Sorveglianza Attiva update

Sorveglianza Attiva update Dr. Sergio Villa Dr. Riccardo Valdagni

www.thelancet.com Published online August 7, 2014 http://dx.doi.org/10.1016/s0140-6736(14)60525-0 the main weakness of screening is a high rate of overdiagnosis (41%) p 0.0007 21% relative reduction in prostate cancer mortality 27% relative risk reduction estimates of cumulative prostate cancer mortality one prostate cancer death averted per 781 men invited (NNI) and 27 excess cases detected (NND)

Not one patient with pathologically confirmed Gleason 6 only has ever died of metastatic prostate cancer Klotz M, 15-year prostate cancer mortality for conservative management of screendetected prostate cancer ranged from 0 to 2% for Gleason scores < 7 pre-screening era! screening era!

October 1989 February 1999 PCM - surgery (vs WW) at 10 ys relative risk : 0.56 absolute difference : 5.3% NNT to prevent one death > 20 PCM - surgery (vs WW) at 18 ys relative risk : 0.56 absolute difference : 11.0% NNT to prevent one death = 8 The goal: NNT = 1

Surgery (vs WW): 2.6% absolute risk reduction in mortality 12y NNT treat is ~34.5 to prevent 1 Pca death As compared with the SPCG-4, PIVOT enrolled a higher percentage of men with nonpalpable tumors (stage T1c, 50% vs. 12%) and with PSA values of 10 ng/ml November 1994 January 2002

Observation Involves monitoring the course of cap with the expectation of providing palliative therapy when symptoms develop or a change in exam or PSA results suggest symptoms are imminent The goal is to maintain QoL by avoiding curative treatment when prostate cancer is unlikely to cause mortality or significant morbidity Observation is applicable to elderly men or frail patients with comorbidity that will likely out-compete cap The main advantage is avoiding possible side effects of unnecessary definitive therapy or ADT Patients may be at risk for urinary retention or pathologic fracture without prior symptoms or increasing PSA level

Active Surveillance Involves actively monitoring the course of the disease with the expectation to intervene if the cancer progresses The goal is deferring treatment and potential side effects Active surveillance is mainly applicable to younger men with seemingly indolent cancer The advantages include: 1) avoiding the side effects of definitive therapy that may not be necessary 2) retaining QoL and normal activities 3) ensuring that small indolent cancers do not receive unnecessary treatment 4) decreasing initial costs The disadvantages include: 1) increased patient anxiety of living with an untreated cancer 2) the requirement for frequent medical examinations and periodic prostate biopsies

Clinical Data on CSS N of pts median age / f-up (mos) CSS (%) Roemeling (Netherland) 2006 278 70 / 41 100-8yr Dall Era (UCSF) 2008 321 63 / 43 100 Stattin (Sweden) 2010 1085 65 / 120 97.6-10yr Klotz (Toronto) 2010 450 70 / 82 97.2-10yr Soloway (Miami) 2010 230 63 / 44 100 PCM at 7-10 yr median f-up: 0-2.8% Adamy (MSKCC) 2011 238 64 / 22 100 Tosoian (JHU) 2011 769 66 / 32 100 Ischia (PRIAS Australia) 2012 154 63/nas 100 Bul (PRIAS) 2013 2454 66 / 19 100 Thomsen (Copenhagen) 2013 167 65/41 100 Salvadurai (R. Marsden) 2013 471 66 / 68 99.6 Valdagni (INT-Mi) 2013 454 66 / 37 100 Godman (Sweden) 2013 439 65 / 72 99.7

Radical Prostatectomy Findings N of Pts Organ confined SM+ Capsular penetration pn1 Klotz et al 2006 24 Duffield et al 2009 48 59% (also GPS 7) 65% (also GPS 7) n.r. n.r. 8% 15% 35% 4.2% Eggener 2009 26 85% 8% 15% 4% v.d. Bergh 2010 69 nr 20.6% 11.8% 2-3% Trock et al 2010 110 (vs 348 PR) 73% (vs 85%) n.r 22% (vs 14%) 2% (vs 0.3%) Dall Era et al 2010 33 (vs 278) 79% ( vs 90%) 18% (vs 12%) 21% n.r. Cooperberg et al 2011 74 (vs 148) 68% (77% LR) (vs 77%) 15% (vs 9%) n.r. 0% (?) Valdagni et al 2013 35 83% 0% 17% 0% (8 pts no LAD; 3 n.r.) Bul et al 2012 PRIAS 167 81% 24.5% n.r. 45pts: 0% 122: Nx Salvadurai 2013 471 87% n.r 13% n.r

