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  • RLE takes into account some of the random error associated with needle deployment; 3mm for transperineal biopsy, based on brachytherapy data . 5 and 10mm error for TRUS, but no data available on this. PSA (if asked) All men had normal DRE; Men had had PSA done (22.5% had PSA >4 ng/ml; 13 or 76% of cancers were among men with no PSA or PSA <4;
  • Biopsy techniques used: 12 core scheme 4 apical, 4 mid gland, 4 base (RLE of 10mm and 15 mm). Red dots on diagram above Optimised TRUS – 14 cores – standardised + 2 transition zone. RLE 5mm. Extended TRUS – addition of anterior (yellow) to TZ (red). 15 mm core length attributed to all simulations. 5mm template used; 3mm random localisation error (RLE) based on brachytherapy data. The orientation of prostate with regard to the template was estimated from patient modelled data from men undergoing template biopsy under GA at UCLH. Line defining apex-base was manually defined, and the rotation with respect to the plane of the USS was measured along with distance from apex of the prostate to the grid.
  • Graphical plot of the true positive on the y axis (sensitivity = true positive rate ie hit the tumour) versus the false negative rate ie don’t hit the tumor (1 – specificity) on the x axis. Area under the curve gives an indication of the utility of the test. 0.5cc chosen as a level of significance based on work of Stamey, assessing cystoprostatectomy specimens for previously undiagnosed disease, where a volume of 0.5cc correlated with a cut off which would identify the 8% of men with the largest volume of tumour. 8% was chosen as this was the percentage of US men deemed to develop clinically significant prostate cancer in their lifetime.
  • 0.2 cc volume chosen according to Epstein definition of clinically insignificant prostate cancer , where men undergoing radical prostatectomy for T1c disease were stratified into those with tumour of more or less than 0.2 cc, and the properative PSA and biopsy characteristics were taken as those which would select for insignificant disease (PSA density <1ng/ml with Gleason 3 + 3 only; intermediate PSAD 0.1 – 0.15 with <3mm low to intermediate gared on 1 specimen only).
  • 79/215 = 37% anterior 136/215 = 63% posterior Template guided transperineal biopsy has much greater utility in those men with anterior lesions.

Transcript

  • 1. Predicting focality Mark Emberton Division of Surgery and Interventional Science UCLH/UCL Comprehensive Biomedical Research Centre
  • 2. Predicting focality before RP?
  • 3. The Challenge Arnauld VILLERS Pierre NEVOUX Mark EMBERTON
  • 4. Distribution of prostate cancer foci 215 lesions / 96(104) prostates / 345 Cystoprostatectomy specimens
  • 5. Distribution of small foci (<0.1cc) 146/215 lesions
  • 6. Multi-focality / Location
  • 7. Mean distance (range) between the centers of the largest surfaces of lesions 1 and 2 Unilateral lesions: 18 mm [8 – 29] All multifocal lesions 23 mm [8 – 39]
  • 8. Observations
    • Cancer distribution free of verification bias
    • Median volume dominant lesion: 0.28 cc
    • Median volume of lesser 0.07cc
    • All high grade disease confined to dominant lesion
    • Unilateral cancer in 54%
    • 95% of contra-lateral lesions to the dominant lesion were Gleason 3+3 and </= 0.2cc
  • 9. Our current strategy of PSA - TRUS biopsy does not predict focality well
  • 10. TRUS detects clinically insignificant disease
    • Clinically insignificant cancers
    • are identified by chance
    • Important cancers are incorrectly
    • classified as unimportant
  • 11. TRUS guided biopsy misses important cancer
    • TRUS biopsies are done
    • in a blinded manner
    • They are subject to random
    • and systematic error
    • Means that they are ‘wrong’
    • about half the time
  • 12.  
  • 13. Methodology
    • Cystoprostatectomy series (346) from Lille, France
      • Prostate cancer in 96 (215 lesions in total)
      • Whole mount 3mm step section prostate pathology (Stanford technique)
      • Hand traced histological maps scanned and digitised
      • Computer generation of 3D models of tumour volumes within prostate volumes
      • 4 different biopsy techniques simulated (500 per prostate per technique)
      • Random localisation error (RLE) incorporated
      • Performance characteristics calculated
  • 14. Biopsy strategies Transrectal biopsies 1. Standard TRUS (a) : 12 cores 10mm RLE 2. Standard TRUS (b) 12 cores 15mm RLE 3. 14 (12 PZ + 2TZ) cores 5mm RLE 4. 18 (12 PZ + 6 Ant) cores 10mmRLE Template guided transperineal biopsy
  • 15. Accuracy of TRUS biopsy at detecting clinically important prostate cancer >/=0.5cc Lecornet et al. BAUS ONC 2010
  • 16. Whole prostate analysis Detection of 0.2cc lesions
  • 17. Accuracy of TRUS biopsy at detecting clinically important prostate cancer >/=0.5cc Anterior subset
  • 18. Kepner & Kepner. Theo Biol Med Modelling 2010
  • 19. Kepner & Kepner. Theo Biol Med Modelling 2010
  • 20. Can Maximum Cancer Core Length Involvement on Template Transperineal Prostate Mapping Biopsies Rule-in and Rule-out Clinically Significant Prostate Cancer?
