PROSTATE CANCER SURVEILLANCE

Transcription

1 PROSTATE CANCER SURVEILLANCE ESMO Preceptorship on Prostate Cancer Singapore, November 2017 Rosa Nadal National Cancer Institute, NIH Bethesda, USA

2 DISCLOSURE No conflicts of interest to declare

3 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

4 BACKGROUND Screening Controversy BENEFITS METASTASIS MORTALITY HARMS UNNECESSARY BIOPSIES OVERDIAGNOSIS OVERTREATMENT

5 OVERDIAGNOSIS AND OVERTREATMENT OF PROSTATE CANCER Loeb,S. Eur. Urol (6): 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

6 SCREENING CONTROVERSY 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 men with incontinence or erectile dysfunction 2 men with severe cardiovascular events 1 venous thrombosis

7 SCREENING CONTROVERSY 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 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

8 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

9 UPTAKE OF ACTIVE SURVEILLANCE Loeb, et al. JAMA Oncology 2017

10 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

11 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-T 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 Singapore Ministry of Health (NCCS). Guidelines on Management of Prostate Cancer. Annals Academy of Medicine, Singapore.(2013).

12 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

13 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

14 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 Median follow-up (months) PPV for Gleason Progression 53% 69% NPV for Gleason Progression 80% 70% Schoots, et al. Eur Urol Walton Diaz, et al. Urol Oncol Felker, et al. J. Urology. 2015

15 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

16 OUTCOMES OF CONSERVATIVE MANAGEMENT HISTORICAL DATA: SURGERY / RT versus OBSERVATION / AS SPCG-4 (Sweden) N=695, % PSA-detected (T1c) PIVOT (USA) WW vs SURGERY N=731, % PSA-detected (T1c) PROTECT (UK) N=1643, % PSA-detected AS vs Bill-Axelson, A. NEJM 370;10, 2014 Wilt, T.J. NEJM 367; Hamdy et al. NEJM SURGERY RADIATION

17 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 ( ) 0.57 ( ) 0.71 ( ) 0.84( ) 0.56 ( ) 0.54 ( ) 0.38 ( ) 0.87 ( ) < < Bill-Axelson, A. NEJM 370;10, 2014

18 PIVOT TRIAL RP versus Watchful Waiting HR (95% CI) P value All cause mortality Prostate Cancer Mortality 0.88 ( ) ( ) 0.09 Subset analysis: Survival benefit for intermediate risk prostate cancer, but not low-risk Wilt, T.J. NEJM 367;3 2012

19 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

20 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

21 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 Ross, et al JCO 2010

22 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

23 CONCLUSIONS & EAU RECOMMENDATIONS

24 THANK YOU VERY MUCH!