The health outcomes associated with delayed treatment due to a false negative mpMRI result in Population 1 are summarised in Table 5. Table Population 1: Summary of findings for the linked evidence comparison of mpMRI, relative to TRUSGB or TPUSGB, in patients at low-concern with suspected prostate cancer with assumed probability (prevalence) of 35% Outcomes Patients/ Studies Quality of evidencea No. per 100 patients with intervention [95% CI]b No. per 100 patients with comparatorc [95% CI] Importance Comments True positives 2,062 patients (10 studies). ⨁⨁⨀⨀ 26 [20, 30] 28 [25, 31] Critical Will undergo biopsy as under current management. False positives 2,062 patients (10 studies). ⨁⨁⨀⨀ 15 [9, 24] 0 [0, 0] Critical Will undergo biopsy as under current management. True negatives 2,062 patients (10 studies). ⨁⨁⨀⨀ 50 [41, 56] 65 [65, 65] Critical Will avoid the potential adverse events resultant from biopsy. False negatives 2,062 patients (10 studies). ⨁⨁⨀⨀ 9 [5, 15] 7 [4, 11] Critical Will avoid the potential adverse events resultant from biopsy but possible detriment due to delayed treatment. Major Infection 45,492 patients (8 studies). ⨁⨁⨀⨀ 0 TRUSGB: Range 0-2 TPUSGB: 0 Critical - Minor infection 132,239 patients (9 studies). ⨁⨁⨀⨀ 0 TRUSGB: Range 0-7 TPUSGB: Range 0-1 Critical - 292,956 patients (9 studies). ⨁⨁⨀⨀ 0 TRUSGB: Range 0-6 TPUSGB: Range 1-2 Critical - Bleeding 334,688 patients (13 studies). ⨁⨀⨀⨀ 0 TRUSGB: Range 1-88 TPUSGB: Range 1-6 Important - Urinary obstruction 132,020 patients (12 studies). ⨁⨀⨀⨀ 0 TRUSGB: Range 1-21 TPUSGB: Range 0-38 Important - Overall survival 41,146 patients (5 studies). ⨁⨀⨀⨀ NA NA Critical Delay did not impact overall survival (results from 5 studies). hospitalisation pre-
Table Summary of findings for the linked evidence comparison of mpMRI, relative to TRUSGB or TPUSGB, in patients at low-concern with suspected prostate cancer with assumed pre-test probability (prevalence) of 35% Outcomes Patients/ Studies Quality of evidencea No. per 100 patients with intervention [95% CI]b No. per 100 patients with comparator [95% CI]c Importance Comments True positives 2,062 patients (10 studies). ⨁⨁⨀⨀ 26 [20,30] 28 [25, 31] Critical Will undergo biopsy as under current management. False positives 2,062 patients (10 studies). ⨁⨁⨀⨀ 15 [9, 24] 0 [0, 0] Critical Will undergo biopsy as under current management. True negatives 2,062 patients (10 studies). ⨁⨁⨀⨀ 50 [41, 56] 65 [65, 65] Critical Will avoid biopsy adverse events. False negatives 2,062 patients (10 studies). ⨁⨁⨀⨀ 9 [5,15] 7 [4, 11] Critical Will avoid the adverse events of biopsy but possible detriment due to delayed treatment. Major infection 45,492 patients (8 studies). ⨁⨁⨀⨀ 0 TRUSGB: Range 0-2 TPUSGB: 0 Critical - Minor infection 132,239 patients (9 studies). ⨁⨁⨀⨀ 0 TRUSGB: Range 0-7 TPUSGB: Range 0-1 Critical - Re-hospitalisation 292,956 patients (9 studies) ⨁⨁⨀⨀ 0 TRUSGB: Range 0-6 TPUSGB: Range 1-2 Critical - Bleeding 334,688 patients (13 studies). ⨁⨀⨀⨀ 0 TRUSGB: Range 1-88 TPUSGB: Range 1-6 Important - Urinary obstruction 132,020 patients (12 studies). ⨁⨀⨀⨀ 0 TRUSGB: Range 1-21 TPUSGB: Range 0-38 Important - Overall survival 41,146 (5 studies). ⨁⨀⨀⨀ NA NA Critical Delay did not impact overall survival (results from 5 studies).
