Global Variation in Magnetic Resonance Imaging Quality of the Prostate.

Background High variability in prostate MRI quality might reduce accuracy in prostate cancer detection. Purpose To prospectively evaluate the quality of MRI scanners taking part in the quality control phase of the global PRIME (Prostate Imaging Using MRI ± Contrast Enhancement) trial using the Prostate Imaging Quality (PI-QUAL) standardized scoring system, give recommendations on how to improve the MRI protocols, and establish whether MRI quality could be improved by these recommendations. Materials and Methods In the prospective clinical trial (PRIME), for each scanner, centers performing prostate MRI submitted five consecutive studies and the MRI protocols (phase I). Submitted data were evaluated in consensus by two expert genitourinary radiologists using the PI-QUAL scoring system that evaluates MRI diagnostic quality using five points (1 and 2 = nondiagnostic; 3 = sufficient; 4 = adequate, 5 = optimal) between September 2021 and August 2022. Feedback was provided for scanners not achieving a PI-QUAL 5 score, and centers were invited to resubmit new imaging data using the modified protocol (phase II). Descriptive comparison of outcomes was made between the MRI scanners, feedback provided, and overall PI-QUAL scores. Results In phase I, 41 centers from 18 countries submitted a total of 355 multiparametric MRI studies from 71 scanners, with nine (13%) scanners achieving a PI-QUAL score of 3, 39 (55%) achieving a score of 4, and 23 (32%) achieving a score of 5. Of the 48 (n = 71 [68%]) scanners that received feedback to improve, the dynamic contrast-enhanced sequences were those that least adhered to the Prostate Imaging Reporting and Data System, version 2.1, criteria (44 of 48 [92%]), followed by diffusion-weighted imaging (20 of 48 [42%]) and T2-weighted imaging (19 of 48 [40%]). In phase II, 36 centers from 17 countries resubmitted revised studies, resulting in a total of 62 (n = 64 [97%]) scanners with a final PI-QUAL score of 5. Conclusion Substantial variation in global prostate MRI acquisition parameters as a measure of quality was observed, particularly with DCE sequences. Basic evaluation and modifications to MRI protocols using PI-QUAL can lead to substantial improvements in quality. Clinical trial registration no. NCT04571840 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Almansour and Chernyak in this issue.

External validation of a risk model predicting failure of salvage focal ablation for prostate cancer.

OBJECTIVES: To externally validate a published model predicting failure within 2 years after salvage focal ablation in men with localised radiorecurrent prostate cancer using a prospective, UK multicentre dataset. PATIENTS AND METHODS: Patients with biopsy-confirmed ≤T3bN0M0 cancer after previous external beam radiotherapy or brachytherapy were included from the FOcal RECurrent Assessment and Salvage Treatment (FORECAST) trial (NCT01883128; 2014-2018; six centres), and from the high-intensity focussed ultrasound (HIFU) Evaluation and Assessment of Treatment (HEAT) and International Cryotherapy Evaluation (ICE) UK-based registries (2006-2022; nine centres). Eligible patients underwent either salvage focal HIFU or cryotherapy, with the choice based predominantly on anatomical factors. Per the original multivariable Cox regression model, the predicted outcome was a composite failure outcome. Model performance was assessed at 2 years post-salvage with discrimination (concordance index [C-index]), calibration (calibration curve and slope), and decision curve analysis. For the latter, two clinically-reasonable risk threshold ranges of 0.14-0.52 and 0.26-0.36 were considered, corresponding to previously published pooled 2-year recurrence-free survival rates for salvage local treatments. RESULTS: A total of 168 patients were included, of whom 84/168 (50%) experienced the primary outcome in all follow-ups, and 72/168 (43%) within 2 years. The C-index was 0.65 (95% confidence interval 0.58-0.71). On graphical inspection, there was close agreement between predicted and observed failure. The calibration slope was 1.01. In decision curve analysis, there was incremental net benefit vs a 'treat all' strategy at risk thresholds of ≥0.23. The net benefit was therefore higher across the majority of the 0.14-0.52 risk threshold range, and all of the 0.26-0.36 range. CONCLUSION: In external validation using prospective, multicentre data, this model demonstrated modest discrimination but good calibration and clinical utility for predicting failure of salvage focal ablation within 2 years. This model could be reasonably used to improve selection of appropriate treatment candidates for salvage focal ablation, and its use should be considered when discussing salvage options with patients. Further validation in larger, international cohorts with longer follow-up is recommended.

Multiparametric ultrasound versus multiparametric MRI to diagnose prostate cancer (CADMUS): a prospective, multicentre, paired-cohort, confirmatory study.

