Comparative efficacy and safety of treatments for localised prostate cancer: an application of network meta-analysis.

CONTEXT: There is ongoing uncertainty about the optimal management of patients with localised prostate cancer. OBJECTIVE: To evaluate the comparative efficacy and safety of different treatments for patients with localised prostate cancer. DESIGN: Systematic review with Bayesian network meta-analysis to estimate comparative ORs, and a score (0-100%) that, for a given outcome, reflects average rank order of superiority of each treatment compared against all others, using the Surface Under the Cumulative RAnking curve (SUCRA) statistic. DATA SOURCES: Electronic searches of MEDLINE without language restriction. STUDY SELECTION: Randomised trials comparing the efficacy and safety of different primary treatments (48 papers from 21 randomised trials included 7350 men). DATA EXTRACTION: 2 reviewers independently extracted data and assessed risk of bias. RESULTS: Comparative efficacy and safety evidence was available for prostatectomy, external beam radiotherapy (different types and regimens), observational management and cryotherapy, but not high-intensity focused ultrasound. There was no evidence of superiority for any of the compared treatments in respect of all-cause mortality after 5 years. Cryotherapy was associated with less gastrointestinal and genitourinary toxicity than radiotherapy (SUCRA: 99% and 77% for gastrointestinal and genitourinary toxicity, respectively). CONCLUSIONS: The limited available evidence suggests that different treatments may be optimal for different efficacy and safety outcomes. These findings highlight the importance of informed patient choice and shared decision-making about treatment modality and acceptable trade-offs between different outcomes. More trial evidence is required to reduce uncertainty. Network meta-analysis may be useful to optimise the power of evidence synthesis studies once data from new randomised controlled studies in this field are published in the future

Optimising the Diagnosis of Prostate Cancer in the Era of Multiparametric Magnetic Resonance Imaging : A Cost-effectiveness Analysis Based on the Prostate MR Imaging Study (PROMIS)

Background The current recommendation of using transrectal ultrasound-guided biopsy (TRUSB) to diagnose prostate cancer misses clinically significant (CS) cancers. More sensitive biopsies (eg, template prostate mapping biopsy [TPMB]) are too resource intensive for routine use, and there is little evidence on multiparametric magnetic resonance imaging (MPMRI). Objective To identify the most effective and cost-effective way of using these tests to detect CS prostate cancer. Design, setting, and participants Cost-effectiveness modelling of health outcomes and costs of men referred to secondary care with a suspicion of prostate cancer prior to any biopsy in the UK National Health Service using information from the diagnostic Prostate MR Imaging Study (PROMIS). Intervention Combinations of MPMRI, TRUSB, and TPMB, using different definitions and diagnostic cut-offs for CS cancer. Outcome measurements and statistical analysis Strategies that detect the most CS cancers given testing costs, and incremental cost-effectiveness ratios (ICERs) in quality-adjusted life years (QALYs) given long-term costs. Results and limitations The use of MPMRI first and then up to two MRI-targeted TRUSBs detects more CS cancers per pound spent than a strategy using TRUSB first (sensitivity = 0.95 [95% confidence interval {CI} 0.92–0.98] vs 0.91 [95% CI 0.86–0.94]) and is cost effective (ICER = £7,076 [€8350/QALY gained]). The limitations stem from the evidence base in the accuracy of MRI-targeted biopsy and the long-term outcomes of men with CS prostate cancer. Conclusions An MPMRI-first strategy is effective and cost effective for the diagnosis of CS prostate cancer. These findings are sensitive to the test costs, sensitivity of MRI-targeted TRUSB, and long-term outcomes of men with cancer, which warrant more empirical research. This analysis can inform the development of clinical guidelines. Patient summary We found that, under certain assumptions, the use of multiparametric magnetic resonance imaging first and then up to two transrectal ultrasound-guided biopsy is better than the current clinical standard and is good value for money. The use of multiparametric magnetic resonance imaging before transrectal ultrasound-guided biopsy can detect more clinically significant prostate cancer and be cost effective compared with the use of imaging post-biopsy

Empirical estimates of prostate cancer overdiagnosis by age and prostate-specific antigen

