51-Assessment of RiskDemographic – Age, race, medical health /longevityHistory to rule out confoundersFamily HistoryDRE – to compliment the PSA valueInvestigations – MSU and Ultrasound (comorbid illness will take precedence)
62- PSA Serum Protease – Kallikrien family of proteins Functions in semen liquefactionHalf life is 3 daysProstate Specific not disease specificVery non-specific as a testImperfect screening test BUT best we haveDO NOT RELY SOLELY on it
8PSA REFINEMENTS Aimed at decreasing unnecessary biopsies Age adjusted rangesPSA VelocityPSA densityPSA free : total ratio
9Age adjusted PSA AGE (years) Age specific reference (ng/ml) 40-49 50-5960-6970-790 – 2.50 – 3.50 – 4.50 – 6.5
10PSAV and PSADPSAV – describes rate of change slope of line of regression assumes a linear relation of PSA /TIMETraditionally was > 0.75 ng/ml/yrNow MVA > 0.5 ng/ml/yr (Loeb et al AUA 2006)PSAD – Ratio of PSA level to size on TRUSPSAD of > 0.15 warrant a biopsy!!!!! Reliability is questionable due to variation in measurements.
11PSA FREE:TOTAL ratio Most PSA is bound to ACT or MG CaP cases have a lower free componentImproves spec for CaP detection in PSA 4-10 ng/ml where risk overall is 25%Threshold is controversial BUT its use is agreedf/t ratio< 15% - warrant Biopsy Risk 28-56%15-25% - consider biopsy Risk12-19%>25% - may avoid Bx if DRE normal Risk 8%
13How best to use it ?Multiple guidelines exist – NCCN guide hereNCCN
14A national recommendation Single PSA test as a predictor for the long term risk of CaP around mid 40sPSA > 0.65 ng/ml further PSA testing should be considered as per Australasian CaP SymposiumPSA level (ng/ml)Action needed<0.650.65 – 1>1Low risk repeat test in mid 50sPSA test every 2-4 yrsAnnual PSA to assess PSAV
15To test or NOT to test??The PSA testing debate between the US and EuroIndividualize the debate to patientsWhats good for the economist is not always good for patientUse risk adapted approach
16PLCO (US trial)Controversy continues over PSA testing for prostate cancer, CanadaStill Confusion about the Usefulness of PSA-screening, USA.Does cancer screening save lives? Not nearly as many as you might guess
17PLCO Methods1993 – 200176,693 men aged years enrolled at 10 sitesScreened: Annual PSA for 6yrs + DRE for 4yrsControl: “usual care”PSA >4ng/ml “considered positive for prostate cancer”Analysis – based on intent to screen comparison of mortality between groups
18Results -- Baseline Screening group Control group 44.0% previous PSA testControl group44.1% previous PSA test
19PLCO 40% first year 52% sixth year DRE 41-46% Screened group – 85% compliance, 15% didn’t have a PSAControl group – contamination40% first year52% sixth yearDRE 41-46%So 85% testing vs. 52% testingStudy terminated at 7 yrs – effect starts 7-9yrs
20Concerns/explanation for results 44% of EACH group already had prior PSA15% of “screened” group didn’t get screened52% of “control” group were screenedLow biopsy compliance.Too short follow upOnly 67% have reached 10year follow-up(ERSPC: 12 year lead time)Too few events (174 deaths from 76,693 men)
21ERSPC: European Randomized Study of Screening for Prostate Cancer 182,000 men, 7 centres – different procedures for each site.Men 50-74years oldScreened group: PSA+DRE every 4yrs (range 2-7)Any PSA >3-4 (10 in Belgium) sextant biopsiesPrimary outcome death
22Prostate Cancer Deaths 214 prostate cancer deaths in screening group326 in control group27% reduction for those who underwent screening (20%as intention to screen)Adjusted rate ratio 0.80 in screened groupCI: 0.67 to 0.95Rates diverged after 7-8 years
23ERSPC Prostate Cancer Deaths ERSPC 9years median follow-up7yrs PLCO review time point
24Conclusions Breast cancer (781) Colorectal cancer (1250) 20-27% reduction in death from prostate cancer in screened groupRate of over diagnosis estimated at 50% in screening group.Need to screen 1068 men and treat 48 men to prevent one prostate cancer deathBreast cancer (781)Colorectal cancer (1250)
