Publications by authors named "Derek Rosario"

80 Publications

Embedding supervised exercise training for men on androgen deprivation therapy into standard prostate cancer care: a feasibility and acceptability study (the STAMINA trial).

Sci Rep 2021 06 14;11(1):12470. Epub 2021 Jun 14.

Allied Health Professionals, Radiotherapy and Oncology, Sheffield Hallam University, Sheffield, UK.

Lifestyle interventions involving exercise training offset the adverse effects of androgen deprivation therapy in men with prostate cancer. Yet provision of integrated exercise pathways in cancer care is sparse. This study assessed the feasibility and acceptability of an embedded supervised exercise training intervention into standard prostate cancer care in a single-arm, multicentre prospective cohort study. Feasibility included recruitment, retention, adherence, fidelity and safety. Acceptability of behaviourally informed healthcare and exercise professional training was assessed qualitatively. Despite the imposition of lockdown for the COVID-19 pandemic, referral rates into and adherence to, the intervention was high. Of the 45 men eligible for participation, 79% (n = 36) received the intervention and 47% (n = 21) completed the intervention before a government mandated national lockdown was enforced in the United Kingdom. Patients completed a mean of 27 min of aerobic exercise per session (SD = 3.48), at 77% heart rate maximum (92% of target dose), and 3 sets of 10 reps of 3 resistance exercises twice weekly for 12 weeks, without serious adverse event. The intervention was delivered by 26 healthcare professionals and 16 exercise trainers with moderate to high fidelity, and the intervention was deemed highly acceptable to patients. The impact of societal changes due to the pandemic on the delivery of this face-to-face intervention remain uncertain but positive impacts of embedding exercise provision into prostate cancer care warrant long-term investigation.
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http://dx.doi.org/10.1038/s41598-021-91876-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203669PMC
June 2021

The development of a theory and evidence-based intervention to aid implementation of exercise into the prostate cancer care pathway with a focus on healthcare professional behaviour, the STAMINA trial.

BMC Health Serv Res 2021 Mar 25;21(1):273. Epub 2021 Mar 25.

Institute for Population Health Sciences, Queen Mary, University of London, London, UK.

Background: Twice-weekly supervised aerobic and resistance exercise for 12 weeks reduces fatigue and improves quality of life in men on Androgen Deprivation Therapy for prostate cancer. Despite the National Institute for Health and Care Excellence (NICE) proposing this as standard of care, it does not routinely take place in practice. Healthcare professionals are in a prime position to deliver and integrate these recommendations. A change in the behaviour of clinical teams is therefore required. In this paper, we describe the development of a training package for healthcare professionals using theory and evidence to promote delivery of such recommendations as standard care.

Methods: The intervention development process was guided by the Medical Research Council guidance for complex interventions and the Behaviour Change Wheel. Target behaviours were identified from the literature and thirty-five prostate cancer care healthcare professionals (including oncologists, consultant urologists, clinical nurse specialists, physiotherapists, general practitioners and commissioners) were interviewed to understand influences on these behaviours. The Theoretical Domains Framework was used to identify theoretical constructs for change. Behaviour change techniques were selected based on theory and evidence and were translated into intervention content. The intervention was refined with the input of stakeholders including healthcare professionals, patients, and exercise professionals in the form of rehearsal deliveries, focus groups and a workshop.

Results: Seven modifiable healthcare professional target behaviours were identified to support the delivery of the NICE recommendations including identifying eligible patients suitable for exercise, recommending exercise, providing information, exercise referral, providing support and interpret and feedback on progress. Ten domains from the Theoretical Domain's Framework were identified as necessary for change, including improving knowledge and skills, addressing beliefs about consequences, and targeting social influences. These were targeted through twenty-two behaviour change techniques delivered in a half-day, interactive training package. Based on initial feedback from stakeholders, the intervention was refined in preparation for evaluation.

Conclusions: We designed an intervention based on theory, evidence, and stakeholder feedback to promote and support the delivery of NICE recommendations. Future work will aim to test this training package in a multi-centre randomised trial. If proven effective, the development and training package will provide a template for replication in other clinical populations, where exercise has proven efficacy but is insufficiently implemented.
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http://dx.doi.org/10.1186/s12913-021-06266-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992804PMC
March 2021

Remote interventions to improve exercise behaviour in sedentary people living with and beyond cancer: a systematic review and meta-analysis.

BMC Cancer 2021 Mar 24;21(1):308. Epub 2021 Mar 24.

College of Health, Wellbeing and Life Sciences, Sheffield Hallam University, Sheffield, UK.

Background: The COVID-19 pandemic has forced many cancer services to consider a transition to a remote format of delivery that is largely untested. Accordingly, we sought to perform a systematic review of the effects of remotely delivered interventions to improve exercise behaviour in sedentary adults living with and beyond cancer.

Methods: Eligible studies were randomised controlled trials comparing a remotely delivered exercise intervention to a usual care comparison in sedentary people over 18 years old with a primary cancer diagnosis. Nine electronic databases were searched from inception to November 2020.

Results: The review included three trials, totalling 186 participants. Two of the included trials incorporated prescriptions that meet current aerobic exercise recommendations, one of which also meets the guidelines for resistance exercise. No trials reported an intervention adherence of 75% or more for a set prescription that meets current exercise guidelines.

Conclusion: There is little evidence suggesting that remote exercise interventions promote exercise behaviours or improve physical function in sedentary adults living with and beyond cancer. The development and evaluation of novel remote exercise interventions is needed to establish their usefulness for clinical practice. Given the social response to the COVID-19 pandemic, further research in this area is urgently needed.
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http://dx.doi.org/10.1186/s12885-021-07989-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987748PMC
March 2021

Towards implementing exercise into the prostate cancer care pathway: development of a theory and evidence-based intervention to train community-based exercise professionals to support change in patient exercise behaviour (The STAMINA trial).

BMC Health Serv Res 2021 Mar 22;21(1):264. Epub 2021 Mar 22.

Institute for Population Health Sciences, Queen Mary University of London, London, UK.

Background: The National Institute for Health and Care Excellence (NICE) recommend that men on androgen deprivation therapy (ADT) for prostate cancer should receive supervised exercise to manage the side-effects of treatment. However, these recommendations are rarely implemented into practice. Community-based exercise professionals (CBEPs) represent an important target group to deliver the recommendations nationally, yet their standard training does not address the core competencies required to work with clinical populations, highlighting a need for further professional training. This paper describes the development of a training package to support CBEPs to deliver NICE recommendations.

Methods: Development of the intervention was guided by the Medical Research Council guidance for complex interventions and the Behaviour Change Wheel. In step one, target behaviours, together with their barriers and facilitators were identified from a literature review and focus groups with CBEPs (n = 22) and men on androgen deprivation therapy (n = 26). Focus group outputs were mapped onto the Theoretical Domains Framework (TDF) to identify theoretical constructs for change. In step two, behaviour change techniques and their mode of delivery were selected based on psychological theories and evidence to inform intervention content. In step three, the intervention was refined following delivery and subsequent feedback from intervention recipients and stakeholders.

Results: Six modifiable CBEPs target behaviours were identified to support the delivery of the NICE recommendations. Nine domains of the TDF were identified as key determinants of change, including: improving knowledge and skills and changing beliefs about consequences. To target the domains, we included 20 BCTs across 8 training modules and took a blended learning approach to accommodate different learning styles and preferences. Following test delivery to 11 CBEPs and feedback from 28 stakeholders, the training package was refined.

Conclusion: Established intervention development approaches provided a structured and transparent guide to intervention development. A training package for CBEPs was developed and should increase trust amongst patients and health care professionals when implementing exercise into prostate cancer care. Furthermore, if proven effective, the development and approach taken may provide a blueprint for replication in other clinical populations where exercise has proven efficacy but is insufficiently implemented.
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http://dx.doi.org/10.1186/s12913-021-06275-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982309PMC
March 2021

A critical evaluation of visual proportion of Gleason 4 and maximum cancer core length quantified by histopathologists.

