The Effect of Oral Laxatives on Rectal Distension and Image Quality in Magnetic Resonance Imaging of the Prostate.

Introduction Increasing rectal size is associated with increased artefacts on magnetic resonance imaging (MRI) of the prostate and has the potential to degrade image quality. The objective of this study was to analyse the effect of oral laxative medication on rectal distension and image quality in prostate MRI. Methods Eighty patients prospectively received either 15 mg of oral senna (laxative group) or no medication (control group). Patients underwent prostate MRI according to standard local protocol and seven rectal dimensions on axial and sagittal images were measured. A subjective assessment of rectal distension was also made using a five-point Likert scale. Finally, artefacts on diffusion-weighted sequences were assessed using a four-point Likert scale. Results There was a small reduction in rectal diameter on sagittal images in the laxative group compared to the control group, with mean diameters of 27.1 mm and 30.0 mm respectively, p=0.02. There was no significant difference in rectal measurements of anteroposterior diameter, transverse diameter, or rectal circumference on axial imaging. Subjective scoring also demonstrated no significant difference in diffusion-weighted imaging quality between the laxative group and control group, p=0.82. Conclusion Bowel preparation with the oral laxative, senna, provided only a marginal decrease in rectal distension on one measure and no reduction in artefacts on diffusion-weighted sequences. The findings of this study do not support the routine use of this medication in patients undergoing prostate MRI.

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

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.

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

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.

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

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.

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

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.

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

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 Health 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.

Prospective randomised trial comparing diethylstilboestrol and flutamide in the treatment of hormone relapsed prostate cancer.

BACKGROUND: Patients with hormone relapsed prostate cancer (HRPC) are often treated with flutamide or diethylstilboestrol. However, which of these two options is the best treatment for HRPC remains unclear. METHODS: We carried out a prospective study to determine and compare the prostate-specific antigen (PSA) response and survival in patients with hormone relapsed prostate cancer (HRPC), all of whom had previously shown a good response to medical or surgical castration. The patients were randomised to treatment with diethylstilboestrol (DES) and aspirin, or the antiandrogen flutamide. In addition, quality of life was determined by interview and questionnaire. RESULTS: Twenty-eight patients were randomised for treatment options. There was a significantly greater fall in the PSA (65% vs 35%; P = 0.034) after treatment with diethylstilboestrol compared to treatment with flutamide. Median survival also rose after treatment with diethylstilboestrol (18 months) compared to flutamide (11 months), but this difference did not reach statistical significance. There was no difference in the quality of life parameters between the two groups. There were no cardiovascular complications in the stilboestrol group. CONCLUSIONS: In HRPC, treatment with stilboestrol is associated with a greater PSA fall and an increase in median survival when compared to flutamide treatment.