BACKGROUND: Multiparametric MRI of the prostate followed by targeted biopsy is recommended for patients at risk of prostate cancer. However, multiparametric ultrasound is more readily available than multiparametric MRI. Data from paired-cohort validation studies and randomised, controlled trials support the use of multiparametric MRI, whereas the evidence for individual ultrasound methods and multiparametric ultrasound is only derived from case series. We aimed to establish the overall agreement between multiparametric ultrasound and multiparametric MRI to diagnose clinically significant prostate cancer. METHODS: We conducted a prospective, multicentre, paired-cohort, confirmatory study in seven hospitals in the UK. Patients at risk of prostate cancer, aged 18 years or older, with an elevated prostate-specific antigen concentration or abnormal findings on digital rectal examination underwent both multiparametric ultrasound and multiparametric MRI. Multiparametric ultrasound consisted of B-mode, colour Doppler, real-time elastography, and contrast-enhanced ultrasound. Multiparametric MRI included high-resolution T2-weighted images, diffusion-weighted imaging (dedicated high B 1400 s/mm2 or 2000 s/mm2 and apparent diffusion coefficient map), and dynamic contrast-enhanced axial T1-weighted images. Patients with positive findings on multiparametric ultrasound or multiparametric MRI underwent targeted biopsies but were masked to their test results. If both tests yielded positive findings, the order of targeting at biopsy was randomly assigned (1:1) using stratified (according to centre only) block randomisation with randomly varying block sizes. The co-primary endpoints were the proportion of positive lesions on, and agreement between, multiparametric MRI and multiparametric ultrasound in identifying suspicious lesions (Likert score of ≥3), and detection of clinically significant cancer (defined as a Gleason score of ≥4 + 3 in any area or a maximum cancer core length of ≥6 mm of any grade [PROMIS definition 1]) in those patients who underwent a biopsy. Adverse events were defined according to Good Clinical Practice and trial regulatory guidelines. The trial is registered on ISRCTN, 38541912, and ClinicalTrials.gov, NCT02712684, with recruitment and follow-up completed. FINDINGS: Between March 15, 2016, and Nov 7, 2019, 370 eligible patients were enrolled; 306 patients completed both multiparametric ultrasound and multiparametric MRI and 257 underwent a prostate biopsy. Multiparametric ultrasound was positive in 272 (89% [95% CI 85-92]) of 306 patients and multiparametric MRI was positive in 238 patients (78% [73-82]; difference 11·1% [95% CI 5·1-17·1]). Positive test agreement was 73·2% (95% CI 67·9-78·1; κ=0·06 [95% CI -0·56 to 0·17]). Any cancer was detected in 133 (52% [95% CI 45·5-58]) of 257 patients, with 83 (32% [26-38]) of 257 being clinically significant by PROMIS definition 1. Each test alone would result in multiparametric ultrasound detecting PROMIS definition 1 cancer in 66 (26% [95% CI 21-32]) of 257 patients who had biopsies and multiparametric MRI detecting it in 77 (30% [24-36]; difference -4·3% [95% CI -8·3% to -0·3]). Combining both tests detected 83 (32% [95% CI 27-38]) of 257 clinically significant cancers as per PROMIS definition 1; of these 83 cancers, six (7% [95% CI 3-15]) were detected exclusively with multiparametric ultrasound, and 17 (20% [12-31]) were exclusively detected by multiparametric MRI (agreement 91·1% [95% CI 86·9-94·2]; κ=0·78 [95% CI 0·69-0·86]). No serious adverse events were related to trial activity. INTERPRETATION: Multiparametric ultrasound detected 4·3% fewer clinically significant prostate cancers than multiparametric MRI, but it would lead to 11·1% more patients being referred for a biopsy. Multiparametric ultrasound could be an alternative to multiparametric MRI as a first test for patients at risk of prostate cancer, particularly if multiparametric MRI cannot be carried out. Both imaging tests missed clinically significant cancers detected by the other, so the use of both would increase the detection of clinically significant prostate cancers compared with using each test alone. FUNDING: The Jon Moulton Charity Trust, Prostate Cancer UK, and UCLH Charity and Barts Charity.

Effect of Robot-Assisted Radical Cystectomy With Intracorporeal Urinary Diversion vs Open Radical Cystectomy on 90-Day Morbidity and Mortality Among Patients With Bladder Cancer: A Randomized Clinical Trial.

Importance: Robot-assisted radical cystectomy is being performed with increasing frequency, but it is unclear whether total intracorporeal surgery improves recovery compared with open radical cystectomy for bladder cancer. Objectives: To compare recovery and morbidity after robot-assisted radical cystectomy with intracorporeal reconstruction vs open radical cystectomy. Design, Setting, and Participants: Randomized clinical trial of patients with nonmetastatic bladder cancer recruited at 9 sites in the UK, from March 2017-March 2020. Follow-up was conducted at 90 days, 6 months, and 12 months, with final follow-up on September 23, 2021. Interventions: Participants were randomized to receive robot-assisted radical cystectomy with intracorporeal reconstruction (n = 169) or open radical cystectomy (n = 169). Main Outcomes and Measures: The primary outcome was the number of days alive and out of the hospital within 90 days of surgery. There were 20 secondary outcomes, including complications, quality of life, disability, stamina, activity levels, and survival. Analyses were adjusted for the type of diversion and center. Results: Among 338 randomized participants, 317 underwent radical cystectomy (mean age, 69 years; 67 women [21%]; 107 [34%] received neoadjuvant chemotherapy; 282 [89%] underwent ileal conduit reconstruction); the primary outcome was analyzed in 305 (96%). The median number of days alive and out of the hospital within 90 days of surgery was 82 (IQR, 76-84) for patients undergoing robotic surgery vs 80 (IQR, 72-83) for open surgery (adjusted difference, 2.2 days [95% CI, 0.50-3.85]; P = .01). Thromboembolic complications (1.9% vs 8.3%; difference, -6.5% [95% CI, -11.4% to -1.4%]) and wound complications (5.6% vs 16.0%; difference, -11.7% [95% CI, -18.6% to -4.6%]) were less common with robotic surgery than open surgery. Participants undergoing open surgery reported worse quality of life vs robotic surgery at 5 weeks (difference in mean European Quality of Life 5-Dimension, 5-Level instrument scores, -0.07 [95% CI, -0.11 to -0.03]; P = .003) and greater disability at 5 weeks (difference in World Health Organization Disability Assessment Schedule 2.0 scores, 0.48 [95% CI, 0.15-0.73]; P = .003) and at 12 weeks (difference in WHODAS 2.0 scores, 0.38 [95% CI, 0.09-0.68]; P = .01); the differences were not significant after 12 weeks. There were no statistically significant differences in cancer recurrence (29/161 [18%] vs 25/156 [16%] after robotic and open surgery, respectively) and overall mortality (23/161 [14.3%] vs 23/156 [14.7%]), respectively) at median follow-up of 18.4 months (IQR, 12.8-21.1). Conclusions and Relevance: Among patients with nonmetastatic bladder cancer undergoing radical cystectomy, treatment with robot-assisted radical cystectomy with intracorporeal urinary diversion vs open radical cystectomy resulted in a statistically significant increase in days alive and out of the hospital over 90 days. However, the clinical importance of these findings remains uncertain. Trial Registration: ISRCTN Identifier: ISRCTN13680280; ClinicalTrials.gov Identifier: NCT03049410.

