Active Surveillance Current status and future directions. Laurence Klotz Professor of Surgery Sunnybrook Health Sciences Centre University of Toronto

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1 Active Surveillance Current status and future directions. Laurence Klotz Professor of Surgery Sunnybrook Health Sciences Centre University of Toronto

2 Case 1 60 year old healthy male, PSA 6, no family history, DRE 40 cc benign feeling prostate PSA increased to 8 over 2 years Biopsy: Gleason 3+3=6 in 4/12 cores (bilateral), 10-30% core involvement I am most likely to offer him 1. Radical prostatectomy 2. Brachytherapy 3. IMRT 4. Active surveillance 5. Other (Focal/cryo/HIFU)

3 Our world has changed over last decade Benefits of PSA unquestioned by urological community Enthusiasm for 5 ARI for chemoprevention (Thompson 2003) Optimism about Vit E and Selenium (SELECT) Benefit of RP on Pca mortality confirmed (SPCG-4, NEJM 2002) Menon RALP lecture SUO % of low grade Pca treated radically USPSTF Grade D recommendation on PSA screening (Chou et al Ann Int Med 2011) Chemoprevention dead FDA denies 5 ARI approval SELECT trial negative, increased Pca Vit E arm No impact of RP on all cause mortality and Pca mortality in PIVOT (Wilt, NEJM 2012) In US: Open RP on life support, >80% RALP Active Surveillance

4 Active Surveillance for low risk PCa What has changed (Klotz, Choo J Urol Urol, 167: 1664, 2002) g (,,, ) Greater recognition of overtreatment problem, wider acceptance of surveillance Molecular characterization of Gleason pattern 3 vs 4 Better understanding of nature of occult high grade disease New definition of clinically insignificant disease Better understanding of flaws of PSA kinetics Increasing data on multiparametric MRI New modelling studies Longer follow up of surveillance cohorts Randomized data on role of 5 ARIs

5 If the past quarter century has brought minimally invasive procedures, the next may bring the elimination of invasion. N Engl J Med 2012;366:

6 .strong consideration should be given to modifying the anxietyprovoking term cancer for this condition

7 US Preventive Services Task Force summary on PSA screening 10/2011: small to no reduction in 10 year prostate cancer-specific mortality; harms related to false-positive test results, subsequent evaluation, and therapy, including overdiagnosis and overtreatment. optimal screening intervals and PSA thresholds remain uncertain. The Task Force recommends against PSA- based screening a Grade D recommendation.

8 Laurence Klotz, Professor of Surgery (Urology) April 1, 2013 The US Preventive Services Task Force recommendation was a wake up call to the urological and radiation oncology communities that something had to change. Trends in Urology blog, submitted at request of R. Kirby Mr Sandy Tyndale-Biscoe April 2, 2013 Wake up call, eh? Apity it is at the expense of the thousands of men who ll die unnecessarily because their primary care physicians, not being specialists, and not understanding the complex issues, advise their patients not to know their PSA. I m not sure that wake up call is quite the term I d use; what about culpable homicide? There is an encouraging trend towards litigation by patients who are diagnosed with metastatic PCa having been earlier denied a PSA test by their doctors. My organisation has helped some of them. It s the only recourse in the face of the arrogance of those who argue that t a man is better off not knowing his PSA.

9 2 reactions to USPSTF Head in sand, or reduce overdx/overtreatment t t

10 NYT Oct from

11 Causes of overdiagnosis Redefinition of disease Imaging studies Screening tests

12 Effect of lower diagnostic thresholds on the number of sick Americans Disease Change in Old Disease New Thresholdh Prevalence Disease Prevalence New Cases Diabetes Fasting 11,700,000 13,380,000 1,620,000 14% Glucose Increase Hypertension Systolic 38,700, ,180,, ,480, % Diast Hyperlipidemia Osteoporosis in women Androgen deficiency Total Chol T score Total Testost < 11 nm (320 ng/dl) 49,480,000 92,127,000 42,647,000 86% 8,010,000 14,800,000 6,790,000 85% 20% of men > 70, 30% > 80 10,000,000

