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Prostate cancer - PSA and PSA kinetics

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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.

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Prostate cancer - PSA and PSA kinetics

  1. 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. 2. Introduction • PSA physiology • PSA parameters • for diagnosis of CAP • for prognosis of CAP • Summary and conclusion
  3. 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. 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. 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. 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. 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. 8. Attempts to improve sens-spec of PSA • Age-specific PSA • PSA density • Total • TZ • % free PSA • PSA kinetics • PHI • others
  9. 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. 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. 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. 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. 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. 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. 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. 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. 17. VERDICT Schroder FH et al. Eur Urol 2008; 53: 468-477
  18. 18. PSA Doubling Time • Useful for monitoring and prognostication after diagnosis of CAP Ali et al. Int J cancer 2006; 120: 170-4
  19. 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. 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. 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. 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. 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. 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. 25. VERDICT Maffezzini M et al. Eur Urol 2007; 51: 605-613. Pound CR et al. JAMA 1999; 281: 1591-7
  26. 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. 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. 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. 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. 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. 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. 32. SUMMARY AND CONCLUSION • In absence of conclusive evidences, logic must prevail

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