25What is Active Surveillance? Conservative management option for localised prostate cancer• Active intervention has not been ruled out whereas Watchful Waiting generally implies observation until necessary to commence hormonal therapy• Men on AS may–Ultimately have active intervention–Change over to Watchful Waiting protocol–Continue on the AS protocol
26Criteria for Offering Active Surveillance • Patient Factors– Age, comorbidity• PSA– Absolute levels• Upper thresholds vary from <10 up to <20 ng/mL– PSA density – Pre-diagnosis PSAV and PSADT not usually addressed• DRE– Clinically impalpable or at most any T2 disease• Gleason Score– Gleason !6 or !7– Absence of any high grade cancer– 3+4 vs 4+3 not generally addressed where GS 7 allowed• Biopsy Core parameters– Less than 3 biopsy cores involved– No more than 50% involvement of any core
27Criteria for Departure From AS • Patient Factors– Patient request for treatment or watchful waiting– Development of co-morbidity and move to watchful waiting• PSA– Absolute threshold level– PSADT/PSAV• DRE – Local progression• Repeat Biopsy parameters– Presence/absence of cancer in 2ndbiopsy– Increased numbers of positive cores– Increased % core involvement– Increased Gleason score– Any presence of high grade cancer
28IF A/S is CONSIDERED Predictors of Progression Univariate analysis p-value.Positive second biopsyPSA (baseline)PSAD (baseline)Clinical Stage >T1aPredicted 5 year PFP (baseline)Gleason score (baseline)PSA doubling timeClinical stage (baseline)No. of positive cores (1st biopsy)Proportion of cores positive (1st biopsy) 0.988
29PRIAS Study Criteria for inclusion: 1.Histologically proven carcinoma of the prostate2.patient should be fit for curative treatment3.PSA-level at diagnosis ! 10 ng/mL4.PSA density (PSA D) less than 0,25.Clinical stage T1C or T26.Appropriate biopsy sampling (see ‘biopsy protocol’)7.Gleason score 3+3=6 (or less)8.One or 2 cores invaded with prostate cancer9.Participants be willing to attend the follow-up
30Case 1 Mr R B 58 yrs Medically well No FHx of CaP DRE = benign moderately enlarged prostatePSA 4.1 ug/lPSA repeat 4.7ug/l
31Case 1 cont’d Biopsy Options?? AS LDR BRACHY Surgery PROSTATE TRUS BIOPSIES X 12:- PROSTATIC ADENOCARCINOMA, GLEASON SCORE 6 (3 + 3), PRESENT IN ONE CORE (RIGHT BASE LATERAL)- FOCAL PERINEURAL INVASION- NO EVIDENCE OF VASCULAR INVASION OR EXTRAPROSTATIC EXTENSION.Options??ASLDR BRACHYSurgeryAny other options!!!! Obviously there are 4 !!!!
32Case 1 cont’d Repeat biopsy Options now?? PROSTATE TRUS BIOPSIES: - GLEASON SCORE = 7 PROSTATIC ADENOCARCINOMA INVOLVING SEVENBIOPSY SITES; RIGHT LOBE- PERINEURAL INVASION IDENTIFIED- NO EVIDENCE OF EXTRAPROSTATIC EXTENSIONOptions now??Its easy answer now….. Ok next case
33Case 2 Mr R S 65 yrs old Medically well Nil FHx of CaP DRE – Significantly enlarged benign prostatePSA20072008200920126.96.36.199.7
34Case 2 cont’d Biopsy – Prostate volume 75cc Options?? PROSTATIC TRUS BIOPSIES:- PROSTATIC ADENOCARCINOMA OF ACINAR / USUAL TYPE;- ONE BIOPSY POSITIVE FOR CARCINOMA, SPECIMEN 8 LEFT BASE MEDIAL,MICROSCOPIC FOCUS < 5%, < 1MM;- GLEASON SCORE = 6;- NO PERINEURAL INVASION;- NO EXTRAPROSTATIC EXTENSIONOptions??ASSURGERY OR LDR BRACHYTHERAPY!!!
35Case 2 cont’d Active surveillance put in place Aug 2011 PSA Nov 2011 – 4.3PSA Mar 2012 – 6.3PSA June 2012 – 7.6PSA Aug 2012 – 5.7Time for Protocol biopsy on PRIAS study
36Case 2 cont’d Repeat biopsy 12 Tissue core 2 cores positive for Adenocarcinoma ProstateRight Apex lateral and left base medial3+3=6 Gleason score5 and 20% of each core +ve respectivelyNo perineural inv or Extraprostatic extensionOPTIONS now???
37Case 2 –Yeah last slide !! Opted for continued AS PSA Dec 2012 – 4.6 PSA Mar 2013 – 5.1Where to from here!!!!!!!!