Background: Prostate cancer screening depends on a careful balance of benefits, in terms of reduced prostate cancer mortality, and harms, in terms of overdiagnosis and overtreatment. We aimed to estimate the effect on overdiagnosis of restricting prostate specific antigen (PSA) testing by age and baseline PSA.Methods: Estimates of the effects of age on overdiagnosis were based on population based incidence data from the US Surveillance, Epidemiology and End Results database. To investigate the relationship between PSA and overdiagnosis, we used two separate cohorts subject to PSA testing in clinical trials (n = 1,577 and n = 1,197) and a population-based cohort of Swedish men not subject to PSA-screening followed for 25 years (n = 1,162).Results: If PSA testing had been restricted to younger men, the number of excess cases associated with the introduction of PSA in the US would have been reduced by 85%, 68% and 42% for age cut-offs of 60, 65 and 70, respectively. The risk that a man with screen-detected cancer at age 60 would not subsequently lead to prostate cancer morbidity or mortality decreased exponentially as PSA approached conventional biopsy thresholds. For PSAs below 1 ng/ml, the risk of a positive biopsy is 65 (95% CI 18.2, 72.9) times greater than subsequent prostate cancer mortality.Conclusions: Prostate cancer overdiagnosis has a strong relationship to age and PSA level. Restricting screening in men over 60 to those with PSA above median (>1 ng/ml) and screening men over 70 only in selected circumstances would importantly reduce overdiagnosis and change the ratio of benefits to harms of PSA-screening

Ablative therapy for people with localised prostate cancer : a systematic review and economic evaluation

The research reported in this issue of the journal was funded by the HTA programme as project number 10/136/01. The contractual start date was in April 2012. The draft report began editorial review in October 2013 and was accepted for publication in April 2014. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. Acknowledgements We thank l the people recruited from the local UCAN for providing valuable consumer insight and advice through their participation as members of the project focus group: - Mark Emberton (Professor of Interventional Oncology), Damian Greene (consultant urologist), Axel Heidenreich (Professor and Director of Department of Urology), Christoph von Klot (specialist in brachytherapy), Roger Kockelbergh (BAUS chairman and Clinical Director of Urology) and Axel Merserburger (Deputy Clinical Director of Urology and Urologic Oncology) for providing their clinical expertise as members of the project advisory group - Edgar Paez (consultant urologist) and Gill Lawrence (Head of Radiotherapy Physics) for providing a list of staff time by grade and specialty involved in EBRT - Debbie Bennett (Radiotherapy Service Manager) for providing estimates for the expected number of uses for EBRT - Ian Pedley (clinical director/clinical oncologist) and Gill Lawrence for providing a list of all resource inputs relevant to brachytherapy - Steve Locks (Consultant Clinical Scientist in Radiotherapy) for providing a list of reusable equipment and consumables used during brachytherapy, along with their unit costs - Sue Asterling (urology research nurse) and Mark Kelly (Acting Divisional General Manager – Theatres) for providing a list of all resource inputs relevant to cryotherapy - Lara Kemp for providing secretarial support. The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health Directorates.Peer reviewedPublisher PD

Factors Influencing Men's Choice of and Adherence to Active Surveillance for Low-risk Prostate Cancer:A Mixed-method Systematic Review

Context: Despite support for active surveillance (AS) as a first treatment choice for men with low-risk prostate cancer (PC), this strategy is largely underutilised. Objective: To systematically review barriers and facilitators to selecting and adhering to AS for low-risk PC. Evidence acquisition: We searched PsychINFO, PubMed, Medline 2000-now, Embase, CINAHL, and Cochrane Central databases between 2002 and 2017 using the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. The Purpose, Respondents, Explanation, Findings and Significance (PREFS) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) quality criteria were applied. Forty-seven studies were identified. Evidence synthesis: Key themes emerged as factors influencing both choice and adherence to AS: (1) patient and tumour factors (age, comorbidities, knowledge, education, socioeconomic status, family history, grade, tumour volume, and fear of progression/side effects); (2) family and social support; (3) provider (speciality, communication, and attitudes); (4) healthcare organisation (geography and type of practice); and (5) health policy (guidelines, year, and awareness). Conclusions: Many factors influence men's choice and adherence to AS on multiple levels. It is important to learn from the experience of other chronic health conditions as well as from institutions/countries that are making significant headway in appropriately recruiting men to AS protocols, through standardised patient information, clinician education, and nationally agreed guidelines, to ultimately decrease heterogeneity in AS practice. Patient summary: We reviewed the scientific literature for factors affecting men's choice and adherence to active surveillance (AS) for low-risk prostate cancer. Our findings suggest that the use of AS could be increased by addressing a variety of factors such as information, psychosocial support, clinician education, and standardised guidelines. Selection of and adherence to active surveillance in low-risk prostate cancer could be improved using strategies currently employed in other chronic health conditions, for example, standardisation of treatment counselling, online educational/supportive resources, self-management techniques, and nationally agreed guidelines.</p

