Hashim U. Ahmed

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).

Systematic Review of Complications of Prostate Biopsy

CONTEXT Prostate biopsy is commonly performed for cancer detection and management. The benefits and risks of prostate biopsy are germane to ongoing debates about prostate cancer screening and treatment. OBJECTIVE To perform a systematic review of complications from prostate biopsy. EVIDENCE ACQUISITION A literature search was performed using PubMed and Embase, supplemented with additional references. Articles were reviewed for data on the following complications: hematuria, rectal bleeding, hematospermia, infection, pain, lower urinary tract symptoms (LUTS), urinary retention, erectile dysfunction, and mortality. EVIDENCE SYNTHESIS After biopsy, hematuria and hematospermia are common but typically mild and self-limiting. Severe rectal bleeding is uncommon. Despite antimicrobial prophylaxis, infectious complications are increasing over time and are the most common reason for hospitalization after biopsy. Pain may occur at several stages of prostate biopsy and can be mitigated by anesthetic agents and anxiety-reduction techniques. Up to 25% of men have transient LUTS after biopsy, and <2% have frank urinary retention, with slightly higher rates reported after transperineal template biopsy. Biopsy-related mortality is rare. CONCLUSIONS Preparation for biopsy should include antimicrobial prophylaxis and pain management. Prostate biopsy is frequently associated with minor bleeding and urinary symptoms that usually do not require intervention. Infectious complications can be serious, requiring prompt management and continued work into preventative strategies.

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.

Detection of Clinically Significant Prostate Cancer Using Magnetic Resonance Imaging-Ultrasound Fusion Targeted Biopsy: A Systematic Review.

CONTEXT The current standard for diagnosing prostate cancer in men at risk relies on a transrectal ultrasound-guided biopsy test that is blind to the location of the cancer. To increase the accuracy of this diagnostic pathway, a software-based magnetic resonance imaging-ultrasound (MRI-US) fusion targeted biopsy approach has been proposed. OBJECTIVE Our main objective was to compare the detection rate of clinically significant prostate cancer with software-based MRI-US fusion targeted biopsy against standard biopsy. The two strategies were also compared in terms of detection of all cancers, sampling utility and efficiency, and rate of serious adverse events. The outcomes of different targeted approaches were also compared. EVIDENCE ACQUISITION We performed a systematic review of PubMed/Medline, Embase (via Ovid), and Cochrane Review databases in December 2013 following the Preferred Reported Items for Systematic reviews and Meta-analysis statement. The risk of bias was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. EVIDENCE SYNTHESIS Fourteen papers reporting the outcomes of 15 studies (n=2293; range: 13-582) were included. We found that MRI-US fusion targeted biopsies detect more clinically significant cancers (median: 33.3% vs 23.6%; range: 13.2-50% vs 4.8-52%) using fewer cores (median: 9.2 vs 37.1) compared with standard biopsy techniques, respectively. Some studies showed a lower detection rate of all cancer (median: 50.5% vs 43.4%; range: 23.7-82.1% vs 14.3-59%). MRI-US fusion targeted biopsy was able to detect some clinically significant cancers that would have been missed by using only standard biopsy (median: 9.1%; range: 5-16.2%). It was not possible to determine which of the two biopsy approaches led most to serious adverse events because standard and targeted biopsies were performed in the same session. Software-based MRI-US fusion targeted biopsy detected more clinically significant disease than visual targeted biopsy in the only study reporting on this outcome (20.3% vs 15.1%). CONCLUSIONS Software-based MRI-US fusion targeted biopsy seems to detect more clinically significant cancers deploying fewer cores than standard biopsy. Because there was significant study heterogeneity in patient inclusion, definition of significant cancer, and the protocol used to conduct the standard biopsy, these findings need to be confirmed by further large multicentre validating studies. PATIENT SUMMARY We compared the ability of standard biopsy to diagnose prostate cancer against a novel approach using software to overlay the images from magnetic resonance imaging and ultrasound to guide biopsies towards the suspicious areas of the prostate. We found consistent findings showing the superiority of this novel targeted approach, although further high-quality evidence is needed to change current practice.

The Role of Focal Therapy in the Management of Localised Prostate Cancer: A Systematic Review

Context The incidence of localised prostate cancer is increasing worldwide. In light of recent evidence, current, radical, whole-gland treatments for organ-confined disease have being questioned with respect to their side effects, cancer control, and cost. Focal therapy may be an effective alternative strategy. Objective To systematically review the existing literature on baseline characteristics of the target population; preoperative evaluation to localise disease; and perioperative, functional, and disease control outcomes following focal therapy. Evidence acquisition Medline (through PubMed), Embase, Web of Science, and Cochrane Review databases were searched from inception to 31 October 2012. In addition, registered but not yet published trials were retrieved. Studies evaluating tissue-preserving therapies in men with biopsy-proven prostate cancer in the primary or salvage setting were included. Evidence synthesis A total of 2350 cases were treated to date across 30 studies. Most studies were retrospective with variable standards of reporting, although there was an increasing number of prospective registered trials. Focal therapy was mainly delivered to men with low and intermediate disease, although some high-risk cases were treated that had known, unilateral, significant cancer. In most of the cases, biopsy findings were correlated to specific preoperative imaging, such as multiparametric magnetic resonance imaging or Doppler ultrasound to determine eligibility. Follow-up varied between 0 and 11.1 yr. In treatment-naïve prostates, pad-free continence ranged from 95% to 100%, erectile function ranged from 54% to 100%, and absence of clinically significant cancer ranged from 83% to 100%. In focal salvage cases for radiotherapy failure, the same outcomes were achieved in 87.2–100%, 29–40%, and 92% of cases, respectively. Biochemical disease-free survival was reported using a number of definitions that were not validated in the focal-therapy setting. Conclusions Our systematic review highlights that, when focal therapy is delivered with intention to treat, the perioperative, functional, and disease control outcomes are encouraging within a short- to medium-term follow-up. Focal therapy is a strategy by which the overtreatment burden of the current prostate cancer pathway could be reduced, but robust comparative effectiveness studies are now required.

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.

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.

Will focal therapy become a standard of care for men with localized prostate cancer

The current treatment choice for men with localized prostate cancer lies between active surveillance and radical therapy. The difference between these two extremes of care is 5% in terms of cancer-related absolute mortality at 8 years. It is generally accepted that this small difference will decrease for men diagnosed in the prostate-specific-antigen era. Radical therapy is associated with considerable adverse effects (e.g. incontinence, impotence, rectal problems) because it treats the whole gland, and damages surrounding structures in up to half of men. Men are being diagnosed at a younger age with lower-risk disease, and many have unifocal or unilateral disease. We propose a new concept whereby only the tumor focus and a margin of normal tissue are treated. This paradigm might decrease adverse effects whilst, at the same time, retaining effective cancer control. The arguments for and against active surveillance and radical therapy are reviewed in this article, with focal therapy presented as a means for bridging these two approaches.