Sci Rep 2020 10 14;10(1):17177. Epub 2020 Oct 14.

Department of Urology, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK.

Gleason score 7 prostate cancer with a higher proportion of pattern 4 (G4) has been linked to genomic heterogeneity and poorer patient outcome. The current assessment of G4 proportion uses estimation by a pathologist, with a higher proportion of G4 more likely to trigger additional imaging and treatment over active surveillance. This estimation method has been shown to have inter-observer variability. Fifteen patients with Prostate Grade Group (GG) 2 (Gleason 3 + 4) and fifteen patients with GG3 (Gleason 4 + 3) disease were selected from the PROMIS study with 192 haematoxylin and eosin-stained slides scanned. Two experienced uropathologists assessed the maximum cancer core length (MCCL) and G4 proportion using the current standard method (visual estimation) followed by detailed digital manual annotation of each G4 area and measurement of MCCL (planimetric estimation) using freely available software by the same two experts. We aimed to compare visual estimation of G4 and MCCL to a pathologist-driven digital measurement. We show that the visual and digital MCCL measurement differs up to 2 mm in 76.6% (23/30) with a high degree of agreement between the two measurements; Visual gave a median MCCL of 10 ± 2.70 mm (IQR 4, range 5-15 mm) compared to digital of 9.88 ± 3.09 mm (IQR 3.82, range 5.01-15.7 mm) (p = 0.64) The visual method for assessing G4 proportion over-estimates in all patients, compared to digital measurements [median 11.2% (IQR 38.75, range 4.7-17.9%) vs 30.4% (IQR 18.37, range 12.9-50.76%)]. The discordance was higher as the amount of G4 increased (Bias 18.71, CI 33.87-48.75, r 0.7, p < 0.0001). Further work on assessing actual G4 burden calibrated to clinical outcomes might lead to the use of differing G4 thresholds of significance if the visual estimation is used or by incorporating semi-automated methods for G4 burden measurement.
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http://dx.doi.org/10.1038/s41598-020-73524-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561724PMC
October 2020

False Positive Multiparametric Magnetic Resonance Imaging Phenotypes in the Biopsy-naïve Prostate: Are They Distinct from Significant Cancer-associated Lesions? Lessons from PROMIS.

Eur Urol 2021 01 10;79(1):20-29. Epub 2020 Oct 10.

UCL Division of Surgery & Interventional Science, University College London, London, UK; Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK.

Background: False positive multiparametric magnetic resonance imaging (mpMRI) phenotypes prompt unnecessary biopsies. The Prostate MRI Imaging Study (PROMIS) provides a unique opportunity to explore such phenotypes in biopsy-naïve men with raised prostate-specific antigen (PSA) and suspected cancer.

Objective: To compare mpMRI lesions in men with/without significant cancer on transperineal mapping biopsy (TPM).

Design, Setting, And Participants: PROMIS participants (n=235) underwent mpMRI followed by a combined biopsy procedure at University College London Hospital, including 5-mm TPM as the reference standard. Patients were divided into four mutually exclusive groups according to TPM findings: (1) no cancer, (2) insignificant cancer, (3) definition 2 significant cancer (Gleason ≥3+4 of any length and/or maximum cancer core length ≥4mm of any grade), and (4) definition 1 significant cancer (Gleason ≥4+3 of any length and/or maximum cancer core length ≥6mm of any grade).

Outcome Measurements And Statistical Analysis: Index and/or additional lesions present in 178 participants were compared between TPM groups in terms of number, conspicuity, volume, location, and radiological characteristics.

Results And Limitations: Most lesions were located in the peripheral zone. More men with significant cancer had two or more lesions than those without significant disease (67% vs 37%; p< 0.001). In the former group, index lesions were larger (mean volume 0.68 vs 0.50 ml; p< 0.001, Wilcoxon test), more conspicuous (Likert 4-5: 79% vs 22%; p< 0.001), and diffusion restricted (mean apparent diffusion coefficient [ADC]: 0.73 vs 0.86; p< 0.001, Wilcoxon test). In men with Likert 3 index lesions, logPSA density and index lesion ADC were significant predictors of definition 1/2 disease in a logistic regression model (mean cross-validated area under the receiver-operator characteristic curve: 0.77 [95% confidence interval: 0.67-0.87]).

Conclusions: Significant cancer-associated MRI lesions in biopsy-naïve men have clinical-radiological differences, with lesions seen in prostates without significant disease. MRI-calculated PSA density and ADC could predict significant cancer in those with indeterminate MRI phenotypes.

Patient Summary: Magnetic resonance imaging (MRI) lesions that mimic prostate cancer but are, in fact, benign prompt unnecessary biopsies in thousands of men with raised prostate-specific antigen. In this study we found that, on closer look, such false positive lesions have different features from cancerous ones. This means that doctors could potentially develop better tools to identify cancer on MRI and spare some patients from unnecessary biopsies.
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http://dx.doi.org/10.1016/j.eururo.2020.09.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772750PMC
January 2021

Strategies adopted by men to deal with uncertainty and anxiety when following an active surveillance/monitoring protocol for localised prostate cancer and implications for care: a longitudinal qualitative study embedded within the ProtecT trial.

BMJ Open 2020 09 9;10(9):e036024. Epub 2020 Sep 9.

Department of Urology, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, UK.

Objectives: Active surveillance (AS) enables men with low risk, localised prostate cancer (PCa) to avoid radical treatment unless progression occurs; lack of reliable AS protocols to determine progression leaves uncertainties for men and clinicians. This study investigated men's strategies for coping with the uncertainties of active monitoring (AM, a surveillance strategy within the Prostate testing for cancer and Treatment, ProtecT trial) over the longer term and implications for optimising supportive care.

Design: Longitudinal serial in-depth qualitative interviews every 2-3 years for a median 7 (range 6-14) years following diagnosis.

Setting: Four centres within the UK Protect trial.

Participants: Purposive sample of 20 men with localised PCa: median age at diagnosis 64 years (range 52-68); 15 (75%) had low-risk PCa; 12 randomly allocated to, 8 choosing AM. Eleven men continued with AM throughout the study period (median 7 years). Nine received radical treatment after a median 4 years (range 0.8-13.8 years).

Intervention: AM: 3-monthly serum prostate-specific antigen (PSA)-level assessment (year 1), 6-12 monthly thereafter; increase in PSA ≥50% during previous 12 months or patient/clinician concern triggered review.

Main Outcomes: Thematic analysis of 73 interviews identified strategies to accommodate uncertainty and anxiety of living with untreated cancer; implications for patient care.

Results: Men sought clarity, control or reassurance, with contextual factors mediating individual responses. Trust in the clinical team was critical for men in balancing anxiety and facilitating successful management change/continued monitoring. Only men from ProtecT were included; men outside ProtecT may have different experiences.

Conclusion: Men looked to clinicians for clarity, control and reassurance. Where provided, men felt comfortable continuing AM or having radical treatments when indicated. Clinicians build patient trust by clearly describing uncertainties, allowing patients control wherever possible and being aware of how context influences individual responses. Insights indicate need for supportive services to build trust and patient engagement over the long term.

Trial Registration Number: ISRCTN20141297; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-036024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482454PMC
September 2020

Active monitoring, radical prostatectomy and radical radiotherapy in PSA-detected clinically localised prostate cancer: the ProtecT three-arm RCT.

Health Technol Assess 2020 08;24(37):1-176

Department of Urology, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Background: Prostate cancer is the most common cancer among men in the UK. Prostate-specific antigen testing followed by biopsy leads to overdetection, overtreatment as well as undertreatment of the disease. Evidence of treatment effectiveness has lacked because of the paucity of randomised controlled trials comparing conventional treatments.