13 Problems of overdiagnosis Asthma Canadian study: 30% with diagnosis may not have asthma, 66% may not require medications Attention deficit hyperactivity disorder Widened definitions & overdiagnosis Boys born at end of the school year have 30% higher chance of diagnosis and 40% higher chance of medication than those born at beginning of year Breast cancer one third of screening detected cancers may be overdiagnosed Chronic kidney disease egfr definition classifies 1 in 10 as having disease concerns about overdiagnosis of many elderly people Gestational ti diabetes Expanded definition classifies 1 in 5 pregnant women High blood pressure Systematic review suggests substantial overdiagnosis High cholesterol up l to 80% with mild elevation cholesterol l overdiagnosed d Lung cancer 25% of screening detected lung cancers overdiagnosed Osteoporosis Expanded E d d definitions--many iti treated t low risk women have net harm from treatment Pulmonary embolism Increased diagnostic sensitivity detection of small emboli. Many may not require anticoagulant treatment Thyroid cancer Much of the observed increase in incidence overdiagnosis

14 Factors promoting overdiagnosis of cancer Welch H G, Black W C JNCI J Natl Cancer Inst 2010;102: Existence of a silent disease reservoir Activities leading to its detection, ie screening Long natural history hence modest cancer specific mortality

15 Two distinct patterns of rapid rises in the rate of diagnosis Welch H G, Black W C JNCI J Natl Cancer Inst 2010;102:

16 Rate of new diagnoses and death SEER 1975 to Epidemic or Epidemic or overdiagnosis?

17 Rates of new diagnosis and death for five types of cancer in the US, Epidemic or overdiagnosis? Moynihan R et al. BMJ 2012;344:bmj.e3502

18 Natural history of breast cancers detected in the Swedish mammography screening programme Zahl P et al Lancet Oncology 12 (12), , Nov , women screened x 6 yrs vs 320, controls screened at study end Screened group: Higher 6-year incidence of invasive cancer 1443 per vs 1269 per ; RR 1 14 Expected Observed Disappeare d cancers

19 10% of impalpable 2 cm breast cancers, 50% of 1 cm cancers, and 99% of 1 mm cancers disappear S. Narod, Professor of Epidemiology, Dalla Lana School of Public Health, University of Toronto

20 Extended lung cancer incidence follow-up in the Mayo Lung Project and overdiagnosis. Marcus PM et al, JNCI Jun 7;98(11): Randomized trial of CXR and sputum cytology screening End point lung cancers detected at 6 years, 46 extra cancers in screened group.

21 Drivers of overdiagnosis Technological l changes detecting ti ever smaller abnormalities Sincere interest in finding/preventing life threatening disease Commercial and professional vested interests Conflicted panels producing expanded disease definitions and writing guidelines Legal incentives that punish underdiagnosis but not overdiagnosis Health system incentives favouring more tests t and treatments Cultural beliefs that more is better; faith in early detection unmodified by its risks

22 Prevalence of invasive prostate cancer in men dying of trauma. Sakr W, Eur Urol 30:138, /1/2014

23 Prevalence of Autopsy Prostate Canceron Unscreened Caucasian and Asian Men Zlotta A, Klotz L, Egawa S, Pushkar D JNCI J Natl Cancer Inst Jul 17;105(14): Asian and 226 Russian men dying of other causes Unscreened PCaPrevalence 35 and 37% Age % with Gleason 7 Asian N % Russian N % /1 0 4/ /8 25 4/ / /34 29

24 Hallmarks of Cancer Hannahan and Weinberg, Cell 2011

25 Molecular pathways mediating the hallmarks of cancer Adapted from Hanahan and Weinberg, Cell 2011 Dysregulated cellular energetics Avoiding Immune destruction