New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer.

BACKGROUND: The TARGIT-A trial reported risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer to be as effective as whole-breast external beam radiotherapy (EBRT). Here, we present further detailed analyses. METHODS: In total, 2298 women (≥45 years, invasive ductal carcinoma ≤3.5 cm, cN0-N1) were randomised. We investigated the impact of tumour size, grade, ER, PgR, HER2 and lymph node status on local recurrence-free survival, and of local recurrence on distant relapse and mortality. We analysed the predictive factors for recommending supplemental EBRT after TARGIT-IORT as part of the risk-adapted approach, using regression modelling. Non-breast cancer mortality was compared between TARGIT-IORT plus EBRT vs. EBRT. RESULTS: Local recurrence-free survival was no different between TARGIT-IORT and EBRT, in every tumour subgroup. Unlike in the EBRT arm, local recurrence in the TARGIT-IORT arm was not a predictor of a higher risk of distant relapse or death. Our new predictive tool for recommending supplemental EBRT after TARGIT-IORT is at https://targit.org.uk/addrt . Non-breast cancer mortality was significantly lower in the TARGIT-IORT arm, even when patients received supplemental EBRT, HR 0.38 (95% CI 0.17-0.88) P = 0.0091. CONCLUSION: TARGIT-IORT is as effective as EBRT in all subgroups. Local recurrence after TARGIT-IORT, unlike after EBRT, has a good prognosis. TARGIT-IORT might have a beneficial abscopal effect. TRIAL REGISTRATION: ISRCTN34086741 (21/7/2004), NCT00983684 (24/9/2009).

MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis.

BACKGROUND: Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography-guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited. METHODS: In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12-core, transrectal ultrasonography-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. RESULTS: A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, -13 percentage points; 95% CI, -19 to -7; P<0.001). CONCLUSIONS: The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027 .).

Prostate Radiofrequency Focal Ablation (ProRAFT) Trial: A Prospective Development Study Evaluating a Bipolar Radiofrequency Device to Treat Prostate Cancer.

PURPOSE: We determined the early efficacy of bipolar radiofrequency ablation with a coil design for focal ablation of clinically significant localized prostate cancer visible at multiparametric magnetic resonance imaging. MATERIALS AND METHODS: A prospective IDEAL phase 2 development study (Focal Prostate Radiofrequency Ablation, NCT02294903) recruited treatment-naïve patients with a single focus of significant localized prostate cancer (Gleason 7 or 4 mm or more of Gleason 6) concordant with a lesion visible on multiparametric magnetic resonance imaging. Intervention was a focal ablation with a bipolar radiofrequency system (Encage™) encompassing the lesion and a predefined margin using nonrigid magnetic resonance imaging-ultrasound fusion. Primary outcome was the proportion of men with absence of significant localized disease on biopsy at 6 months. Trial followup consisted of serum prostate specific antigen, multiparametric magnetic resonance imaging at 1 week, and 6 and 12 months post-ablation. Validated patient reported outcome measures for urinary, erectile and bowel functions, and adverse events monitoring system were used. Analyses were done on a per-protocol basis. RESULTS: Of 21 patients recruited 20 received the intervention. Baseline characteristics were median age 66 years (IQR 63-69) and preoperative median prostate specific antigen 7.9 ng/ml (5.3-9.6). A total of 18 patients (90%) had Gleason 7 disease with median maximum cancer 7 mm (IQR 5-10), for a median of 2.8 cc multiparametric magnetic resonance imaging lesions (IQR 1.4-4.8). Targeted biopsy of the treated area (median number of cores 6, IQR 5-8) showed absence of significant localized prostate cancer in 16/20 men (80%), concordant with multiparametric magnetic resonance imaging. There was a low profile of side effects at patient reported outcome measures analysis and there were no serious adverse events. CONCLUSIONS: Focal therapy of significant localized prostate cancer associated with a magnetic resonance imaging lesion using bipolar radiofrequency showed early efficacy to ablate cancer with low rates of genitourinary and rectal side effects.

NeuroSAFE frozen section during robot-assisted radical prostatectomy: peri-operative and histopathological outcomes from the NeuroSAFE PROOF feasibility randomized controlled trial.

