PSA and PROSTATE CANCER Dr Kiran Hazratwala Urologist

FORMAT PSA Refinements of PSA Prostate cancer – Natural history Investigate Localised Prostate cancer Options of treatment of localised cancer Active surveillance vs Active intervention Case studies.

1-Assessment of Risk Demographic – Age, race, medical health /longevity History to rule out confounders Family History DRE – to compliment the PSA value Investigations – MSU and Ultrasound (comorbid illness will take precedence)

2- PSA Serum Protease – Kallikrien family of proteins Functions in semen liquefaction Half life is 3 days Prostate Specific not disease specific Very non-specific as a test Imperfect screening test BUT best we have DO NOT RELY SOLELY on it

PSA FALSE POSITIVE

PSA REFINEMENTS Aimed at decreasing unnecessary biopsies Age adjusted ranges PSA Velocity PSA density PSA free : total ratio

Age adjusted PSA AGE (years) Age specific reference (ng/ml) 40-49 50-59 60-69 70-79 0 – 2.5 0 – 3.5 0 – 4.5 0 – 6.5

PSAV and PSAD PSAV – describes rate of change slope of line of regression assumes a linear relation of PSA /TIME Traditionally was > 0.75 ng/ml/yr Now MVA > 0.5 ng/ml/yr (Loeb et al AUA 2006) PSAD – Ratio of PSA level to size on TRUS PSAD of > 0.15 warrant a biopsy !!!!! Reliability is questionable due to variation in measurements.

PSA FREE:TOTAL ratio Most PSA is bound to ACT or MG CaP cases have a lower free component Improves spec for CaP detection in PSA 4-10 ng/ml where risk overall is 25% Threshold is controversial BUT its use is agreed f/t ratio < 15% - warrant Biopsy Risk 28-56% 15-25% - consider biopsy Risk12-19% >25% - may avoid Bx if DRE normal Risk 8%

How best to use it ? Multiple guidelines exist – NCCN guide here NCCN

A national recommendation Single PSA test as a predictor for the long term risk of CaP around mid 40s PSA > 0.65 ng/ml  further PSA testing should be considered as per Australasian CaP Symposium PSA level (ng/ml) Action needed <0.65 0.65 – 1 >1 Low risk repeat test in mid 50s PSA test every 2-4 yrs Annual PSA to assess PSAV

To test or NOT to test?? The PSA testing debate between the US and Euro Individualize the debate to patients Whats good for the economist is not always good for patient Use risk adapted approach

PLCO (US trial) Controversy continues over PSA testing for prostate cancer, Canada Still Confusion about the Usefulness of PSA-screening, USA. Does cancer screening save lives? Not nearly as many as you might guess

PLCO Methods 1993 – 2001 76,693 men aged 55-74 years enrolled at 10 sites Screened: Annual PSA for 6yrs + DRE for 4yrs Control: “usual care” PSA >4ng/ml “considered positive for prostate cancer” Analysis – based on intent to screen comparison of mortality between groups

Results -- Baseline Screening group Control group 44.0% previous PSA test Control group 44.1% previous PSA test

PLCO 40% first year 52% sixth year DRE 41-46% Screened group – 85% compliance, 15% didn’t have a PSA Control group – contamination 40% first year 52% sixth year DRE 41-46% So 85% testing vs. 52% testing Study terminated at 7 yrs – effect starts 7-9yrs

Concerns/explanation for results 44% of EACH group already had prior PSA 15% of “screened” group didn’t get screened 52% of “control” group were screened Low biopsy compliance. Too short follow up Only 67% have reached 10year follow-up (ERSPC: 12 year lead time) Too few events (174 deaths from 76,693 men)

ERSPC: European Randomized Study of Screening for Prostate Cancer 182,000 men, 7 centres – different procedures for each site. Men 50-74years old Screened group: PSA+DRE every 4yrs (range 2-7) Any PSA >3-4 (10 in Belgium) sextant biopsies Primary outcome death

Prostate Cancer Deaths 214 prostate cancer deaths in screening group 326 in control group 27% reduction for those who underwent screening (20%as intention to screen) Adjusted rate ratio 0.80 in screened group CI: 0.67 to 0.95 Rates diverged after 7-8 years

ERSPC Prostate Cancer Deaths ERSPC 9years median follow-up 7yrs PLCO review time point

Conclusions Breast cancer (781) Colorectal cancer (1250) 20-27% reduction in death from prostate cancer in screened group Rate of over diagnosis estimated at 50% in screening group. Need to screen 1068 men and treat 48 men to prevent one prostate cancer death Breast cancer (781) Colorectal cancer (1250)

What 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

Criteria 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

Criteria 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

IF A/S is CONSIDERED Predictors of Progression Univariate analysis p-value. Positive second biopsy 0.002 PSA (baseline) 0.012 PSAD (baseline) 0.034 Clinical Stage >T1a 0.053 Predicted 5 year PFP (baseline) 0.102 Gleason score (baseline) 0.241 PSA doubling time 0.300 Clinical stage (baseline) 0.479 No. of positive cores (1st biopsy) 0.590 Proportion of cores positive (1st biopsy) 0.988

PRIAS Study Criteria for inclusion: 1.Histologically proven carcinoma of the prostate 2.patient should be fit for curative treatment 3.PSA-level at diagnosis ! 10 ng/mL 4.PSA density (PSA D) less than 0,25.Clinical stage T1C or T2 6.Appropriate biopsy sampling (see ‘biopsy protocol’) 7.Gleason score 3+3=6 (or less) 8.One or 2 cores invaded with prostate cancer 9.Participants be willing to attend the follow-up

Case 1 Mr R B 58 yrs Medically well No FHx of CaP DRE = benign moderately enlarged prostate PSA 4.1 ug/l PSA repeat 4.7ug/l

Case 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?? AS LDR BRACHY Surgery Any other options!!!! Obviously there are 4 !!!!

Case 1 cont’d Repeat biopsy Options now?? PROSTATE TRUS BIOPSIES: - GLEASON SCORE 3 + 4 = 7 PROSTATIC ADENOCARCINOMA INVOLVING SEVEN BIOPSY SITES; RIGHT LOBE - PERINEURAL INVASION IDENTIFIED - NO EVIDENCE OF EXTRAPROSTATIC EXTENSION Options now?? Its easy answer now….. Ok next case

Case 2 Mr R S 65 yrs old Medically well Nil FHx of CaP DRE – Significantly enlarged benign prostate PSA 2007 2008 2009 2011 2.4 2.1 3.4 4.7

Case 2 cont’d Biopsy – Prostate volume 75cc Options?? 1 - 12. 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 3 + 3 = 6; - NO PERINEURAL INVASION; - NO EXTRAPROSTATIC EXTENSION Options?? AS SURGERY OR LDR BRACHYTHERAPY!!!

Case 2 cont’d Active surveillance put in place Aug 2011 PSA Nov 2011 – 4.3 PSA Mar 2012 – 6.3 PSA June 2012 – 7.6 PSA Aug 2012 – 5.7 Time for Protocol biopsy on PRIAS study

Case 2 cont’d Repeat biopsy 12 Tissue core 2 cores positive for Adenocarcinoma Prostate Right Apex lateral and left base medial 3+3=6 Gleason score 5 and 20% of each core +ve respectively No perineural inv or Extraprostatic extension OPTIONS now???

Case 2 –Yeah last slide !! Opted for continued AS PSA Dec 2012 – 4.6 PSA Mar 2013 – 5.1 Where to from here!!!!!!!!