26 Emerging hallmarks and enabling characteristics Hanahan and Weinberg, Cell 2011

27 Gleason 3 lacks hallmarks of cancer Characteristic/Pathway Gleason 3 Gleason4 Expression of pro-proliferation embryonic, neuronal, hematopoietic stem cell genes, EGF, EGFR No Overexpressed AKT pathway: MAP2K4, RALA, PHLPP, PML No Aberrant HER2/neu No Amplified Insensitivity to Antigrowth signals (Cyclin D2 methylation, CKDN1β) Expressed Absent Resisting apoptosis: DAD1 Negative Strong Exp BCL2 Mostly Neg. Upregulated Absence of senescence: TMPRSS2-ERG ERG normal Increased Sustained angiogenesis: VEGF Expression of other pro-angiogenic factors, microvessel density Expression low Normal Increased Increased Tissue invasion/metastasis markers (CXCR4, others) Normal Overexpressed Clinical evidence of metastasis/mortality Absent Present

28 20 Year Prostate Cancer Specific Mortality After Radical Prostatectomy. Eggener S, Scardino P, Walsh P et al N=23,910 12,000 Gleason 2-6 Risk of Pca death after RP in men age 60-69: 02%at20 0.2% 20 years (although significant PSA failure rate) J Urol 185 (3), March 2011

29 Does Gleason Score <=6 Metastasize to Lymph Nodes? Ross HM et al American Journal of Surgical Pathology 36(9), September 2012, p ,123 cases of path. confirmed Gleason 6 22 cases with positive LN. 100% of these had higher grade than originally reported NOT A SINGLE CASE of confirmed Gleason 6 tumor with LN mets

30 PIVOT Prostate cancer survival Wilt T et al, NEJM 367;3, July 2012:

31 But biology is rarely so black and white

32 The clonal origin of lethal prostate cancer Haffner M, Yegasubramanian et al, JCI, epub Oct year old male, RP 1995: Gleason 4+3 pt3a N1 Died of CRPC 2012; Warm autopsy acquisition of 7 metastatic sites Whole-genome sequencing & molecular profiling Whole-genome sequencing & molecular profiling Small Gleason 3+3 focus source of original metastasis (lung)

33 The clonal origin of lethal prostate cancer Haffner M, Yegasubramanian et al, JCI, epub Oct

34 Linear vs bifurcated models of Pca development (Droller M et al 2012) Haffner

35 Rate of upgrading from time of diagnostic biopsy Slope = 1.0%/year

36 Analysis of the Tumor Volume Threshold for Clinically Insignificant PCa from ERSPC. Wolters T, Roobol M, Schröder F, van der Kwast T. J Urol 185, , Stamey 1982 Wolter et al, ERSPC 8% incidence of clinical Pca Diagnosis rate in 8% of cysto-prostatectomy unscreened arm 50% of specimens had > 0.5 cc Gleason that t in screened arm 3 or some 4 Volume of 325 RP Cancers 4/3πr 3 =1.0cc diameter sphere Threshold volume = 1.3 cc (1.4 cc diameter sphere) for Gleason 6 4/1/ cm

37 For Which Older Men is Surveillance a Safe Management Option? Low risk (D Amico) Stage T1c/T2a PSA <10ng/ml Gleason score <6 Very low risk (Epstein) Stage T1c PSAD <0.15 Gleason score <6 <3 cores with cancer <50% core involvement Favorable Risk

38 National Comprehensive Cancer Network Practice Guidelines RECURRENCE EXPECTED INITIAL RISK SURVIVAL THERAPY Very Low (Epstein Criteria) <20 yr Active Surveillance Preferred Low Risk >20 yr 1) Active Surveillance (D Amico Criteria) >10yr 2) Radiotherapy 3) Radical Prostatectomy Mohler et al, J Natl Compr Canc Netw. 2010

39 Predictive factors for upgrading: Volume counts. Toronto cohort. Higher volume Gleason 6 predicts for increased risk of higher grade cancer Multivariate Model Variable OR 95% CI p-value Clinical T-stage (T2 vs T1) Higher PSA at baseline % cores involved <.0001 at diagnostic biopsy

40 Predictive factors for Gleason upgrading in candidates for active surveillance: Tosoian J, Epstein J, Carter HB et al, J Urol 2013 N=7,486 RPs since 1975 with LR or VLR disease LR Low risk VLR Very low risk

