A double blind paired cohort study comparing multi-parametric ultrasound to multi-parametric MRI in diagnosing prostate cancer: the CADMUS trial

Background Multiparametric MRI (mpMRI) of the prostate followed by targeted biopsy is recommended in patients at risk of prostate cancer. Multiparametric ultrasound (mpUSS) is more readily available. mpMRI and mpUSS visualise tissue anatomy, density and vascularity. Whilst there has been a large body of evidence supporting mpMRI incorporating paired cohort validation and randomised controlled trials, the evidence for ultrasound modalities on their own and mpUSS includes case series. Methods We conducted a prospective multicentre, paired-cohort, confirmatory study to compare mpUSS and mpMRI in diagnosing clinically-important prostate cancer. Patients at risk of prostate cancer aged 18 years and over without an upper limit for age, with an elevated prostate specific antigen (PSA) level and/or an abnormal digital rectal examination underwent both tests at 7 UK hospitals, with conduct and reporting blinded to the results of the other. mpUSS consisted of b-mode, colour Doppler, real time elastography and contrast enhanced ultrasound. mpMRI included high resolution T2-weighted images, diffusion weighted imaging (b>1400 as well as ADC map) and dynamic contrast enhanced axial T1-weighted images. Patients with a positive mpUSS or mpMRI underwent targeted biopsies but were blinded to exact test results. If both tests were positive, the order of their targeting at biopsy was randomised using stratified (according to centre only) block randomisation with randomly varying block sizes. Co-primary outcomes were, a) proportion of positive mpMRI and mpUSS and b) detection of clinically-important cancer (Gleason>/=4+3 of any length or maximum cancer core length of >/=6mm of any grade). The study was registered on ISRCTN:38541912. Findings Between 15th/March/2016 and 7th/November/2019, 370 patients were enrolled with recruitment and follow-up completed; 306 completed both tests and 257 underwent a prostate biopsy. mpUSS and mpMRI were positive in 278/306 (88.9%; 95%CI=(84.8%, 92.2%)) and 238/306 (77.8%; 95%CI=(72.7%, 82.3%)) (difference +11.1% (95%CI=5.1,17.1%). Positive test agreement was 73.2% (95% CI=(67.9%, 78.1%), kappa=0.06). Cancer was detected in 133/257 (51.8%, 95%CI=(45.5%, 58.0%)) with 83/257 (32.3%; 95%CI=(26.6%, 38.4%)) clinically-important. Each test alone would result in mpUSS detecting 66/257 (25.7%; 95%CI=(20.5%, 31.5%)) clinically-important cancers and mpMRI detecting 77/257 (30.0%; 95%CI=(24.4%, 36.0%)) (difference -4.3%, 95%CI=-8.3%, -0.3%). Combining both tests detected 83 clinically-important cancers (32.3%; 95%CI=(26.6%, 38.4%)); of these, mpUSS detected 6 (7.2%; 95%CI=(2.7%, 15.0%)) missed by mpMRI and mpMRI detected 17 (20.5%; 95% CI=(12.4%, 30.8%)) missed by mpUSS (agreement 91.1%; 95%CI=(86.9%, 94.2%); kappa=0.78). mpUSS and mpMRI detected 36/257 (14%%; 95%CI=(10.0%, 18.9%)) and 44/257 (17%; 95%CI=(12.7%, 22.3%)) clinically-unimportant cancers (by definition 1), respectively. Interpretation mpUSS detected 4.3% fewer clinically-important prostate cancers compared to mpMRI although would lead to 11.1% more patients being biopsied. mpUSS is an alternative to mpMRI as a first test for patients at risk of prostate cancer, particularly where mpMRI cannot be carried out. Both imaging tests missed clinically-important cancers detected by the other, so using both would increase the detection of clinically-important prostate cancers compared to using each test alone