OBJECTIVES: To report on the methods, peri-operative outcomes and histopathological concordance between frozen and final section from the NeuroSAFE PROOF feasibility study (NCT03317990). PATIENTS AND METHODS: Between May 2018 and March 2019, 49 patients at two UK centres underwent robot-assisted radical prostatectomy (RARP). Twenty-five patient were randomized to NeuroSAFE RARP (intervention arm) and 24 to standard RARP (control arm). Frozen section was compared to final paraffin section margin assessment in the 25 patients in the NeuroSAFE arm. Operation timings and complications were collected prospectively in both arms. RESULTS: Fifty neurovascular bundles (NVBs) from 25 patients in the NeuroSAFE arm were analysed. When analysed by each pathological section (n = 250, average five per side), we noted a sensitivity of 100%, a specificity of 99.2%, and an area under the curve (AUC) of 0.994 (95% confidence interval [CI] 0.985 to 1; P ≤0.001). On an NVB basis (n = 50), sensitivity was 100%, specificity was 92.7%, and the AUC was 0.963 (95% CI 0.914 to 1; P ≤0.001). NeuroSAFE RARP lasted a mean of 3 h 16 min (knife to skin to off table, 95% CI 3 h 2 min-3 h 30 min) compared to 2 h 4 min (95% CI 2 h 2 min-2 h 25 min; P ≤0.001) for standard RARP. There was no morbidity associated with the additional length of operating time on in the NeuroSAFE arm. CONCLUSION: This feasibility study demonstrates the safety, reproducibility and excellent histopathological concordance of the NeuroSAFE technique in the NeuroSAFE PROOF trial. Although the technique increases the duration of RARP, this does not cause short-term harm. Confirmation of feasibility has led to the opening of the fully powered NeuroSAFE PROOF randomized controlled trial, which is currently under way at four sites in the UK.

Pulmonary metastasectomy in colorectal cancer: health utility scores by EQ-5D-3L in a randomized controlled trial show no benefit from lung metastasectomy.

AIM: The aim was to assess the health utility of lung metastasectomy in the treatment of patients with colorectal cancer (CRC) using the EQ-5D-3L questionnaire. METHODS: Multidisciplinary CRC teams at 14 sites recruited patients to a two-arm randomized controlled trial-Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC). Remote randomization was used, stratified by site and with minimization for seven known confounders. Participants completed the EQ-5D-3L questionnaire together with other patient reported outcome measures at randomization and then again at 3, 6, 12 and 24 months. These were returned by post to the coordinating centre. RESULTS: Between December 2010 and December 2016, 93 participants were randomized, 91 of whom returned questionnaires. Survival and patient reported quality of life have been published previously, revealing no significant differences between the trial arms. Described here are patient reported data from the five dimensions of the EQ-5D-3L and the visual analogue scale (VAS) health state. No significant difference was seen at any time point. The estimated difference between control and metastasectomy patients was -0.23 (95% CI -0.113, 0.066) for the composite 0 to 1 index scale based on the descriptive system and 0.123 (95% CI -7.24, 7.49) for the 0 to 100 VAS scale. CONCLUSIONS: Following lung metastasectomy for CRC, no benefit was demonstrated for health utility, which alongside a lack of a survival or quality of life benefit calls into question the widespread use of the procedure.

The Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) burden of care study: Analysis of local treatments for lung metastases and systemic chemotherapy in 220 patients in the PulMiCC cohort.

AIM: The aim of this work was to examine the burden of further treatments in patients with colorectal cancer following a decision about lung metastasectomy. METHOD: Five teams participating in the Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) study provided details on subsequent local treatments for lung metastases, including the use of chemotherapy. For patients in three groups (no metastasectomy, one metastasectomy or multiple local interventions), baseline factors and selection criteria for additional treatments were examined. RESULTS: The five teams recruited 220 patients between October 2010 and January 2017. No lung metastasectomy was performed in 51 patients, 114 patients had one metastasectomy and 55 patients had multiple local interventions. Selection for initial metastasectomy was associated with nonelevated carcinoembryonic antigen, fewer metastases and no prior liver metastasectomy. These patients also had better Eastern Cooperative Oncology Group scores and lung function at baseline. Four sites provided information on chemotherapy in 139 patients: 79 (57%) had one to five courses of chemotherapy, to a total of 179 courses. The patterns of survival after one or multiple metastasectomy interventions showed evidence of guarantee-time bias contributing to an impression of benefit over no metastasectomy. After repeated metastasectomy, a significantly higher risk of death was observed, with no apparent reduction in chemotherapy usage. CONCLUSION: Repeated metastasectomy is associated with a higher risk of death without reducing the use of chemotherapy. Continued monitoring without surgery might reassure patients with indolent disease or allow response assessment during systemic treatment. Overall, the carefully collected information from the PulMICC study provides no indication of an important survival benefit from metastasectomy.

The Pulmonary Metastasectomy in Colorectal Cancer cohort study: Analysis of case selection, risk factors and survival in a prospective observational study of 512 patients.

AIM: We wanted to examine survival in patients with resected colorectal cancer (CRC) whose lung metastases are or are not resected. METHODS: Teams participating in the study of Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) identified potential candidates for lung metastasectomy and invited their consent to join Stage 1. Baseline data related to CRC and fitness for surgery were collected. Eligible patients were invited to consent for randomization in the PulMiCC randomized controlled trial (Stage 2). Sites were provided with case report forms for non-randomized patients to record adverse events and death at any time. They were all reviewed at 1 year. Baseline and survival data were analysed for the full cohort. RESULTS: Twenty-five clinical sites recruited 512 patients from October 2010 to January 2017. Data collection closed in October 2020. Before analysis, 28 patients with non-CRC lung lesions were excluded and three had withdrawn consent leaving 481. The date of death was known for 292 patients, 136 were alive in 2020 and 53 at earlier time points. Baseline factors and 5-year survival were analysed in three strata: 128 non-randomized patients did not have metastasectomy; 263 had elective metastasectomy; 90 were from the randomized trial. The proportions of solitary metastases for electively operated and non-operated patients were 69% and 35%. Their respective 5-year survivals were 47% and 22%. CONCLUSION: Survival without metastasectomy was greater than widely presumed. Difference in survival appeared to be largely related to selection. No inference can be drawn about the effect of metastasectomy on survival in this observational study.

Exploring patients' experience and perception of being diagnosed with bladder cancer: a mixed-methods approach.

