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 cutoff positivo/negativo)
Cut-off positivo/negativo
Limiti
• Analitici
• Biologici
4 ng/mL,
Vuol dire sempre …
4 ng/mL ?
(AUA, 1999)
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
Abbott AxSym Total PSA*
3,0
Abbott AxSym PSA
3,6
589 men
clinically NED
23 t-PSA assays
Baxter/Dade Stratus II 4,0
Bayer/Chiron ACS PSA
3,5
Bayer Immuno 1
3,6
bioMérieux Vidas TPSA
3,6
bioMérieux Vidas PSA**
4,4
Boehringer Elecsys
3,4
Boehringer Enzymun ES 700
2,9
Brahms Kryptor
3,1
Byk-Sangtec IRMA-Mat
2,6
Byk-Sangtec Liaison
2,7
Chiron ACS PSA 2***
2,9
DPC Coat-A-Count IRMA
3,7
DPC Immulite 3. Generation
3,5
DPC Immulite standard
3,7
Eurogenetics/Tosoh AIA
4,1
Hybritech/Beckman Access
3,7
Hybritech Tandem-E
3,7
Hybritech Tandem-R
3,8
Roche Cobas Core II 3,0
Wallac Delfia Dual Label
3,0
Wallac Delfia EQM
3,1
1,5
2,0
2,5
3,0
3,5
4,0
95-Perzentile t-PSA [ng/ml]
4,5
5,0
Fornara & Semjonow: PSA: Der Weg
zum Befund, Zuckschwerdt Verlag
München, 2002
Byk / IRMA-Mat
Cut-offs
equivalent to
traditional 4-10
Boehringer / ES700
Boehringer / Elecsys 2010 „alt“
CIS / Kryptor
Chiron / ACS 2
Wallac / Dual Label
Wallac / EQM
Abbott / AxSym (Mono-Mono) „neu“
Roche / Cobas Core II
Abbott / AxSym (Mono-Poly) „alt“
Dade / Stratus II
DPC / Immulite 3. Generation
Bayer / Immuno
DPC / IRMA CoataCount
DPC / Immulite Standard
Hybritech / Tandem-E
Hybritech / Tandem-R
BioMerieux / Vidas „neu“
Tosoh / AIA 600
Behring / Nephelometer
Biomerieux / Vidas „alt“
2
3
4
5
6
7
8
9
10 11
Total PSA [ng/ml]
12
13
Fornara & Semjonow: PSA: Der Weg
zum Befund, Zuckschwerdt Verlag
München, 2002
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?
Oggi è disponibile uno standard
internazionale WHO
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
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
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
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
Distribution of patients according to the tPSA
cut-off value. Unadjusted WHO clinical cut-off
JS. Blanchet, T. Brinkmann, JMB 27,161-168,2008
Impact of different PSA standardization on the cut-off
definition and clinical interpretation of results
JS. Blanchet, T. Brinkmann, JMB 27,161-168,2008
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
Distribution of patients according to the tPSA
cut-off value. Adjusted WHO clinical cut-off
JS. Blanchet, T. Brinkmann, JMB 27,161-168,2008
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
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
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
AxSym
Centaur Elecsys
2.5 ng/mL
True positive
True negative
4.0 ng/mL
True positive
True negative
92
41
90
40
93
34
73
23
70
57
81
51
C. Stephan et al, BJU International, 2007
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
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)
Strategie per migliorare l’accuratezza
diagnostica del PSA
Derivati del PSA
Derivati del PSA
• Intervalli di riferimento aggiustati per età
• PSA Density
• Isoforme di PSA cancro-specifiche
• PSA Velocity
PSA Velocity
Possibili campi di applicazione
• Diagnosi/screening
• Risk assessment
• Prognosi
PSA Velocity
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?
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
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
Method of calculating
• 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)
ROC curves of three methods of PSA velocity
calculation for prostate cancer diagnosis
(D. Connolly, et al, Eur Urol 52, 1044–1051, 2007)
PSA Velocity
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]
Nell’attesa della standardizzazione
della PSA Velocity …
.... cosa fare del PSA?
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
Medicine and the Media.
PSA testing: press coverage in UK and US
is an ocean apart
Deborah Cohen
BMJ 27 March 2009;338:b1287
USA press
"Prostate test found to save few lives"
New York Times, 10.03.09
"Verdict out on prostate screening"
Daily Herald (Chicago), 23.03.09
(D. Cohen, BMJ 2009;338:b1287)
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)
The angle for the press might different
in UK and in USA
• 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
(D. Cohen, BMJ 2009;338:b1287)
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
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
1. PSA level
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)
R.D. Etzioni et al. J Natl Cancer Inst 2007
• 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)
Diagnostic cut-off
Clinicians must be aware that the choice of the cut-off
point is an arbitrary decision since,
1. a “positive” PSA value does not rule in cancer,
2. a “negative” PSA value does not rule out cancer
PSA is therefore a “prostate tissue marker” that must
be balanced with all the available information of the
diagnostic process
Il valore tradizionalmente accettato oltre il quale
eseguire una biopsia prostatica
4 ng/mL
Non ha sensibilità e specificità diagnostica
soddisfacente per la neoplasia prostatica
(AUA, 1999)