Objectives: To evaluate the effectiveness of conventional treatments for localised prostate cancer (active monitoring, radical prostatectomy and radical radiotherapy) in men aged 50-69 years.

Design: A prospective, multicentre prostate-specific antigen testing programme followed by a randomised trial of treatment, with a comprehensive cohort follow-up.

Setting: Prostate-specific antigen testing in primary care and treatment in nine urology departments in the UK.

Participants: Between 2001 and 2009, 228,966 men aged 50-69 years received an invitation to attend an appointment for information about the Prostate testing for cancer and Treatment (ProtecT) study and a prostate-specific antigen test; 82,429 men were tested, 2664 were diagnosed with localised prostate cancer, 1643 agreed to randomisation to active monitoring ( = 545), radical prostatectomy ( = 553) or radical radiotherapy ( = 545) and 997 chose a treatment.

Interventions: The interventions were active monitoring, radical prostatectomy and radical radiotherapy.

Trial Primary Outcome Measure: Definite or probable disease-specific mortality at the 10-year median follow-up in randomised participants.

Secondary Outcome Measures: Overall mortality, metastases, disease progression, treatment complications, resource utilisation and patient-reported outcomes.

Results: There were no statistically significant differences between the groups for 17 prostate cancer-specific ( = 0.48) and 169 all-cause ( = 0.87) deaths. Eight men died of prostate cancer in the active monitoring group (1.5 per 1000 person-years, 95% confidence interval 0.7 to 3.0); five died of prostate cancer in the radical prostatectomy group (0.9 per 1000 person-years, 95% confidence interval 0.4 to 2.2 per 1000 person years) and four died of prostate cancer in the radical radiotherapy group (0.7 per 1000 person-years, 95% confidence interval 0.3 to 2.0 per 1000 person years). More men developed metastases in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring,  = 33 (6.3 per 1000 person-years, 95% confidence interval 4.5 to 8.8); radical prostatectomy,  = 13 (2.4 per 1000 person-years, 95% confidence interval 1.4 to 4.2 per 1000 person years); and radical radiotherapy,  = 16 (3.0 per 1000 person-years, 95% confidence interval 1.9 to 4.9 per 1000 person-years;  = 0.004). There were higher rates of disease progression in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring ( = 112; 22.9 per 1000 person-years, 95% confidence interval 19.0 to 27.5 per 1000 person years); radical prostatectomy ( = 46; 8.9 per 1000 person-years, 95% confidence interval 6.7 to 11.9 per 1000 person-years); and radical radiotherapy ( = 46; 9.0 per 1000 person-years, 95% confidence interval 6.7 to 12.0 per 1000 person years;  < 0.001). Radical prostatectomy had the greatest impact on sexual function/urinary continence and remained worse than radical radiotherapy and active monitoring. Radical radiotherapy's impact on sexual function was greatest at 6 months, but recovered somewhat in the majority of participants. Sexual and urinary function gradually declined in the active monitoring group. Bowel function was worse with radical radiotherapy at 6 months, but it recovered with the exception of bloody stools. Urinary voiding and nocturia worsened in the radical radiotherapy group at 6 months but recovered. Condition-specific quality-of-life effects mirrored functional changes. No differences in anxiety/depression or generic or cancer-related quality of life were found. At the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year, the probabilities that each arm was the most cost-effective option were 58% (radical radiotherapy), 32% (active monitoring) and 10% (radical prostatectomy).

Limitations: A single prostate-specific antigen test and transrectal ultrasound biopsies were used. There were very few non-white men in the trial. The majority of men had low- and intermediate-risk disease. Longer follow-up is needed.

Conclusions: At a median follow-up point of 10 years, prostate cancer-specific mortality was low, irrespective of the assigned treatment. Radical prostatectomy and radical radiotherapy reduced disease progression and metastases, but with side effects. Further work is needed to follow up participants at a median of 15 years.

Trial Registration: Current Controlled Trials ISRCTN20141297.

Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 37. See the National Institute for Health Research Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443739PMC
August 2020

The ProtecT randomised trial cost-effectiveness analysis comparing active monitoring, surgery, or radiotherapy for prostate cancer.

Br J Cancer 2020 09 16;123(7):1063-1070. Epub 2020 Jul 16.

Bristol Medical School, University of Bristol, Bristol, UK.

Background: There is limited evidence relating to the cost-effectiveness of treatments for localised prostate cancer.

Methods: The cost-effectiveness of active monitoring, surgery, and radiotherapy was evaluated within the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial from a UK NHS perspective at 10 years' median follow-up. Prostate cancer resource-use collected from hospital records and trial participants was valued using UK reference-costs. QALYs (quality-adjusted-life-years) were calculated from patient-reported EQ-5D-3L measurements. Adjusted mean costs, QALYs, and incremental cost-effectiveness ratios were calculated; cost-effectiveness acceptability curves and sensitivity analyses addressed uncertainty; subgroup analyses considered age and disease-risk.

Results: Adjusted mean QALYs were similar between groups: 6.89 (active monitoring), 7.09 (radiotherapy), and 6.91 (surgery). Active monitoring had lower adjusted mean costs (£5913) than radiotherapy (£7361) and surgery (£7519). Radiotherapy was the most likely (58% probability) cost-effective option at the UK NICE willingness-to-pay threshold (£20,000 per QALY). Subgroup analyses confirmed radiotherapy was cost-effective for older men and intermediate/high-risk disease groups; active monitoring was more likely to be the cost-effective option for younger men and low-risk groups.

Conclusions: Longer follow-up and modelling are required to determine the most cost-effective treatment for localised prostate cancer over a man's lifetime.

Trial Registration: Current Controlled Trials number, ISRCTN20141297: http://isrctn.org (14/10/2002); ClinicalTrials.gov number, NCT02044172: http://www.clinicaltrials.gov (23/01/2014).
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http://dx.doi.org/10.1038/s41416-020-0978-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524753PMC
September 2020

The Impact of Centralised Services on Metric Reflecting High-quality Performance: Outcomes from 1110 Consecutive Radical Cystectomies at a Single Centre.

Eur Urol Focus 2021 May 21;7(3):554-565. Epub 2020 Jun 21.

Academic Urology Unit, University of Sheffield, Sheffield, UK; Department of Urology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. Electronic address:

Background: The 2002 National Institute for Health and Care Excellence guidance on centralisation of radical cystectomy (RC) coincided with changes in practice: use of neoadjuvant chemotherapy (NAC) and pelvic lymph node dissection (PLND), and RC for high-risk non-muscle-invasive bladder cancer (HR-NMIBC).

Objective: To report the outcomes of RC at a single centre and to compare trends in survival with respect to centralisation and change in RC practice.

Design, Setting, And Participants: Data were collected retrospectively between 1 January 1994 and 31 December 2016. Patients with urothelial cell carcinoma (UCC) were selected. Outcomes from 1994 to 2007 (before centralisation, era 1) were compared with those from 2008 to 2016 (after centralisation, era 2).

Outcome Measurements And Statistical Analysis: The primary outcome was disease-specific mortality. Secondary outcomes were survival and use of NAC and PLND.

Results And Limitations: Overall, 1100 RCs (era 1, 316; era 2, 794) were performed for UCC. Median (interquartile range [IQR]) follow-up was 28.5 (11.9-57.4) mo. RC for NMIBC was 36.2% versus 51.3% (p<0.001), NAC use was 2.2% versus 31.6% (p<0.001), and PLND use was 59.7% versus 76.4% (p<0.001) in era 1 versus era 2. The 30-d (1.6% [era 1] vs 0.8% [era 2], p=0.21) and 90-d (4.1% vs 2.6%, p=0.2) mortality rates did not differ with respect to RC year. Five-year disease-specific survival (DSS) was 56.0% in era 1 versus 79.0% in era 2 (p<0.001). RC for patients aged ≥75 yr was 13.9% versus 28.1% (p<0.001) and 30-d mortality in this group was 4.5% versus 0% (p=0.001) in era 1 versus era 2. The study is limited by its retrospective design.

