Alex Freeman

Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study.

BACKGROUND Men with high serum prostate specific antigen usually undergo transrectal ultrasound-guided prostate biopsy (TRUS-biopsy). TRUS-biopsy can cause side-effects including bleeding, pain, and infection. Multi-parametric magnetic resonance imaging (MP-MRI) used as a triage test might allow men to avoid unnecessary TRUS-biopsy and improve diagnostic accuracy. METHODS We did this multicentre, paired-cohort, confirmatory study to test diagnostic accuracy of MP-MRI and TRUS-biopsy against a reference test (template prostate mapping biopsy [TPM-biopsy]). Men with prostate-specific antigen concentrations up to 15 ng/mL, with no previous biopsy, underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. The conduct and reporting of each test was done blind to other test results. Clinically significant cancer was defined as Gleason score ≥4 + 3 or a maximum cancer core length 6 mm or longer. This study is registered on ClinicalTrials.gov, NCT01292291. FINDINGS Between May 17, 2012, and November 9, 2015, we enrolled 740 men, 576 of whom underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. On TPM-biopsy, 408 (71%) of 576 men had cancer with 230 (40%) of 576 patients clinically significant. For clinically significant cancer, MP-MRI was more sensitive (93%, 95% CI 88-96%) than TRUS-biopsy (48%, 42-55%; p<0·0001) and less specific (41%, 36-46% for MP-MRI vs 96%, 94-98% for TRUS-biopsy; p<0·0001). 44 (5·9%) of 740 patients reported serious adverse events, including 8 cases of sepsis. INTERPRETATION Using MP-MRI to triage men might allow 27% of patients avoid a primary biopsy and diagnosis of 5% fewer clinically insignificant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy for all. MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by a quarter. MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer. FUNDING PROMIS is funded by the UK Government Department of Health, National Institute of Health Research-Health Technology Assessment Programme, (Project number 09/22/67). This project is also supported and partly funded by UCLH/UCL Biomedical Research Centre and The Royal Marsden and Institute for Cancer Research Biomedical Research Centre and is coordinated by the Medical Research Council Clinical Trials Unit (MRC CTU) at UCL. It is sponsored by University College London (UCL).

Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study

Summary Background Radical whole-gland therapy can lead to significant genitourinary and rectal side-effects for men with localised prostate cancer. We report on whether selective focal ablation of unifocal and multifocal cancer lesions can reduce this treatment burden. Methods Men aged 45–80 years were eligible for this prospective development study if they had low-risk to high-risk localised prostate cancer (prostate specific antigen [PSA] ≤15 ng/mL, Gleason score ≤4 + 3, stage ≤T2), with no previous androgen deprivation or treatment for prostate cancer, and who could safely undergo multiparametric MRI and have a general anaesthetic. Patients received focal therapy using high-intensity focused ultrasound, delivered to all known cancer lesions, with a margin of normal tissue, identified on multiparametric MRI, template prostate-mapping biopsies, or both. Primary endpoints were adverse events (serious and otherwise) and urinary symptoms and erectile function assessed using patient questionnaires. Analyses were done on a per-protocol basis. This study is registered with ClinicalTrials.gov, number NCT00561314. Findings 42 men were recruited between June 27, 2007, and June 30, 2010; one man died from an unrelated cause (pneumonia) 3 months after treatment and was excluded from analyses. After treatment, one man was admitted to hospital for acute urinary retention, and another had stricture interventions requiring hospital admission. Nine men (22%, 95% CI 11–38) had self-resolving, mild to moderate, intermittent dysuria (median duration 5·0 days [IQR 2·5–18·5]). Urinary debris occurred in 14 men (34%, 95% CI 20–51), with a median duration of 14·5 days (IQR 6·0–16·5). Urinary tract infection was noted in seven men (17%, 95% CI 7–32). Median overall International Index of Erectile Function-15 (IIEF-15) scores were similar at baseline and at 12 months (p=0·060), as were median IIEF-15 scores for intercourse satisfaction (p=0·454), sexual desire (p=0·644), and overall satisfaction (p=0·257). Significant deteriorations between baseline and 12 months were noted for IIEF-15 erectile (p=0·042) and orgasmic function (p=0·003). Of 35 men with good baseline function, 31 (89%, 95% CI 73–97) had erections sufficient for penetration 12 months after focal therapy. Median UCLA Expanded Prostate Cancer Index Composite (EPIC) urinary incontinence scores were similar at baseline as and 12 months (p=0·045). There was an improvement in lower urinary tract symptoms, assessed by International Prostate Symptom Score (IPSS), between baseline and 12 months (p=0·026), but the IPSS-quality of life score showed no difference between baseline and 12 months (p=0·655). All 38 men with no baseline urinary incontinence were leak-free and pad-free by 9 months. All 40 men pad-free at baseline were pad-free by 3 months and maintained pad-free continence at 12 months. No significant difference was reported in median Trial Outcomes Index scores between baseline and 12 months (p=0·113) but significant improvement was shown in median Functional Assessment of Cancer Therapy (FACT)-Prostate (p=0·045) and median FACT-General scores (p=0·041). No histological evidence of cancer was identified in 30 of 39 men biopsied at 6 months (77%, 95% CI 61–89); 36 (92%, 79–98) were free of clinically significant cancer. After retreatment in four men, 39 of 41 (95%, 95% CI 83–99) had no evidence of disease on multiparametric MRI at 12 months. Interpretation Focal therapy of individual prostate cancer lesions, whether multifocal or unifocal, leads to a low rate of genitourinary side-effects and an encouraging rate of early absence of clinically significant prostate cancer. Funding Medical Research Council (UK), Pelican Cancer Foundation, and St Peters Trust.