41 Factors predicting upgrading in a Swedish RP cohort Bratt O, Klotz L et al JCO N=1286 low risk patients OR 95% CI p-value Clinical i l stage T1c 1.00 ( Reference ) T ( ) No. of positive biopsies ( Reference ) ( ) ( ) < ( ) 0.02 Cancer extent < 4mm 1.00 ( Reference ) 4 8mm 1.21 ( ) mm 1.69 ( ) < mm 1.88 ( ) <0.001

42 Factors predicting upgrading in a Swedish RP cohort Bratt O, Klotz L et al JCO Cancer extent and pos cores

43 Medium-term Outcomes of Active Surveillance for Localised Prostate Cancer: Selvadurai E, Parker C et al European Urol Feb N=471 Median f/u 5.7 yr 27 deaths 2 from Pca Both had early upgrading Adverse histology=gleason 4+3 or PPC > 50%%.

44 Predicting adverse pathology in 4,500 low risk men from NPCR who underwent RP: Vellekoop A, Stattin P et al, The Journal of Urology, Volume 191, Issue 2, 2014,

45 How?

46 Selection criteria for active surveillance Author Dall Era Gleason Positive %core score cores involvement 6 (no 4 or 5 pattern) % positive PSA PSA density cores <33 <10 2a Ercole 6 2 <50 <10 2a Klotz 6 10* 2b Soloway Tosoian 6 2 <50 <0.15 1c Ischia 6 <10 2a Bul Godtman 6 <10 2a Thomsen 6 3 < a Selvadurai 6 50 <15 2 ct stage

47 Follow-up Toronto and PRIAS (Rotterdam) DRE/PSA every 3 months for 2yrs, then every 6 months Biopsy 6-12 months after enrollment, then every 3-5 yrs Johns Hopkins DRE/PSA at 6 month intervals Biopsy annually until age 75yrs

48 Progression criteria used in active surveillance Publication Gleason Positive % of core % pos PSAdt score* cores involved cores (years) PSAv (ng/ml/ye ar) ct stage Dall Era Increase >0.75 Ercole Progression Increase Increase Change Klotz 4+3 <3 Increase Soloway (grade) >3 >2 Tosoian >6 >2 >50 Ischia Upgrade * Upstage Bul Godtman Upgrade * Upstage Thomsen 3+4 >3 <3/5* Increase Selvadurai >50 >1 *Patients with PSAdt<3 years were recommended curative treatment while treatment options were discussed with patients with a PSAdt 3-5 years

49 Comparing PSA Triggers for Intervention in Men With Stable Prostate Cancer on Active Surveillance Loblaw A, Klotz L J Urol 184(5) 1942 (2010) 305/453 men whose disease was stable by all criteria No metastasis, t no radical intervention, ti no upgrading to > 3+4 PSA trigger Percent triggered ( Median # of times triggered PSA DT < 3 yrs by linear regression 50% 3 PSA velocity > 2 ng/ml/yr 42% 3 1 year PSA Vel > 2 51% 2 PSA > 10 38% 3 PSA > 20 13% 1

50 Systematic Review of Pretreatment PSA Velocity and Doubling Time As PCA Predictors. Vickers A J Clin Oncol 27: Studies with > 200 patients Author Study Performance of PSA velocity vs PSA Eggener 995 neg initial bx PPV Velocity 3% higher Djavan 559 Bx result Worse AUC Sun Ca screen Worse AUC (Verification bias) Moul Ca screen Worse AUC Carter 980 Ca death long term Velocity AUC 0.75 vs PSA 0.74 Berger 4800 Ca screen Velocity 0.87 vs PSA 0.65 (VB) Whittemore 320 Ca death long term Worse AUC Loeb 6844 Ca screen AUC 0.83 vs 0.81 (VB) Thompson 5519 Bx in PCPT No difference Verification bias (VB): Men not having a biopsy assumed to be cancer free Little evidence that pretreatment PSA velocity or doubling time are of value for early-stage prostate cancer.