probabilities of these treatment-related complications, an Australian quality of life study from the New South Wales Cancer Registry paper () was used. The probability of erectile dysfunction was 50 per cent for radical prostatectomy and 33 per cent for external beam radiotherapy, with a weighted (50/50, see Subsection D.4) average of 41.5 per cent in the “intermediate to high risk prostate cancer” health state. The probability of urinary incontinence was 10 per cent for radical prostatectomy and 2.4 per cent for external beam radiotherapy, with a weighted (50/50, see Subsection D.4) average of 6.2 per cent in the “intermediate to high risk prostate cancer” health state. A summary of each of the translational issues discussed in Section C and their use in Section D is provided in Table 46. Table Example of summary of results of pre-modelling studies and their uses in the economic evaluation Section Pre-modelling study Results used in Section D Results used in Subsection D.6 Applicability Subsection C.2 Comparison of patient and intervention characteristics between the key clinical studies and Australian registry data, Population 1 The economic model is based on the Australian patient population. D.2 Sensitivity analyses will be performed with the lower and upper values of the 95% CIs for accuracy results. Also, Australia-specific accuracy results will be used (sensitivity 54.3%, specificity 87.2%), obtained from a subsample of three, Australian studies. D.6 Subsection C.2 Comparison of patient and intervention characteristics between the key clinical studies and Australian registry data, Population 2 The economic model is based on the Australian patient population. D.2 Sensitivity analyses will be performed with the lower and upper values of the 95% CIs for accuracy results. D.6 Extrapolation Subsection C.3 Literature review for prostate cancer mortality and the impact of false diagnosis on prognosis. Alignment of transition probabilities with the evaluation for MR-guided biopsy procedures for diagnosis of PCa (CA 1424). No impact of false diagnosis on prognosis. D.4 None NA
Transformation Subsection C.4 Targeted literature review for utility values General Australian population of males aged 61-70y, 0.82; low/intermediate risk PCa on AS, 0.796; high/intermediate risk PCa receiving Active treatment/ follow-up, 0.789; disutility of biopsy, 0.035; acute sepsis, 0.47; erectile dysfunction, 0.10; urinary incontinence, 0.20 D.4 The disutility associated with prostate biopsy will be varied in sensitivity analyses, between 0 and 0.05, consistent with the assessment of MRIGB (CA 1424). D.6 Other Subsection C.5 Literature review for the frequencies of adverse events. mpMRI: no adverse events. Biopsy: 1.2% sepsis. Prostate cancer treatment: 25.9% erectile dysfunction disutility) and 0.55% urinary incontinence (1-year disutility). D.4 None NA AS = active surveillance, CI = confidence interval, mpMRI = multiparametric MRI, PCa = prostate cancer, MRIGB = MRI guided biopsy, CA = contracted assessment.
Figure Markov transition states A comparison of the economic model presented in this assessment (CA 1397) and the economic model presented by Gordon et al. (2016) is provided in Table 54. The main differences between the models are the number of health states and perspectives presented. The economic evaluation presented by Gordon et al. (2016) presented 20 health states (17 health states for patients with PCa, and 3 additional states for patients undergoing screening) and in this assessment 5 health states are presented. Gordon et al. (2016) included out-of-pocket costs for patients, whereas this assessment only takes the perspective of the MBS. The key structural assumptions are the same; mean age of the cohort is 65-66 years, time horizon applied for a lifetime up to age 90 years, costs and benefits are discounted at 5 per cent. Table Comparison of key economic evaluations: CA 1397 and Gordon et al. (2016) CA 1397 Gordon et al. 2016 Perspective MBS, health care system (Australia) Health care system (Australia); Out of pocket costs for patients. Population Population 1 Men with suspected PCa. Population 2 Men with low to intermediate risk PCa in AS. Population 1 Men with suspected PCa who have not had a prior biopsy. Interventions mpMRI ± TRUSGB/TPUSGB [75%:25%] Strategy 2: mpMRI ± MRIGB Strategy 3: mpMRI ± (MRIGB or TRUSGB or TPUSGB) [33.3% of each type of biopsy] Comparator TRUSGB/TPUSGB Strategy 1: