NY Prostate Cancer Conference - A. Stephenson - Session 4: Predicting clinical and biochemical...

Predicting Clinical and Predicting Clinical and Biochemical Endpoints after Biochemical Endpoints after

Radical ProstatectomyRadical Prostatectomy

Andrew J. Stephenson, MD FRCSC FACSAndrew J. Stephenson, MD FRCSC FACS

Director, Urologic OncologyDirector, Urologic Oncology

Glickman Urological and Kidney InstituteGlickman Urological and Kidney Institute

Cleveland ClinicCleveland Clinic

Postoperative Predictions: Why?Postoperative Predictions: Why?

• Patient counselingPatient counseling

• Surveillance scheduleSurveillance schedule

• Secondary therapySecondary therapy–Adjuvant or salvageAdjuvant or salvage

– Local or systemicLocal or systemic

• Clinical trial designClinical trial design

• Build a better preop model…Build a better preop model…

Postoperative vs. Pretreatment ModelsPostoperative vs. Pretreatment Models

• Generally perform with greater accuracyGenerally perform with greater accuracy

• Limitations of clinical grading and stagingLimitations of clinical grading and staging–Biopsy Gleason 2-6 Biopsy Gleason 2-6 2-3% pathological Gleason 8- 2-3% pathological Gleason 8-

1010

5-7% pathological Gleason 4+35-7% pathological Gleason 4+3

–Clinical stage T1Clinical stage T1 20-25% non-organ-confined 20-25% non-organ-confined

5% SVI or LN metastases5% SVI or LN metastases

–Clinical stage T3Clinical stage T3 20-25% organ-confined 20-25% organ-confined

• Ability to consider more parameters (e.g. surgical Ability to consider more parameters (e.g. surgical margins) that may influence prognosismargins) that may influence prognosis

Postoperative NomogramPostoperative Nomogram

Kattan et al. Kattan et al. J Clin OncolJ Clin Oncol 1999; Graefen et al. 1999; Graefen et al. J Clin OncolJ Clin Oncol 2002; 2002; Bianco et al. Bianco et al. J UrolJ Urol 2003 2003

Single surgeon, 996 pts, open RP, 1983-1997, Single surgeon, 996 pts, open RP, 1983-1997, BCR Endpoint: PSA 0.4 ng/mL and rising BCR Endpoint: PSA 0.4 ng/mL and rising

Bootstrapped c-index: 0.88 Bootstrapped c-index: 0.88

Model predictions Model predictions remarkably robust when remarkably robust when

applied to diverse external applied to diverse external validation populationsvalidation populations

C-index 0.80-0.83C-index 0.80-0.83

Postoperative Nomogram v. 2.0Postoperative Nomogram v. 2.0

• 2 surgeons, 1881 pts2 surgeons, 1881 pts

• Externally-validated on Externally-validated on two cohorts (> 3000 pts)two cohorts (> 3000 pts)

• 10-year endpoint10-year endpoint

• Predictions adjusted for Predictions adjusted for year of surgery and year of surgery and adjuvant radiotherapyadjuvant radiotherapy

• C-index: 0.79-0.81C-index: 0.79-0.81

Stephenson et al. Stephenson et al. J Clin OncolJ Clin Oncol 2005 2005

Deciding Upon Secondary TherapyDeciding Upon Secondary Therapy

• Nomogram predicting outcome of adjuvant RTNomogram predicting outcome of adjuvant RT

Stephenson et al. Stephenson et al. In preparationIn preparation

N = 326 pts, median FU 70 mos, externally-validated on SWOG 8794, c-index 0.67N = 326 pts, median FU 70 mos, externally-validated on SWOG 8794, c-index 0.67

Building a Better Nomogram?Building a Better Nomogram?