Conclusions: Centralisation was associated with higher rates of NAC and PLND use, and increased RC performed for older patients and patients with HR-NMIBC. DSS was higher and RC appeared to be safer for older patients (fewer postoperative mortalities) after centralisation.

Patient Summary: We looked at outcomes from bladder removal for bladder cancer. Survival outcomes improved following centralisation of services. Surgery appeared to be safer for older patients, as there were fewer postoperative mortalities after centralisation. Centralisation of radical cystectomy (RC) services was associated with higher rates of neoadjuvant chemotherapy and pelvic lymph node dissection use, and increased usage of RC for older patients with high-risk non-muscle-invasive bladder cancer. Survival outcomes from RC were superior after centralisation and safer for older patients undergoing RC (fewer postoperative mortalities).
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http://dx.doi.org/10.1016/j.euf.2020.05.011DOI Listing
May 2021

What Type of Prostate Cancer Is Systematically Overlooked by Multiparametric Magnetic Resonance Imaging? An Analysis from the PROMIS Cohort.

Eur Urol 2020 08 1;78(2):163-170. Epub 2020 May 1.

UCL Division of Surgery & Interventional Science, University College London, London, UK; Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK.

Background: All risk stratification strategies in cancer overlook a spectrum of disease. The Prostate MR Imaging Study (PROMIS) provides a unique opportunity to explore cancers that are overlooked by multiparametric magnetic resonance imaging (mpMRI).

Objective: To summarise attributes of cancers that are systematically overlooked by mpMRI.

Design, Setting, And Participants: PROMIS tested performance of mpMRI and transrectal ultrasonography (TRUS)-guided biopsy, using 5 mm template mapping (TPM) biopsy as the reference standard.

Outcome Measurements And Statistical Analysis: Outcomes were overall and maximum Gleason scores, maximum cancer core length (MCCL), and prostate-specific antigen density (PSAD). Cancer attributes were compared between cancers that were overlooked and those that were detected.

Results And Limitations: Of men with cancer, 7% (17/230; 95% confidence interval [CI] 4.4-12%) had significant disease overlooked by mpMRI according to definition 1 (Gleason ≥ 4 + 3 of any length or MCCL ≥ 6 mm of any grade) and 13% (44/331; 95% CI 9.8-17%) according to definition 2 (Gleason ≥ 3 + 4 of any length or MCCL ≥ 4 mm). In comparison, TRUS-guided biopsy overlooked 52% (119/230; 95% CI 45-58%) of significant disease by definition 1 and 40% (132/331; 95% CI 35-45%) by definition 2. Prostate cancers undetected by mpMRI had significantly lower overall and maximum Gleason scores (p = 0.0007; p < 0.0001) and shorter MCCL (median difference: 3 mm [5 vs 8 mm], p < 0.0001; 95% CI 1-3) than cancers that were detected. No tumours with overall Gleason score > 3 + 4 (Gleason Grade Groups 3-5; 95% CI 0-6.4%) or maximum Gleason score > 4 + 3 (Gleason Grade Groups 4-5; 95% CI 0-8.0%) on TPM biopsy were undetected by mpMRI. Application of a PSAD threshold of 0.15 reduced the proportion of men with undetected cancer to 5% (12/230; 95% CI 2.7-8.9%) for definition 1 and 9% (30/331; 95% CI 6.2-13%) for definition 2. Application of a PSAD threshold of 0.10 reduced the proportion of men with undetected disease to 3% (6/230; 95% CI 1.0-5.6%) for definition 1 cancer and to 3% (11/331; 95% CI 1.7-5.9%) for definition 2 cancer. Limitations were post hoc analysis and uncertain significance of undetected lesions.

Conclusions: Overall, a small proportion of cancers are overlooked by mpMRI, with estimates ranging from 4.4% (lower boundary of 95% CI for definition 1) to 17% (upper boundary of 95% CI for definition 2). Prostate cancers undetected by mpMRI are of lower grade and shorter length than cancers that are detected.

Patient Summary: Prostate cancers that are undetected by magnetic resonance imaging (MRI) are smaller and less aggressive than those that are detected, and none of the most aggressive cancers are overlooked by MRI.
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http://dx.doi.org/10.1016/j.eururo.2020.04.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397509PMC
August 2020

Additional Value of Dynamic Contrast-enhanced Sequences in Multiparametric Prostate Magnetic Resonance Imaging: Data from the PROMIS Study.

Eur Urol 2020 10 18;78(4):503-511. Epub 2020 Apr 18.

University Hospital Southampton NHS Foundation Trust, Southampton, UK.

Background: Multiparametric magnetic resonance imaging (MP-MRI) is established in the diagnosis of prostate cancer, but the need for enhanced sequences has recently been questioned.

Objective: To assess whether dynamic contrast-enhanced imaging (DCE) improves accuracy over T2 and diffusion sequences.

Design, Setting, And Participants: PROMIS was a multicentre, multireader trial, with, in this part, 497 biopsy-naïve men undergoing standardised 1.5T MP-MRI using T2, diffusion, and DCE, followed by a detailed transperineal prostate mapping (TPM) biopsy at 5 mm intervals. Likert scores of 1-5 for the presence of a significant tumour were assigned in strict sequence, for (1) T2 + diffusion and then (2) T2 + diffusion + dynamic contrast-enhanced images.

Outcome Measurements And Statistical Analysis: For the primary analysis, the primary PROMIS outcome measure (Gleason score ≥4 + 3 or ≥6 mm maximum cancer length) on TPM was used, and an MRI score of ≥3 was considered positive.

Results And Limitations: Sensitivity without and with DCE was 94% and 95%, specificity 37% and 38%, positive predictive value 51% and 51%, and negative predictive value 90% and 91%, respectively (p >  0.05 in each case). The number of patients avoiding biopsy (scoring 1-2) was similar (123/497 vs 121/497, p =  0.8). The number of equivocal scores (3/5) was slightly higher without DCE (32% vs 28% p =  0.031). The proportion of MRI equivocal (3/5) and positive (4-5) cases showing significant tumours were similar (23% and 71% vs 20% and 69%). No cases of dominant Gleason 4 or higher were missed with DCE, compared with a single case with T2 + diffusion-weighted imaging. No attempt was made to correlate lesion location on MRI and histology, which may be considered a limitation. Radiologists were aware of the patient's prostate-specific antigen.

Conclusions: Contrast adds little when MP-MRI is used to exclude significant prostate cancer.

Patient Summary: An intravenous injection of contrast may not be necessary when magnetic resonance imaging is used as a test to rule out significant tumours in the prostate.
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October 2020

The ProtecT trial: analysis of the patient cohort, baseline risk stratification and disease progression.

BJU Int 2020 04 12;125(4):506-514. Epub 2020 Feb 12.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.

Objective: To test the hypothesis that the baseline clinico-pathological features of the men with localized prostate cancer (PCa) included in the ProtecT (Prostate Testing for Cancer and Treatment) trial who progressed (n = 198) at a 10-year median follow-up were different from those of men with stable disease (n = 1409).

Patients And Methods: We stratified the study participants at baseline according to risk of progression using clinical disease stage, pathological grade and PSA level, using Cox proportional hazard models.

Results: The findings showed that 34% of participants (n = 505) had intermediate- or high-risk PCa, and 66% (n = 973) had low-risk PCa. Of 198 participants who progressed, 101 (51%) had baseline International Society of Urological Pathology Grade Group 1, 59 (30%) Grade Group 2, and 38 (19%) Grade Group 3 PCa, compared with 79%, 17% and 5%, respectively, for 1409 participants without progression (P < 0.001). In participants with progression, 38% and 62% had baseline low- and intermediate-/high-risk disease, compared with 69% and 31% of participants with stable disease (P < 0.001). Treatment received, age (65-69 vs 50-64 years), PSA level, Grade Group, clinical stage, risk group, number of positive cores, tumour length and perineural invasion were associated with time to progression (P ≤ 0.005). Men progressing after surgery (n = 19) were more likely to have a higher Grade Group and pathological stage at surgery, larger tumours, lymph node involvement and positive margins.