TRUSGB Type of economic evaluation CEA and CUA CEA and CUA Sources of evidence Systematic review and meta-analysis of clinical trials (presented in Section B) Systematic literature review Time horizon Lifetime time horizon (25 years) in the model Lifetime: ~30 years, maximum is when men reach age 90 unless they die earlier. Outcomes No. of biopsies Costs QALYs No. of biopsies Costs LYs QALYs Methods used to generate results Combined decision tree and Markov model using cohort expected value analysis Markov model using cohort expected value analysis Health states No prostate cancer Low to intermediate risk prostate cancer (insignificant cancer) Intermediate to high risk prostate cancer The base model consisted of 17 health states (Markov model), which was altered to address research question and included additional health states (n=3):
Jambor et al. (2014) - key study Yes Case series NR Retrospective III-2 Finland Tertiary hospital n: 55 Age: median 66 (range 47-76) PSA: median 7.4 (range 4-14) Prior biopsy: 0% 3.0T Coil: body coil Contrast: Dotaren or Gadovist NR TRUSGB + cog-MRI TP, TN, FP, FN ≥ 4 Lista et al. 2015 - key study Yes Case series NR Prospective III-2 Spain Tertiary hospital n: 150 Age: mean 66.2 (SD 5) PSA mean 11.3 (SD 9.6) Prior biopsy: 100% 1.5T Coil: PPAC+ERC Contrast: NR NR TRUSGB TP, TN, FP, FN ≥ 4 Pokorny et al. (2014) - key study Yes Case series Consecutive Prospective II Australia Hospital n: 226 Age: Median 63 (IQR 57-68) PSA: median 5.3 (IQR 4.1-6.6) Prior biopsy: NR 3.0T Coil: NR – no ERC Contrast: NR 3 radiologists with: 1 year, 1 year or 19 years’ experience. Dedicated training of readers TRUSGB TP, TN, FP, FN ≥ 4 Thompson et al. (2014) - key study Yes Case series Consecutive Prospective III-2 Australia clinic n: 150 Age: Median 62.4 (IQR 55-66.4) PSA: median 5.6 (IQR 4.5-7.5) Prior biopsy: NR 1.5T or 3.0T Coil: NR – no ERC Contrast: gadolinum acid 2 radiologists each with >1000 prior prostate mpMRIs TRUSGB + cog-MRI TP, TN, FP, FN ≥ 4 tertiary
Thompson et al. 2016 - key study Yes Case series NR Prospective III-2 Australia clinic n: 344 Age: Median 62.9 (IQR 55.9-67.1) PSA: median 5.2 (IQR 3.7-7.1) Prior biopsy: NR 1.5T or 3.0T Coil: NR – no ERC Contrast: gadolinum acid 2 radiologists each with >1000 prior prostate mpMRIs TRUSGB + cog-MRI or TRUS/MRI FGB TP, TN, FP, FN ≥ 4 Wang et al. (2015) - key study Yes Case series Consecutive NR III-2 China Tertiary hospital n: 586 Age: mean 70.0 (SD 8.3) PSA: NR Prior biopsy: NR 1.5T Coil: PPAC + ERC Contrast: Gadopenteic dimeglumine 2 radiologists with 10 or 3 years’ experience TRUSGB TP, TN, FP, FN ≥ 4 Zhao et al. (2016) - key study Yes Case series NR Retrospective III-2 China Tertiary hospital n: 372 Age: mean 68.5 (SD 9.2) PSA: mean 15.0 (SD 13.3) Prior biopsy: NR 3.0T Coil: body coil Contrast: NR 2 radiologists experienced in PI-RADS v2 TRUSGB + cog-MRI TP, TN, FP, FN ≥ 4 Abd-Alazeez et al. 2014b - per hemisphere No Case series NR Prospective III-2 UK Tertiary hospital n: 54 Age: median 64 (range 39-75) PSA: median 10 (range 2-23) Prior biopsy: 100% 1.5T or 3.0T Coil: PPAC Contrast: gadoterate meglumine 8 radiologists with 3-8 years’ experience TRUSGB + cog-MRI TP, TN, FP, FN ≥ 4 Busetto et al. (2013) No Case series Consecutive Prospective III-2 Italy Tertiary hospital n: 163 Age: mean 66.4 (SD 5.3) PSA: mean 6.8 (SD 1.6) Prior biopsy: NR 3.0T Coil: PPAC + ERC Contrast: NR TRUSGB + cog-MRI TP, TN, FP, FN NA
De Visschere et al. (2016) No Case series Consecutive Retrospective III-2 Belgium Tertiary hospital n: 830 Age: mean 64.8 (range 40-83) PSA: median 8.34 (range 0.41-200) Prior biopsy: 35.8% 1.5T Coil: PPAC + ERC Contrast: NR 1 uroradiologist with >10 years’ experience TRUSGB TP, TN, FP, FN NA Ferda et al. (2013) No Case series NR Prospective III-2 Czech Republic Tertiary hospital n: 191 Age: (range 47-79) PSA: (range 4.2-123) Prior biopsy: NR 3.0T Coil: PPAC Contrast: gadobenate dimeglumine NR TRUSGB TP, TN, FP, FN NA Girometti et al. (2012) No Case series Consecutive Prospective III-2 Italy Tertiary hospital n: 26 Age: median 64 (range 51-74) PSA: median 5.95 (range 2.52-9.74) 3.0T Coil: perineum loop coil Contrast: gadobenate dimeglumine 2 experienced radiologists TRUSGB + cog-MRI TP, TN, FP, FN NA Haffner et al. (2011) No Case series Consecutive Retrospective III-2 France Tertiary hospital n: 555 Age: median 64 (range 47-83)] PSA: median 6.75 (range 0.18-100) Prior biopsy: 0% 1.5T Coil: PPAC Contrast: contrast 2 senior radiologists TRUSGB + cog-MRI TP, TN, FP, FN ≥ 3 Hauth et al. (2015) No Case series Consecutive NR III-2 Germany Tertiary hospital n: 94 Age: mean 63 (range 43-83) PSA: mean 9 (range 3-31) Prior biopsy: NR 1.5T Coil: PPAC Contrast: gadobutrol 2 radiologists with > 3 years’ experience TRUSGB + cog-MRI TP, TN, FP, FN ≥ 3
