1. PSA e diagnosi di carcinoma prostatico 1.Il test diagnostico è usato con intento classificativo per riconoscere la persona affetta dalla patologia di interesse da quella non affetta 2.Un test classificativo si basa in genere su un criterio dicotomico (valore soglia o cut- off positivo/negativo)

2. Cut-off positivo/negativo Limiti Analitici Biologici

3. Vuol dire sempre … (AUA, 1999) 4 ng/mL ? 4 ng/mL,

4. The clinical impact of different assays for prostate specific antigen A. Semjonow, G. De Angelis, F. Oberpenning, HP. Schmid, B. Brandt, L. Hertle BJU International 86, 590-597, 2000

5. 589 men clinically NED 23 t-PSA assays Fornara & Semjonow: PSA: Der Weg zum Befund, Zuckschwerdt Verlag München, 2002

6. Cut-offs equivalent to traditional 4-10 Fornara & Semjonow: PSA: Der Weg zum Befund, Zuckschwerdt Verlag München, 2002

7. La variabilità fra metodi può essere dovuta alla mancanza di un standard unico L’adozione di uno standard internazionale di riferimento può eliminare il problema?

8. Oggi è disponibile uno standard internazionale WHO

9. Toward metrological traceability in the determination of PSA: calibrating Beckman Coulter Hybritech Access PSA assays to WHO standards compared with the traditional Hybritech standards C. Stephan, A.M. Kahrs, S. Klotzek, J Reiche, C. Muller, M Lein, S. Deger, K. Miller, K Ju Clin Chem Lab Med 46(5):623–629, 2008

10. Toward metrological traceability in the determination of PSA: calibrating Beckman Coulter Hybritech Access PSA assays to WHO standards compared with the traditional Hybritech standards C. Stephan, A.M. Kahrs, S. Klotzek, J Reiche, C. Muller, M Lein, S. Deger, K. Miller, K Ju Clin Chem Lab Med 46(5):623–629, 2008

11. Total Access PSA based on the measurements with the traditional Hybritech calibration and the new WHO-aligned calibration C. Stephan et al, Clin Chem Lab Med 2008;46:623–629

12. Recalibration to WHO standards Calibration to the WHO standard could lead to a proportional negative bias in mass units of approximately 20% compared with the non-WHO calibrated assay Can the same cut-off point be used for either WHO and Hybritech calibration? C. Stephan et al, Clin Chem Lab Med 2008;46:623–629

13. Distribution of patients according to the tPSA cut-off value. Unadjusted WHO clinical cut-off JS. Blanchet, T. Brinkmann, JMB 27,161-168,2008

14. Impact of different PSA standardization on the cut-off definition and clinical interpretation of results JS. Blanchet, T. Brinkmann, JMB 27,161-168,2008

15. Recalibration to WHO standards An appropriate clinical decision point of 3.1 ng/mL was identified to preserve the clinical performance of the assay calibrated to the WHO standard JS. Blanchet, T. Brinkmann, JMB 27,161-168,2008

16. Distribution of patients according to the tPSA cut-off value. Adjusted WHO clinical cut-off JS. Blanchet, T. Brinkmann, JMB 27,161-168,2008

17. Different PSA assays give different results on the same blood sample: an obstacle to recommending uniform limits for prostate biopsies C. Stephan, J. Kramer, H-A. Meyer, G. Kristiansen, S. Ziemer, S. Deger, M. Lein, S. A. Loening, K. Jung BJU International 99,1427–143, 2007

18. Different PSA assays give different results on the same blood sample: an obstacle to recommending uniform limits for prostate biopsies C. Stephan, J. Kramer, H-A. Meyer, G. Kristiansen, S. Ziemer, S. Deger, M. Lein, S. A. Loening, K. Jung BJU International 99,1427–143, 2007

19. Classification of 314 men with and 282 without PCa using fixed tPSA thresholds of 2.5 and 4.0 ng/mL for the three tPSA assays calibrated against the WHO standard Selected Threshold% of classified patients AxSymCentaurElecsys 2.5 ng/mL True positive929093 True negative414034 4.0 ng/mL True positive737081 True negative235751 C. Stephan et al, BJU International, 2007

20. Recalibration to WHO standards Even WHO calibrated assays do not deliver similar tPSA values Thus, calibration might be an important, but not the exclusive factor, to improve the harmonization among the various assays The 3.1 ng/mL cut-off cannot be applied to any WHO calibrated tPSA assay, since an appropriate clinical decision point should be defined for each tPSA assay JS. Blanchet, T. Brinkmann, JMB 27,161-168,2008

21. There is no legitimate PSA cut-off point A threshold is scientifically and statistically baseless in the screening or diagnosis setting and is completely meaningless for any patient who has undergone treatment for prostate cancer Flagging PSA results as ‘‘normal’’ or ‘‘abnormal’’ is no longer justifiable Laboratories should eliminate any artificial PSA cut-off value when reporting results (Jones JS, Eur Urol 2008;53,10–12)

22. Strategie per migliorare l’accuratezza diagnostica del PSA Derivati del PSA

23. Intervalli di riferimento aggiustati per età PSA Density Isoforme di PSA cancro-specifiche PSA Velocity

24. Possibili campi di applicazione Diagnosi/screening Risk assessment Prognosi PSA Velocity

25. Studi diversi, anche se condotti da gruppi affidabili su casistiche consistenti, portano a risultati significativamente diversi sulla efficacia della PSA Velocity sia come criterio diagnostico che come indicatore di rischio. Perche?