Conclusions: We demonstrate that one-third of the ProtecT cohort consists of people with intermediate-/high-risk disease, and the outcomes data at an average of 10 years' follow-up are generalizable beyond men with low-risk PCa.
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http://dx.doi.org/10.1111/bju.14987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187290PMC
April 2020

Ten-year Mortality, Disease Progression, and Treatment-related Side Effects in Men with Localised Prostate Cancer from the ProtecT Randomised Controlled Trial According to Treatment Received.

Eur Urol 2020 03 24;77(3):320-330. Epub 2019 Nov 24.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.

Background: The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer (PCa) randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy.

Objective: To determine report outcomes according to treatment received in men in randomised and treatment choice cohorts.

Design, Setting, And Participants: This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy.

Intervention: Two cohorts included 1643 men who agreed to be randomised; 997 declined randomisation and chose treatment.

Outcome Measurements And Statistical Analysis: Health-related quality of life impacts on urinary, bowel, and sexual function were assessed using patient-reported outcome measures. Analysis was carried out based on treatment received for each cohort and on pooled estimates using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores.

Results And Limitations: According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p=0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p=0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6mo) and urinary incontinence (55% at 6mo) after surgery, and of sexual dysfunction (88% at 6mo) and bowel dysfunction (5% at 6mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and outdating of the interventions being evaluated during the lengthy follow-up required in trials of screen-detected PCa.

Conclusions: Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group.

Patient Summary: More than 90 out of every 100 men with localised prostate cancer do not die of prostate cancer within 10yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are much better after active monitoring, but the risks of spreading of prostate cancer are more common.
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http://dx.doi.org/10.1016/j.eururo.2019.10.030DOI Listing
March 2020

Prescription switching: Rationales and risks.

Int J Clin Pract 2020 Jan 7;74(1):e13429. Epub 2019 Oct 7.

Royal Hallamshire Hospital, Sheffield, UK.

Background: Therapeutic drug switching is commonplace across a broad range of indications and, within a drug class, is often facilitated by the availability of multiple drugs considered equivalent. Such treatment changes are often considered to improve outcomes via better efficacy or fewer side effects, or to be more cost-effective. Drug switching can be both appropriate and beneficial for several reasons; however, switching can also be associated with negative consequences.

Aim: To consider the impact of switching in two situations: the use of statins as a well-studied example of within-class drug switching, and gonadotropin-releasing hormone (GnRH)-targeting drug switching as an example of cross-class switching.

Results: With the example of statins, within-class switching may be justified to reduce side effects, although the decision to switch is often also driven by the lower cost of generic formulations. With the example of GnRH agonists/antagonists, switching often occurs without the realisation that these drugs belong to different classes, with potential clinical implications.

Conclusion: Lessons emerging from these examples will help inform healthcare practitioners who may be considering switching drug prescriptions.
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http://dx.doi.org/10.1111/ijcp.13429DOI Listing
January 2020

Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers.

Eur Urol 2019 12 16;76(6):831-842. Epub 2019 Sep 16.

International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland.

Background: Mutations in BRCA2 cause a higher risk of early-onset aggressive prostate cancer (PrCa). The IMPACT study is evaluating targeted PrCa screening using prostate-specific-antigen (PSA) in men with germline BRCA1/2 mutations.

Objective: To report the utility of PSA screening, PrCa incidence, positive predictive value of PSA, biopsy, and tumour characteristics after 3 yr of screening, by BRCA status.

Design, Setting, And Participants: Men aged 40-69 yr with a germline pathogenic BRCA1/2 mutation and male controls testing negative for a familial BRCA1/2 mutation were recruited. Participants underwent PSA screening for 3 yr, and if PSA > 3.0 ng/ml, men were offered prostate biopsy.

Outcome Measurements And Statistical Analysis: PSA levels, PrCa incidence, and tumour characteristics were evaluated. Statistical analyses included Poisson regression offset by person-year follow-up, chi-square tests for proportion t tests for means, and Kruskal-Wallis for medians.

Results And Limitations: A total of 3027 patients (2932 unique individuals) were recruited (919 BRCA1 carriers, 709 BRCA1 noncarriers, 902 BRCA2 carriers, and 497 BRCA2 noncarriers). After 3 yr of screening, 527 men had PSA > 3.0 ng/ml, 357 biopsies were performed, and 112 PrCa cases were diagnosed (31 BRCA1 carriers, 19 BRCA1 noncarriers, 47 BRCA2 carriers, and 15 BRCA2 noncarriers). Higher compliance with biopsy was observed in BRCA2 carriers compared with noncarriers (73% vs 60%). Cancer incidence rate per 1000 person years was higher in BRCA2 carriers than in noncarriers (19.4 vs 12.0; p =  0.03); BRCA2 carriers were diagnosed at a younger age (61 vs 64 yr; p =  0.04) and were more likely to have clinically significant disease than BRCA2 noncarriers (77% vs 40%; p =  0.01). No differences in age or tumour characteristics were detected between BRCA1 carriers and BRCA1 noncarriers. The 4 kallikrein marker model discriminated better (area under the curve [AUC] = 0.73) for clinically significant cancer at biopsy than PSA alone (AUC = 0.65).

Conclusions: After 3 yr of screening, compared with noncarriers, BRCA2 mutation carriers were associated with a higher incidence of PrCa, younger age of diagnosis, and clinically significant tumours. Therefore, systematic PSA screening is indicated for men with a BRCA2 mutation. Further follow-up is required to assess the role of screening in BRCA1 mutation carriers.

Patient Summary: We demonstrate that after 3 yr of prostate-specific antigen (PSA) testing, we detect more serious prostate cancers in men with BRCA2 mutations than in those without these mutations. We recommend that male BRCA2 carriers are offered systematic PSA screening.
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http://dx.doi.org/10.1016/j.eururo.2019.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880781PMC
December 2019

Cardiovascular Disease and the Androgen Receptor: Here We Go Again?

Eur Urol 2020 02 28;77(2):167-169. Epub 2019 Aug 28.

Sheffield Hallam University, Sheffield, UK.

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http://dx.doi.org/10.1016/j.eururo.2019.08.017DOI Listing
February 2020

Comparison of Transrectal Ultrasound Biopsy to Transperineal Template Mapping Biopsies Stratified by Multiparametric Magnetic Resonance Imaging Score in the PROMIS Trial.

J Urol 2020 01 23;203(1):100-107. Epub 2019 Jul 23.

Department of Urology, Imperial College Healthcare NHS (National Health Service) Trust, London, United Kingdom.

Purpose: We evaluated the performance of transrectal ultrasound guided systematic and transperineal template mapping biopsies with a 5 mm sampling frame stratified by the multiparametric magnetic resonance imaging Likert score in the PROMIS (Prostate MR Imaging Study).

Materials And Methods: Biopsy naïve men due to undergo prostate biopsy for elevated prostate specific antigen and/or abnormal digital rectal examination underwent multiparametric magnetic resonance imaging, and transperineal template mapping and transrectal ultrasound guided systematic biopsies, which were performed and reported while blinded to other test results. Clinically significant prostate cancer was primarily defined as Gleason 4 + 3 or greater, or a maximum cancer core length of 6 mm or more of any grade. It was secondarily defined as Gleason 3 + 4 or greater, or a maximum cancer core length of 4 mm or more of any grade.