Itatani et al. (2014) No Case series Consecutive Retrospective III-2 Japan Tertiary hospital n: 193 Age: mean 68.9 (SD 8.4) PSA: median 7.9 (range 1.2-159) Prior biopsy: NR 1.5T Coil: cardiac coil Contrast: gadopentate dimeglumine 3 radiologists with 5, 7 or 22 years’ experience with prostate MRI TRUSGB TN, FN NA Komai et al. (2013) No Case series NR Prospective III-2 Japan Tertiary hospital n: 324 Age: men 64 (range 40-79) PSA: mean 6.8 (range 2.8-20) Prior biopsy: NR 1.5T Coil: body coil Contrast: gadopentetate dimeglumine Single radiologist with > 7 years’ experience TRUSGB + cog-MRI TP, TN, FP, FN ≥ 3 Lamb et al. 2015 No Case series Consecutive Retrospective III-2 UK Tertiary hospital n: 173 Age: G1 mean 65.1 (SD 8.1) G2 mean68.0 (SD 10.8) PSA: G1 mean 17.5 (SD 33.5), G2 mean 7.8 (SD 3.2) Prior biopsy: NR 1.5T Coil: NR Contrast: NR Consultant radiologists TRUSGB TP, TN, FP, FN NA Panebianco et al. (2015) No Case series Consecutive Prospective III-2 Italy Tertiary hospital n: 570 Age: mean 64 (range 51-82) PSA: >4 Prior biopsy: 0% 3.0T Coil: PPAC + ERC Contrast: NR 2 genitourinary radiologists with 13 or 14 years’ experience TRUSGB + cog-MRI TP, TN, FP, FN ≥3 Pepe et al. (2014) No Case series NR Prospective III-2 Italy Tertiary hospital N: 168 Age: median 65 (range 49-75) PSA: mean 10.4 (range 3.7-45) Prior biopsy: 100% 3.0T Coil: PPAC Contrast: gadobutro 2 radiologists, experience NR Saturation biopsy + cog-MRI TP, TN, FP, FN NA
Felker et al. (2016) No Case series Retrospective Consecutive III-2 USA Tertiary hospital n: 49 Age: mean 65 (range 47-80) PSA: median 5 (IQR 2.5-6.4) Gleason: 6 3.0T Coil: NR Contrast: NR 2 Fellowship trained genitourinary radiologists with >1,000 mpMRIs experience TRUSGB + cog-MRI TP, TN, FP, FN NA Margel et al. (2012) No Case series Prospective Consecutive III-2 Canada Tertiary hospital n: 60 Age: G1 mean 62.6 (SD 7), G2 mean 63.5 (SD 6), G3 mean 64 (SD 8.2) PSA: G1 median 5.9 (range 1.7-10), G2 median 4.4 (range 1.1-9.1), G3 median 4.1 (range 1.1-9.9) Gleason: ≤ 6 1.5T Coil: PPAC + ERC Contrast: acid Single experienced radiologist TRUSGB + cog-MRI TP, TN, FP, FN NA Mullins et al. 2013 No Case series Retrospective Consecutive III-2 USA Tertiary hospital n: 37 Age: median 67 (range 49-80) PSA: median 4.5 (range 0.4-18.6) Gleason: ≤ 6 3.0T Coil: body coil + ERC Contrast: gadopentetate Single radiologists with >10 years’ experience in prostate MRI TRUSGB TP, TN, FP, FN NA Sahibzada et al. 2016 No Case series Retrospective Consecutive III-2 UK Tertiary hospital n: 100 Age: mean 69.8 (range 59.1-85.9) PSA: mean 6.5 (range 3.4-17.5) Gleason: ≤ 6 1.5T or 3.0T Coil: NR Contrast: NR Single radiologists with >10 years’ experience in prostate MRI TRUSGB TP, TN, FP, FN NA
Siddiqui et al. 2015 No Case series Retrospective NR III-2 USA Tertiary hospital n: 60 Age: mean 60.2 PSA: mean 4.8 Gleason: ≤ 6 3.0T Coil: cardiac coil + ERC Contrast: NR NR TRUSGB + cog-MRI Graphical outcomes only NA Stamatakis et al. (2013) No Case series Retrospective NR III-2 USA Tertiary hospital n: 85 Age: mean 60.2 (range 40-79) PSA: mean 4.8 (0.2-10.9) Gleason: ≤ 6 3.0T Coil: cardiac coil + ERC Contrast: NR NR TRUSGB + cog-MRI TP, TN, FP, FN NA Vos et al. 2016 No Case series Prospective NR III-2 USA Tertiary hospital n: 24 Age: median 65 (range 51-75) PSA: median 6.4 (range 1.4-14.3) Gleason: ≤ 6 3.0T Coil: built-in body coil Contrast: ProHance NR NR TP, TN, FP, FN 3 Walton Diaz et al. (2015) No Case series Retrospective NR III-2 USA Tertiary hospital n: 58 Age: mean 61.4 (range 40-79) PSA: mean 5.2 (range 0.2-23.3) Gleason: ≤ 6 3.0T Coil: body coil + ERC Contrast: NR 2 experienced genitourinary radiologists with 7 or 14 years prostate MRI experience TRUSGB + cog-MRI TP, TN, FP, FN NA Wysock et al. (2016) No Case series Prospective Consecutive III-2 USA Tertiary hospital n: 73 Age: median 63 (IQR 57-68) PSA: median 5.4 (IQR 1.7-6.5) Gleason: 6 3.0T Coil: PPAC Contrast: NR Single fellowship trained radiologist with expertise in prostate imaging TRUSGB TN, FN 1 a: Describes consecutive or non-consecutive enrolment. b: Describes a retrospective or prospective study design.