51 Toronto cohort: Intervention free survival N=840

52 Toronto Cohort overall survival 2014 N=840

53 Proportion discontinuing surveillance at 3, 5, and 10 years Publication, year Study design No patients Median Median T follow-up from Dx (years) to Rx 5 years (%) 10 years (%) Pca mortality Dall Era P Na 0 Ercole R Na 0 Klotz P NR Soloway R Na 0 Tosoian P Ischia R (mean) Bul RP /40 50/70 0 Godtman RP NR Thomsen P NR 40 Na 0 Selvadura i 3% 10 yr P Na 2% 8 yr Ttl 4453

54 PRIAS results: Active therapy free survival over time Bul et al, European Urology 63 (4) April 2013:

55 Prostate cancer survival with active surveillance Age > or < 70

56 Time to PSA failure as a proportion of all patients 6.3% of cohort had PSA failure after surgery or radiation

57 22/993 men developed metastasis Overall Survival in this group Median: 7.3yr

58 Cox Regression Analysis p-value Odds ratio 95%CI Age Age 70 vs 70< PSA PSA 10 vs 10< Clinical Stage T1 vs T Treatment PSADT 3y vs 3y< PSADT 2y vs 2y< Primary Biopsy GS 6 vs Positive core 2 vs 2< Positive Core rate 50 vs 50< Confirmatory biopsy N/A vs Available GS 6 vs 7 vs Positive core 2 vs 2< Positive Core rate 50 vs 50<

59 Time from diagnosis to post-treatment PSA failure

60 RP Pathology Is Favorable in Men Following Initial Active Surveillance Hong SK, Toujier K, Eastham J et al Euro Urol Epub Aug 2013

61 Cumulative hazard ratio for prostate cancer and other cause mortality Overall Stratified by age or > 70

62 Prospective active surveillance studies Median Freedom from bned after deferred Prostate cancer Mortality from other Study n follow up yr treatment treatment mortality % causes UCSF % at 5 yr 1 recurrence at 3 yr 0 0 University of 10 yr OS: Toronto % at 5 yr 5 yr bned: 47% 3% at 15 yr 68% Multicentre PRIAS % at 2 yr No data 0 4 yr OS: 87% University of Miami % at 5 yr No recurrences 0 No data Johns 90.6% recurrence free 1.8% of Hopkins % at 5 yr at 2 yr 0 cohort Royal Marsden % at 5 yr 85% PSA failure free at 5 yr 2% at 8 yr 9% at 8 yr

63 Comparison of mortality outcome: Surveillance vs radical treatment with propensity score analysis. Stephenson A, Klotz L et al ,881 men treated between AS, 6485 RP, 2264 XRT, 1680 Brachy AS: 71% low risk, 16% intermediate, 5% high Radical Rx: 57% low, 31% int, 12% high Increased all cause mortality in treated group HR1.5 (XRT and brachy, not RP) No difference in prostate cancer mortality

64 Multivariable competing risk regression analysis Cancer specific mortality Other cause mortality HR CI P Value HR CI P Value Radical Therapy vs. Active Surveillance Year of Diagnosis < Age at Diagnosis PSA at Diagnosis Clinical Stage Biopsy Gleason Score Comorbidity < T2b vs T1ab T2c vs T1ab T3 vs T1ab vs < vs < Mild vs. None < Moderate vs. None < Severe vs. None < 0.001

65 Threshold Analysis of Utility of Active Surveillance and Probability of Prostate Cancer Specific Death (PCSD) x Hayes, J. H. et al. JAMA 2010;304: Copyright restrictions may apply.

66 PRIAS results: Bul et al, European Urology 63 (4) April 2013: Reason for deferred therapy in 527 treated patients Treatment type No. (%) Radical prostatectomy 253 (48.0) Radiotherapy 238 (45.2) Hormonal therapy 8 (1.5) Other* or unknown therapy 28 (5.3) Reason for treatment t t Protocol based 387 (73.4) Gleason score >6** 61 (15.8) More than two positive cores 146 (37.7) Gleason score >6 and more than two positive cores 99 (25.6) PSA DT <3 yr 81 (20.9) Anxiety 47 (8.9) Other*** 93 (17.6)