Results: In 41 months 740 men were recruited at a total of 11 centers, of whom 576 underwent all 3 tests. Eight of the 150 men (5.1%) with a multiparametric magnetic resonance imaging score of 1-2 had any Gleason 3 + 4 or greater disease on transrectal ultrasound guided systematic biopsy. Of the 75 men in whom transrectal ultrasound guided systematic biopsy showed Gleason 3 + 3 of any maximum cancer core length 61 (81%) had Gleason 3 + 4, 8 (11%) had Gleason 4 + 3 and 0 (0%) had Gleason 4 + 5 or greater disease. For definition 1 (clinically significant prostate cancer) transrectal ultrasound guided systematic biopsy sensitivity remained stable and low across multiparametric magnetic resonance imaging Likert scores of 35% to 52%. For definition 2 (clinically significant prostate cancer and any cancer) sensitivity increased with higher multiparametric magnetic resonance imaging scores. The negative predictive value varied due to varying disease prevalence but for all cancer thresholds it declined with increasing multiparametric magnetic resonance imaging scores.

Conclusions: In the setting of multiparametric magnetic resonance imaging Likert scores 1-2 transrectal ultrasound guided systematic biopsy revealed Gleason 3 + 4 disease in only 1 of 20 men. Further, for any clinically significant prostate cancer definition transrectal ultrasound guided systematic biopsy had poor sensitivity and variable but a low negative predictive value across multiparametric magnetic resonance imaging scores. Men who undergo transrectal ultrasound guided systematic biopsy without targeting in the setting of a multiparametric magnetic resonance imaging score of 3 to 5 should be advised to undergo repeat (targeted) biopsy.
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http://dx.doi.org/10.1097/JU.0000000000000455DOI Listing
January 2020

In-bore Multiparametric Magnetic Resonance Imaging Targeted Biopsy: As Good as it Gets?

Eur Urol 2019 04 15;75(4):579-581. Epub 2018 Dec 15.

Department of Radiology, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK.

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http://dx.doi.org/10.1016/j.eururo.2018.12.001DOI Listing
April 2019

Partial ablation versus radical prostatectomy in intermediate-risk prostate cancer: the PART feasibility RCT.

Health Technol Assess 2018 09;22(52):1-96

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.

Background: Prostate cancer (PCa) is the most common cancer in men in the UK. Patients with intermediate-risk, clinically localised disease are offered radical treatments such as surgery or radiotherapy, which can result in severe side effects. A number of alternative partial ablation (PA) technologies that may reduce treatment burden are available; however the comparative effectiveness of these techniques has never been evaluated in a randomised controlled trial (RCT).

Objectives: To assess the feasibility of a RCT of PA using high-intensity focused ultrasound (HIFU) versus radical prostatectomy (RP) for intermediate-risk PCa and to test and optimise methods of data capture.

Design: We carried out a prospective, multicentre, open-label feasibility study to inform the design and conduct of a future RCT, involving a QuinteT Recruitment Intervention (QRI) to understand barriers to participation.

Setting: Five NHS hospitals in England.

Participants: Men with unilateral, intermediate-risk, clinically localised PCa.

Interventions: Radical prostatectomy compared with HIFU.

Primary Outcome Measure: The randomisation of 80 men.

Secondary Outcome Measures: Findings of the QRI and assessment of data capture methods.

Results: Eighty-seven patients consented to participate by 31 March 2017 and 82 men were randomised by 4 May 2017 (41 men to the RP arm and 41 to the HIFU arm). The QRI was conducted in two iterative phases: phase I identified a number of barriers to recruitment, including organisational challenges, lack of recruiter equipoise and difficulties communicating with patients about the study, and phase II comprised the development and delivery of tailored strategies to optimise recruitment, including group training, individual feedback and 'tips' documents. At the time of data extraction, on 10 October 2017, treatment data were available for 71 patients. Patient characteristics were similar at baseline and the rate of return of all clinical case report forms (CRFs) was 95%; the return rate of the patient-reported outcome measures (PROMs) questionnaire pack was 90.5%. Centres with specific long-standing expertise in offering HIFU as a routine NHS treatment option had lower recruitment rates (Basingstoke and Southampton) - with University College Hospital failing to enrol any participants - than centres offering HIFU in the trial context only.

Conclusions: Randomisation of men to a RCT comparing PA with radical treatments of the prostate is feasible. The QRI provided insights into the complexities of recruiting to this surgical trial and has highlighted a number of key lessons that are likely to be important if the study progresses to a main trial. A full RCT comparing clinical effectiveness, cost-effectiveness and quality-of-life outcomes between radical treatments and PA is now warranted.

Future Work: Men recruited to the feasibility study will be followed up for 36 months in accordance with the protocol. We will design a full RCT, taking into account the lessons learnt from this study. CRFs will be streamlined, and the length and frequency of PROMs and resource use diaries will be reviewed to reduce the burden on patients and research nurses and to optimise data completeness.

Trial Registration: Current Controlled Trials ISRCTN99760303.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 22, No. 52. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta22520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187111PMC
September 2018

Interventions for promoting habitual exercise in people living with and beyond cancer.

Cochrane Database Syst Rev 2018 09 19;9:CD010192. Epub 2018 Sep 19.

Centre for Sport and Exercise Science, Sheffield Hallam University, A124 Collegiate Hall, Collegiate Crescent, Sheffield, South Yorkshire, UK, S10 2BP.

Background: This is an updated version of the original Cochrane Review published in the Cochrane Library 2013, Issue 9. Despite good evidence for the health benefits of regular exercise for people living with or beyond cancer, understanding how to promote sustainable exercise behaviour change in sedentary cancer survivors, particularly over the long term, is not as well understood. A large majority of people living with or recovering from cancer do not meet current exercise recommendations. Hence, reviewing the evidence on how to promote and sustain exercise behaviour is important for understanding the most effective strategies to ensure benefit in the patient population and identify research gaps.

Objectives: To assess the effects of interventions designed to promote exercise behaviour in sedentary people living with and beyond cancer and to address the following secondary questions: Which interventions are most effective in improving aerobic fitness and skeletal muscle strength and endurance? Which interventions are most effective in improving exercise behaviour amongst patients with different cancers? Which interventions are most likely to promote long-term (12 months or longer) exercise behaviour? What frequency of contact with exercise professionals and/or healthcare professionals is associated with increased exercise behaviour? What theoretical basis is most often associated with better behavioural outcomes? What behaviour change techniques (BCTs) are most often associated with increased exercise behaviour? What adverse effects are attributed to different exercise interventions?

Search Methods: We used standard methodological procedures expected by Cochrane. We updated our 2013 Cochrane systematic review by updating the searches of the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, Embase, AMED, CINAHL, PsycLIT/PsycINFO, SportDiscus and PEDro up to May 2018. We also searched the grey literature, trial registries, wrote to leading experts in the field and searched reference lists of included studies and other related recent systematic reviews.

Selection Criteria: We included only randomised controlled trials (RCTs) that compared an exercise intervention with usual care or 'waiting list' control in sedentary people over the age of 18 with a homogenous primary cancer diagnosis.

Data Collection And Analysis: In the update, review authors independently screened all titles and abstracts to identify studies that might meet the inclusion criteria, or that could not be safely excluded without assessment of the full text (e.g. when no abstract is available). We extracted data from all eligible papers with at least two members of the author team working independently (RT, LS and RG). We coded BCTs according to the CALO-RE taxonomy. Risk of bias was assessed using the Cochrane's tool for assessing risk of bias. When possible, and if appropriate, we performed a fixed-effect meta-analysis of study outcomes. If statistical heterogeneity was noted, a meta-analysis was performed using a random-effects model. For continuous outcomes (e.g. cardiorespiratory fitness), we extracted the final value, the standard deviation (SD) of the outcome of interest and the number of participants assessed at follow-up in each treatment arm, to estimate the standardised mean difference (SMD) between treatment arms. SMD was used, as investigators used heterogeneous methods to assess individual outcomes. If a meta-analysis was not possible or was not appropriate, we narratively synthesised studies. The quality of the evidence was assessed using the GRADE approach with the GRADE profiler.