greater risk of discontinuing AS clinical stage T2 (HR: 1.63; p < 0.001) lower risk of discontinuing AS men aged 65 70 yr (HR: 0.69; p < 0.001) by 5 yr, 64% of the men remained on AS

active surveillance is recommended for these subsets of patients (EPS > 10 y)

Despite this evidence, and despite guidelines recommending the use of AS, up to 90% of patients eligible for AS still undergo primary definitive therapy. Cooperberg MR. J Clin Oncol. 2010;28:1117 some patients with apparently low-risk disease actually harbour unfavourable disease due to inaccuracies in currently used (repeat) biopsy protocols Dall Era MA, et al. Eur Urol 2012; 62:976 Bul M, et al. Eur Urol 2012; 62:195

There is an unmet need for better tools that could be used to select patients and to monitor them

tumor risk patient selection communication with patient

tumor risk multiparametric magnetic resonance imaging (mp-mri) may provide improved predictive accuracy for correctly classifying tumors as low versus higher risk Lee DH, et al. J Urol 2013 Lee DH, et al. Jpn J Clin Oncol 2013 Guzzo TJ, et al.urol Oncol 2012 Turkbey B, et al. Radiology 2013 Ploussard G, et al. BJU Int 2011 Vargas HA, et al. J Urol 2012 Fradet V, et al. Radiology 2010 Stamatakis L, et al. Cancer 2013 Vasarainen H,et al. Scand J Urol 2013 Margel D, et al. J Urol 2012 Mullins JK, et al. BJU Int 2013 van As NJ, et al. Eur Urol 2009 Somford DM,et al. Invest Radiol 2013 Morgan VA, et al. Br J Radiol 2011 PRO Potential association with disease stage and grade over clinical criteria Additional value of multiparametric analysis and ADC High specificity for low-risk disease MRI showed sensitivity of 93%, and overall accuracy of 92% in predicting insignificant pathologic disease (tumour volume <0.5 ml, no Gleason pattern 4) outperforming Epstein, d Amico and CAPRA criteria Turkbey 2013

tumor risk multiparametric magnetic resonance imaging (mp-mri) may provide improved predictive accuracy for correctly classifying tumors as low versus higher risk high suspicion score on MRI showed high sensitivity (0.87-0.98) for biopsy upgrading, but relatively low specificity (0.22-0.37) Turkbey 2013 CON Relatively low sensitivity for higher risk disease Unsolved issues on interobserver variability, reproducibility, selection bias, costs

tumor risk multiparametric magnetic resonance imaging (mp-mri) may provide improved predictive accuracy for correctly classifying tumors as low versus higher risk Mp-MRI data need to be presented, using a structured reporting scheme, which consists of the following items: PI-RADS score Location and, probability of extra-prostatic disease Pertinent incidental findings CON Relatively low sensitivity for higher risk disease Unsolved issues on interobserver variability, reproducibility, selection bias, costs

Systematic TRUS biopsy Gleason 3 + 4 1 of 6 cores GPS 3+3 GPS 3+4 GPS 4+4

Systematic TRUS biopsy Gleason 3 + 4 1 of 6 cores GPS 3+3 GPS 3+4 GPS 4+4 Gleason 4 + 4 2 of 3 cores Image-guided biopsy

Active surveillance 1.3.7 Offer active surveillance (in line with recommendation 1.3.8) as an option to men with low-risk localised prostate cancer for whom radical prostatectomy or radical radiotherapy is suitable. [new 2014] Prostate cancer: diagnosis and treatment Issued: January 2014 NICE clinical guideline 175 guidance.nice.org.uk/cg175 1.3.8 Consider using the protocol in table 2 for men who have chosen active surveillance. [new 2014] Table 2 Protocol for active surveillance Timing At enrolment in active surveillance Tests (1) Multiparametric MRI if not previously performed (1) If there is concern about clinical or PSA changes at any time during active surveillance, reassess with multiparametric MRI and/or rebiopsy.