26. Is Prostate-Specific Antigen Velocity Useful in Early Detection of Prostate Cancer? A Critical Appraisal of the Evidence R.D. Etzioni, D.P. Ankerst, N.S. Weiss, L.Y. T. Inoue, I.M. Thompson J Natl Cancer Inst 2007;99: 1510 – 5

27. Role of PSAV in early detection remains a matter of controversy Variables affecting PSAV 1.PSA level 2.Mode of PCa detection 3.Type of study (association vs classification studies) 4.Timing, cut-off, method of calculating … Etzioni RD et al, J Natl Cancer Inst 2007

28. 2204 men with initial PSA < 10.0 ng/ml and a subsequent diagnosis (716 PCa, 1488 BPH) 3 PSA tests before diagnosis carried out over a minimum of 18 mo were included. PSAV was calculated on at least 3 PSA tests by using three mathematical methods (D. Connolly, et al, Eur Urol 52, 1044–1051, 2007) Method of calculating

29. ROC curves of three methods of PSA velocity calculation for prostate cancer diagnosis (D. Connolly, et al, Eur Urol 52, 1044–1051, 2007)

30. La PSA Velocity sembra il più promettente ed “innovativo” derivato del PSA per la diagnosi precoce Prima del possibile uso clinico è però necessaria una rigorosa standardizzazione delle variabili di interesse [es. (i) disegno dello studio, (ii) frequenza di campionamento, (iii) distanza fra i campionamenti (iv) variabilità analitica e biologica (vi) algoritmi di calcolo] PSA Velocity

31. Nell’attesa della standardizzazione della PSA Velocity ….... cosa fare del PSA?

32. The Great Prostate Mistake EACH year some 30 million American men undergo testing for PSA The test’s popularity has led to a hugely expensive public health disaster The test is hardly more effective than a coin toss Richard J. Ablin, The New York Times, March 9, 2010

33. Medicine and the Media. PSA testing: press coverage in UK and US is an ocean apart Deborah Cohen BMJ 27 March 2009;338:b1287

34. USA press "Verdict out on prostate screening" Daily Herald (Chicago), 23.03.09 "Prostate test found to save few lives" New York Times, 10.03.09 (D. Cohen, BMJ 2009;338:b1287)

35. UK press "Prostate cancer screening could cut deaths by 20%" The Guardian, 18.03.09 "Screening all older men for prostate cancer could reduce deaths by a fifth’" Daily Mail, 19.03.09 (D. Cohen, BMJ 2009;338:b1287)

36. in USA they will be questioning if people are paying for something they don’t need, whereas in the UK they will be questioning whether there’s a good thing that the NHS aren’t giving them The angle for the press might different in UK and in USA (D. Cohen, BMJ 2009;338:b1287)

37. The Great Prostate Mistake EACH year some 30 million American men undergo testing for PSA The test’s popularity has led to a hugely expensive public health disaster The test is hardly more effective than a coin toss Congress searches for ways to cut costs in our health care system, a significant savings could come from changing the way the antigen is used to screen for prostate cancer Richard J. Ablin, The New York Times, March 9, 2010

38. Should I Get the Prostate Cancer Test? The debate over prostate cancer testing is inappropriately focused on the PSA test itself We should be focusing on how test results are being interpreted and affecting treatment decisions A.J. Bueschen, President of AUA, The New York Times, March 11, 2010

43. PSA and PSA velocity (PSAV) from the Prostate Cancer Prevention Trial. Closed circles PCa; open circles, participants with a negative biopsy (Spearman’s correlation coefficient, r =.70) 1. PSA level R.D. Etzioni et al. J Natl Cancer Inst 2007

44. The method used to calculate PSAV can produce markedly different results from the same PSA data, which may affect the decision to proceed with prostate biopsy (D. Connolly, et al, Eur Urol 52, 1044–1051, 2007)

45. Diagnostic cut-off 1.a “ positive ” PSA value does not rule in cancer, 2.a “negative” PSA value does not rule out cancer Clinicians must be aware that the choice of the cut-off point is an arbitrary decision since, PSA is therefore a “prostate tissue marker” that must be balanced with all the available information of the diagnostic process

46. Il valore tradizionalmente accettato oltre il quale eseguire una biopsia prostatica (AUA, 1999) 4 ng/mL Non ha sensibilità e specificità diagnostica soddisfacente per la neoplasia prostatica