Main Results: We included 23 studies in this review, involving a total of 1372 participants (an addition of 10 studies, 724 participants from the original review); 227 full texts were screened in the update and 377 full texts were screened in the original review leaving 35 publications from a total of 23 unique studies included in the review. We planned to include all cancers, but only studies involving breast, prostate, colorectal and lung cancer met the inclusion criteria. Thirteen studies incorporated a target level of exercise that could meet current recommendations for moderate-intensity aerobic exercise (i.e.150 minutes per week); or resistance exercise (i.e. strength training exercises at least two days per week).Adherence to exercise interventions, which is crucial for understanding treatment dose, is still reported inconsistently. Eight studies reported intervention adherence of 75% or greater to an exercise prescription that met current guidelines. These studies all included a component of supervision: in our analysis of BCTs we designated these studies as 'Tier 1 trials'. Six studies reported intervention adherence of 75% or greater to an aerobic exercise goal that was less than the current guideline recommendations: in our analysis of BCTs we designated these studies as 'Tier 2 trials.' A hierarchy of BCTs was developed for Tier 1 and Tier 2 trials, with programme goal setting, setting of graded tasks and instruction of how to perform behaviour being amongst the most frequent BCTs. Despite the uncertainty surrounding adherence in some of the included studies, interventions resulted in improvements in aerobic exercise tolerance at eight to 12 weeks (SMD 0.54, 95% CI 0.37 to 0.70; 604 participants, 10 studies; low-quality evidence) versus usual care. At six months, aerobic exercise tolerance was also improved (SMD 0.56, 95% CI 0.39 to 0.72; 591 participants; 7 studies; low-quality evidence).

Authors' Conclusions: Since the last version of this review, none of the new relevant studies have provided additional information to change the conclusions. We have found some improved understanding of how to encourage previously inactive cancer survivors to achieve international physical activity guidelines. Goal setting, setting of graded tasks and instruction of how to perform behaviour, feature in interventions that meet recommendations targets and report adherence of 75% or more. However, long-term follow-up data are still limited, and the majority of studies are in white women with breast cancer. There are still a considerable number of published studies with numerous and varied issues related to high risk of bias and poor reporting standards. Additionally, the meta-analyses were often graded as consisting of low- to very low-certainty evidence. A very small number of serious adverse effects were reported amongst the studies, providing reassurance exercise is safe for this population.
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http://dx.doi.org/10.1002/14651858.CD010192.pub3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513653PMC
September 2018

Supportive interventions to improve physiological and psychological health outcomes among patients undergoing cystectomy: a systematic review.

BMC Urol 2018 Aug 24;18(1):71. Epub 2018 Aug 24.

Faculty of Health and Wellbeing, Sheffield Hallam University, Sheffield, UK.

Background: Our understanding of effective perioperative supportive interventions for patients undergoing cystectomy procedures and how these may affect short and long-term health outcomes is limited.

Methods: Randomised controlled trials involving any non-surgical, perioperative interventions designed to support or improve the patient experience for patients undergoing cystectomy procedures were reviewed. Comparison groups included those exposed to usual clinical care or standard procedure. Studies were excluded if they involved surgical procedure only, involved bowel preparation only or involved an alternative therapy such as aromatherapy. Any short and long-term outcomes reflecting the patient experience or related urological health outcomes were considered.

Results: Nineteen articles (representing 15 individual studies) were included for review. Heterogeneity in interventions and outcomes across studies meant meta-analyses were not possible. Participants were all patients with bladder cancer and interventions were delivered over different stages of the perioperative period. The overall quality of evidence and reporting was low and outcomes were predominantly measured in the short-term. However, the findings show potential for exercise therapy, pharmaceuticals, ERAS protocols, psychological/educational programmes, chewing gum and nutrition to benefit a broad range of physiological and psychological health outcomes.

Conclusions: Supportive interventions to date have taken many different forms with a range of potentially meaningful physiological and psychological health outcomes for cystectomy patients. Questions remain as to what magnitude of short-term health improvements would lead to clinically relevant changes in the overall patient experience of surgery and long-term recovery.
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http://dx.doi.org/10.1186/s12894-018-0382-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6109292PMC
August 2018

Multiparametric MRI to improve detection of prostate cancer compared with transrectal ultrasound-guided prostate biopsy alone: the PROMIS study.

Health Technol Assess 2018 07;22(39):1-176

Division of Surgery and Interventional Science, Faculty of Medical Sciences, University College London, London, UK.

Background: Men with suspected prostate cancer usually undergo transrectal ultrasound (TRUS)-guided prostate biopsy. TRUS-guided biopsy can cause side effects and has relatively poor diagnostic accuracy. Multiparametric magnetic resonance imaging (mpMRI) used as a triage test might allow men to avoid unnecessary TRUS-guided biopsy and improve diagnostic accuracy.

Objectives: To (1) assess the ability of mpMRI to identify men who can safely avoid unnecessary biopsy, (2) assess the ability of the mpMRI-based pathway to improve the rate of detection of clinically significant (CS) cancer compared with TRUS-guided biopsy and (3) estimate the cost-effectiveness of a mpMRI-based diagnostic pathway.

Design: A validating paired-cohort study and an economic evaluation using a decision-analytic model.

Setting: Eleven NHS hospitals in England.

Participants: Men at risk of prostate cancer undergoing a first prostate biopsy.

Interventions: Participants underwent three tests: (1) mpMRI (the index test), (2) TRUS-guided biopsy (the current standard) and (3) template prostate mapping (TPM) biopsy (the reference test).

Main Outcome Measures: Diagnostic accuracy of mpMRI, TRUS-guided biopsy and TPM-biopsy measured by sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) using primary and secondary definitions of CS cancer. The percentage of negative magnetic resonance imaging (MRI) scans was used to identify men who might be able to avoid biopsy.

Results: Diagnostic study - a total of 740 men were registered and 576 underwent all three tests. According to TPM-biopsy, the prevalence of any cancer was 71% [95% confidence interval (CI) 67% to 75%]. The prevalence of CS cancer according to the primary definition (a Gleason score of ≥ 4 + 3 and/or cancer core length of ≥ 6 mm) was 40% (95% CI 36% to 44%). For CS cancer, TRUS-guided biopsy showed a sensitivity of 48% (95% CI 42% to 55%), specificity of 96% (95% CI 94% to 98%), PPV of 90% (95% CI 83% to 94%) and NPV of 74% (95% CI 69% to 78%). The sensitivity of mpMRI was 93% (95% CI 88% to 96%), specificity was 41% (95% CI 36% to 46%), PPV was 51% (95% CI 46% to 56%) and NPV was 89% (95% CI 83% to 94%). A negative mpMRI scan was recorded for 158 men (27%). Of these, 17 were found to have CS cancer on TPM-biopsy. Economic evaluation - the most cost-effective strategy involved testing all men with mpMRI, followed by MRI-guided TRUS-guided biopsy in those patients with suspected CS cancer, followed by rebiopsy if CS cancer was not detected. This strategy is cost-effective at the TRUS-guided biopsy definition 2 (any Gleason pattern of ≥ 4 and/or cancer core length of ≥ 4 mm), mpMRI definition 2 (lesion volume of ≥ 0.2 ml and/or Gleason score of ≥ 3 + 4) and cut-off point 2 (likely to be benign) and detects 95% (95% CI 92% to 98%) of CS cancers. The main drivers of cost-effectiveness were the unit costs of tests, the improvement in sensitivity of MRI-guided TRUS-guided biopsy compared with blind TRUS-guided biopsy and the longer-term costs and outcomes of men with cancer.

