NY Prostate Cancer Conference - L. Klotz - Session 3: Active surveillance: PSA kinetics and biomarkers

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NY Prostate Cancer Conference - L. Klotz - Session 3: Active surveillance: PSA kinetics and biomarkers

  1. 1. ACTIVE SURVEILLANCE: PSA KINETICS AND BIOMARKERS Laurence Klotz, MD Sunnybrook Health Sciences Centre Professor of Surgery
  2. 2. RELEVANT DISCLOSURES: <ul><li>None. </li></ul>07/08/11
  3. 3. Defining ‘Clinically significant’ prostate cancer <ul><li>Stamey definition: < 0.5 cc Gleason 6 disease </li></ul><ul><ul><li>Based on analysis of cystoprostatectomy specimens </li></ul></ul><ul><ul><li>Lifetime prevalence of 8% assumed to reflect proportion of men with clinically significant disease </li></ul></ul><ul><ul><li>8% of cancers had > 0.5 cc or Gleason 4/5 pattern </li></ul></ul><ul><li>Never validated although widely adopted </li></ul><ul><li>0.5 cc sphere has 1 cm diameter (4/3 ∏ R 3 ) </li></ul><ul><li>Likely understates true proportion </li></ul>07/08/11
  4. 4. A Critical Analysis of the Tumor Volume Threshold for Clinically Insignificant Prostate Cancer Using a Data Set of a Randomized Screening Trial. Wolters T, Roobol M, Schröder F, van der Kwast T. J Urol 185, 121-125, 2011 <ul><li>ERSPC data applied to Stamey technique </li></ul><ul><li>Lifetime risk of screen diagnosis: 13% </li></ul><ul><li>Lifetime risk of clinical diagnosis: 6.4% </li></ul><ul><li>Assuming 49% clinically significant, determined the volume of 49% largest cancers in 325 RP specimens </li></ul><ul><li>Threshold volume for clinically significant Gleason 6 disease: </li></ul><ul><ul><li>Index tumor 1.3 ml (1.4 cm diameter sphere) </li></ul></ul><ul><ul><li>Total tumor volume 2.5 ml </li></ul></ul><ul><li>CAVEAT: 34% had Gleason 4 pattern </li></ul><ul><ul><li>Likely underestimates threshold volume for Gleason 3 </li></ul></ul>
  5. 5. RISK OF PCA DEATH AFTER RP, MEN 60-69, WITH GLEASON 6: EGGENER S, AUA 2010 <ul><li>24,321 RPs with 20 year F/U </li></ul><ul><li>Gleason 6 20 year Pca mortality 0.2% </li></ul>
  6. 6. ACTIVE SURVEILLANCE: WHO IS A CANDIDATE? <ul><li>Favorable risk (D ’ Amico): </li></ul><ul><ul><li>Gleason ≤ 6 </li></ul></ul><ul><ul><li>PSA ≤ 10 </li></ul></ul><ul><ul><li>T1c/T2a </li></ul></ul><ul><li>In younger patients </li></ul><ul><ul><li>≤ 1/3 cores positive </li></ul></ul><ul><ul><li>< 50% involvement of any one core </li></ul></ul><ul><ul><li>Ideally PSA stable with density < 0.15 </li></ul></ul><ul><li>About 40% of newly diagnosed patients in a screened population eligible </li></ul>07/08/11
  7. 7. Nomogram to predict indolent cancer 24 E.W. Steyerberg, F Schroeder J Urol January 2007
  8. 8. CONSERVATIVE MANAGEMENT: 20-YEAR OUTCOMES ALBERTSEN P JAMA. 2005;293:2095-2101 Lead Time effect 0 10 20 30 Years 0 10 20 30 Gleason score shift 0 10 20 30 Estimating the rate of progression to fatal disease