Clinical intervals and diagnostic characteristics in a cohort of prostate cancer patients in Spain: a multicentre observational study

Background: Little is known about the healthcare process for patients with prostate cancer, mainly because hospital-based data are not routinely published. The main objective of this study was to determine the clinical characteristics of prostate cancer patients, the diagnostic process and the factors that might influence intervals from consultation to diagnosis and from diagnosis to treatment. Methods: We conducted a multicentre, cohort study in seven hospitals in Spain. Patients' characteristics and diagnostic and therapeutic variables were obtained from hospital records and patients' structured interviews from October 2010 to September 2011. We used a multilevel logistic regression model to examine the association between patient care intervals and various variables influencing these intervals (age, BMI, educational level, ECOG, first specialist consultation, tumour stage, PSA, Gleason score, and presence of symptoms) and calculated the odds ratio (OR) and the interquartile range (IQR). To estimate the random inter-hospital variability, we used the median odds ratio (MOR). Results: 470 patients with prostate cancer were included. Mean age was 67.8 (SD: 7.6) years and 75.4 % were physically active. Tumour size was classified as T1 in 41.0 % and as T2 in 40 % of patients, their median Gleason score was 6.0 (IQR:1.0), and 36.1 % had low risk cancer according to the D'Amico classification. The median interval between first consultation and diagnosis was 89 days (IQR:123.5) with no statistically significant variability between centres. Presence of symptoms was associated with a significantly longer interval between first consultation and diagnosis than no symptoms (OR:1.93, 95%CI 1.29-2.89). The median time between diagnosis and first treatment (therapeutic interval) was 75.0 days (IQR:78.0) and significant variability between centres was found (MOR:2.16, 95%CI 1.45-4.87). This interval was shorter in patients with a high PSA value (p = 0.012) and a high Gleason score (p = 0.026). Conclusions: Most incident prostate cancer patients in Spain are diagnosed at an early stage of an adenocarcinoma. The period to complete the diagnostic process is approximately three months whereas the therapeutic intervals vary among centres and are shorter for patients with a worse prognosis. The presence of prostatic symptoms, PSA level, and Gleason score influence all the clinical intervals differently

Long-term Risks of Depression and Suicide Among Men with Prostate Cancer: A National Cohort Study

BACKGROUND: A diagnosis of prostate cancer (PC) may cause psychosocial distress that worsens quality of life; however, long-term mental health outcomes are unclear. OBJECTIVE: To determine the long-term risks of major depression and death by suicide in a large population-based cohort. DESIGN, SETTING, AND PARTICIPANTS: This was a national cohort study of 180 189 men diagnosed with PC during 1998-2017 and 1 801 890 age-matched, population-based, control men in Sweden. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Major depression and death by suicide were ascertained from nationwide outpatient, inpatient, and death records up to 2018. Cox regression was used to compute hazard ratios (HRs) adjusted for sociodemographic factors and comorbidities. Subanalyses assessed differences by PC treatment during 2005-2017. RESULTS AND LIMITATIONS: Men diagnosed with high-risk PC had higher relative rates of major depression (adjusted HR [aHR] 1.82, 95% confidence interval [CI] 1.75-1.89) and death by suicide (aHR 2.43, 95% CI 2.01-2.95). These associations persisted for ≥10 yr after PC diagnosis. The relative increase in major depression was lower among those treated with radiation (aHR 1.44, 95% CI 1.31-1.57) or surgery (aHR 1.60, 95% CI 1.31-1.95) in comparison to androgen deprivation therapy (ADT) alone (aHR 2.02, 95% CI 1.89-2.16), whereas the relative rate of suicide death was higher only among those treated solely with ADT (aHR 2.83, 95% CI 1.80-4.43). By contrast, men with low- or intermediate-risk PC had a modestly higher relative rate of major depression (aHR 1.19, 95% CI 1.16-1.23) and higher relative rate of suicide death at 3-12 mo after PC diagnosis (aHR 1.88, 95% CI 1.11-3.18) but not across the entire follow-up period (aHR 1.02, 95% CI 0.84-1.25). This study was limited to Sweden and will need replication in other populations. CONCLUSIONS: In this large cohort, high-risk PC was associated with substantially higher relative rates of major depression and death by suicide, which persisted for ≥10 yr after PC diagnosis. PC survivors need close follow-up for timely detection and treatment of psychosocial distress. PATIENT SUMMARY: In a large Swedish population, men with aggressive prostate cancer had higher long-term relative rates of depression and suicide