67 Outcome of repeat biopsies (N=592) Toronto Cohort

68 RP vs WW in Early PCa Bill-Axelson A, Holmberg L NEJM 364;18, May NNT 15; 7 for men < 65 yrs

69 Mortality in low risk disease Scandinavian trial vs Sunnybrook active surveillance. Klotz L, Thompson I NEJM 265(6): Low Risk Disease Active surveillance

70 Long term quality-of-life outcomes after radical prostatectomy or watchful waiting: SPCG-4 randomised trial Johansson E, Gunnar Steineck. Lancet Oncol 12(9), 891, 2011 No difference in any measure of psychological functioning Between RP and WW group at 12 years

71 Dutasteride in surveillance: time to pathological progression 302 patients t randomized d between dutasteride t and placebo Biopsy Biopsy Relative Risk Reduction 44.3% 57.4%% P = P = REDEEM: DS Figure 7.1, Table 7.4

72 5 ARIs in surveillance. Chiang A, Klotz L et al, CUAJ 2013, 7(11-12), 12) men on AS placed on 5 ARI, 3 PSAs pre and post treatment. Median F/U 6 years Median PSA DT pre treatment 56 months, post treatment 25 months Percent change in pre 5 ARI vs post-nadir PSA DT

73 How we can do surveillance better 1. Broader inclusion (Gleason 3 + small amount of 4)

74 Challenges in active surveillance Classification To risk stratify accurately Responsiveness To detect change when it occurs Harm reduction To reduce the burden of the biopsy

75 Limitations of current approach Systematic biopsy: Doesn t exclude significant cancer May overdiagnose some clinically insignificant disease Urosepsis rate after biopsy 4% Many men elect treatment without objective change in disease Men don t like it PSA limitations Labile analyte Unreliable DRE: normal in most men on surveillance

76 Case 2 60 year old healthy male, PSA 8, no family history, DRE 40 cc benign feeling prostate Biopsy: Gleason 3+4=7 in 2/12 cores, 10-15% core involvement, 10% pattern 4 I am most likely to offer him 1. Radical prostatectomy 2. Brachytherapy 3. IMRT 4. Active surveillance 5. Other (focal/cryo/hifu)

77 Difference between original and modified (2005) Gleason scoring system

78 Effect of tangential cutting on Gleason grade 25% of surveillance candidates Condordance between GU pathologists for these lesions 27% McKenney ey J, Carroll P J Urol (2), pg

79 Modified Gleason scoring 2005: Grade inflation Reference Traditional Gleason Modified d Gleason Helpap Gleason 6 48% 22% Gleason 7 26% 68% Billis Gleason 6 68% 49% Gleason 7 26% 39% Helpap B Virchows Arch 2006 Dec;449(6):622-7 pp ; ( ) Billis A J Urol Aug;180(2):548-52

80 1 Gleason score not predictive of progression in surveillance cohort: Choo R, Klotz L J Urol 167(4):1664-9

81 Slide 80 1 Laurence Klotz; 17/02/2012

82 Time to progression for patients with low- and intermediate-risk risk prostate cancer on surveillance. 90 men with intermediate risk disease 1/3 had Gleason 7, 2/3 PSA > 10 No difference in any outcome compared to low risk Cooperberg M R et al. JCO 2011;29: by American Society of Clinical Oncology

83 How we can do surveillance better 2. Earlier identification of high risk patients

84 Pathology at RP by Race in men managed with surveillance followed by RP Sundi D, Epstein J et al. J Urol 191 (1) 2014: Dominant nodules Very low risk Very low risk upgraded

85 The role of multiparametric MRI in managing early prostate cancer 1. Not readily available; I don t use it. 2. Would use it more, but cost prohibitive 3. Unsure of its role; use selectively for staging g 4. Use routinely in men considering surveillance 5. I obtain it in all newly diagnosed patients

86 Multiparametric Prostate MRI = Comprehensive Morphologic/Biologic l i Imaging T2w-MRI DCE-MRI 3D- 1 H-MRSI DW-MRI (ADC) Morphology Perfusion Metabolism Cell Density/Grade