  9. 9. “ IF YOU ARE GOING TO DO AN UNNECCESSARY OPERATION, IT IS IMPORTANT THAT YOU DO IT WELL”. PAT WALSH, AUA DEBATE 2010 VS KLOTZ, D’AMICO “WHAT IS THE OPTIMAL TREATMENT FOR FAVORABLE RISK PROSTATE CANCER” 07/08/11
  10. 10. ACTIVE SURVEILLANCE: CRITERIA FOR DETECTING HIGHER RISK CANCERS <ul><li>PSA DT < 3 years </li></ul><ul><ul><li>PSA q 3/12 x 2 years then q 6/12; 8-9 data points ideal </li></ul></ul><ul><li>Biopsy strategies: </li></ul><ul><ul><li>Year one, then q 3-4 years to age 80 </li></ul></ul><ul><li>Grade progression </li></ul><ul><ul><li>15-20% </li></ul></ul><ul><ul><li>Usually small component Gleason 4 pattern </li></ul></ul><ul><li>Guidelines, not rules </li></ul>07/08/11
  11. 11. TORONTO SURVEILLANCE COHORT: DEMOGRAPHICS (N=453) <ul><li>Median age 70.3 (40-88) </li></ul><ul><li>Median PSA 6.2 </li></ul><ul><li>Median F/U (survivors) 7.9 years (1.4-14.8) </li></ul><ul><li>Clinical stage </li></ul><ul><ul><li>T1b 6% </li></ul></ul><ul><ul><li>T1c 67% </li></ul></ul><ul><ul><li>T2a 18% </li></ul></ul><ul><ul><li>T2b 5% </li></ul></ul><ul><li>Lost to follow up: 5% </li></ul><ul><li>PSA > 10: 13% </li></ul><ul><li>Gleason >6: 13.5% </li></ul>07/08/11
  12. 12. DISTRIBUTION OF PSA DOUBLING TIMES ON SURVEILLANCE. 07/08/11 <1 2 3 4 5 6 7 8 9 10 10-15 20 30 40 50 100 >100 PSA Doubling time Median 7 years %
  13. 13. PSA VELOCITY DISTRIBUTION IN UNTREATED LOCALIZED PCA: VENKITARAMAN R, PARKER C ET AL, BJU INT 2007 07/08/11
  14. 14. PSA KINETICS WEBSITE WWW.ASURE.CA 07/08/11
  15. 15. Comparing PSA Triggers for Intervention in Men With Stable Prostate Cancer on Active Surveillance Loblaw A, Klotz L J Urol 184(5) 1942 (2010) <ul><li>305/453 men whose disease was stable by all criteria </li></ul><ul><li>No metastasis, no radical intervention, no upgrading to > 3+4 </li></ul>
  16. 16. COMPARING PSA TRIGGERS FOR INTERVENTION IN MEN WITH STABLE PCA ON AS. LOBLAW A, KLOTZ L. J UROL. 2010 NOV;184(5):1942-6. <ul><li>305/453 men whose disease was stable by all criteria </li></ul><ul><li>No metastasis, no radical intervention, no upgrading to > 3+4 </li></ul><ul><li>PSA Trigger Patients triggered (%) </li></ul><ul><li>GLMM < 3 years 0 </li></ul><ul><li>Total PSA > 10 108 (37%) </li></ul><ul><li>Total PSA > 20 29 (10%) </li></ul><ul><li>Linear regression of ln(PSA) 114 (40%) </li></ul><ul><li>Actual PSA velocity >2 ng/ml/yr 146 (50%) </li></ul>07/08/11
  17. 17. PSA KINETICS ARE AN UNRELIABLE TRIGGER FOR INTERVENTION IN A PROSTATE CANCER SURVEILLANCE PROGRAM ROSS AE, CARTER HB, WALSH PC ET AL. JCO 28:2810-2816. 2010 07/08/11 Biopsy RP <ul><li>290 men on AS (Epstein criteria) </li></ul><ul><li>35% developed path progression (beyond Epstein) </li></ul><ul><li>PSA kinetics not predictive of adverse biopsy findings or RP pathology </li></ul>
