Screening for prostate cancer using PSA has several limitations. It It is an organ specific marker, however, pathology specificity is low (elevated in all, prostatitis, prostatomegaly, prostate cancer, prostate manipulation). Attempts have been made to improve specificity while retaining its sensitivity, e.g. PSA density, PSA % free, PSA velocity, prostate health index (which takes into account p2PSA as well). after diagnosis of prostate cancer, PSA doubling time is used for assessment of indication of treatment for patients on active surveillance as well as that for indication of salvage treatment for patients with biochemical recurrence after initial treatment.

1. Prostate specific antigen (PSA)
​Dr Mayank Mohan Agarwal
MBBS, MS, MRCS(Ed), ​DNB, MCh (PGIMER, Chandigarh)
VMMF and IAUA Fellowships Uro-Oncology, Pelvic Floor Reconstruction
(MSKCC, NY; UCLA, LA; WFUBMC, NC)​
Formerly Associate Professor of Urology, PGIMER, Chandigarh
Formerly Consultant & Head of Urology, NMC specialty Hospital, Abu Dhabi
Consultant and Head of Urology
(Aster) Dr. Ramesh Cardiac and Multispecialty Hospitals Pvt. Ltd.
Guntur (AP), India

2. Introduction
• PSA physiology
• PSA parameters
• for diagnosis of CAP
• for prognosis of CAP
• Summary and conclusion

3. Population based PSA screening
• Population based RCT n = 182000
0
0.2
0.4
0.6
0.8
1
1.2
50-54 55-59 60-64 65-69 70-74
CAP specific deaths per 1000 person-year
screening control
Schroder FH et al. N Engl J Med 2009;360:1320-8.

4. PSA (human Kallikrein peptidase 3)
• Serine protease, member of a family of 15 hkp’s
• preproPSA  proPSA  PSA  _mg/ml into semen
A millionth (_ng/ml)
unprocessed
Processed
in prostate
(70-80%)
(90-95%)
(5-10%)
(1-2%)
(20-30%)

5. PSA (human Kallikrein peptidase 3)
• Serine protease, member of a family of 15 hkp’s
• preproPSA  proPSA  PSA  _mg/ml into semen
A millionth (_ng/ml)
unprocessed
Processed
in prostate
(70-80%)
(90-95%)
(5-10%)
(1-2%)IN
CANCER
(<20-30%)

6. PSA (human Kallikrein peptidase 3)
• Organ specific (almost)
– breast tissue, breast milk, breast/kidney/adrenal cancer, parotid
• Disease non-specific
– prostatic hyperplasia, prostatitis, prostate manipulation, prostate cancer

7. Risk of CAP based on PSA
• PSA is a continuous variable
• There is actually no “normal” value
• “probability” of having CAP proportional to PSA
0
20
40
60
80
100
0.0-0.5 0.6-1.0 1.1-2.0 2.1-3.0 3.1-4.0 4.1-10.0 10.1-20.0 >20.1
% risk of CAP
Thompson, I.M., et al. N Engl J Med 2004; 350: 2239.

8. Attempts to improve sens-spec of PSA
• Age-specific PSA
• PSA density
• Total
• TZ
• % free PSA
• PSA kinetics
• PHI
• others

9. AGE REFERENCED PSA
Age PSA
40-49 0.0 – 2.5
50-59 0.0 – 3.5
60-69 0.0 – 4.5
70-79 0.0 – 6.5
Oesterling JE et al. JAMA 1993; 270: 860-864
0
20
40
60
80
100
40-49 50-59 60-69 70-79
PSA sensitivity age-sp PSA sensitivity
PSA specificity age-sp PSA specificity

10. PSA density
• PSA per unit volume (PSAD) 0.10 – 0.15
• PSA per unit TZ volume (PSAD-TZ) ?? 0.20 – 0.30
0
20
40
60
80
100
0.1 0.15 0.2 0.3
sensitivity specificity
PSAD-TZ
0
20
40
60
80
100
0.075 0.1 0.15 0.2 0.25
sensitivity specificity
PSAD

11. Percent free PSA
• “more the merrier”
0
20
40
60
80
100
8 10 11 12 13 14 15 17
perc free PSA
sensitivity specificity
unprocessed
Processed
in prostate
(70-80%)
(90-95%)
(5-10%)
(1-2%)IN
CANCER
(<20-30%)

12. PSA kinetics
• Change of PSA over time
PSA VELOCITY
(ng/ml/YEAR)
PSA DOUBLING TIME
(MONTHS)
V1
V2
V3
Vav = (V1+V2+V3)/3
Before
diagnosis
After
diagnosis

13. PSA velocity
• Various cutoffs sensitivity – specificity balance poor
• Valid only in long term follow up (at least 3 values, at least 18m duration)
• For PSA 2-4 cutoffs as low as 0.1ng/ml/yr predict cancer probability over
10 year period