Is it time to consider a role for MRI before prostate biopsy

The use of MRI in prostate cancer management is controversial and current guidelines underplay its role. Technological advances over the past 5 years, however, demand a re-evaluation of this position. In this article, we propose an increased use of MRI, not only in those with a diagnosis of prostate cancer but also for men before a prostate biopsy. The use of MRI before a biopsy can serve as a triage test in men with raised serum prostate-specific antigen levels, in order to select those for biopsy with significant cancer that requires treatment. This strategy could avoid biopsy, and hence unnecessary treatment, in those with no disease or insignificant cancer. In addition, avoidance of postbiopsy artifact caused by hemorrhage will lead to better local staging accuracy, while determining more accurately the disease burden. This approach could improve risk stratification by selecting those who require adjuvant therapy or dose escalation. Furthermore, MRI evaluation of cancer burden could be important in active surveillance regimens to select those needing intervention.

Characterizing Clinically Significant Prostate Cancer Using Template Prostate Mapping Biopsy

PURPOSE Definitions of prostate cancer risk are limited since accurate attribution of the cancer grade and burden is not possible due to the random and systematic errors associated with transrectal ultrasound guided biopsy. Transperineal prostate mapping biopsy may have a role in accurate risk stratification. We defined the transperineal prostate mapping biopsy characteristics of clinically significant disease. MATERIALS AND METHODS A 3-dimensional model of each gland and individual cancer was reconstructed using 107 radical whole mount specimens. We performed 500 transperineal prostate mapping simulations per case by varying needle targeting errors to calculate sensitivity, specificity, and negative and positive predictive value to detect lesions 0.2 ml or greater, or 0.5 ml or greater. Definitions of clinically significant cancer based on a combination of Gleason grade and cancer burden (cancer core length) were derived. RESULTS Mean±SD patient age was 61±6.4 years (range 44 to 74) and mean prostate specific antigen was 9.7±5.9 ng/ml (range 0.8 to 36.2). We reconstructed 665 foci. The total cancer core length from all positive biopsies for a particular lesion that detected more than 95% of lesions 0.5 ml or greater and 0.2 ml or greater was 10 mm or greater and 6 mm or greater, respectively. The maximum cancer core length that detected more than 95% of lesions 0.5 ml or greater and 0.2 ml or greater was 6 mm or greater and 4 mm or greater, respectively. We combined these cancer burden thresholds with dominant and nondominant Gleason pattern 4 to derive 2 definitions of clinically significant disease. CONCLUSIONS Transperineal prostate mapping may provide an effective method to risk stratify men with localized prostate cancer. The definitions that we present require prospective validation.