    • Methods:
    • 126 RP step-section specimens 1999 – 2001
    • Scanned and digitized with tumours delineated
    • 3D reconstruction
    • Fixation related shrinkage taken into account
    • Computer TPM simulations conducted
  • 21. Accuracy values for ≥ 0.5 cc lesion detection for increasing cancer core length (CCL) thresholds Validity of biopsy max CCL against reference
  • 22. Accuracy values for ≥ 0.2 cc lesion detection for increasing cancer core length (CCL) thresholds Validity of biopsy max CCL against reference
  • 23. Is there an easier way?
  • 24. T2-Weighted
  • 25. Dynamic Contrast Enhanced
  • 26. 12 11 6 16 20 14 18 4 10 2 8 + No Gl Max + No Gl Max + No Gl Max + No Gl Max + No Gl Max + No Gl Max + No Gl Max + No Gl Max + No Gl Max + No Gl Max 15 5 17 13 19 9 3 7 1 Apex Base + No Gl Max + No Gl Max + No Gl Max + No Gl Max + No Gl Max + No Gl Max + No Gl Max + No Gl Max Gleason 4+4 CCLmax 4mm 1 of 2 cores +ve Targeted (24 cores)
  • 27. CLINICAL PHENOTYPE PSA 3.1-3.7 (PSAd=0.1) Prostate volume 30cc Normal DRE Positive FH TRUS biopsy negative (x2) Which has the greater validity / utility?
  • 28. A. Left para ant apex : Benign prostatic core with atrophy. B. Left para ant base : Benign prostatic core with atrophy. C. Right para ant apex : Benign prostatic core with atrophy. D. Right para ant base : Benign prostatic core with atrophy. E. Mid apex : Benign prostatic core with atrophy. F. Mid base : Benign prostatic core with atrophy. G. Left med ant apex : No specimen was received. H. Left med ant base : No specimen was received. I. Right med ant apex : No specimen was received. J. Right med ant base : No specimen was received. K. Left lateral : Benign prostatic core with atrophy. L. Right lateral : Prostatic core with focal high grade PIN. M. Left para post apex : Benign prostatic core with atrophy. N. Left para post base : Benign prostatic core with atrophy. O. Right para post apex : Benign prostatic core with atrophy. P. Right para post base : Benign prostatic core with atrophy. Q. Targeted anteroseptal : Adenocarcinoma Gleason 3+4 in 2 of 5 cores, 1mm (10%) and 4mm (40%). Interrogating the radiological phenotype
  • 29.
    • MICROSCOPIC DESCRIPTION
    • Left para ant apex : Benign prostatic core with atrophy.
    • B. Left para ant base : Benign fibromuscular core.
    • C. Right para ant apex : Benign prostatic core with atrophy.
    • D. Right para ant base : Benign prostatic core with atrophy.
    • E. Mid apex : No specimen was received.
    • F. Mid base : No specimen was received.
    • G. Left med ant apex : Prostatic core with focal high grade PIN.
    • H. Left med ant base : Adenocarcinoma Gleason 3+4 in 1 of 2 cores, 1mm (10%).
    • I. Right med ant apex : Benign prostatic core with atrophy.
    • J. Right med ant base : Benign prostatic core with atrophy.
    • K. Left lateral : Benign fibromuscular core including striated muscle.
    • L. Right lateral : Benign prostatic core with atrophy.
    • M. Left para post apex : Adenocarcinoma Gleason 3+3 , 2mm (20%).
    • N. Left para post base : Benign prostatic core with atrophy.
    • O. Right para post apex : Benign prostatic core with atrophy.
    • P. Right para post base : Adenocarcinoma Gleason 3+4 in 1 of 2 cores, 1mm (20%).
    • Q. Left med post apex : Prostatic core with focal high grade PIN.
    • R. Left med post base : Benign prostatic core with atrophy.
    • S. Right med post apex : Benign prostatic core with atrophy.
    • T. Right med post base : Benign prostatic core with atrophy.
