARP. HFMEA identified 84 failure modes and 46 potential causes with a hazard score ≥8. Content validation created the RARP Assessment Score: 17 stages and 41 steps. The RARP Assessment Score was acceptable (56.67%), feasible (96.67%), and had educational impact (100%). Fifteen robotic surgery trainees were assessed for 8 mo. In 426 RARP cases (range: 4-79), all procedural steps were attempted by trainees. Trainees were assessed with the RARP Assessment Score by their expert mentors, and LCs for individual steps were plotted. LCs demonstrated plateaus for anterior bladder neck transection (16 cases), posterior bladder neck transection (18 cases), posterior dissection (9 cases), dissection of prostatic pedicle and seminal vesicles (15 cases), and anastomosis (17 cases). Other steps did not plateau during data collection. CONCLUSIONS: The RARP Assessment Score based on HFMEA methodology identified critical steps for focused RARP training and assessed surgeons. LCs demonstrate the experience necessary to reach a level of competence in technical skills to protect patients. PATIENT SUMMARY: We developed a safety and assessment tool to gauge the technical skills of surgeons performing robot-assisted radical prostatectomy. Improvement was monitored, and measures of progress can be used in future to guide mentors when training surgeons to operate safely.

Evaluation of the Learning Curve for Holmium Laser Enucleation of the Prostate Using Multiple Outcome Measures.

OBJECTIVE: To assess and quantify the surgical learning curve of holmium laser enucleation of the prostate (HoLEP) of a single surgeon. METHODS: A retrospective analysis of 253 consecutive cases performed by the same surgeon from 2006 to 2013 was conducted. Primary outcomes included enucleation ratio and morcellation efficiencies and complication rates. Three-month postoperative prostate-specific antigen values were used as secondary measures. Cases were divided into cohorts of 20 cases to assess changes in means analyzed through Analysis of Variance (ANOVA) tests. Scatter plots of cases with a best-fit line were drawn to analyze the learning curve. RESULTS: The mean age of patients across the cases was 69.21 years with an average transrectal ultrasound prostate volume of 95.84 cc. Enucleation ratio efficiency was significantly different between cohorts (P = .02) plateau after 50-60 cases conducted. Similarly, a significant difference is shown for morcellation efficiency (P = .01) with stabilization in performance after 60 cases. Complication rates decreased through the caseload but did not show a statistical difference (P = .62) or plateauing on the graph. Finally, no difference between 3-month postoperative prostate-specific antigen values was seen (P = .083); however, a learning curve of 50 cases was observed graphically. CONCLUSION: Within our single-surgeon cohort, we experienced a learning curve of 40-60 cases for the HoLEP procedure. Large variability in performance late into the caseload demonstrates the technical difficulty of HoLEP. Owing to this, adjuncts to training such as simulation-based training may be of use for the new surgeon to shorten the initial phase of learning.