tumor risk improved utilization of biomarkers (PSA isoforms, phi, PCA3) will help to distinguish those patients who will most benefit from a biopsy -2proPSA: correlates with increasing GPS (p<0.001) and with cancer aggressiveness (p=0.03) THE JOURNAL OF UROLOGY Vol. 188, 1131-1136, October 2012 higher baseline and longitudinal -2proPSA (p 0.0001), -[2]proPSA/%fPSA (p 0.026) and PHI (p 0.0001) associated to risk reclassification during AS -2proPSA and PHI: plus biopsy tissue DNA content predictors of reclassification during Active Surveillance

tumor risk improved utilization of biomarkers (PSA isoforms, phi, PCA3) will help to distinguish those patients who will most benefit from a biopsy PCA3 not associated aggressiveness progression in AS PCA3 correlates with: Cancer vol > 0.5 ml ECE Positive surgical margins GPS (6 vs 7) pstage (pt0/2 vs pt3/4) % pos cores 33% vs <33%

patient selection Guidelines consistently recommend that patients only undergo definitive therapy for low-risk prostate cancer if they have over a 10-year life expectancy only 23% of urologists and radiation oncologists utilize prediction tools for helping to estimate their patients life expectancy Kim SP. J Urol. 2013;189:2092 there are few tools developed from contemporary cohorts for specifically predicting patients risk of nonprostate cancer mortality and existing tools require validation Kutikov A. Prostate Cancer Prostatic Dis. 2012;15:374

communication with patients Promotion of communication strategies regarding prognosis, risks and benefits, and shared decision making is essential to increasing patients interest in AS, particularly when most patients diagnosed with cancer are focused on the concept of cure.

communication with patients consultation at a multidisciplinary clinic were significantly associated with pursuit of active surveillance. (OR, 2.15; 95% CI, 1.13 to 4.10; P.02)

CONCLUSION 1. Indolent cancer does exist! not all prostate cancers are life threatening 2. If indolent (clinically insignificant) cancer exists, there might be a significant overtreatment 3. Delaying the definitive treatment does not appear to increase the risk of cancer progression 4. Tools to recognize indolent vs aggressive cancer are available, even if still suboptimal 5. Most men will remain in Active Surveillance

ACTIVE SURVEILLANCE IN INT protocols ongoing SAINT start Mar 2005 221 pts PRIAS start Nov 2007 401 pts

ACTIVE SURVEILLANCE IN INT eligibility criteria SAINT start Mar 2005 221 pts PRIAS start Nov 2007 401 pts ipsa 10ng/ml clinical stage T2a GPS 3+3 biopsy positive cores 20% max core length with cancer 50% ipsa 10ng/ml clinical stage T1c or T2a GPS 3+3 biopsy positive cores 2 PSAD 0.20 ng/ml/cc

ACTIVE SURVEILLANCE IN INT baseline patient characteristics SAINT start Mar 2005 221 pts PRIAS start Nov 2007 401 pts ipsa 10ng/ml ipsa 10ng/ml mean age at inclusion (64.4yr in PRIAS vs. 66.3yr in SAINT, t-test p=0.0014) clinical stage T2a GPS mean 3+3 PSA at diagnosis (5.3ng/ml vs. 6.9ng/ml, p<0.001) GPS 3+3 clinical stage T1c or T2a biopsy positive cores 20% biopsy positive cores 2 mean PSAd (0.11ng/ml/cc vs. 0.17ng/ml/cc, p<0.001) max core length with cancer 50% PSAD 0.20 ng/ml/cc number of core+ at diagnosis (69.6% vs. 60.5% pts with 1 core+ p=0.0005) prostate volume and clinical stages were similar

ACTIVE SURVEILLANCE IN INT 625 pts

ACTIVE SURVEILLANCE IN INT PRIAS vs SAINT

ACTIVE SURVEILLANCE IN INT PRIAS vs SAINT

ACTIVE SURVEILLANCE IN INT PRIAS vs SAINT... grazie!