What surgical resection margins are required to achieve oncological control in men with primary penile cancer

To evaluate the surgical excision margin required for local oncological control in primary penile cancers, as patients with penile cancer who undergo radical amputation suffer marked psychological, functional and cosmetic sequelae, and although organ‐sparing surgery has improved the quality of life of these men, the optimum surgical excision margin to achieve oncological control is unknown.

Parallel changes in bladder suburothelial vanilloid receptor TRPV1 and pan‐neuronal marker PGP9.5 immunoreactivity in patients with neurogenic detrusor overactivity after intravesical resiniferatoxin treatment

To compare PGP9.5 and transient receptor potential vanilloid receptor (TRPV1) suburothelial immunoreactivity between controls and patients with spinal neurogenic detrusor overactivity (NDO) before and after treatment with intravesical resiniferatoxin, as suburothelial PGP9.5‐staining nerve fibres decrease in patients with spinal NDO who respond to intravesical capsaicin, and TRPV1 is present on these suburothelial nerve fibres in normal and overactive human urinary bladder.

Focal Therapy for Localized Prostate Cancer: A Phase I/II Trial

PURPOSE Men with localized prostate cancer currently face a number of treatment options that treat the entire prostate. These can cause significant sexual and urinary side effects. Focal therapy offers a novel strategy that targets the cancer rather than the prostate in an attempt to preserve tissue and function. MATERIALS AND METHODS A prospective, ethics committee approved trial was conducted to determine the side effects of focal therapy using high intensity focused ultrasound. Multiparametric magnetic resonance imaging (T2-weighted, dynamic contrast enhanced, diffusion-weighted) and template transperineal prostate mapping biopsies were used to identify unilateral disease. Genitourinary side effects and quality of life outcomes were assessed using validated questionnaires. Posttreatment biopsies were performed at 6 months and followup was completed to 12 months. RESULTS A total of 20 men underwent high intensity focused ultrasound hemiablation. Mean age was 60.4 years (SD 5.4, range 50 to 70) with mean prostate specific antigen 7.3 ng/ml (SD 2.8, range 3.4 to 11.8). Of the men 25% had low risk and 75% had intermediate risk cancer. Return of erections sufficient for penetrative sex occurred in 95% of men (19 of 20). In addition, 90% of men (18 of 20) were pad-free, leak-free continent while 95% were pad-free. Mean prostate specific antigen decreased 80% to 1.5 ng/ml (SD 1.3) at 12 months. Of the men 89% (17 of 19, 1 refused biopsy) had no histological evidence of any cancer, and none had histological evidence of high volume or Gleason 7 or greater cancer in the treated lobe. In addition, 89% of men achieved the trifecta status of pad-free, leak-free continence, erections sufficient for intercourse and cancer control at 12 months. CONCLUSIONS Our results appear sufficiently promising to support the further evaluation of focal therapy as a strategy to decrease some of the harms and costs associated with standard whole gland treatments.

Transperineal Magnetic Resonance Image Targeted Prostate Biopsy Versus Transperineal Template Prostate Biopsy in the Detection of Clinically Significant Prostate Cancer.

