psa volatility index (pvi) & update on psa kinetics john phillips, md 19 november, 2010 new york...
TRANSCRIPT
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PSA VOLATILITY INDEX (PVI)
& UPDATE ON PSA KINETICS
John Phillips, MD 19 November, 2010
New York Medical College Hackensack University Medical Center
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PSA VOLATILITY INDEX (PVI)
& UPDATE ON PSA KINETICS
John Phillips, MD 19 November, 2010
New York Medical College Hackensack University Medical Center
![Page 3: PSA VOLATILITY INDEX (PVI) & UPDATE ON PSA KINETICS John Phillips, MD 19 November, 2010 New York Medical College Hackensack University Medical Center](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e7d5503460f94b8047b/html5/thumbnails/3.jpg)
PSA VOLATILITY INDEX (PVI)
& UPDATE ON PSA KINETICS
John Phillips, MD 19 November, 2010
New York Medical College Hackensack University Medical Center
203,415 men developed prostate cancer 28,372 men died from prostate cancer
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J Mol Biol (2008), 376, 1021-33
•34 kD
•Serine protease
•19q13
•Kallikrein-related peptidase III
•Half-life total PSA 2-3 days
•Free PSA <8 hours
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Serum Proteins
Alpha-2-macroglobulin
Alpha-Chymotrypsin
Free isoforms: B-PSA, I-PSA, and pro-PSA
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SCR-270 Radar
Balancing true signal with interference
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Receiver Operating Characteristic (ROC)
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Receiver Operating Characteristic (ROC)
Area Under Curve*
0.500= worthless
0.650=lukewarm
0.700=very good
0.800=outstanding*trapezoidal method
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PSA cut-offs
•1986 “99% of healthy men < 4.0”
•1992 20-30% men > 4.0
•1994 24,000 screened q 6 months # cancers 2.6-4 identical to 4-10 ng/ml
•1995 6,691 men PSA 4.1 missed 82% of cancers in men <50
•2001 PSA 2.5 ng/ml for men <50
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PSA cut-offs
•1986 “99% of healthy men < 4.0”
•1992 20-30% men > 4.0
•1994 24,000 screened q 6 months # cancers 2.6-4 identical to 4-10 ng/ml
•1995 6,691 men PSA 4.1 missed 82% of cancers in men <50
•2001 PSA 2.5 ng/ml for men <50
•Placebo arm of the 2004 PCPT trial
•<2.1 ng/ml 15 % of men had cancer
•Significant number had high grade disease
•Stacey Loeb 14,000 BLAS
•Median PSA 0.7 age 40-49: 0.7-2.5= 14.6 fold increased risk of prostate ca
•Median PSA 0.9 age 50-59: 0.9-2.5=7.6 fold increased risk of prostate ca
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•AUA Guidelines•PSA testing begin at 40 years of age + DRE if > 10 year life expectancy
•Repeat PSA annually especially if above median for age
•Prostate Cancer exists at all PSA levels
•No absolute cut-off but PSA represents a “continuum of risk”
•PSA presents an odds to a patient, then they can determine comfort zone
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Other Scalar Tests
• [-2] pro PSA AUC=.76 Sokoll et al. CEBM 2010• TMPRSS2-ERG• PSAD >0.155• TZ-PSAD• PCA3
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Dynamic Tests
• PSA doubling time (PSAdt)• Classically described after radiation therapy• Originally identified as a surrogate for failure• PSA dt < 3 months associated with decreased CSS• PSA dt < 6 months associated with increased BCF• Difficult to calculate
i
PSAPSA
timetimein
n nn
nn
1 1
1
)log(
)(*2log
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Dynamic Tests
• PSA Velocity • Carter B.L.S.A.• PSA < 4• PSAV was associated with CSS 25 years
later• 92 % survival <.35 ng/ml/yr• 54% survival >.35 ng/ml/yr• Loeb: 0.75 cut off PSA 4-10• 0.35 cut off PSA 2.5-4.0
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Dynamic Tests• Can PSAV be used to help with screening?• Vickers et al. J U 184: 907-912 2010• European Randomized Screening Study for Prostate
Cancer ERSPC• N=2,742• Median PSA 4.47 vs 4.69 (No Ca versus Ca)• Median volume 47 vs 36 (No Ca versus Ca)• PSAV 0.26 vs 0.28 ng/ml/yr (No Ca versus Ca)• AUC PSA 0.522 PSAV 0.551 PSA+PSAV 0.621• “Little support for any clinically useful role for PSA velocity to help
determine initial biopsy”• “May be useful after an initial negative biopsy”
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Dynamic Tests• Can PSAV be used as a trigger in active surveillance?• Andrew Loblaw et al. (Laurence Klotz’ group) JU 184: 1942, 2010• N=305 untreated men 6.1 years (range 0.5-13.3)• Zero prostate cancer deaths• Trigger for Treatment (TT)• PSA of 10 ng/ml TT 38% of the time• PSAV associated with TT 42-84% of the time• www.ASURE.com
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PSA
• Incredibly useful
• Incredibly misused
• Multiple forms
• PSA, free PSA, proPSA
• PSAV, PSAdt, Ln(PSA)
• TMPRSS2ERG
• PCA3
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Volatility: A measure of bidirectional variation over time
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Volatility: A measure of bidirectional variation over time.