OBJECTIVE: To determine patient experience and perception following a diagnosis of non-muscle-invasive bladder cancer (NMIBC). PATIENT AND METHODS: Patients were part of a prospective multicentre observational study recruiting patients with NMIBC for a urine biomarker study (DETECT II; ClinicalTrials.gov: NCT02781428). A mixed-methods approach comprising: (i) the Brief Illness Perception Questionnaire (Brief-IPQ) and (ii) semi-structured interviews to explore patients' experience of having haematuria, and initial and subsequent experience with a NMIBC diagnosis. Both assessments were completed at 6 months after NMIBC diagnosis. RESULTS: A total of 213 patients completed the Brief-IPQ. Patients felt that they had minimal symptoms (median [interquartile range, IQR] score 2 [0-5]) and were not particularly affected emotionally (median [IQR] score 3 [1-6]) with a minimal effect to their daily life (median [IQR] score 2 [0-5]). However, they remained concerned about their cancer diagnosis (median [IQR] score 5 [3-8]) and felt that they had no personal control over the cancer (median [IQR] score 2 [2-5]) and believed that their illness would affect them for some time (median [IQR] score 6 [3-10]). A significant association with a lower personal control of the disease (P < 0.05) and a poorer understanding of the management of NMIBC (P < 0.05) was seen in patients aged >70 years. Many patients were uncertain about the cause of bladder cancer. Qualitative analysis found that at initial presentation of haematuria, most patients were not aware of the risk of bladder cancer. Patients were most anxious and psychologically affected between the interval of cystoscopy diagnosis and transurethral resection of bladder tumour (TURBT). Following TURBT, most patients were positive about their cancer prognosis. CONCLUSION: Patients with NMIBC have a poor perception of disease control and believe that their disease will continue over a prolonged period of time. This is particularly more pertinent in the elderly. Patients are most psychologically affected during the interval between cancer diagnosis following cystoscopy and TURBT. Health awareness about bladder cancer remained poor with a significant number of patients unaware of the causes of bladder cancer. Psychological support and prompt TURBT following bladder cancer diagnosis would help improve the mental health of patients with NMIBC.

Mixed-methods approach to exploring patients' perspectives on the acceptability of a urinary biomarker test in replacing cystoscopy for bladder cancer surveillance.

OBJECTIVES: To determine the minimal accepted sensitivity (MAS) of a urine biomarker that patients are willing to accept to replace cystoscopy and to assess qualitatively their views and reasons. PATIENTS AND METHODS: Patients were part of a prospective multicentre observational study recruiting people with bladder cancer for a urine biomarker study (DETECT II; ClinicalTrials.gov: NCT02781428). A mixed-methods approach comprising (1) a questionnaire to assess patients' experience with cystoscopy and patients' preference for cystoscopy vs urinary biomarker, and (2) semi-structured interviews to understand patient views, choice and reasons for their preference. RESULTS: A urine biomarker with an MAS of 90% would be accepted by 75.8% of patients. This was despite a high self-reported prevalence of haematuria (51.0%), dysuria/lower urinary tract symptoms (69.1%) and urinary tract infection requiring antibiotics (25.8%). There was no association between MAS with patient demographics, adverse events experienced, cancer characteristics or distance of patients' home to hospital. The qualitative analysis suggested that patients acknowledge that cystoscopy is invasive, embarrassing and associated with adverse events but are willing to tolerate the procedure because of its high sensitivity. Patients have confidence in cystoscopy and appreciate the visual diagnosis of cancer. Both low- and high-risk patients would consider a biomarker with a reported sensitivity similar to that of cystoscopy. CONCLUSION: Patients value the high sensitivity of cystoscopy despite the reported discomfort and adverse events experienced after it. The sensitivity of a urinary biomarker must be close to cystoscopy to gain patients' acceptance.

Does urinary cytology have a role in haematuria investigations?

OBJECTIVES: To determine the diagnostic accuracy of urinary cytology to diagnose bladder cancer and upper tract urothelial cancer (UTUC) as well as the outcome of patients with a positive urine cytology and normal haematuria investigations in patients in a multicentre prospective observational study of patients investigated for haematuria. PATIENT AND METHODS: The DETECT I study (clinicaltrials.gov NCT02676180) recruited patients presenting with haematuria following referral to secondary case at 40 hospitals. All patients had a cystoscopy and upper tract imaging (renal bladder ultrasound [RBUS] and/ or CT urogram [CTU]). Patients, where urine cytology were performed, were sub-analysed. The reference standard for the diagnosis of bladder cancer and UTUC was histological confirmation of cancer. A positive urine cytology was defined as a urine cytology suspicious for neoplastic cells or atypical cells. RESULTS: Of the 3 556 patients recruited, urine cytology was performed in 567 (15.9%) patients from nine hospitals. Median time between positive urine cytology and endoscopic tumour resection was 27 (IQR: 21.3-33.8) days. Bladder cancer was diagnosed in 39 (6.9%) patients and UTUC in 8 (1.4%) patients. The accuracy of urinary cytology for the diagnosis of bladder cancer and UTUC was: sensitivity 43.5%, specificity 95.7%, positive predictive value (PPV) 47.6% and negative predictive value (NPV) 94.9%. A total of 21 bladder cancers and 5 UTUC were missed. Bladder cancers missed according to grade and stage were as follows: 4 (19%) were ≥ pT2, 2 (9.5%) were G3 pT1, 10 (47.6%) were G3/2 pTa and 5 (23.8%) were G1 pTa. High-risk cancer was confirmed in 8 (38%) patients. There was a marginal improvement in sensitivity (57.7%) for high-risk cancers. When urine cytology was combined with imaging, the diagnostic performance improved with CTU (sensitivity 90.2%, specificity 94.9%) superior to RBUS (sensitivity 66.7%, specificity 96.7%). False positive cytology results were confirmed in 22 patients, of which 12 (54.5%) had further invasive tests and 5 (22.7%) had a repeat cytology. No cancer was identified in these patients during follow-up. CONCLUSIONS: Urine cytology will miss a significant number of muscle-invasive bladder cancer and high-risk disease. Our results suggest that urine cytology should not be routinely performed as part of haematuria investigations. The role of urine cytology in select cases should be considered in the context of the impact of a false positive result leading to further potentially invasive tests conducted under general anaesthesia.