PURPOSE Multiparametric magnetic resonance imaging can be used to guide prostate biopsy by targeting biopsies to areas in the prostate at high risk for cancer. We compared the detection of clinically significant and insignificant cancer by transperineal magnetic resonance imaging targeted biopsy and transperineal template guided prostate biopsy. MATERIALS AND METHODS A total of 182 men with a lesion suspicious for cancer on multiparametric magnetic resonance imaging underwent transperineal magnetic resonance imaging targeted biopsy using a cognitive registration technique, followed by systematic transperineal template guided prostate biopsy. The primary outcome was the detection rate of clinically significant prostate cancer. Clinical significance was defined using maximum cancer core length 4 mm or greater and/or Gleason grade 3 + 4 or greater (University College London definition 2). We secondarily evaluated other commonly used thresholds of clinically significant disease, including maximum cancer core length 6 mm or greater and/or Gleason grade 4 + 3 or greater, maximum cancer core length 3 mm or greater and/or Gleason grade 3 + 4 or greater, and maximum cancer core length 2 or greater mm and/or Gleason grade 3 + 4 or greater. Strategies were statistically compared with the McNemar test. RESULTS Mean ± SD patient age was 63.3 ± 7.2 years. Median prostate specific antigen was 6.7 ng/ml (IQR 4.7-10.0). Clinically significant cancer was detected by magnetic resonance imaging targeted biopsy and template guided prostate biopsy in 103 (57%) and 113 of the 182 men (62%) (p = 0.174), and clinically insignificant cancer was detected in 17 (9.3%) and 31 (17.0%), respectively (p = 0.024). CONCLUSIONS Prostate biopsy targeted to suspicious lesions on multiparametric magnetic resonance imaging has encouraging rates of detection of clinically significant cancer while also decreasing the detection rate of clinically insignificant cancer. This is achieved with fewer biopsy cores than for systematic template guided biopsy. Further prospective, multicenter, comparative trials of the performance of targeting strategies are needed to consider magnetic resonance imaging targeted biopsy an alternative to conventional systematic biopsy.

Multiparametric MR Imaging for Detection of Clinically Significant Prostate Cancer: A Validation Cohort Study with Transperineal Template Prostate Mapping as the Reference Standard

PURPOSE To evaluate the diagnostic performance of multiparametric (MP) magnetic resonance (MR) imaging for prostate cancer detection by using transperineal template prostate mapping (TTPM) biopsies as the reference standard and to determine the potential ability of MP MR imaging to identify clinically significant prostate cancer. MATERIALS AND METHODS Institutional review board exemption was granted by the local research ethics committee for this retrospective study. Included were 64 men (mean age, 62 years [range, 40-76]; mean prostate-specific antigen, 8.2 ng/mL [8.2 μg/L] [range, 2.1-43 ng/mL]), 51 with biopsy-proved cancer and 13 suspected of having clinically significant cancer that was biopsy negative or without prior biopsy. MP MR imaging included T2-weighted, dynamic contrast-enhanced and diffusion-weighted imaging (1.5 T, pelvic phased-array coil). Three radiologists independently reviewed images and were blinded to results of biopsy. Two-by-two tables were derived by using sectors of analysis of four quadrants, two lobes, and one whole prostate. Primary target definition for clinically significant disease necessary to be present within a sector of analysis on TTPM for that sector to be deemed positive was set at Gleason score of 3+4 or more and/or cancer core length involvement of 4 mm or more. Sensitivity, negative predictive value, and negative likelihood ratio were calculated to determine ability of MP MR imaging to rule out cancer. Specificity, positive predictive value, positive likelihood ratio, accuracy (overall fraction correct), and area under receiver operating characteristic curves were also calculated. RESULTS Twenty-eight percent (71 of 256) of sectors had clinically significant cancer by primary endpoint definition. For primary endpoint definition (≥ 4 mm and/or Gleason score ≥ 3+4), sensitivity, negative predictive value, and negative likelihood ratios were 58%-73%, 84%-89%, and 0.3-0.5, respectively. Specificity, positive predictive value, and positive likelihood ratios were 71%-84%, 49%-63%, and 2.-3.44, respectively. Area under the curve values were 0.73-0.84. CONCLUSION Results of this study indicate that MP MR imaging has a high negative predictive value to rule out clinically significant prostate cancer and may potentially have clinical use in diagnostic pathways of men at risk.

A prospective study of 100 cases of penile cancer managed according to European Association of Urology guidelines

To prospectively assess the outcome of patients treated according to the European Association of Urology (EAU) guidelines on the management of penile cancer, a system originally based on retrospective series.