PROSTATE CANCER SURVEILLANCE ESMO Preceptorship on Prostate Cancer Singapore, 15-16 November 2017 Rosa Nadal National Cancer Institute, NIH Bethesda, USA
DISCLOSURE No conflicts of interest to declare
OUTLINE Rational for active surveillance Defining active surveillance versus watchful waiting Patient selection and monitoring Outcomes of active surveillance and watchful waiting Challenge and future directions
BACKGROUND Screening Controversy BENEFITS METASTASIS MORTALITY HARMS UNNECESSARY BIOPSIES OVERDIAGNOSIS OVERTREATMENT
OVERDIAGNOSIS AND OVERTREATMENT OF PROSTATE CANCER Loeb,S. Eur. Urol. 2014 65(6): 1046-1055 Up to 67% of cases were overdiagnosed depending on the population and criteria Historically the majority of low-risk patients (favorable prognosis) received radical treatment Overtreatement Unnecessary side effects
SCREENING CONTROVERSY 2012- USPSTF Grade D recommendation Recommends against the service Moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits Per 1000 men screened: 1 fewer prostate cancer death 30-40 men with incontinence or erectile dysfunction 2 men with severe cardiovascular events 1 venous thrombosis www.uspreventativeservicetaskforce.org
SCREENING CONTROVERSY 2012- USPSTF Grade D recommendation Melbourne Consensus statement: Prostate Cancer Recommends Diagnosis against must the be service uncoupled from prostate Moderate cancer or high intervention certainty that the service has no net benefit or that the harms outweigh the benefits For Per PSA 1000 men screening screened: to be cost-effective, it needs to be 1 used fewer conservatively prostate cancer death and ideally in combination 30-40 men with with a incontinence conservative or erectile management dysfunction approach for low-risk disease 2 men with severe cardiovascular events 1 venous thrombosis Murphy, et al. BJU Int 2014 Roth, et al. JAMA Oncol. 2016
MANAGEMENT OF LOCALIZED PROSTATE CANCER Conservative Management Definitive Treatment Watchful Waiting Active Surveillance Focal Therapy Radiation Surgery Active Surveillance (AS) Treatment Intent Curative Palliative Watchful-waiting Follow-up Predefined scheduled Patients specific Assessment/markers used DRE, PSA, re-biopsy, mpmri Not pre-defined Life expectancy > 10 years < 10 years Aim Comments Minimize treatment-related toxicity without compromising survival Only for low-risk patients Minimize treatment-related toxicity Can apply to patients at all stages
UPTAKE OF ACTIVE SURVEILLANCE Loeb, et al. JAMA Oncology 2017
ELIGIBILITY FOR ACTIVE SURVILLANCE PSA < 10 or < 15 ng/ml Optional: PSA density (PSA/prostate volume): < 0.15 or < 0.2 Clinical stage T1 (non-palpable) ± T2 (palpable) Biopsy Features Gleason Score: 6 ± 3+4=7 Extent of disease: < 2-3 positive cores total ( or 33 or 50% of all cores +) 20-50% maximal cancerous involvement of any core Tosoian, et al. Nat Rev Urol. 2016
EAU GUIDELINES & NCCS Guidelines Risk category Clinical stage PSA (ng/ml) Biopsy GS PSA density (ng/ml/g) Positive cores (n) Max. extent cancer/core Min. core sampled (n) EAU* Low T1c-T2 10 6 NR 2 50% NR NCCS Low T2a < 10 6 (no Gleason grade 4-5) < 0.15 <3 50% NR * No an option for intermediate-risk PC Mottet. et al. Eur. Urol. 2016 Singapore Ministry of Health (NCCS). Guidelines on Management of Prostate Cancer. Annals Academy of Medicine, Singapore.(2013).