Can Renal and Bladder Ultrasound Replace Computerized Tomography Urogram in Patients Investigated for Microscopic Hematuria?

PURPOSE: Computerized tomography urogram is recommended when investigating patients with hematuria. We determined the incidence of urinary tract cancer and compared the diagnostic accuracy of computerized tomography urogram to that of renal and bladder ultrasound for identifying urinary tract cancer. MATERIALS AND METHODS: The DETECT (Detecting Bladder Cancer Using the UroMark Test) I study is a prospective observational study recruiting patients 18 years old or older following presentation with macroscopic or microscopic hematuria at a total of 40 hospitals. All patients underwent cystoscopy and upper tract imaging comprising computerized tomography urogram and/or renal and bladder ultrasound. RESULTS: A total of 3,556 patients with a median age of 68 years were recruited in this study, of whom 2,166 underwent renal and bladder ultrasound, and 1,692 underwent computerized tomography urogram in addition to cystoscopy. The incidence of bladder, renal and upper tract urothelial cancer was 11.0%, 1.4% and 0.8%, respectively, in macroscopic hematuria cases. Patients with microscopic hematuria had a 2.7%, 0.4% and 0% incidence of bladder, renal and upper tract urothelial cancer, respectively. The sensitivity and negative predictive value of renal and bladder ultrasound to detect renal cancer were 85.7% and 99.9% but they were 14.3% and 99.7%, respectively, to detect upper tract urothelial cancer. Renal and bladder ultrasound was poor at identifying renal calculi. Renal and bladder ultrasound sensitivity was lower than that of computerized tomography urogram to detect bladder cancer (each less than 85%). Cystoscopy had 98.3% specificity and 83.9% positive predictive value. CONCLUSIONS: Computerized tomography urogram can be safely replaced by renal and bladder ultrasound in patients who have microscopic hematuria. The incidence of upper tract urothelial cancer is 0.8% in patients with macroscopic hematuria and computerized tomography urogram is recommended. Patients with suspected renal calculi require noncontrast renal tract computerized tomography. Imaging cannot replace cystoscopy to diagnose bladder cancer.

DETECT I & DETECT II: a study protocol for a prospective multicentre observational study to validate the UroMark assay for the detection of bladder cancer from urinary cells.

BACKGROUND: Haematuria is a common finding in general practice which requires visual inspection of the bladder by cystoscopy as well as upper tract imaging. In addition, patients with non-muscle invasive bladder cancer (NMIBC) often require surveillance cystoscopy as often as three monthly depending on disease risk. However, cystoscopy is an invasive procedure which is uncomfortable, requires hospital attendance and is associated with a risk of urinary tract infection. We have developed the UroMark assay, which can detect 150 methylation specific alteration specific to bladder cancer using DNA from urinary sediment cells. METHODS: DETECT I and DETECT II are two multi-centre prospective observational studies designed to conduct a robust validation of the UroMark assay. DETECT I will recruit patients having diagnostic investigations for haematuria to determine the negative predictive value of the UroMark to rule out the presence of bladder cancer. DETECT II will recruit patients with new or recurrent bladder cancer to determine the sensitivity of the UroMark in detecting low, intermediate and high grade bladder cancer. NMIBC patients in DETECT II will be followed up with three monthly urine sample collection for 24 months while having surveillance cystoscopy. DETECT II will include a qualitative analysis of semi-structured interviews to explore patients' experience of being diagnosed with bladder cancer and having cystoscopy and a urinary test for bladder cancer surveillance. Results of the UroMark will be compared to cystoscopy findings and histopathological results in patients with bladder cancer. DISCUSSION: A sensitive and specific urinary biomarker will revolutionise the haematuria diagnostic pathway and surveillance strategies for NMIBC patients. None of the six approved US Food and Drug Administration urinary test are recommended as a standalone test. The UroMark assay is based on next generation sequencing technology which interrogates 150 loci and represents a step change compared to other biomarker panels. This enhances the sensitivity of the test and by using a random forest classifier approach, where the UroMark results are derived from a cut off generated from known outcomes of previous samples, addresses many shortcomings of previous assays. TRIAL REGISTRATION: Both trails are registered on clinicaltrials.gov. DETECT I: NCT02676180 (18th December 2015). DETECT II: NCT02781428 (11th May 2016).

Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial.