87 Diffusion weighted image and grade. Hambrock et al, May 2011 Radiology, 259,

88 Potential for MRI in active surveillance

89 Biopsy Missed Tumors (Anterior/Base/Apex) 30% 70% Copyright Radiological Society of North America, 2007 Choi, Y. J. et al. Radiographics 2007;27:63-75

90 Central Gland Tumors 30% of tumors involve the central gland central zone + transition zone + periurethral glands

91 T2 ADC DCE MRI k ep map

92 Can we target a prostate cancer tumour on MRI TARGET: 2/5 cores positive: 1 and 4mm CCLmax Gleason (20%) NON-TARGET 28 cores negative

93 64-year-old PSA 3.7 ng/ml, one positive biopsy core Gleason 6. All MR images negative. RP: Gleason 6 pt2 T2WI DWI DCEI

94 66-year-old, PSA 4.81 ng/ml, one positive biopsy core Gleason T MRI: decreased T2, DWI, and abnormal DCE left PZ. RP: Gleason 7 (3+4), pt2

95 388 men low D Amico risk score MRI and confirmatory biopsy within 6 months of initial biopsy MRI 1-2/5 0-4% upgrade (NPV 97%) MRI score 5/ % upgrade 94

96 60 men with biopsy suitable for AS Negative MRI: 38% Concordant MRI: 40% Discordant MRI: 22% (13/60) of which 10/13 (77%) showed upgrade on confirmatory biopsy

97

98 Template vs MRI targeted biopsy Characteristic MRI-Targeted Template Prostate Biopsy Biopsy Total number of cores, n Number of cores per patient, median (IQR) Median sampling density, number of biopsies/ml of prostate t (IQR) Number of cores positive for any cancer, n (proportion of total cores) 5 (4-6) 30 (22-53) 0.11 ( ) 0.88 ( ) 356 (38.2%) 971 (13.5%)

99 Cancer Detection Rates: Clinic cally Signif ficant Clinically Significant Template Biopsy Clinically Insignificant All Cancer: 78% Clinically Significant Cancer: 64% Clin nically Insig gnificant MRI- -Targe eted Biops sy No cance er No cancer Totals Totals

100 Commercial systems Eigen Artemis: 3D TRUS-guided biopsy Compatible with wide range of TRUS probes Non-rigid, surface-based registration ti 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

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

102 Tumour targeting using the SmartTarget TM system

103 Systematic versus image-guided guided biopsies Systematic TRUS biopsy Gleason 3 plus 4 1 of 12 cores +ve CCLmax 3mm

104 Systematic versus image-guided guided biopsies Image-guided biopsy Gleason 4 plus 4 100% positive CCLmax=8mm

105 Risk shift using targeted biopsies Robertson NL et al. Eur Urol. 2013

106 Active Surveillance Magnetic Resonance Imaging Study (ASIST TRIAL) Laurence Klotz (study chair) 1 Andrew Loblaw (co-chair) 2 Masoom Haider (co-chair) 3,4 Aaron Fenster 6 Linda Sugar 7 Theo Van der Kwast 8 Robert Bristow 9 Danny Vesprini 2 This study was funded by an Ontario Instit of Cancer Research gr

107 ASIST Trial Summary Randomize (within 6-12 months of initial diagnostic biopsy) ARM 1 Active surveillance with core biopsy at 9 months (6-13 months) after initial biopsy, and serial PSA determinations ARM 2 Active surveillance with MR imaging and guided biopsy at 9 months (6-13 months) after initial biopsy, and serial PSA determinations Pathologic Upgrading N of pts having treatment Clinical i l stage Number, size, location of radiographic lesions PSA failure post treatment Clinical progression 275 bj t ill b d f th ti i ti C di U l R h 275 subjects will be accrued from three participating Canadian Urology Research Consortium (CURC) sites in an estimated time of 2 years. Primary analysis is planned one year after study recruitment is

108 Modern challenges in active surveillance Classification To risk stratify with precision Responsiveness To be able to detect change when it occurs Prediction To reduce the burden AS