TRUSGB Table Studies rpeorting safety outcomes associated with TRUSGB Study ID Used in Study type Enrolmenta Designb Level of evidencec Location Setting Study population characteristics n Age years PSA ng/ml PSA density Prior biopsy (%) Description of Biopsy type Cores Enema (%) Needle thickness Relevant outcomes assessed (i.e. related to outcomes specified in PICO) Anastasiadis et al. (2015) No Case series Non-consecutive Prospective IV UK Multiple hospitals n: 198,361 Age: 45-54: 3.2% 55-64: 21.5% 65-74: 40.5% 75-84: 28.9% ≥85: 5.9% PSA: NR Prior biopsy: NR TRUSGB Cores: 10-12 Enema: NR Needle: NR UTI Urinary obstruction Haematuria Hospitalisation Carignan et al. (2012) No Case-control Consecutive Retrospective III-2 Canada Tertiary hospital n: 5,798 Age: 66.7 [61.8-72.0] PSA: NR Prior biopsy: NR TRUSGB Cores: 12 Enema: 28 Needle: NR Major infection UTI Hospitalisation Bacteraemia Nam et al. (2013) No Case series Non-consecutive Retrospective IV Canada Multiple hospitals n: 75,190 Age: <50=3.1 51-59=21.1 70-79=41.6 ≥80=4.7 PSA: NR Prior biopsy: 0 TRUSGB Cores: NR Enema: NR Needle: NR Minor infection Urinary obstruction Hospitalisation bleeding
Roth et al. (2015) No Case series Non-consecutive Retrospective IV Australia Multiple hospitals n: 34,865 Age: mean 64 PSA: NR Prior biopsy: mix TRUSGB Cores: NR Enema: NR Needle: NR Minor infection Major infection UTI Urinary obstruction Haematuria Hospitalisation Prostatitis Fever Pinksy et al. (2014) No Cohort study Consecutive Prospective III-2 USA Multiple hospitals n: 4,836 Age: 65.5 (5.3) PSA: NR Prior biopsy: mix Route: NR Guidance: NR Cores: NR Enema: NR Needle: NR Minor infection Urinary obstruction Rectal bleeding Death Roberts et al. (2002) No Case series Non-consecutive retrospective IV USA Multiple hospitals n: 1,776 Age: <60=23% 60-69=36% 70-79=32% >80=9% PSA: ≤4.0=1% 4.1-10.0=30% ≥10.1=20% unknown=49% Prior biopsy: mix Route: mix Guidance: NR Cores: 1-5=46% 6=17% ≥7=19% unknown=18% Enema: 0 Needle: 18G Minor infection UTI Urinary obstruction Haematuria Rectal bleeding Blood in ejaculate Pain Bacteraemia Hospitalisation
Marino et al. (2015) No Cohort study with concurrent controls Non-consecutive Retrospective III-2 USA Tertiary hospital n: 455 Age: median 65 PSA: NR Prior biopsy: NR TRUSGB Cores: NR Enema: NR Needle: NR Major infection UTI Mohammed et al. (2016) No Comparative study with historical controls Consecutive Retrospective III-3 Ireland Tertiary hospital n: 286 Age: Group A: 59.6 (6.6) Group B: 61 (6.2) PSA: Group A: 9 (5.1) Group B: 8.5 (4.6) Prior biopsy: mix TRUSGB Cores: 6/12 Enema: 100 Needle: NR Bacteraemia Hospitalisation Petteffi et al. (2002) No RCT Consecutive Prospective II Brazil Multiple hospitals n: 105 Age: Group A: 65 (7) Group B: 64 (8) PSA: NR Prior biopsy: NR TRUSGB Cores: NR Enema: 100 Needle: 18G UTI Fever Hospitalisation Sahin et al. (2015) No Comparative study with concurrent controls Non-consecutive Prospective III-2 Turkey Tertiary hospital n: 480 Age: 65.9 (7.8) PSA: 12.5 (18.8) Prior biopsy: 28 TRUSGB Cores: 12 Enema: 100 Needle: 18G Minor infection Major infection UTI
Solberg et al. (2011) No RCT Consecutive Prospective II Norway, Sweden Multiple hospitals n: 875 Age: 66.1 (5.9) PSA: 16 (8-27) Prior biopsy: 100 TRUSGB Cores: NR Enema: 0 Needle: NR Urinary obstruction Pain Utrera et al. (2011a) No Case series Non-consecutive Prospective IV Spain Tertiary hospital n: 220 Age: 69.5 (7.9) PSA: 12.7 (28.7) Prior biopsy: mix TRUSGB Cores: 13.5 (1.7) Enema: 100 Needle: NR Urinary obstruction Bacteraemia Bacteriuria Fever Hospitalisation Utrera et al. (2011b) No Case series Non-consecutive Retrospective IV Spain Tertiary hospital n: 144 Age: 66 (6.4) PSA: 14.4 (12.6) Prior biopsy: 100 TRUSGB Cores: 30.4 (3.8) Enema: 100 Needle: NR Major infection Urinary obstruction Haematuria Prostatitis Rectal bleeding Loeb et al. (2013) No Systematic review NR NR IV USA Multiple hospitals n: 11 studies, 2,705 patients Age: NR PSA: NR Prior biopsy: NR TRUSGB Cores: NR Enema: NR Needle: NR Haematuria Haematospermia Rectal bleeding Erectile dysfunction a: Describes consecutive or non-consecutive enrolment. b: Describes a retrospective or prospective study design. c: Source: = not reported, PSA = prostate specific antigen, TRUSGB = trans-rectal ultrasound guided biopsy, RCT = randomised controlled trial, UTI = urinary tract infection, PICO = participant intervention comparator outcome.