BACKGROUND: The TARGIT-A trial compared risk-adapted radiotherapy using single-dose targeted intraoperative radiotherapy (TARGIT) versus fractionated external beam radiotherapy (EBRT) for breast cancer. We report 5-year results for local recurrence and the first analysis of overall survival. METHODS: TARGIT-A was a randomised, non-inferiority trial. Women aged 45 years and older with invasive ductal carcinoma were enrolled and randomly assigned in a 1:1 ratio to receive TARGIT or whole-breast EBRT, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy: randomisation occurred either before lumpectomy (prepathology stratum, TARGIT concurrent with lumpectomy) or after lumpectomy (postpathology stratum, TARGIT given subsequently by reopening the wound). Patients in the TARGIT group received supplemental EBRT (excluding a boost) if unforeseen adverse features were detected on final pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute difference in local recurrence in the conserved breast, with a prespecified non-inferiority margin of 2·5% at 5 years; prespecified analyses included outcomes as per timing of randomisation in relation to lumpectomy. Secondary outcomes included complications and mortality. This study is registered with ClinicalTrials.gov, number NCT00983684. FINDINGS: Patients were enrolled at 33 centres in 11 countries, between March 24, 2000, and June 25, 2012. 1721 patients were randomised to TARGIT and 1730 to EBRT. Supplemental EBRT after TARGIT was necessary in 15·2% [239 of 1571] of patients who received TARGIT (21·6% prepathology, 3·6% postpathology). 3451 patients had a median follow-up of 2 years and 5 months (IQR 12-52 months), 2020 of 4 years, and 1222 of 5 years. The 5-year risk for local recurrence in the conserved breast was 3·3% (95% CI 2·1-5·1) for TARGIT versus 1·3% (0·7-2·5) for EBRT (p=0·042). TARGIT concurrently with lumpectomy (prepathology, n=2298) had much the same results as EBRT: 2·1% (1·1-4·2) versus 1·1% (0·5-2·5; p=0·31). With delayed TARGIT (postpathology, n=1153) the between-group difference was larger than 2·5% (TARGIT 5·4% [3·0-9·7] vs EBRT 1·7% [0·6-4·9]; p=0·069). Overall, breast cancer mortality was much the same between groups (2·6% [1·5-4·3] for TARGIT vs 1·9% [1·1-3·2] for EBRT; p=0·56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8-2·5] vs 3·5% [2·3-5·2]; p=0·0086), attributable to fewer deaths from cardiovascular causes and other cancers. Overall mortality was 3·9% (2·7-5·8) for TARGIT versus 5·3% (3·9-7·3) for EBRT (p=0·099). Wound-related complications were much the same between groups but grade 3 or 4 skin complications were significantly reduced with TARGIT (four of 1720 vs 13 of 1731, p=0·029). INTERPRETATION: TARGIT concurrent with lumpectomy within a risk-adapted approach should be considered as an option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative to postoperative EBRT. FUNDING: University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research.

Urinary and Sexual Impact of Robotic Radical Prostatectomy: Reporting of Patient-reported Outcome Measures in the First Year after Radical Prostatectomy in a Contemporary Multicentre Cohort in the United Kingdom.

Background and objective: Radical prostatectomy (RP) is an established treatment for localised prostate cancer that can have a significant impact on urinary and sexual function, with recovery over time. Our aim was to describe functional recovery in the first year after RP, reporting descriptive outcomes alongside validated patient-reported outcome measure scores (Expanded Prostate Cancer Index Composite, EPIC-26). Methods: Men undergoing RP between September 2015 and November 2019 completed EPIC-26 at baseline and 1, 3, 6, and 12 mo. Key findings and limitations: Overall, 2030 men consented to participation, underwent RP, and completed EPIC-26. At baseline, 97% were pad-free (1928/1996; 95% confidence interval [CI] 96-97%) and 77% were leak-free and pad-free (1529/1996; 95% CI 75-78), with a median EPIC-26 incontinence domain score of 100 (interquartile range [IQR] 86-100). At 12 mo, 65% were pad-free (904/1388; 95% CI 63-68%) and 42% were leak-free and pad-free (583/1388; 95% CI 39-45%), with a median EPIC-26 score of 76 (IQR 61-100). While one in three men reported wearing a pad at 12 mo, fewer than one in ten men needed more than 1 pad/d. At baseline, 1.9% reported a "moderate or big problem" with urine leakage, which increased to 9.7% at 12 mo. At baseline, the median sexual domain score among 1880 men was 74 (IQR 43-92) and 52% had erections sufficient for intercourse without medication (975/1880; 95% CI 50-54%). Among these 975 men, 630 responded at 12 mo, of whom 17% reported sufficient erections for intercourse (105/630; 95% CI 14-20%), without medication in 6% (37/630; 95% CI 4-8%) and needing medication in 11% (68/630; 95% CI 9-13%); the median EPIC-26 domain score was 26 (IQR 13-57). Conclusions and clinical implications: Reporting of functional outcomes after RP in terms of easily understood concepts such as pad-free and leak-free status, and erections with and with medication, alongside the classical report using EPIC-26 domain scores, increases the understanding of RP recovery patterns over the first year. Patient summary: At 12 months after surgery for prostate cancer, one in ten men reported a moderate or big problem with urine leakage and one in five men reported sufficient erections.

The Role of Multiparametric MRI and MRI-targeted Biopsy in the Diagnosis of Radiorecurrent Prostate Cancer: An Analysis from the FORECAST Trial.

