M Emberton Professor of Interventional Oncology Division of Surgical and Interventional Sciences, University College London Screening, diagnosis and management

What are the challenges? Over-diagnosis (over-treatment) Missed diagnoses (under-treatment) Harms of therapy Escalating costs Nihilism Speed of change

DIAGNOSIS

TRUS detects clinically insignificant disease Clinically insignificant cancers are identified by chance Important cancers are incorrectly classified as unimportant

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

A sampling strategy predicated on chance 7

8

2009 Apr;6(4):

MICROSCOPIC DESCRIPTION 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%).

SCREENING

Welch’s screening conundrum, JAMA 2011 ‘small changes in cancer-specific mortality’ VERSUS ‘a boatload of hassle factors and fear, some unnecessary treatment, some resulting complications, and even a very few deaths (that can be missed in the measurement of cancer- specific mortality)’ 12 “My value judgment is simple: It’s an awful deal. I’m happy to forgo the test and accept that I may be the one man out of 1000 who could have benefited, simply to avoid these much more common harms”

Villers et al. J Urol December 2006 Tumour vol0.2cc 0.5cc Sensitivity 77% 90% Specificity91% 88% PPV86% 77% NPV85% 95%

15 Definition 2 – ≥ Gleason or any CCL ≥ 4mm ReporterSensitivitySpecificity Positive Predictive Value (PPV) Negative Predictive Value (NPV) R10.73 (0.63, 0.81)0.70 (0.67, 0.73)0.47 (0.41, 0.52)0.88 (0.83, 0.91) R20.58 (0.49, 0.67)0.83 (0.79, 0.86)0.55 (0.46, 0.63)0.85 (0.81, 0.88) R30.75 (0.63, 0.85)0.84 (0.78, 0.89)0.63 (0.52, 0.74)0.90 (0.85, 0.94) Area under curve Sensitivity: NPV: Sensitivity: NPV:

Definition 1 – ≥ Gleason 4+3 or any CCL ≥ 6mm ReporterSensitivitySpecificity Positive Predictive Value (PPV) Negative Predictive Value (NPV) R10.84 (0.71, 0.92)0.66 (0.64, 0.68)0.30 (0.25, 0.33)0.96 (0.93, 0.98) R20.63 (0.49, 0.76)0.78 (0.76, 0.80)0.33 (0.25, 0.39)0.93 (0.90, 0.95) R30.84 (0.68, 0.93)0.77 (0.71, 0.83)0.39 (0.29, 0.50)0.97 (0.92, 0.99) Area under curve Sensitivity: NPV: Sensitivity: NPV:

Usefulness of prebiopsy multiparametric magnetic resonance imaging and clinical variables to reduce initial prostate biopsy in men with suspected clinically localized prostate cancer. Numao N, et al. J Urol Mar 6. [Epub] In men with a PSA </=10ug/L a normal MRI was associated with a NPV of for clinically significant disease

TRUS biopsy versus mp-MRI in ruling out clinically significant prostate cancer? Negative Predictive Value MRI % TRUS biopsy %

Distribution of prostate cancer foci 215 lesions / 96(104) prostates / 345 Cystoprostatectomy specimens Nerveux, Emberton, Montrioni and Villers (J Urol 2012). NEGATIVE ?POSITIVE? POSITIVE NPV for clinically significant disease is 97%

TREATMENT

Lancet Oncology on line early 17 April 2012

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 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)

UCL Trials in Focal Therapy using HIFU Hemi-HIFU TrialFocal-HIFU TrialLesion Control HIFU Trial

“... 89% of men achieved the trifecta status of pad-free, leak-free continence, erections sufficient for intercourse and cancer control at 12 months.” Hemi-HIFU Trial J Urol Apr;185(4):

Lancet Oncology on line early 17 April 2012

Eur Urol April 2012

Functional outcomes Pad free rate 71/71 (100%) Erections sufficient for penetration (n=42) –74% at 12 months –86% at 27 months –7 (range 2-28) months time to recovery

Cancer control 1/71 men in field recurrence –Gleason 4 plus 4 –1 core positive, CCLmax 2mm 11/71 men had out of field recurrence –6 low risk –3 moderate risk –2 high risk

Vascular targeted photodynamic therapy European Multi-centre Phase III Randomised Controlled Trial Low risk disease Active surveillance versus Photodynamic therapy

6 month biopsy negative for cancer

THE FUTURE

Commercial systems Eigen Artemis: –3D TRUS-guided biopsy –Compatible with wide range of TRUS probes –Non-rigid, surface-based registration –MR-TRUS TRE ~3.1 +/- 1.4mm (Narayanan et al., 2009) –4-5mm (Cool et al. 2011) –Accounting for probe-induced prostate deformation after repositioning the probe for each biopsy sample can lead to a time- consuming procedure

Commercial systems MedCom/Pi Medical BiopSee® –3D-image-guided transperineal biopsy and therapy –Integrated solution –Rigid registration –Accuracy not fully quantified (Zagel et al. 2011)

PSA 6.7 Targeted biopsies – GLEASON 3+4 CCLmax 5mm – 3 of 4 cores positive Non-targeted biopsies –No cancer detected

Rubinsky, B., Onik G., Mikus, P. “Irreversible Electroporation: A New Ablation Modality - Clinical Implications.” Technology in Cancer Research and Treatment, Vol 6 No 1, pp 37-48, NanoKnife ® Irreversible Electroporation

Minimally-Invasive Prostate Intervention (MIPI) Group Division of Surgery and Interventional Science, UCL Prof Mark Emberton (Professor of Interventional Oncology) Mr Manit Arya (Consultant Urologist) Mr Paul Cathcart (Consultant Urologist) Mr Hashim Uddin Ahmed (MRC Research Fellow) Mrs Caroline Moore (Clinical Lecturer) Mr Paul Cathcart (NIHR Academic Clinical Lecturer) Miss Louise Dickinson (NIHR Academic Clinical Fellow) Miss Lucy Simmons (Research Fellow) Miss Nicola Robertson (Research Fellow) Mr Mohamed Abd-Alazeez (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) Dr Charles Jameson (Consultant Histopathologist) Centre for Medical Imaging Science, UCL Professor David Hawkes Dr Dean Barratt (Royal Academy Senior 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