time, t
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Volatility: A measure of bidirectional variation over time.
time, t
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Volatility: A measure of bidirectional variation over time.
time, t
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Volatile (Bidirectional) Variables
Options Pricing
Treasuries
Sunspot Activity
Global Warming
PSA
Source: Stockcharts.com
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Volatile (Bidirectional) Variables
Options Pricing
Treasuries
Sunspot Activity
Global Warming
PSA
Source: Stockcharts.com
6-month-ahead Eurodollar rate (Rudebusch et al.)
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Volatile (Bidirectional) Variables
Options Pricing
Treasuries
Sunspot Activity
Global Warming
PSA
Daily GOES readings: Nat’l Geophysical Data Canter
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Volatile (Bidirectional) Variables
Options Pricing
Treasuries
Sunspot Activity
Global Warming
PSA
Source: Global Temperature Land-Ocean Index: Goddard Institute, NASA
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Volatile (Bidirectional) Variables
Options Pricing
Treasuries
Sunspot Activity
Global Warming
PSA
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PSA kinetics
• PSAV: 1 ng/dl/mo
0
2
4
6
8
10
12
14
1 2 3 4 5 6 7 8 9 10 11 12
Year
PS
A
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PSA velocity
• PSAV: How accurate with volatile PSAs?
0
2
4
6
8
10
12
14
1 2 3 4 5 6 7 8 9 10 11 12
Year
PS
A
• Same average PSA, , t-test
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PSA velocity
0
2
4
6
8
10
12
14
1 2 3 4 5 6 7 8 9 10 11 12
Year
PS
A
PSA velocity
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PSA velocity
0
2
4
6
8
10
12
14
1 2 3 4 5 6 7 8 9 10 11 12
Year
PS
A
PSA velocity
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PSA velocity
0
2
4
6
8
10
12
14
1 2 3 4 5 6 7 8 9 10 11 12
Year
PS
A
PSA velocity
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PSA volatility
• Hypothesis : Can a PVI discriminate benign from malignant states?
0
2
4
6
8
10
12
14
1 2 3 4 5 6 7 8 9 10 11 12
Year
PS
A
PSA volatility (PVI)
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INCLUSIONAt least 3 PSAsAt least 1 (one) prostate biopsy (TRUS or TP)
EXCLUSIONNo Urothelial CaNo h/o pelvic RTNo h/o hormone deprivation
PVI: Retrospective Study Population
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Quantitating PVI
Q
QVolatility
t
t
1log
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Financial Models
tNKet
trKsSNC rt
)2/()/ln( 2
(Black & Sholes, 1973)
(Rattray & Shah, 2003)
2
02
2 11
)(2
K
F
TKQe
K
K
T iRT
i i
i
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PSA Volatility Index (PVI)
HYPOTHESIS
An e-based normalization for PSA scatter
and a PVI may predict Ca from BPH
slopee
SE
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N1=932
Retrospective Study Population
N2=279
107 Cancer
172 BPH (e.g. BPH, atrophy, prostatitis, PIN)
Independent variables
Age, race, IPSS, ASA, Meds, TRUS data, Grade, volume/core, # cores, surgical pathology
aPSA, aPSAV, aPSAdt, PSAD, Ln(PSA), PVI
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Descriptives
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Jan-93 Oct-95 Jul-98 Apr-01 Jan-04 Oct-06 Jul-09
0
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Jun-94 Oct-95 Mar-97 Jul-98 Dec-99 Apr-01 Sep-02 Jan-04 May-05 Oct-06 Feb-08 Jul-09
Prostate Ca (n=107) BPH (n=179)
Total PSA ng/dl 1993-2010
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BENIGN n=172 CANCER n=107 P-Value
Age 64.75 ± 8.67 65.14 ± 9.22 0.89
Caucasian (%) 82.94 80.95 0.85
ASA Class I-II (%) 66.48 64.58 0.88
ASA Class III-IV (%) 33.52 35.42
AUA-SS (0-40) 8.15 ± 5.67 6.42 ± 5.58 <.01
Nocturia (voids/night) 1.40 ± 1.16 1.38 ± 0.89 0.49
Study Interval (yrs) 5.10 ± 3.33 4.04 ± 2.96 <.01
Treated for LUTS (%) 58.82 48.82 0.07