BACKGROUND: The role of multiparametric magnetic resonance imaging (MRI) for detecting recurrent prostate cancer after radiotherapy is unclear. OBJECTIVE: To evaluate MRI and MRI-targeted biopsies for detecting intraprostatic cancer recurrence and planning for salvage focal ablation. DESIGN, SETTING, AND PARTICIPANTS: FOcal RECurrent Assessment and Salvage Treatment (FORECAST; NCT01883128) was a prospective cohort diagnostic study that recruited 181 patients with suspected radiorecurrence at six UK centres (2014 to 2018); 144 were included here. INTERVENTION: All patients underwent MRI with 5 mm transperineal template mapping biopsies; 84 had additional MRI-targeted biopsies. MRI scans with Likert scores of 3 to 5 were deemed suspicious. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: First, the diagnostic accuracy of MRI was calculated. Second, the pathological characteristics of MRI-detected and MRI-undetected tumours were compared using the Wilcoxon rank sum test and chi-square test for trend. Third, four biopsy strategies involving an MRI-targeted biopsy alone and with systematic biopsies of one to two other quadrants were studied. Fisher's exact test was used to compare MRI-targeted biopsy alone with the best other strategy for the number of patients with missed cancer and the number of patients with cancer harbouring additional tumours in unsampled quadrants. Analyses focused primarily on detecting cancer of any grade or length. Last, eligibility for focal therapy was evaluated for men with localised (≤T3bN0M0) radiorecurrent disease. RESULTS AND LIMITATIONS: Of 144 patients, 111 (77%) had cancer detected on biopsy. MRI sensitivity and specificity at the patient level were 0.95 (95% confidence interval [CI] 0.92 to 0.99) and 0.21 (95% CI 0.07 to 0.35), respectively. At the prostate quadrant level, 258/576 (45%) quadrants had cancer detected on biopsy. Sensitivity and specificity were 0.66 (95% CI 0.59 to 0.73) and 0.54 (95% CI 0.46 to 0.62), respectively. At the quadrant level, compared with MRI-undetected tumours, MRI-detected tumours had longer maximum cancer core length (median difference 3 mm [7 vs 4 mm]; 95% CI 1 to 4 mm, p < 0.001) and a higher grade group (p = 0.002). Of the 84 men who also underwent an MRI-targeted biopsy, 73 (87%) had recurrent cancer diagnosed. Performing an MRI-targeted biopsy alone missed cancer in 5/73 patients (7%; 95% CI 3 to 15%); with additional systematic sampling of the other ipsilateral and contralateral posterior quadrants (strategy 4), 2/73 patients (3%; 95% CI 0 to 10%) would have had cancer missed (difference 4%; 95% CI -3 to 11%, p = 0.4). If an MRI-targeted biopsy alone was performed, 43/73 (59%; 95% CI 47 to 69%) patients with cancer would have harboured undetected additional tumours in unsampled quadrants. This reduced but only to 7/73 patients (10%; 95% CI 4 to 19%) with strategy 4 (difference 49%; 95% CI 36 to 62%, p < 0.0001). Of 73 patients, 43 (59%; 95% CI 47 to 69%) had localised radiorecurrent cancer suitable for a form of focal ablation. CONCLUSIONS: For patients with recurrent prostate cancer after radiotherapy, MRI and MRI-targeted biopsy, with or without perilesional sampling, will diagnose cancer in the majority where present. MRI-undetected cancers, defined as Likert scores of 1 to 2, were found to be smaller and of lower grade. However, if salvage focal ablation is planned, an MRI-targeted biopsy alone is insufficient for prostate mapping; approximately three of five patients with recurrent cancer found on an MRI-targeted biopsy alone harboured further tumours in unsampled quadrants. Systematic sampling of the whole gland should be considered in addition to an MRI-targeted biopsy to capture both MRI-detected and MRI-undetected disease. PATIENT SUMMARY: After radiotherapy, magnetic resonance imaging (MRI) is accurate for detecting recurrent prostate cancer, with missed cancer being smaller and of lower grade. Targeting a biopsy to suspicious areas on MRI results in a diagnosis of cancer in most patients. However, for every five men who have recurrent cancer, this targeted approach would miss cancers elsewhere in the prostate in three of these men. If further focal treatment of the prostate is planned, random biopsies covering the whole prostate in addition to targeted biopsies should be considered so that tumours are not missed.

Cost-Effectiveness of Robot-Assisted Radical Cystectomy vs Open Radical Cystectomy for Patients With Bladder Cancer.

Importance: The value to payers of robot-assisted radical cystectomy with intracorporeal urinary diversion (iRARC) when compared with open radical cystectomy (ORC) for patients with bladder cancer is unclear. Objectives: To compare the cost-effectiveness of iRARC with that of ORC. Design, Setting, and Participants: This economic evaluation used individual patient data from a randomized clinical trial at 9 surgical centers in the United Kingdom. Patients with nonmetastatic bladder cancer were recruited from March 20, 2017, to January 29, 2020. The analysis used a health service perspective and a 90-day time horizon, with supplementary analyses exploring patient benefits up to 1 year. Deterministic and probabilistic sensitivity analyses were undertaken. Data were analyzed from January 13, 2022, to March 10, 2023. Interventions: Patients were randomized to receive either iRARC (n = 169) or ORC (n = 169). Main Outcomes and Measures: Costs of surgery were calculated using surgery timings and equipment costs, with other hospital data based on counts of activity. Quality-adjusted life-years were calculated from European Quality of Life 5-Dimension 5-Level instrument responses. Prespecified subgroup analyses were undertaken based on patient characteristics and type of diversion. Results: A total of 305 patients with available outcome data were included in the analysis, with a mean (SD) age of 68.3 (8.1) years, and of whom 241 (79.0%) were men. Robot-assisted radical cystectomy was associated with statistically significant reductions in admissions to intensive therapy (6.35% [95% CI, 0.42%-12.28%]), and readmissions to hospital (14.56% [95% CI, 5.00%-24.11%]), but increases in theater time (31.35 [95% CI, 13.67-49.02] minutes). The additional cost of iRARC per patient was £1124 (95% CI, -£576 to £2824 [US $1622 (95% CI, -$831 to $4075)]) with an associated gain in quality-adjusted life-years of 0.01124 (95% CI, 0.00391-0.01857). The incremental cost-effectiveness ratio was £100 008 (US $144 312) per quality-adjusted life-year gained. Robot-assisted radical cystectomy had a much higher probability of being cost-effective for subgroups defined by age, tumor stage, and performance status. Conclusions and Relevance: In this economic evaluation of surgery for patients with bladder cancer, iRARC reduced short-term morbidity and some associated costs. While the resulting cost-effectiveness ratio was in excess of thresholds used by many publicly funded health systems, patient subgroups were identified for which iRARC had a high probability of being cost-effective. Trial Registration: ClinicalTrials.gov Identifier: NCT03049410.