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PSA VOLATILITY INDEX (PVI) & UPDATE ON PSA KINETICS

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.

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PSA VOLATILITY INDEX (PVI) & UPDATE ON PSA KINETICS

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  1. PSA VOLATILITY INDEX (PVI) & UPDATE ON PSA KINETICS John Phillips, MD 19 November, 2010 New York Medical College Hackensack University Medical Center

  2. PSA VOLATILITY INDEX (PVI) & UPDATE ON PSA KINETICS John Phillips, MD 19 November, 2010 New York Medical College Hackensack University Medical Center

  3. 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

  4. 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

  5. Serum Proteins Alpha-2-macroglobulin Alpha-Chymotrypsin Free isoforms: B-PSA, I-PSA, and pro-PSA

  6. SCR-270 Radar Balancing true signal with interference

  7. Receiver Operating Characteristic (ROC)

  8. Receiver Operating Characteristic (ROC) Area Under Curve* 0.500= worthless 0.650=lukewarm 0.700=very good 0.800=outstanding *trapezoidal method

  9. 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

  10. 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

  11. 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

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

  13. 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

  14. 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

  15. 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”

  16. 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

  17. PSA • Incredibly useful • Incredibly misused • Multiple forms • PSA, free PSA, proPSA • PSAV, PSAdt, Ln(PSA) • TMPRSS2ERG • PCA3

  18. Volatility: A measure of bidirectional variation over time

  19. Volatility: A measure of bidirectional variation over time. time, t

  20. Volatility: A measure of bidirectional variation over time. time, t

  21. Volatility: A measure of bidirectional variation over time. time, t

  22. Volatile (Bidirectional) Variables • Options Pricing • Treasuries • Sunspot Activity • Global Warming • PSA Source: Stockcharts.com

  23. Volatile (Bidirectional) Variables Options Pricing • Treasuries • Sunspot Activity • Global Warming • PSA Source: Stockcharts.com 6-month-ahead Eurodollar rate (Rudebusch et al.)

  24. Volatile (Bidirectional) Variables Options Pricing Treasuries • Sunspot Activity • Global Warming • PSA Daily GOES readings: Nat’l Geophysical Data Canter

  25. Volatile (Bidirectional) Variables Options Pricing Treasuries Sunspot Activity • Global Warming • PSA Source: Global Temperature Land-Ocean Index: Goddard Institute, NASA

  26. Volatile (Bidirectional) Variables Options Pricing Treasuries Sunspot Activity Global Warming • PSA

  27. PSA kinetics • PSAV: 1 ng/dl/mo

  28. PSA velocity • PSAV: How accurate with volatile PSAs? • Same average PSA, s, t-test

  29. PSA velocity PSA velocity

  30. PSA velocity PSA velocity

  31. PSA velocity PSA velocity

  32. PSA volatility PSA volatility (PVI) • Hypothesis : Can a PVI discriminate benign from malignant states?

  33. 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

  34. Quantitating PVI

  35. Financial Models (Black & Sholes, 1973) (Rattray & Shah, 2003)

  36. PSA Volatility Index (PVI) HYPOTHESIS An e-based normalization for PSA scatter and a PVI may predict Ca from BPH

  37. Retrospective Study Population N1=932 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

  38. Descriptives Prostate Ca (n=107) BPH (n=179) Total PSA ng/dl 1993-2010

  39. Demographics

  40. Descriptives

  41. PVI Correlations

  42. PVI Correlations

  43. Linear Regression y=mx+b

  44. Linear Regression y=mx+b For each increase of 1 unit of x, y increases by 4.88 %

  45. PSA volatility and % cancer Or, as cancer volume decreases, PSA volatility increases

  46. Logistic Regression = yes or no For each change in x, the probability of the outcome goes up by y

  47. Logistic Regression = yes or no

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