  18. 18. PSA DT PREDICTS OUTCOME AFTER AS. AXEN E, HUGOSSON J, STRANNE J. EAU 3/2011 <ul><li>269 men in Gothenburg screening trial managed with initial surveillance </li></ul><ul><li>Median DT 5 yr </li></ul><ul><li>85 had RP; 13% of these had PSA recurrence </li></ul><ul><ul><li>PSA DT % PSA failure </li></ul></ul><ul><ul><li>< 2 yrs 57 </li></ul></ul><ul><ul><li>2-4 yrs 11 </li></ul></ul><ul><ul><li>4 yrs 2 </li></ul></ul>07/08/11
  19. 19. SYSTEMATIC REVIEW OF PRETREATMENT PSA VELOCITY AND DOUBLING TIME AS PCA PREDICTORS. VICKERS A J CLIN ONCOL 27:398-403. 2008 07/08/11 Verification bias (VB): Men not having a biopsy assumed to be cancer free <ul><li>Stu dies with > 200 patients </li></ul>Author Study Performance of PSA velocity vs PSA Eggener 995 neg initial bx PPV Velocity 3% higher Djavan 559 Bx result Worse AUC Sun 120780 Ca screen Worse AUC (Verification bias) Moul 11861 Ca screen Worse AUC Carter 980 Ca death long term Velocity AUC 0.75 vs PSA 0.74 Berger 4800 Ca screen Velocity 0.87 vs PSA 0.65 (VB) Whittemore 320 Ca death long term Worse AUC Loeb 6844 Ca screen AUC 0.83 vs 0.81 (VB) Thompson 5519 Bx in PCPT No difference
  20. 20. SYSTEMATIC REVIEW OF PRETREATMENT PSA VELOCITY AND DOUBLING TIME AS PCA PREDICTORS. VICKERS A J CLIN ONCOL 27:398-403 2008 “… little evidence that pretreatment PSA velocity or DT are of value for early-stage prostate cancer….. no justification for use of PSA dynamics in the clinical setting or as an inclusion criterion for trials… .. ” <ul><li>Few studies had robust end point </li></ul>
  21. 21. PATIENTS REMAINING FREE OF INTERVENTION KLOTZ L, ET AL, J CLIN ONCOL. 2010 JAN 1;28(1):126-31 07/08/11 62% free of intervention at 10 years 70% remain on surveillance
  22. 22. PATIENTS TREATED ON SURVEILLANCE: TORONTO 07/08/11 Reason for intervention Intervention RT RP ADT Total 88 (65%) 33 (25%) 14 (10%) 135 PSA DT Grade increase Volume progression T stage Pt. preference Unknown 59 (44%) 32 (24%) 4(3%) 5(4%) 15 (11%) 14%
  23. 23. 07/08/11 Overall survival in 452 patients Klotz L, et al, J Clin Oncol. 2010 Jan 1;28(1):126-31 22% died 10 year survival 68%
  24. 24. PCA SPECIFIC SURVIVAL: 97% AT 10 YEARS KLOTZ L, ET AL, J CLIN ONCOL. 2010 JAN 1;28(1):126-31 07/08/11 <ul><li>5/452 patients </li></ul>10 year CSS 97% All PSA DT ≤ 1.6 years 3.7 5.2 5.3 8.7 9.6
  25. 25. PSA FAILURE BY TREATMENT MODALITY KLOTZ L, ET AL, J CLIN ONCOL. 2010 JAN 1;28(1):126-31 07/08/11 <ul><li>33 RP </li></ul><ul><li>88 XRT </li></ul><ul><li>(most 66 Gy) </li></ul>P=.12
  26. 26. CUMULATIVE HAZARD FUNCTION OVER TIME: CAUSE SPECIFIC VS NON PROSTATE CANCER SURVIVAL KLOTZ L, ET AL, J CLIN ONCOL. 2010 JAN 1;28(1):126-31 07/08/11 HR 18.6
  27. 27. PCA3 Assay Correlates With Tumor Volume: Selecting Candidates for Active Surveillance. Nakanishi H J Urol 2008: 179, 1804-1810 N=96 RPs