Positive surgical margins 14,413 patients (6 studies). not serious not serious serious1 not serious none One study reported a delay >9 months was associated with an increase in the rate of positive surgical margins in patients with intermediate risk disease. 8 studies reported no impact from delayed treatment ⨁⨀⨀⨀ VERY LOW Important a: GRADE Working Group grades of evidence () ⨁⨁⨁⨁ High quality: We are very confident that the true effect lies close to that of the estimate of effect. ⨁⨁⨁⨀ Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. ⨁⨁⨀⨀ Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. ⨁⨀⨀⨀ Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect. 1: Indirectness was rated serious: this was due to the delay in the included studies being shorted than what would likely be experienced by patients in our population. 2: Noting the small number of included studies; however both studies had >300 patients. 3: Noting the small number of included studies; however median sample size was >300 patients. QoE = quality of evidence.
2 B6.3) Table QUADAS-2 results: Population 2 Risk of bias Applicability concerns Study Patient selection Index test Reference standard Flow and timing Patient selection Index test Reference standard Abd-Alazeez et al. (2014) ? Almeida et al. (2016) ? ? ? Bonekamp et al. (2013) ? ? de Cobelli et al. 2015 ? ? ? ? Felker et al. (2016) ? Flavell et al. (2014) ? ? Margel et al. (2012) ? Mullins et al. 2013 ? Porpiglia et al. (2015) ? ? Rebcal et al. 2016) ? Sahibzada et al. 2016 ? ? Siddiqui et al. 2015 ? ? ? Stamatakis et al. (2013) ? ? Vos et al. 2016 ? ? Walton Diaz et al. (2015) ? ? ? Wysock et al. (2016) ? ? ? ? = low risk, = high risk, ? = unclear risk.
H B5) Table Summary of studies assessing impact of delayed treatment in Population 1 Study Length of delay Length of N [I] N [D] Disease risk profile Overall survival Cancer specific survival Metastases Formation Biochemical recurrence Extra capsular extension Lymph node positive Positive surgical margins Tumour upgrade Abern et al. [I] <9m [D] >9m 5 years [I] 1503 [D] 58 [I] [D] In- 43% . . . 37% vs. 70% (intermediate disease only) NS . 30% vs. 76% (intermediate disease only) NS Andrews et al. [I] <3m [D1] 3-9 m [D2] >9 m 5 years [I] 633 [D1] 623 [D2] 62 Total: L-42%, In-39%, H-19% NS NS NS NS . . . . Dall'era et al. [I] median 3m [D] median 18m Median 27 months (range 1-162) [I] 1345 [D] 63 [I] 21% low, 79% high [D] 52% low, 48% high . . . . NS . NS NS
Graefen et al. [I] <1 month [D] >4 months Mean 33 months (range 1-116) [I] 111 [D] 42 Total: 59.6% low 36.7% int 3.7% high . . . NS . . . . Holmstrom et al. [I] median 3.5 months [D] median 19.2 months Median 8 years [I] 2344 [D] 222 Total: 100% low . . . . NS . NS 25% vs. 38% p<0.001 Khan et al. [I] <2 months [D] >2 months 10 years [I] 162 [D] 764 Total: <5% high risk . . . NS . NS . . Korets et al. [I] < 2months [D1] 2-3 months [D2] >3 months Median 64 months (IQR 30, 93) [I] 1098 [D1] 303 [D2] 167 [I] 34% low, 54% int, 12% high [D1] 37% low, 54% int, 9% high [D2] 48% low, 47% int, 5% high NS . . NS NS NS . NS
Sun et al. [I] <3 months [D] >3 months (median 11.5 months) 18 months [I] 14577 vs. [C] 2576 100% low NS . . . . . . NS van den Bergh et al. [I] median 0.5 years [D] median 2.6 years Mean 5.7 years (SD 3.2 years) [I] 158 [D] 69 100% low . . . NS NS . . NS Vickers et al. [I] <90 days [D] 90-365 days 10 years [I] 2258 [D] 891 5% high risk . . . NS . . . . Warlick et al. [I] median 3 months [D] median 26.5 months 10 years [I] 150 [D] 38 100% low . . NS . . . . . Redaniel et al. [I] 0-3 months [D] 4-6 months 10 years [I] 8522 [D] 8521 NR NS . . . . . . . Eroglu et al. NR NR 290 NR . . . . . . . Delay associated with upgrade to Gleason score
Dong et Al. [I] <3 months [D1] 3-6 months [D2] 6-9 months [D3] 9-24 months Median 64 months [I] 1611 vs. [D1] 1956 [D2] 323 [D3] 174 Total: 38% low, 40% int, 22 high NS . NS NS . . . . Boorjian et al. [I] <3 months [D] >3 months 5.4 years (IQR 2.2-7.9) [I] 2258 [D] 891 [I] 67% low, 27% int, 6% high [D] 76% low, 21% int, 3% high . . . NS . . . . O'Kelly et al. [I] <12 months, [D1] 12-18 months, [D2] >18 months NR 350 78.4% low 21.6% int/high . . . . . . . Gleason >= 7 17% vs. 35% vs. 82%, p<0.001