• New biomarkers:New biomarkers:– IL-6sR, TGF-IL-6sR, TGF-ββ1, VCAM1, uPA improved accuracy of model 1, VCAM1, uPA improved accuracy of model

when added to standard postoperative parameters when added to standard postoperative parameters (bootstrapped c-index 0.86 vs. 0.82)(bootstrapped c-index 0.86 vs. 0.82)

• New clinical parameters:New clinical parameters:–SM’s: focal v. extensive, solitary v. multiple, apex v. otherSM’s: focal v. extensive, solitary v. multiple, apex v. other

–C-index: 0.851 v. 0.850 v. 850C-index: 0.851 v. 0.850 v. 850

–Surgeon experience: Surgeon experience: –7724 pts, 72 urologists, C-index 0.812 v. 0.811 +/- surgeon experience7724 pts, 72 urologists, C-index 0.812 v. 0.811 +/- surgeon experience

Svatek et al. Svatek et al. ProstateProstate 2009; Stephenson et al. 2009; Stephenson et al. J Urol J Urol 2009; 2009; Vickers et al. Vickers et al. CancerCancer 2009 2009

Building a Better Nomogram: Clinical EndpointsBuilding a Better Nomogram: Clinical Endpoints

• Current treatment decision-making and prediction tools Current treatment decision-making and prediction tools largely based on PSA recurrence endpointlargely based on PSA recurrence endpoint– Not a surrogate for PCSM or overall survivalNot a surrogate for PCSM or overall survival

– At 15 years, risk of PCSM (32%) is similar to death from other causes At 15 years, risk of PCSM (32%) is similar to death from other causes (34%) for men with rising PSA(34%) for men with rising PSA

• Need to understand natural history of screen-detected Need to understand natural history of screen-detected cancers treated by radical prostatectomycancers treated by radical prostatectomy

• Need for nomograms that predict probability of PCSM for Need for nomograms that predict probability of PCSM for treatment decision-making and clinical trial designtreatment decision-making and clinical trial design

Postoperative Nomogram for PCSMPostoperative Nomogram for PCSM• Modeling cohortModeling cohort: 11,521 patients treated at Cleveland Clinic, MSKCC, Baylor : 11,521 patients treated at Cleveland Clinic, MSKCC, Baylor

College of Medicine, University of Michigan between 1987-2005College of Medicine, University of Michigan between 1987-2005

• Validation cohortValidation cohort: 12,893 patients treated at Johns Hopkins University between : 12,893 patients treated at Johns Hopkins University between 1987-20051987-2005

• All pathological specimens reviewed by genitourinary pathologists at each All pathological specimens reviewed by genitourinary pathologists at each institutioninstitution

• Endpoint: PCSMEndpoint: PCSM– Death attributed to prostate cancer by review of death certificate and documented Death attributed to prostate cancer by review of death certificate and documented

evidence of castrate-resistant metastatic diseaseevidence of castrate-resistant metastatic disease

• Median follow-up 56 and 92 months in the modeling and validation cohorts, Median follow-up 56 and 92 months in the modeling and validation cohorts, respectivelyrespectively– 22% and 16% of eligible patients lost to follow-up at 10 and 15 years22% and 16% of eligible patients lost to follow-up at 10 and 15 years– 3163 and 638 surviving patients with > 10 and 15 year follow-up3163 and 638 surviving patients with > 10 and 15 year follow-up

• Deaths:Deaths:– Prostate cancer: 338Prostate cancer: 338– Other causes: 1204Other causes: 1204

Eggener et al. Eggener et al. J Urol J Urol 20112011

Postoperative Nomogram for PCSMPostoperative Nomogram for PCSM

• Prostate cancer-specific mortality at 15 yearsProstate cancer-specific mortality at 15 years– Modeling: 7% (95% CI: 6-9)Modeling: 7% (95% CI: 6-9)

– Validation: 4% (95% CI: 3-5)Validation: 4% (95% CI: 3-5)

• All-cause mortality at 15 yearsAll-cause mortality at 15 years– Modeling: 33% (95% CI: 30-36)Modeling: 33% (95% CI: 30-36)

– Validation: 16% (95% CI: 14-17)Validation: 16% (95% CI: 14-17)

• Predictors of PCSM in multivariable analysisPredictors of PCSM in multivariable analysis– Primary and secondary Gleason grade 4/5, seminal vesicle invasion, Primary and secondary Gleason grade 4/5, seminal vesicle invasion,

year of surgery (year of surgery (P <P < 0.001 for all) 0.001 for all)

