1. PSA and PROSTATE CANCER
Dr Kiran Hazratwala
Urologist

2. 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.

5. 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)

6. 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

7. PSA FALSE POSITIVE

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

9. 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

10. 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.

11. 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%

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

14. 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

15. 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

16. 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

17. PLCO Methods
1993 – 2001
76,693 men aged 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

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

19. 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

20. 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)

21. 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

22. 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

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

24. 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)

25. 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

26. 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

27. 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

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

29. 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

30. 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

31. 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 !!!!

32. Case 1 cont’d Repeat biopsy Options now?? PROSTATE TRUS BIOPSIES:
- GLEASON SCORE = 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

33. 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

34. Case 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 EXTENSION
Options?? AS
SURGERY OR LDR BRACHYTHERAPY!!!

35. 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

36. 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???

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