Tackling overtreatment of prostate cancer

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87027/1/26106_ftp.pd

Estimating the harms and benefits of prostate cancer screening as used in common practice versus recommended good practice : A microsimulation screening analysis

BACKGROUND: Prostate-specific antigen (PSA) screening and concomitant treatment can be implemented in several ways. The authors investigated how the net benefit of PSA screening varies between common practice versus “good practice.”. METHODS: Microsimulation screening analysis (MISCAN) was used to evaluate the effect on quality-adjusted life-years (QALYs) if 4 recommendations were followed: limited screening in older men, selective biopsy in men with elevated PSA, active surveillance for low-risk tumors, and treatment preferentially delivered at high-volume centers. Outcomes were compared with a base model in which annual screening started at ages 55 to 69 years and were simulated using data from the European Randomized Study of Screening for Prostate Cancer. RESULTS: In terms of QALYs gained compared with no screening, for 1000 screened men who were followed over their lifetime, recommended good practice led to 73 life-years (LYs) and 74 QALYs gained compared with 73 LYs and 56 QALYs for the base model. In contrast, common practice led to 78 LYs gained but only 19 QALYs gained, for a greater than 75% relative reduction in QALYs gained from unadjusted LYs gained. The poor outcomes for common practice were influenced predominantly by the use of aggressive treatment for men with low-risk disease, and PSA testing in older men also strongly reduced potential QALY gains. CONCLUSIONS: Commonly used PSA screening and treatment practices are associated with little net benefit. Following a few straightforward clinical recommendations, particularly greater use of active surveillance for low-risk disease and reducing screening in older men, would lead to an almost 4-fold increase in the net benefit of prostate cancer screening. Cancer 2016;122:3386–3393

The prostate cancer conundrum revisited

BACKGROUND: Prostate cancer mortality rates in the United States declined by >40% between 1991 and 2005. The impact of changes in primary treatment and adjuvant and neoadjuvant hormone therapy on this decline is unknown. METHODS: The authors applied 3 independently developed models of prostate cancer natural history and disease detection under common assumptions about treatment patterns, treatment efficacy, and survival in the population. Primary treatment patterns were derived from the Surveillance, Epidemiology, and End Results registry; data on the frequency of hormone therapy were obtained from the CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) database; and treatment efficacy was based on estimates from randomized trials and comparative effectiveness studies of treatment alternatives. The models projected prostate cancer mortality without prostate‐specific antigen screening and in the presence and absence of treatment benefit. The impact of primary treatment was expressed as a fraction of the difference between observed mortality and projected mortality in the absence of treatment benefit. RESULTS: The 3 models projected that changes in treatment explained 22% to 33% of the mortality decline by 2005. These contributions were accounted for mostly by surgery and radiation therapy, which increased in frequency until the 1990s, whereas hormone therapies contributed little to the mortality decline by 2005. Assuming that treatment benefit was less for older men, changes in treatment explained only 16% to 23% of the mortality decline by 2005. CONCLUSIONS: Changes in primary treatment explained a minority of the observed decline in prostate cancer mortality. The remainder of the decline probably was because of other interventions, such as prostate‐specific antigen screening and advances in the treatment of recurrent and progressive disease. Cancer 2012. © 2012 American Cancer Society. Three models of prostate cancer natural history are combined with data on patterns of primary treatment, including hormone therapies and trial‐based estimates of treatment efficacy. The results indicate that changes in these treatments explain 22% to 33% of the observed decline in prostate cancer mortality between 1991 and 2005.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94469/1/27594_ftp.pd