ACTIVE SURVEILLANCE IS HETEROGENEOUS PSA test every 3-6 months Digital Rectal Exam every 6-12 months Repeat biopsies every 1-5 years Variable use of MRI and other new markers Loeb, et al. Rev Urol. 2014
multiparametric MRI mpmri: high NPV value for lesion upgrading and for staging anterior prostate lesions The added value of mpmri and targeted biopsies could be promising in: Reducing misclassifications at initial diagnosis and follow-up; Reducing unnecessary (targeted or systematic) biopsies at follow-up, and; Ading in monitoring patients on surveillance
SYSTEMATIC REVIEW & Co MRI positive with lesion suspicious for prostate cancer: 2/3 of men otherwise suitable for AS A confirmatory biopsy in men who did not have an mpmri before: reclassification rate due to targeted biopsies : 2-22% Combined data of confirmatory and surveillance repeat biopsies: reclassification rate due to targeted biopsies: 2-14% Most likely the identification of clinically significant disease No robust data on the use of repeat MRI in AS (Monitoring) Walton Diaz et al Felker et al N 58 49 Median follow-up (months) 16 28.3 PPV for Gleason Progression 53% 69% NPV for Gleason Progression 80% 70% Schoots, et al. Eur Urol. 2015 Walton Diaz, et al. Urol Oncol. 2015 Felker, et al. J. Urology. 2015
TRIGGERS TO RECOMMEND INTERVENTION Rising PSA Imaging, biopsy and/or treatment PSA velocity > 0.75 ng/ml/year PSADT < 3 years Biopsy reclassification Recommended treatment Increase in grade Increase in extent of disease Changes in MRI od other markers Tosoian, et al. Nat Rev Urol. 2016
OUTCOMES OF CONSERVATIVE MANAGEMENT HISTORICAL DATA: SURGERY / RT versus OBSERVATION / AS SPCG-4 (Sweden) N=695, 1989-1999 12% PSA-detected (T1c) PIVOT (USA) WW vs SURGERY N=731, 1994-2002 50% PSA-detected (T1c) PROTECT (UK) N=1643, 1999-2008 100% PSA-detected AS vs Bill-Axelson, A. NEJM 370;10, 2014 Wilt, T.J. NEJM 367;3 2012 Hamdy et al. NEJM. 2016 SURGERY RADIATION
SPCG-4 RP versus Watchful Waiting End point Relative Risk with RP vs WW P Value Death any cause Overall population Low Intermediate High Death from PC Overall population Low Intermediate High 0.71 (0.59-0.86) 0.57 (0.40-0.81) 0.71 (0.53-0.95) 0.84(0.60-1.19) 0.56 (0.41-0.77) 0.54 (0.26-1.13) 0.38 (0.23-0.62) 0.87 (0.52-1.46) < 0.001 0.002 0.02 0.34 0.001 0.17 <0.001 0.84 Bill-Axelson, A. NEJM 370;10, 2014
PIVOT TRIAL RP versus Watchful Waiting HR (95% CI) P value All cause mortality Prostate Cancer Mortality 0.88 (0.71-1.08) 0.22 0.63 (0.36-1.09) 0.09 Subset analysis: Survival benefit for intermediate risk prostate cancer, but not low-risk Wilt, T.J. NEJM 367;3 2012
PROTECT TRIAL RP / RDT versus AS Median 10 years follow-up 1% disease-specific mortality 77% GS6 76% ct1 Active monitoring + Disease progression (22%) + Metastatic Disease (6%) Hamdy et al. N. Engl. J. Med. 2016
PROTECT TRIAL RP / RDT versus AS Patients receiving treatment Approx. 80% of men on active monitoring had no signs of progression More than half had received treatment by 10-years 44% of men in active monitoring avoided treatment Hamdy et al. N. Engl. J. Med. 2016
CHALLENGES-INITIATING ACTIVE SURVEILLANCE Increasing acceptance of Active Surveillance Optimizing patient selection PSA, clinical stage and standard biopsy Rates of misclassification: >1/3 Biologic heterogeneity within risk groups Role of imaging and biomarkers to assist patient selection Loeb, et al. Eur Urol. 2013 Ross, et al JCO 2010
CHALLENGES- MONITORING Changes in PSA are not reliable Biopsy-based AS presents significant risk and patient burden Increase in infections over time due to antibiotic resistance Other: bleeding, pain and urinary symptoms Significant source of non-compliance Test received by 1349 men followed on AS for 5 years ( SEER-Medicare) PSA 5 PSA ( yearly) 10 PSA ( 2x/year) Biopsy 2 biopsies 3 biopsies 91% 59% 34% 15% Combination: 10 PSA + 2 biopsies 22% Loeb, et al. J.Urol 2016
CONCLUSIONS & EAU RECOMMENDATIONS
THANK YOU VERY MUCH!