Number of PSAs 6.90 ± 3.82 5.05 ± 2.78 <.01
Abnormal DRE (%) 13.69 20.41 0.15
TRUS vol (cc) 44.08 ± 25.01 40.24 ± 20.59 0.21
Number of Biopsies 1.75 ± 1.03 1.50 ± 0.88 0.06
Demographics
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Descriptives
0
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Jan-93 Oct-95 Jul-98 Apr-01 Jan-04 Oct-06 Jul-09
0
5
10
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30
Jun-94 Oct-95 Mar-97 Jul-98 Dec-99 Apr-01 Sep-02 Jan-04 May-05 Oct-06 Feb-08 Jul-09
BENIGN n=172 CANCER n=107 p-value
PSA ng/ml 5.60 ± 3.05 6.36 ± 5.53 0.7
free PSA (%) 19.78 ± 9.33 16.17 ± 8.51 0.04
PSAV ng/ml/yr -0.39 ± 6.28 0.71 ± 2.86 0.09
PSA dt (mo) 12.81 ± 336.95 241.28 ± 240.18 0.06
slope ln(PSA)*1000 -0.06 ± .00 0.38 ± 1.1 <.0001
PVI 1.56 ± 1.29 0.83 ± 0.83 <.0001
PSAD (ng/ml/cc) 0.15 ± 0.09 0.19 ± 0.20 .04
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PVI Correlations
0
10
20
30
Jan-93 Oct-95 Jul-98 Apr-01 Jan-04 Oct-06 Jul-09
0
5
10
15
20
25
30
Jun-94 Oct-95 Mar-97 Jul-98 Dec-99 Apr-01 Sep-02 Jan-04 May-05 Oct-06 Feb-08 Jul-09
X Y P value R2
PVI PSAV 0.11
PVI # biopsies 0.20
PVI IPSS 0.29
PVI BPH <0.00 .06
PVI PSAD <0.00 0.05
PVI Proscar <0.00 0.06
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PVI Correlations
0
10
20
30
Jan-93 Oct-95 Jul-98 Apr-01 Jan-04 Oct-06 Jul-09
0
5
10
15
20
25
30
Jun-94 Oct-95 Mar-97 Jul-98 Dec-99 Apr-01 Sep-02 Jan-04 May-05 Oct-06 Feb-08 Jul-09
X Y P value R2
PVI PSAV 0.11
PVI # biopsies 0.20
PVI IPSS 0.29
PVI BPH <0.00 .06
PVI PSAD <0.00 0.05
PVI Proscar <0.00 0.06
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Linear Regression y=mx+b
For each increase of 1 unit of x, y increases by 4.88 %
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PSA volatility and % cancer
Or, as cancer volume decreases, PSA volatility increases
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Logistic Regression = yes or no
zezf
1
1)(
For each change in x, the probability of the outcome goes up by y
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Logistic Regression = yes or noUNIVARIATE
Coeff p-value
free PSA -0.05 0.05
PSAD 2.07 0.06
AUA SS -0.06 0.02
Ln(PSA)*1000† 1.43 <.001
PVI -0.77 <.001
MULTIVARIATE
Coeff p-value
Ln(PSA) + AUA SS 1.23 <.001
-0.05 0.05
PVI + AUA SS -0.78 <.001
-0.06 0.03
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ROCs
AUC=.800
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Nomograms=Prediction Tools
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Nomograms=Prediction Tools
Formula for the oxygen consumption of rainbow trout as a function of weight and water temperature. Ron Doerfler Dead Reckonings
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Nomograms=Prediction Tools
•Too Many Variables can Compromise the Model
•Increasing Complexity may Reduce Clinical Usefulness
•“Precision versus Parsimony”-Sengupta and Blute 2006
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PVI Nomogram
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PVI
•PVI > 2 benign, esp. in total PSA range 4-20
•PVI < 1 malignant
•PVI quantifies the PSA instability over time
•www.psastatistics.com
•Multivariable analysis
slopee
SE
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WWW.PSASTATISTICS.COM/PVI
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PVI
•PVI > 2 benign, esp. in total PSA range 4-20
•PVI < 1 malignant
•PVI quantifies the PSA instability over time
•www.psastatistics.com
•Multivariable analysis
slopee
SE
![Page 59: PSA VOLATILITY INDEX (PVI) & UPDATE ON PSA KINETICS John Phillips, MD 19 November, 2010 New York Medical College Hackensack University Medical Center](https://reader036.vdocuments.site/reader036/viewer/2022062314/56649e7d5503460f94b8047b/html5/thumbnails/59.jpg)
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Thanks
Muhammad Choudhury, MD (NYMC)
Andrew Fishman, MD (NYMC)
Basir Tareen, MD (BIMC)
Harris Nagler, MD (BIMC)
Devesh Shah, PhD (Goldman Sachs)