PSA VOLATILITY INDEX (PVI)

& UPDATE ON PSA KINETICS

John Phillips, MD 19 November, 2010

New York Medical College Hackensack University Medical Center

PSA VOLATILITY INDEX (PVI)

& UPDATE ON PSA KINETICS

John Phillips, MD 19 November, 2010

New York Medical College Hackensack University Medical Center

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

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

Serum Proteins

Alpha-2-macroglobulin

Alpha-Chymotrypsin

Free isoforms: B-PSA, I-PSA, and pro-PSA

SCR-270 Radar

Balancing true signal with interference

Receiver Operating Characteristic (ROC)

Receiver Operating Characteristic (ROC)

Area Under Curve*

0.500= worthless

0.650=lukewarm

0.700=very good

0.800=outstanding*trapezoidal method

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

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

•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

Other Scalar Tests

• [-2] pro PSA AUC=.76 Sokoll et al. CEBM 2010• TMPRSS2-ERG• PSAD >0.155• TZ-PSAD• PCA3

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

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

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”

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

PSA

• Incredibly useful

• Incredibly misused

• Multiple forms

• PSA, free PSA, proPSA

• PSAV, PSAdt, Ln(PSA)

• TMPRSS2ERG

• PCA3

Volatility: A measure of bidirectional variation over time

Volatility: A measure of bidirectional variation over time.

time, t

Volatility: A measure of bidirectional variation over time.

time, t

Volatility: A measure of bidirectional variation over time.

time, t

Volatile (Bidirectional) Variables

Options Pricing

Treasuries

Sunspot Activity

Global Warming

PSA

Source: Stockcharts.com

Volatile (Bidirectional) Variables

Options Pricing

Treasuries

Sunspot Activity

Global Warming

PSA

Source: Stockcharts.com

6-month-ahead Eurodollar rate (Rudebusch et al.)

Volatile (Bidirectional) Variables

Options Pricing

Treasuries

Sunspot Activity

Global Warming

PSA

Daily GOES readings: Nat’l Geophysical Data Canter

Volatile (Bidirectional) Variables

Options Pricing

Treasuries

Sunspot Activity

Global Warming

PSA

Source: Global Temperature Land-Ocean Index: Goddard Institute, NASA

Volatile (Bidirectional) Variables

Options Pricing

Treasuries

Sunspot Activity

Global Warming

PSA

PSA kinetics

• PSAV: 1 ng/dl/mo

0

2

4

6

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1 2 3 4 5 6 7 8 9 10 11 12

Year

PS

A

PSA velocity

• PSAV: How accurate with volatile PSAs?

0

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1 2 3 4 5 6 7 8 9 10 11 12

Year

PS

A

• Same average PSA, , t-test

PSA velocity

0

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1 2 3 4 5 6 7 8 9 10 11 12

Year

PS

A

PSA velocity

PSA velocity

0

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1 2 3 4 5 6 7 8 9 10 11 12

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PS

A

PSA velocity

PSA velocity

0

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1 2 3 4 5 6 7 8 9 10 11 12

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PS

A

PSA velocity

PSA volatility

• Hypothesis : Can a PVI discriminate benign from malignant states?

0

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1 2 3 4 5 6 7 8 9 10 11 12

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PS

A

PSA volatility (PVI)

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

Quantitating PVI

Q

QVolatility

t

t

1log

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

PSA Volatility Index (PVI)

HYPOTHESIS

An e-based normalization for PSA scatter

and a PVI may predict Ca from BPH

slopee

SE

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

Descriptives

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

Prostate Ca (n=107) BPH (n=179)

Total PSA ng/dl 1993-2010

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

Descriptives

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

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

PVI Correlations

0

10

20

30

Jan-93 Oct-95 Jul-98 Apr-01 Jan-04 Oct-06 Jul-09

0

5

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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

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

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

Linear Regression y=mx+b

Linear Regression y=mx+b

For each increase of 1 unit of x, y increases by 4.88 %

PSA volatility and % cancer

Or, as cancer volume decreases, PSA volatility increases

Logistic Regression = yes or no

zezf

1

1)(

For each change in x, the probability of the outcome goes up by y

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

ROCs

AUC=.800

Nomograms=Prediction Tools

Nomograms=Prediction Tools

Formula for the oxygen consumption of rainbow trout as a function of weight and water temperature. Ron Doerfler Dead Reckonings

Nomograms=Prediction Tools

•Too Many Variables can Compromise the Model

•Increasing Complexity may Reduce Clinical Usefulness

•“Precision versus Parsimony”-Sengupta and Blute 2006

PVI Nomogram

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

WWW.PSASTATISTICS.COM/PVI

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

Thanks

Muhammad Choudhury, MD (NYMC)

Andrew Fishman, MD (NYMC)

Basir Tareen, MD (BIMC)

Harris Nagler, MD (BIMC)

Devesh Shah, PhD (Goldman Sachs)