Tim Dudderidge

Introduction and Objectives: Luminal Index magnetic resonance imaging (LI‐MRI) is a novel technique that has recently been proposed for prostate cancer (PCa) characterisation. It is based on multi‐echo T2‐weighted sequences and requires <10 min to be performed. However, evidence on its diagnostic performance in the diagnostic evaluation of PCa is lacking. The ‘Comparison of diagnostic accuracy of Luminal Index and standard of care MRI for Accelerated deTEction of prostate cancer’ (CLIMATE) trial aims to compare the diagnostic accuracy of LI‐MRI and standard of care (SOC) MRI (multiparametric or biparametric MRI) for the detection of clinically significant PCa (csPCa). Trial Design: The CLIMATE trial is a prospective, multicentre, paired, non‐randomised comparative trial of LI‐MRI and SOC MRI targeted biopsy in participants with clinically suspected PCa. Endpoints: The primary endpoint of the trial is to compare the per‐participant diagnostic accuracy of LI‐MRI and SOC MRI for csPCa using targeted biopsies as the standard of reference. Patients and Methods: Adult men (aged ≥18 years) with clinical suspicion of PCa and no prior PCa diagnosis or treatment will be invited. Each participant will undergo LI‐MRI and SOC MRI in a single scan session, with each test interpreted without knowledge of the other test images or results. LI‐MRI and SOC MRI will be reported on a 1–5 scale for suspicion of tumour (Likert scale or Prostate Imaging‐Reporting and Data System). Targeted biopsies will be taken for any suspicious lesions detected, defined as MRI score of ≥3. Trial registration: ClinicalTrials.gov Registry (NCT05020522).

Focal therapy treats individual areas of tumour in non-metastatic prostate cancer in patients unsuitable for active surveillance. The aim of this work was to evaluate the cost-effectiveness of focal therapy versus prostatectomy and external beam radiotherapy (EBRT). A Markov cohort health state transition model with four health states (stable disease, local recurrence, metastatic disease and death) was created, evaluating costs and utilities over a 10-year time horizon for patients diagnosed with non-metastatic prostate cancer. National Health Service (NHS) for England perspective was used, based on direct healthcare costs. Clinical transition probabilities were derived from prostate cancer registries in patients undergoing radical prostatectomy, EBRT and focal therapy using cryotherapy (Boston Scientific) or high-intensity focused ultrasound (HIFU) (Sonablate). Propensity score matching was used to ensure at-risk populations were comparable. Variables included age, prostate-specific antigen (PSA), International Society of Urological Pathology (ISUP) grade group, maximum cancer core length (mm), T-stage and year of treatment. Focal therapy was associated with a lower overall cost and higher quality adjusted life year (QALY) gains than either prostatectomy or EBRT, dominating both treatment strategies. Positive incremental net monetary benefit (NMB) values confirm focal therapy as cost effective versus the alternatives at a willingness to pay (WTP) threshold of £30,000/QALY. One-way deterministic sensitivity analyses revealed consistent results. Data used to calculate the transition probabilities were derived from a limited number of hospitals meaning that other potential treatment options were excluded. Limited data were available on later outcomes and none on quality of life data, therefore, literature-based estimates were used. Cost-effectiveness modelling demonstrates use of focal therapy (cryotherapy or HIFU) is associated with greater QALY gains at a lower overall cost than either radical prostatectomy or EBRT, representing good value for money in the NHS.

In this analysis, there was an incremental relationship between prostate cancer burden and the likelihood of a positive MRI signal. Background The effects of regional histopathologic changes on prostate MRI scans have not been accurately quantified in men with an elevated prostate-specific antigen (PSA) level and no previous bi...

Objective To compare cancer control rates of standard compared to dose escalation focal high-intensity focused ultrasound (HIFU) of prostate cancer. Materials and methods A prospectively maintained HIFU (Sonablate® 500) database identified 598 patients were identified who underwent focal HIFU (Sonablate® 500) (March/2007-November/2016). Follow-up occurred with 3-monthly clinic visits and PSA testing in the first year. Thereafter, PSA was measured 6-monthly. mpMRI with biopsy was used for MRI-suspicion of recurrence. Treatments were delivered in a quadrant or hemiablation fashion depending on the gland volume as well as tumour volume and location. Prior to mid-2015, standard focal-HIFU was used (two HIFU blocks); after this date some urologists conducted dose escalation focal-HIFU (3 overlapping HIFU blocks). Propensity matching was used to ensure two matched groups leading to 162 cases for this analysis. Treatment failure was defined by any secondary treatment (systemic therapy, cryotherapy, radiotherapy, prostatectomy, or further HIFU), metastasis from prostate cancer without further treatment, tumour recurrence with Gleason score >/=7 (>/=3+4) on prostate biopsy without further treatment, or prostate cancer-related mortality. Complications and side-effects were also compared. Results Median age was 64.5 years (IQR 60-73.5) in the standard focal-HIFU group and 64.5 years (IQR 60-69) in the dose-escalation group. Median prostate volume was 37ml (IQR 17-103) in standard group and 47.5ml (IQR 19-121) in the dose-escalation group. As tumour volume on mpMRI and Gleason score were major matching criteria these were identical with 0.43ml (IQR 0.05-2.5) and Gleason 3+3=6 in 1/32 (3%), 3+4=7 in 27/32 (84%), and 4+3=7 in 4/32 (13%). Recurrence in treated areas were found in 10/32 (31%) when standard treatment zones were applied, and in 6/32 (19%) of dose-escalation focal-HIFU (p=0.007). Conclusion This exploratory study shows that dose escalation focal-HIFU may achieve higher rates of disease control compared to standard focal-HIFU. Further prospective comparative studies are needed.

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 Health Technology Assessment; Vol. 22, No. 52. See the NIHR Journals Library website for further project information.

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 inHealth Technology Assessment; 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.

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses. Cancer is a genetic disease where changes in DNA cause alterations in the control of cellular systems leading to unchecked growth. Copy number changes, including duplications, amplifications, and deletions, are a common type of DNA change observed in cancer cells but it is not always clear which of the changes are important in driving cancer development. We have examined this class of genetic alteration in prostate cancer by DNA sequencing the whole genome in 103 cancers. 64 recurrent copy number changes were detected, of which 28 were new. For genetic losses our study comprehensively assessed the role of a model called the “Knudson two-hit genetic model” where alterations in both alleles of a gene is required to generate functional alterations. This model was only supported a minor proportion of recurrent deletions (15/40). This observation indicates that other mechanisms, such haploinsufficiency and epigenetic inactivation, may account for the majority of deletions. Our studies highlight several novel changes including those in non-coding lincRNA sequences, the identification ZNF292 as a target gene for a recurrent deletion on chromosome 6, and the common Knudson deletions at the NKX3.1 loci on chromosome 8.