  28. 28. PCA3 accurately predicts tumour volume for active surveillance. Ploussard G et al, European Urol 5 9 (2 01 1 ) 4 2 2 – 4 2 9 <ul><li>106 favorable risk patients having RP </li></ul><ul><li>Multivariate analysis for criteria for favorable disease on RP path </li></ul>RR Unfavorable disease/P value RR Cancer volume > 0.5 cc/P value Significant Pca/P value PCA3 1.8 NS 5.4 0.01 12.7 0.003 Epstein biopsy criteria 3.9 0.03 4.1 0.05 18.8 0.01 PSA density 1.31 NS 2.6 NS 4.7 0.08 MRI 5.0 0.025 1.9 NS 7.7 NS
  29. 29. RP FINDINGS IN PATIENTS IN WHOM ACTIVE SURVEILLANCE FAILS. DUFFIELD A, CARTER B, EPSTEIN J. J UROL 182:2274-9, NOV 2009 07/08/11 <ul><li>48/450 men on surveillance having RP </li></ul><ul><li>RP indicated if annual biopsy showed increased grade or volume beyond Epstein criteria </li></ul><ul><li>65% OC </li></ul><ul><ul><li>16/450 (5% of cohort) had non organ-confined disease at RP) </li></ul></ul><ul><li>100% with tumor volume > 1.0 cm were anterior </li></ul>
  30. 30. MRI GUIDED BIOPSY IN MEN WITH REPEAT NEGATIVE BIOPSIES AND INCREASED PSA: DISTRIBUTION OF BIOPSY CONFIRMED SUSPICIOUS SITES. HAMBROCK T ET AL, J UROL 183(2): 520, 2010 Apex mid apex mid Mid base Base Number of suspicious areas: Red: 5 Orange: 4 Yellow: 3 Green: 2 Blue: 1
  31. 31. DIFFUSION-WEIGHTED MRI FOR MONITORING PROSTATE CANCER PROGRESSION DURING ACTIVE SURVEILLANCE MORGAN VA, PARKER C ET AL, BRITISH JOURNAL OF RADIOLOGY, 84 (2011), 31–37 Whole prostate Tumor
  32. 32. ‘ FAVORABLE RISK’ DISEASE IS HETEROGENEOUS 07/08/11 1 cm ‘ Pseudo-disease’ ‘Evasive anterior cancer’ Favorable but significant Carey map of Africa 1805
  33. 33. IMPACT OF 5 ARIS IN MEN ON SURVEILLANCE. FINELLI A ET AL, EURO UROL 59:509-14, 201 07/08/11 <ul><li>288 men on surveillance, 70 treated with 5 ARI </li></ul>
  34. 34. IMPLICATIONS OF THE PSA FAILURE RATE IN TREATED SURVEILLANCE PATIENTS <ul><li>50% PSA recurrence after RP/XRT is 15% of overall cohort </li></ul><ul><li>The 30% of patients selected by PSA DT < 3 yrs or grade progression (4+3) for treatment are a high risk group </li></ul><ul><li>Post treatment PSA failure ≠ Pca mortality </li></ul><ul><ul><li>May be indolent </li></ul></ul><ul><ul><li>Other cause mortality most common cause of death </li></ul></ul><ul><ul><li>Salvage XRT will convert many recurrences to cure </li></ul></ul><ul><li>Earlier identification of high risk group a priority </li></ul>07/08/11
  35. 35. CONCLUSIONS <ul><li>Active surveillance safe in intermediate time frame </li></ul><ul><li>Ratio of other cause to PCa mortality 19:1 </li></ul><ul><li>PSA kinetics unreliable </li></ul><ul><li>Challenge is identification of high volume/higher grade disease </li></ul><ul><ul><li>Targeted biopsy </li></ul></ul><ul><ul><li>Multiparametric MRI </li></ul></ul><ul><ul><li>Biomarkers: PCA3 </li></ul></ul><ul><li>Validation of intervention triggers a priority </li></ul>07/08/11

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