    • U. Targeted mid post : Adenocarcinoma Gleason 3+4 overall in 5 of 5 cores, 2mm (15%), 4mm (50%), 5mm (30%), 5mm (40%) and 10mm (65%). Perineurial invasion is seen.
    Interrogating the radiological phenotype
  • 30. J Urol December 2006
  • 31. Villers et al. J Urol December 2006 Tumour vol 0.2cc 0.5cc Sensitivity 77% 90% Specificity 91% 88% PPV 86% 77% NPV 85% 95%
  • 32. The reference standard Clinically insignificant disease Gleason 3+3 and max CCL </= 3mm Indeterminate disease Gleason 3+4 and / or max CCL 4-5mm Clinically significant disease Gleason >/= 4+3 and/or max CCL >/+ 6mm Derived by 5mm template prostate mapping
  • 33. Ability of MRI to detect lesions conforming to 3 definitions of prostate cancer The Index test 1.5T MRI (no ERC) Sensitivity Specificity PPV NPV Pos LR Neg LR ROC AUC DEFINITION 1 Any cancer 0.5 0.86 0.79 0.6 3.8 0.6 0.7 DEFINITION 2 Gleason ≥ 3+4 CCL ≥ 4mm 0.75 0.83 0.55 0.88 4.8 0.3 0.83 DEFINITION 3 Gleason ≥ 4+3 CCL ≥ 6mm 0.84 0.77 0.39 0.97 3.7 0.2 0.85
  • 34. T2 weighted images
  • 35. Dynamic Contrast Enhancement
  • 36. Diffusion Weighted Images
  • 37. Reports on targeted sampling Authors Target generation Sampling Performance Turkbey et al. Cancer Imaging. 2011 Mar Mp-MRI TRUS Sn 0.61, Sp 0.73, AUC 0.67 Haffner BJU Int. 2011 Mar Mp-MRI TRUS Sn 0.95, Sp 1.0 Acc 0.98 Chen et al J Magn Reson Imaging. 2011 Feb MRI DIFF TRUS Sn 97%, Sp 98%, PPV 92%, NPV 99%, Acc 98% Franiel T Radiology. 2011 Apr Mp-MRI, MRI spec TRUS Detection rate 100% Negative Bx rate 0% Testa et al. NMR Biomed. 2010 Nov Mp-MRI, MRI spec TRUS AUC PZ 0.77 AUC TZ 0.82
  • 38. Registration of a deformable MR-derived model to TRUS images
    • Surface model extracted from diagnostic MR image(s)
    • Finite element analysis used to predict gland deformation
    • Statistical analysis used to produce a low parameter deformable model
    • “ Model-to-image” registration
    During procedure Before procedure
  • 39. Conclusions / discussion
    • To predict with 95% accuracy requires pre-specified sampling strategies
    • Image guided sampling will undoubtedly be the way forward provided we are happy to over-look lesser lesions
    • Image to image, non-rigid registration will be the enabling technology
  • 40. Minimally-Invasive Prostate Intervention (MIPI) Group Division of Surgery and Interventional Science, UCL Mr Mark Emberton (Professor and Consultant Urologist) Mr Hashim Uddin Ahmed (MRC Research Fellow) Miss Caroline Moore (Clinical Lecturer) Mr Paul Cathcart (NIHR Academic Clinical Lecturer) Mr Paras Singh (NIHR Academic Clinical Fellow) Miss Louise Dickinson (NIHR Academic Clinical Fellow) Miss Fiona McClean (Research Nurse) Miss Lucy Simmons (Research Fellow) Mr Adebiyi Damola (Research Fellow) Mr Sadat Quoraishi (Research Fellow) Department of Academic Radiology, UCLH NHS Trust Dr Clare Allen (Consultant Radiologist) Dr Alex Kirkham (Consultant Radiologist Dr Shonit Punwani (Consultant Radiologist) National Medical Laser Centre Professor Steve Bown Dr Sandy Mosse Department of Histopathology, UCLH NHS Trust Dr Alex Freeman (Consultant Histopathologist) Centre for Medical Imaging Science, UCL Professor David Hawkes Dr Dean Barratt (Royal Academy Senior Research Fellow) Mr Tim Carter (Post-doctoral Research Fellow) Mr Yipeng Hu (MSc Student) Clinical Effectiveness Unit, RCS(England) & LSHTM Professor Jan van der Meulen (Director) Cancer Institute Professor Stephan Beck Dr Chris Bell (Epigenomics group) Commercial Supporters Academic and Charity Supporters
  • 41. Minimally-Invasive Prostate Intervention Research Group
  • 42. [email_address]