Loeb et al. [I] <12 months, [D1] 12-24 months, [D2] >24 months Median 8.1 years (IQR [I] 6864 [D1] 387 [D2] 347 [I] 70% low, 26% int, 2% high, 3% NR [D1] 59% low, 34% int, 3% high, 4% NR [D2] 47% low, 43% int, 5% high, 4% NR . NS . . NS . NS 12-24 months OR 1.64 (95% CI 1.32, 2.03), > 24 months OR 2.93 (95%CI 2.34, 3.68) I = immediate treatment group, D = delayed treatment group, NS = not significant, L = low risk disease, In = intermediate risk disease, high = high risk disease. B7) Table Safety of trans-rectal biopsy Study ID Patients Minor infection Major infection UTI Urinary obstruction Haematuria Others Anastasiadis et al. (2015) UK 198,361 . 1.1% 1.3% 1.4% Hospitalisation 3.7% Carignan et al. (2012) Canada 5,798 . 0.8% 0.8% . . Hospitalisation 0.5% Bacteraemia 0.3%
Nam et al. (2013) Canada 75,190 0.7% . . 0.1% . Hospitalisation 1.4% Bleeding 0.2% Roth et al. (2015) Australia 34,865 0.8% 0.09% 0.8% 0.1% 0.06% Haematoma 0.1% Prostatitis 0.05% Fever 0.006% Pinksy et al. (2014) USA 4,836 0.8% . 0.4% . Death 0.4% Rectal bleeding 0.3% Roberts et al. (2002) USA 1,776 2.7% . 1.3% 1.9% 12.1% Rectal bleeding 1.2% Haematospermia 0.5% Pain 2.0% Bacteraemia 0.1% Hospitalisation 0.4% Rosario et al. (2012) UK 1,147 . . . . 66.0% Rectal bleeding 37.0% Haematospermia 93.0% Pain 44.0% Fever 20.0% Simsir et al. (2010) Turkey 2,023 . 3.0% . . . Death 0.05% Zaytoun et al. (2011) USA 1,438 2.2% 0.2% . 0.8% 4.4% Rectal bleeding 1.5% Haematospermia 0.8% Helfand et al. (2012) USA 85 . . . . . Erectile dysfunction 11.8% Kariotis et al. (2010) Greece 434 . . . . 62% Rectal bleeding 51% Haematospermia 88% Marino et al. (2015) USA 455 . 2.4% 1.5% . . Bacteraemia 0.4% Hospitalisation 5.5% Mohammed et al. (2016) Ireland 286 . 0.4% . . . Petteffi et al. (2002) Brazil 105 . . 30%, 7% . . Fever 15%, 1% Hospitalisation 3.0%
Sahin et al. (2015) Turkey 480 6.9% 0.6% 6.2% . . Solberg et al. (2011) Norway, Sweden 875 . . . 21% . Pain 64% Utrera et al. (2011a) Spain 220 . . . Mild 24.1 %, Intense 0.9% . Bacteraemia 4.5% Bacteriuria 4.5% Fever 3.2% Hospitalisation 0.5% Utrera et al. (2011b) Spain 144 . 0.7% . 5.6% 0.7% Prostatitis 1.4% Rectal bleeding 0.7% Loeb et al. (2013) (Systematic review) 2,243 patients (11 studies) . . . . 27.9-63.0% Haematospermia 6.0-13.8% Rectal bleeding 11.5-39.0% Erectile dysfunction 2.2-91.3% UTI = urinary tract infection, . = not reported. Table Safety of trans-perineal biopsy Study ID Patients Infection Urinary obstruction Haematuria Hospitalisation Mild haematuria Others Mai et al. (2016) China 3,007 0.03% 1.9% 47% 2.1% 0.1% Haematospermia 6.1% Perineal haematoma 0.5% Rectal bleeding 0% Chang et al. (2013) Systematic review 8,044 patients (34 studies) 0.0% 0.4-38.0% 0.2-57.0% 0.7-1.4% . UTI 1.1-8.0% Fever 1.0-5.3% Loeb et al. (2013) Systematic review 3,203 patients (17 studies) 0.0% 1.6-20.6% 0.3-5.2% . 3.7-45.3% . UTI = urinary tract infection, NR. = not reported
Table Ongoing clinical trials Study identifier, population, country Title Inclusion Sponsor Target sample size Time frame Status Finish date Study type Population 1 Australia Can 3-Tesla Magnetic Resonance imaging of the prostate be useful in making the decision to perform prostate biopsy in men with a high or concerning PSA? Men with a high or concerning PSA, or abnormal prostatic rectal examination The Wesley Hospital 225 NR Recruiting NR III-3, diagnostic case-control study NCT01492270 Population 1 UK PICTURE - Prostate Imaging (Multi-parametric MRI and Prostate HistoScanning™) Compared to Ultrasound Guided Biopsy for Significant Prostate Cancer Risk Evaluation. Men who have undergone prior trans-rectal biopsies and are undergoing further evaluation for characterisation. University College London Hospitals NR 1.5 years Unknown – status has not been verified in more than two years NR III-3, diagnostic case-control study NCT02526797 Population 2 Denmark Multiparametric MRI in Men With Prostate Cancer Undergoing Active Surveillance Men with low risk localized PCa enrolled in active surveillance Herlev Hospital 150 3 months Enrolling by invitation June 2015 III-3, diagnostic case-control study NCT02485379 Population 1 France Improvement in the Detection of Aggressive Prostate Cancer by Targeted Biopsies Using Multiparametric MRI Findings Men referred for prostate mpMRI before a first set of prostate biopsies, with a planned time interval of less than 3 months Hospices Civils de Lyon 250 1 – 4 months Recruiting October 2916 III-3, diagnostic case-control study NCT02564549 Population 2 USA Multiparametric Active Surveillance to Avoid the Risks of Serial Biopsies in Men With Low-Risk Prostate Gleason score ≤ 6 Virginia Commonwealth University, Massey Cancer Center, Hunter 192 3 years Recruiting October 2017 III-2