14. PSA velocity
• Various cutoffs sensitivity – specificity balance poor
• Valid only in long term follow up (at least 3 values, at least 18m duration)
• For PSA 2-4 cutoffs as low as 0.1ng/ml/yr predict cancer probability over
10 year period – better still in men <50 years of age
• Proposed cutoff for men <50
• PSA 2.0 - 2.5
• PSAV 0.2 - 0.6
Sun L et al. BJUI 2007; 99: 753-757

15. PSA velocity
• Various cutoffs sensitivity – specificity balance poor
• Valid only in long term follow up (at least 3 values, at least 18m duration)
• For PSA 2-4 cutoffs as low as 0.1ng/ml/yr short term predictability very
poor
Djavan B. UROLOGY 1999; 54: 517–522

16. PSA velocity
• Various cutoffs sensitivity – specificity balance poor
• Valid only in long term follow up (at least 3 values, at least 18m duration)
• For PSA 4-10 cutoffs 0.35-0.75 ng/ml/yr have been used with relatively
high specificity but low sensitivity
Mettlin C. Cancer 1994; 74:1615-20; Lee SC. Korean J Urol 2004;45:747-752

17. VERDICT
Schroder FH et al. Eur Urol 2008; 53: 468-477

18. PSA Doubling Time
• Useful for monitoring and prognostication after diagnosis of CAP
Ali et al. Int J cancer 2006; 120: 170-4

19. PSA Doubling Time
• Useful for monitoring and prognostication after diagnosis of CAP
• Active surveillance
Ali et al. Int J cancer 2006; 120: 170-4

20. PSA Doubling Time
• Useful for monitoring and prognostication after diagnosis of CAP
• Post-radical prostatectomy biochemical recurrence
Pound CR et al. JAMA 1999; 281: 1591-7
METSfreesurvivalprobability

21. PSA Doubling Time
• Useful for monitoring and prognostication after diagnosis of CAP
• Post-radical prostatectomy cancer-specific mortality
Freedland SJ et al. JAMA 2005; 294: 433-9. Freedland SJ et al. J Clin Oncol 2007; 25: 1765-1771

22. PSA Doubling Time
• Useful for monitoring and prognostication after diagnosis of CAP
• Post-radical radiotherapy
Pollack A et al. Cancer 1994; 74:670-8.
PSADT
<5m
5-12m
>12m
Local control Metastasis-free Any relapse

23. PSA Doubling Time
• Useful for monitoring and prognostication after diagnosis of CAP
• Post CRPC status – prognostication and possible aggression of treatment
Smith MR et al. J Clin Oncol 2013; 31:3800-3806

24. PSA Doubling Time
• Useful for monitoring and prognostication after diagnosis of CAP
• Post CRPC status – prognostication and possible aggression of treatment
Armstrong AJ, et al. Clin Cancer Res 2007;13(21). 6396-6403
PSADT
PSA

25. VERDICT
Maffezzini M et al. Eur Urol 2007; 51: 605-613. Pound CR et al. JAMA 1999; 281: 1591-7

26. PROSTATE HEALTH INDEX (PHI)
• PHI = p2PSA x √PSA / fPSA
• PSA 2-10
• Probability of having prostate cancer based on score
10
20
30
40
50
60
0-24.9 25-34.9 35-54.9 ≥55
%cancer risk % ≥7 gleason
Loeb & Catalona. Ther Adv Urol 2014; 6: 74–77

27. PROSTATE HEALTH INDEX (PHI)
• PHI = p2PSA x √PSA / fPSA
• PSA 2-10
• Sensitivity for cancer detection
Loeb & Catalona. Ther Adv Urol 2014; 6: 74–77

28. PROSTATE HEALTH INDEX (PHI)
• PHI = p2PSA x √PSA / fPSA
• PSA 2-10
• Prediction of adverse histology after RP
Guazzoni G et al. Eur Urol 2012; 61: 455-466

29. Other parameters
• 4 kallikrein score (PSA, fPSA, p2PSA, hK2, DRE, age, previous Bx)
• ConfirmDx
• PCA3 (EPS urine)
• ExoDx (PCA3, ERG RNA)
• Mi-prostate score (PSA, PCA3, ERG)
• Select MDx (EPS urine DLX1, HOXC6, KLK3)

30. SUMMARY AND CONCLUSION
• PSA –
• First alert for biopsy
• Risk stratification after diagnosis (<10, 10-20, >20)
• Monitor recurrence after radical treatment
• Alert for salvage treatment
• Prognostication after recurrence
• PSADT -
• Alert for radical treatment in surveillance patients
• Alert for salvage treatment
• Prognostication after recurrence
<3-6m vs
6-12m vs
>12-24m

31. SUMMARY AND CONCLUSION
• PSA parameters –
• %fPSA
• PSAD
• PSAD-TZ
• PSAV
• For aiding timely biopsy
• Possibility for prognostication
once diagnosis made 0
20
40
60
80
100
%fPSA (<15) PSAV
(>0.75)
PSAD
(>0.15)
combined CPC
PSA >4
sensitivity specificity
Murray NP et al. BioMed Res Int; 2014
• PHI
• 4k score

32. SUMMARY AND CONCLUSION
• In absence of conclusive evidences, logic must prevail