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 203,415 men developed prostate cancer 28,372 men died from prostate cancer John Phillips, MD 19 November, 2010 New York Medical College Hackensack University Medical Center

•34 kD •Serine protease •19q13 •Kallikrein-related peptidase III •Half-life total PSA 2-3 days •Free PSA <8 hours J Mol Biol (2008), 376, 1021-33

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

n n

 

i

 1 log 2 log( * (

time n

 1

PSA n

 1  

time PSA n

)

n

)

i

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 14 12 10 8 6 4 2 0 1 2 3 4 5 6 7

Year

8 9 10 11 12

PSA velocity

• PSAV: How accurate with volatile PSAs?

14 12 10 8 6 4 2 0 1 2 3 4 5 6 7

Year

8 9 10 11 12 • Same average PSA, s , t-test

14 12 10 8 6 4 2 0 1 2 3 4 5 6 7

Year

8 9 10 11 12

14 12 10 8 6 4 2 0 1 2 3 4 5 6 7

Year

8 9 10 11 12

14 12 10 8 6 4 2 0 1 2 3 4 5 6 7

Year

8 9 10 11 12

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

14 12 10 8 6 4 2 0 1 2 3 4 5 6 7

Year

8 9 10 11 12

PVI: Retrospective Study Population INCLUSION  At least 3 PSAs  At least 1 (one) prostate biopsy (TRUS or TP) EXCLUSION  No Urothelial Ca  No h/o pelvic RT  No h/o hormone deprivation

Quantitating PVI

Volatility

 s    log   

t Q t

 1

Q

     

Financial Models

C



SN

  ln(

s

/

K

)  (

r

s

t

 s 2 / 2 )

t

  

Ke



rt N

   s

t

 (

Black & Sholes, 1973

) s 2  2

T



i



K i K i

2

e RT Q

(

K i

)  1

T

  

F K

0  1    2 (

Rattray & Shah, 2003)

PSA Volatility Index (PVI)

SE e slope

HYPOTHESIS An e-based normalization for PSA scatter and a PVI may predict Ca from BPH

Retrospective Study Population N 1 =932 N 2 =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

30 25 20 15 10 5 0 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) 30 20 10 0 Jan-93 Oct-95 Jul-98 Apr-01 Jan-04 Oct-06 Jul-09 BPH (n=179) Total PSA ng/dl 1993-2010

Age Caucasian (%) ASA Class I-II (%) ASA Class III-IV (%) AUA-SS (0-40) Nocturia (voids/night) Study Interval (yrs) Treated for LUTS (%) Number of PSAs Abnormal DRE (%) TRUS vol (cc) Number of Biopsies Demographics BENIGN n=172 64.75 ± 8.67

82.94

66.48

33.52

CANCER n=107 65.14 ± 9.22

80.95

64.58

35.42

P-Value 8.15 ± 5.67

1.40 ± 1.16

5.10 ± 3.33

58.82

6.90 ± 3.82

13.69

44.08 ± 25.01

1.75 ± 1.03

6.42 ± 5.58

1.38 ± 0.89

4.04 ± 2.96

48.82

5.05 ± 2.78

20.41

40.24 ± 20.59

1.50 ± 0.88

0.89

0.85

0.88

<.01

0.49

<.01

0.07

<.01

0.15

0.21

0.06

Descriptives

30 25 20 15 10 5 0 Jun-94 Oct-95 Mar-97 Jul-98 Dec-99 Apr-01 Sep-02 Jan-04 May-05 Oct-06 Feb-08 Jul-09 30 20 10 0 Jan-93 Oct-95 Jul-98 Apr-01 Jan-04 Oct-06 Jul-09 PSA ng/ml free PSA (%) PSAV ng/ml/yr PSA dt (mo) slope ln(PSA)*1000 PVI PSAD (ng/ml/cc) BENIGN n=172 5.60 ± 3.05

19.78 ± 9.33

-0.39 ± 6.28

12.81 ± 336.95

-0.06 ± .00

1.56 ± 1.29

0.15 ± 0.09 CANCER n=107 6.36 ± 5.53

16.17 ± 8.51

0.71 ± 2.86

241.28 ± 240.18

0.38 ± 1.1

0.83 ± 0.83

0.19 ± 0.20

p-value 0.7

0.04

0.09

0.06

<.0001

<.0001

.04

PVI Correlations

30 25 20 15 10 5 0 Jun-94 Oct-95 Mar-97 Jul-98 Dec-99 Apr-01 Sep-02 Jan-04 May-05 Oct-06 Feb-08 Jul-09 30 20 10 0 Jan-93 Oct-95 Jul-98 Apr-01 Jan-04 Oct-06 Jul-09 X PVI PVI PVI PVI PVI PVI Y PSAV PSAD Proscar P value 0.11

# biopsies 0.20

IPSS BPH 0.29

<0.00

<0.00

<0.00

R 2 .06

0.05

0.06

PVI Correlations

30 25 20 15 10 5 0 Jun-94 Oct-95 Mar-97 Jul-98 Dec-99 Apr-01 Sep-02 Jan-04 May-05 Oct-06 Feb-08 Jul-09 30 20 10 0 Jan-93 Oct-95 Jul-98 Apr-01 Jan-04 Oct-06 Jul-09 X PVI PVI PVI PVI PVI PVI Y PSAV PSAD Proscar P value 0.11

# biopsies 0.20

IPSS BPH 0.29

<0.00

<0.00

<0.00

R 2 .06

0.05

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

f

(

z

)  1  1

e



z

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

Logistic Regression = yes or no

UNIVARIATE

free PSA PSAD AUA SS Ln(PSA)*1000 † PVI

MULTIVARIATE

Coeff -0.05

2.07

-0.06

1.43

-0.77

p-value 0.05

0.06

0.02

<.001

<.001

Ln(PSA) + AUA SS PVI + AUA SS Coeff 1.23

-0.05

-0.78

p-value <.001

<.001

-0.06

0.05

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

SE e slope

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

SE e slope

Thanks

Muhammad Choudhury, MD (NYMC) Andrew Fishman, MD (NYMC) Basir Tareen, MD (BIMC) Harris Nagler, MD (BIMC) Devesh Shah, PhD (Goldman Sachs)