109 Stable on surveillance Gleason Targeted 3/4 cores positive CCLmax 5mm

110 2009 Progression on surveillance year old man <5% cancer on TURP. MRI 2009, PSA 0.9. PSA rose to 2.6 in Increase in size of right PZ lesion, particularly marked on diffusion

111 PCA3 score association with pathological findings References No. Men Insignificant PCa p Value <.05 Tumor Vol Less Than 05cm p Value <.05 Gleason Score 7 p Value <.05 Auprich 160 No Yes Yes No Whitman 72 No Yes No Yes Nakanishi 83 No Yes Yes No Liss 100 Yes N/A No No Hessels 70 Yes No No N/A van Gils 62 Yes Yes No No Extracapsular Extension p Value

112 Genetic markers for assessment of risk of developing prostate cancer, and for screening, prognosis, and prediction of response to therapy

113 PSA, TMPRSS2:ERG, and PCA3, alone and in combination, for prediction of high Gleason grade ( 7) Lin D W et al. Clin Cancer Res 2013;19: by American Association for Cancer Research

114 If you tell someone they are on fire, they run for a fire extinguisher. We need to communicate a difference message. 4/1/2014

115 Likelihood of a low risk Pca patient being managed by surveillance, by urologist. Hoffman K et al JCO % of patients offered surveillance were managed by care of 3.5% of urologists.

116 Multidisciplinary care and choice of active surveillance Aizer A, D Amico A, JCO 2012 Multidisciplinary clinic doubled the number choosing surveillance

117 Favorable risk disease is heterogeneous Pseudo-disease Evasive anterior cancer Carey map cm 4/1/2014 Favorable but significant

118 Surveillance vs focal vs radical Surveillance Gleason 6 and microfocal or older patients Radical Treatment Most Gleason 7 (4+3 unifocal or 3+4 multifocal) Focal Therapy Gleason 6 with large volume, or Gl 7, unilateral 4/1/2014

119

120 Focal Therapy: Concept Novel imaging and precision biopsy can identify those lesions that are likely to progress Selective therapy to Clinically significant lesions alone will be as effective as whole-gland treatment with less harm

121 Trifecta rate after focal HIFU. Ahmed H, Emberton M et al Lancet Oncology (June 2012), 13 (6), pg Hashim U Ahmed

122 MRI and surveillance: Challenging questions Should men with Gleason 6 and MR visible disease > ~1 cm remain on surveillance? Should MRI be used as a trigger for biopsy or for treatment in men on surveillance? Is biopsy still required if MRI negative? How often should MRI be performed? Role of biomarkers?

123 AS: Current approach Offered to Gleason 6, PSA 10 (accepted by most) Increased volume of Gleason 6 a marker for higher h grade disease, not necessarily intervention PSA kinetics a guide only Confirmatory biopsy within 1 year, targeting g anterior/anterolateral horn Repeat biopsy q 3-5 years (age, risk tolerance, PSA) to 80 MP-MRI for PSA DT < 3 years or volume increase or 3+minor element 4 Consider treating if significant Gleason 4 or PiRADS 5 lesion > 1.3 cc on MRI

124 The future of active surveillance Screening will be image/risk factor based, hence many fewer biopsies and fewer clinically insignificant cancers. Avoid cancer diagnosis in low risk patients In favorable risk disease: Imaging/biomarker to identify aggressive disease at diagnosis Must be affordable, widely available, reproducible In intermediate risk disease: indolent variant identifiable at diagnosis i Goal: NNT = 1.0

125 University of Toronto UroOncology Fellowship Clinical and research training program Experienced UroOncologist faculty Dr. Anthony Finelli Dr. Neil Fleshner Dr. Rob Hamilton Dr. Michael Jewett Dr. Girish Kulkarni Dr. Laurence Klotz Dr. Rob Nam Dr. John Trachtenberg Dr. Alex Zlotta Rotations in Medical and Radiation Oncology Laparoscopic /Robotic training SUO Accredited d One clinical year and up to two research years with graduate degree opportunity Remuneration includes: Salary, travel expenses, tuition if necessary Contact Laurence.klotz@sunnybrook.ca University of Toronto