Limitations: The PROstate Magnetic resonance Imaging Study (PROMIS) was carried out in a selected group and excluded men with a prostate volume of > 100 ml, who are less likely to have cancer. The limitations in the economic modelling arise from the limited evidence on the long-term outcomes of men with prostate cancer and on the sensitivity of MRI-targeted repeat biopsy.

Conclusions: Incorporating mpMRI into the diagnostic pathway as an initial test prior to prostate biopsy may (1) reduce the proportion of men having unnecessary biopsies, (2) improve the detection of CS prostate cancer and (3) increase the cost-effectiveness of the prostate cancer diagnostic and therapeutic pathway. The PROMIS data set will be used for future research; this is likely to include modelling prognostic factors for CS cancer, optimising MRI scan sequencing and biomarker or translational research analyses using the blood and urine samples collected. Better-quality evidence on long-term outcomes in prostate cancer under the various management strategies is required to better assess cost-effectiveness. The value-of-information analysis should be developed further to assess new research to commission.

Trial Registration: Current Controlled Trials ISRCTN16082556 and NCT01292291.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 22, No. 39. See the NIHR Journals Library website for further project information. This project was also supported and partially funded by the NIHR Biomedical Research Centre at University College London (UCL) Hospitals NHS Foundation Trust and UCL and by The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research Biomedical Research Centre and was co-ordinated by the Medical Research Council's Clinical Trials Unit at UCL (grant code MC_UU_12023/28). It was sponsored by UCL. Funding for the additional collection of blood and urine samples for translational research was provided by Prostate Cancer UK.
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http://dx.doi.org/10.3310/hta22390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077599PMC
July 2018

A multi-centre investigation of delivering national guidelines on exercise training for men with advanced prostate cancer undergoing androgen deprivation therapy in the UK NHS.

PLoS One 2018 5;13(7):e0197606. Epub 2018 Jul 5.

Department of Oncology and Metabolism, University of Sheffield, Sheffield United Kingdom.

Background: National guidelines (NICE-CG175) recommended 12 weeks of supervised exercise training for men treated with androgen deprivation therapy (ADT) for prostate cancer to counter debilitating adverse effects of castration. As with other chronic conditions where exercise is indicated, it is uncertain if these services are being delivered in the health services. The aim of this multi-centre investigation was to examine what exercise referral is currently available for men on ADT as provided by the NHS and if a supervised, individually-tailored exercise training package (as per the national NICE guidelines CG175) is embedded within prostate cancer care.

Methods: A multi-centre investigation of current National Health Service (NHS) care involving a web-based survey of NHS prostate cancer care, five focus groups involving 26 men on ADT and 37 semi-structured interviews with healthcare professionals (HCPs) involved in the management of prostate cancer. Descriptive statistics and thematic analysis evaluated quantitative and qualitative data, respectively. Qualitative methods followed COREQ standards.

Results: HCPs and men on ADT asserted that medical castration has a serious and debilitating impact on many features of men's quality of life. There is support for exercise training programmes as part of cancer care and patients would support their initiation soon after diagnosis. Involving the Multidisciplinary Team (MDT) is proposed as key to this. Critically, traditional values in oncology would need to be overcome for widespread acceptance. Specialist further training for HCPs around behaviour change support could encourage this. Given that these schemes are seen as a fundamental part of cancer care, it is felt the NHS should commission and support provision. 79 representatives of 154 NHS trusts (51%) provided survey data on current delivery: only 17% could provide supervised exercise as per CG175.

Conclusions: Evidence-based national exercise guidelines are not being delivered to men on ADT as intended. Traditional values in oncology and the need for NHS financial support are seen as major barriers to provision of current best practice guidelines. Despite this both HCPs and men on ADT are in favour of such programmes being a fundamental part of their cancer care.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197606PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033384PMC
December 2018

Treatment in the STAMPEDE era for castrate resistant prostate cancer in the UK: ongoing challenges and underappreciated clinical problems.

BMC Cancer 2018 Jun 19;18(1):667. Epub 2018 Jun 19.

The Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, UK.

Background: This study aimed to explore the opinions of healthcare professionals regarding the management of men with advanced prostate cancer with particular emphasis on treatment timing and sequencing; treatment adverse-effects and exercise a supportive therapy.

Methods: Semi-structured interviews with a purposively selected group of healthcare professionals involved in prostate cancer care within the NHS, conducted over the phone or face to face. A total of 37 healthcare professionals participated in the interviews including urologists, clinical oncologists, medical oncologists, clinical nurse specialists, general practitioners, physiotherapists, exercise specialists, service managers, clinical commissioners and primary care physicians.

Results: The availability of newer treatments for advanced prostate cancer as well as results from the STAMPEDE and CHAARTED trials has resulted in new challenges for patients and HCPs. This includes the impact of an increased workload on oncologists, a potential lack of clinical continuity between urology and oncology and uncertainties regarding optimal selection, timing and sequencing of chemotherapy and second-line treatment. Fitness for treatment in advanced prostate cancer populations remains a significant barrier to accessing therapies for patients with a poor performance status. Among this, muscle wastage can significantly affect performance status and consequentially compromise cancer therapy. Exercise was regarded as a potential therapy to mitigate the adverse-effects of treatment including the prevention or reduction in muscle wastage.

Conclusions: There is a lack of data guiding clinicians in this post STAMPEDE and CHAARTED era, work is needed to reassess and optimize the prostate cancer care pathway as it evolves. Exercise should be explored as a therapeutic option to mitigate the effects of long term ADT. Further study from a wider cohort of both prostate cancer care specialists and patients will aid in establishing a highly functioning pathway with optimal individualised care.

Trial Registration: Sustained exercise TrAining for Men wIth prostate caNcer on Androgen deprivation: the STAMINA programme (RP-DG-1213-10,010). REC Reference: 15/SW/0260 IRAS Project ID: 178340 Hospital ID: STH 18391 approved on 24/08/2015.
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http://dx.doi.org/10.1186/s12885-018-4527-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006691PMC
June 2018

Overcoming difficulties with equipoise to enable recruitment to a randomised controlled trial of partial ablation vs radical prostatectomy for unilateral localised prostate cancer.

BJU Int 2018 12 15;122(6):970-977. Epub 2018 Aug 15.

Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.

Objective: To describe how clinicians conceptualised equipoise in the PART (Partial prostate Ablation vs Radical prosTatectomy in intermediate-risk unilateral clinically localised prostate cancer) feasibility study and how this affected recruitment.

Subjects And Methods: PART included a QuinteT Recruitment Intervention (QRI) to optimise recruitment. Phase I aimed to understand recruitment, and included: scrutinising recruitment data, interviewing the trial management group and recruiters (n = 13), and audio-recording recruitment consultations (n = 64). Data were analysed using qualitative content and thematic analysis methods. In Phase II, strategies to improve recruitment were developed and delivered.

Results: Initially many recruiters found it difficult to maintain a position of equipoise and held preconceptions about which treatment was best for particular patients. They did not feel comfortable about approaching all eligible patients, and when the study was discussed, biases were conveyed through the use of terminology, poorly balanced information, and direct treatment recommendations. Individual and group feedback led to presentations to patients becoming clearer and enabled recruiters to reconsider their sense of equipoise. Although the precise impact of the QRI alone cannot be determined, recruitment increased (from a mean [range] of 1.4 [0-4] to 4.5 [0-12] patients/month) and the feasibility study reached its recruitment target.

Conclusion: Although clinicians find it challenging to recruit patients to a trial comparing different contemporary treatments for prostate cancer, training and support can enable recruiters to become more comfortable with conveying equipoise and providing clearer information to patients.
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http://dx.doi.org/10.1111/bju.14432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348419PMC
December 2018

Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.

BJU Int 2019 02 22;123(2):284-292. Epub 2018 Jun 22.

Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Objectives: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes.

Particpants And Methods: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented.

Results: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status.

Conclusion: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening.
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http://dx.doi.org/10.1111/bju.14412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378691PMC
February 2019
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