Cancer (MAVERICK) Holmes Mcguire Veteran Affairs Medical Center NCT01292291 Population 1 UK PROMIS - Prostate MRI Imaging Study - Evaluation of Magnetic Resonance Imaging in the Diagnosis and Characterization of Prostate Cancer Men at risk of PCa who have been advised to have a prostate biopsy University College London Hospitals 714 NR Not yet recruiting April 2013 III-3, diagnostic case-control study NCT01858688 Population 1 USA A Phase II, Prospective Study of MRI in the Reclassification of Men Considering Active Surveillance in Prostate Cancer Men with histologically confirmed PCa with all of the following features: Min. 10 core prostate biopsy showing histologically-confirmed PCa within 12 months of enrolment; Gleason ≤3+3; No Gleason grade ≥4; ≤3 total cores positive; ≤50% of any given core involved with cancer; No evidence on biopsy of extracapsular extension; PSA within one month of enrolment: <10 ng/mL; Clinical stage: ≤T2a & N0 or NX & M0 Dana-Farber Cancer Institute 130 2 years Recruiting July 2018 III-3, diagnostic case-control study NCT02388126 Population 1/Other Finland Prostate Magnetic Resonance Imaging in Patient With Previous Negative Biopsies (PROMANEG) Men with clinical suspicion of PCa and/or previous negative prostate biopsies Turku University Hospital 150 3 months Recruiting February 2016 III-3, diagnostic case-control study
NCT02799303 Other Canada A Randomized Clinical Trial Comparing the Efficacy of MRI Versus PSA for Prostate Cancer Screening: The MVP Study (MRI vs PSA) ≤ 50 years of age Sunnybrook Health Sciences Centre NR 3 years Not yet open for June 2020 III-2 NCT02721784 Population 2 UK Serial mpMRI Scanning in Prostate Cancer After Androgen Deprivation Therapy and RadioTherapy (SMART) Men with biopsy confirmed PCa who had mpMRI scan of the prostate pre-biopsy University College, London 10 6 months Not yet open for January 2018 III-3, diagnostic case-control study NCT02524860 Population 1 Canada Targeted Prostate Biopsy Using a Novel Fusion Device in Patients With an Elevated PSA and a Positive Multiparametric MRI Candidates for fusion biopsy; Elevated PSA levels; mpMRI with lesions having a Prostate Imaging Reporting and Data System (PI-RADS) score greater than or equal to 3 Focal Healthcare Inc. NR 1 year Not yet open for July 2016 III-3, diagnostic case-control study NCT02380027 Population 1 UK PRostate Evaluation for Clinically Important Disease: Sampling Using Image-guidance Or Not? (PRECISION) Suspicious PSA and DRE University College, London 470 1 month Recruiting September 2017 III-2, single blind RCT NCT02745496 Population 1 UK Multiparametric Magnetic Resonance Imaging Characterization and Guided Biopsy of the Prostate in Men Suspected of Having Prostate Cancer Men aged 40-75 years, with suspicious PSA and/or DRE University of Dundee 600 4 years Recruiting January 2019 III-2 NCT02678481 Other Italy MR-targeted vs. Random TRUS-guided Prostate Biopsy in Patients With Patients with negative biopsy Fondazione del Piemonte per l'Oncologia 90 3 months Recruiting August 2016 III-2
High PSA Values and Previous Negative Biopsy Results: A Randomized Controlled Trial NCT01354171 Population 2 Canada Active Surveillance Magnetic Resonance Imaging Study (ASIST) Candidate for active surveillance Canadian Urology Research Consortium 250 1 year Unknown – status has not been verified in more than two years September 2014 III-2 NCT02053805 Population 1 Israel Personalized Prostate Cancer Screening Among Men With High Risk Genetic Predisposition- a Prospective Cohort Study Male carrier of mutation in BRCA 1\2 or germ-line mutations in the MMR genes (MLH1, MSH2 , MSH6 or PMS2) Rabin Medical Center 200 2 years Recruiting June 2018 III-3, diagnostic case-control study, screening population NCT02326246 Population 2 Denmark Multi-parametric MRI in the Diagnosis and Surveillance of Low-risk Prostate Cancer Men with low-risk PCa Aarhus University Hospital Skejby 60 1 year Recruiting February 2017 III-3, diagnostic case-control study NR = not reported, PCa = prostate cancer, MRI = magnetic resonance imaging, RCT = randomised controlled trial, mpMRI = Multiparametric MRI.