– Not significant: PSA, age, extraprostatic extension, lymph node Not significant: PSA, age, extraprostatic extension, lymph node metastasis, positive surgical marginsmetastasis, positive surgical margins** ( (P >P > 0.05 for all) 0.05 for all)

Eggener et al. Eggener et al. J Urol J Urol 2011; Stephenson et al. In preparation2011; Stephenson et al. In preparation

* SM’s not associated with PCSM, even after adjusting for postop radiotherapy* SM’s not associated with PCSM, even after adjusting for postop radiotherapy

Prostate Cancer-Specific Survival: Gleason Score AnalysisProstate Cancer-Specific Survival: Gleason Score Analysis

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al

0 5 10 15 20Years After Surgery

PC Death Non-PC DeathSurvival

Age<60, Gleason 6

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al



Age<60, Gleason 3+4

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al



Age<60, Gleason 4+30

.2.4

.6.8

1D

eath

Rat

e

0.2

.4.6

.81

Su

rviv

al



Age<60, Gleason 8

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al



Age 60-69, Gleason 6

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al



Age 60-69, Gleason 3+4

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al




0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al




0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al




0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al




0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al




0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al




Eggener et al. Eggener et al. J UrolJ Urol 2011 2011

Gle

aso

n 6

Gle

aso

n 6

Gls

n 3

+4

Gls

n 3

+4

Gls

n 4

+3

Gls

n 4

+3

Gls

n 8

-10

Gls

n 8

-10

Age < 60Age < 60 Age 60-69Age 60-69 Age > 69Age > 69

Prostate Cancer-Specific Survival: Pathological StageProstate Cancer-Specific Survival: Pathological Stage

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al



Age<60, Organ Confined

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al



Age<60, Extraprostatic Extension

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al



Age<60, Seminal Vesicle Involvement0

.2.4

.6.8

1D

eath

Rat

e

0.2

.4.6

.81

Su

rviv

al



Age<60, Lymph Node Positive

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al



Age 60-69, Organ Confined

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al



Age 60-69, Extraprostatic Extension

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al



Age 60-69, Seminal Vesicle Involvement

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al



Age 60-69, Lymph Node Positive

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al



Age 70-79, Organ Confined

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al



Age 70-79, Extraprostatic Extension

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al



Age 70-79, Seminal Vesicle Involvement

0.2

.4.6

.81

Dea

th R

ate

0.2

.4.6

.81

Su

rviv

al



Age 70-79, Lymph Node Positive


Org

an-

Org

an-

Co

nfi

ned

Co

nfi

ned

EP

EE

PE

SV

IS

VI

LN

IL

NI

Age < 60Age < 60 Age 60-69Age 60-69 Age > 69Age > 69

Nomogram Predicting 15-year PCSMNomogram Predicting 15-year PCSM

• Externally-validated concordance Externally-validated concordance index: 0.92index: 0.92

• Nomogram predictions adjusted Nomogram predictions adjusted for treatment yearfor treatment year

• Model assumes the patient is Model assumes the patient is treated in 2005treated in 2005

• Effect of treatment year has Effect of treatment year has stabilized since mid-1990’sstabilized since mid-1990’s

Stephenson et al. Stephenson et al. J Clin OncolJ Clin Oncol 2009 2009


Building a Better Postoperative PCSM NomogramBuilding a Better Postoperative PCSM Nomogram

• Unlikely that new biomarkers will improve predictive accuracy Unlikely that new biomarkers will improve predictive accuracy to justify inclusion into standard practiseto justify inclusion into standard practise

• New biomarkers: Systems pathology to predict clinical failureNew biomarkers: Systems pathology to predict clinical failure– Stephenson et al. Stephenson et al. J Clin OncolJ Clin Oncol 2005: c-index 0.85 2005: c-index 0.85

– Cox model based on std parameters: c-index 0.84Cox model based on std parameters: c-index 0.84

– Systems pathology model 1: c-index 0.81Systems pathology model 1: c-index 0.81

– Systems pathology model 2: c-index 0.85Systems pathology model 2: c-index 0.85

• To build a better preop nomogram….To build a better preop nomogram….

• Try to predict pathological Gleason score 8-10 and SVI/LNI Try to predict pathological Gleason score 8-10 and SVI/LNI (treatment intensification) or Gleason score 6 and organ-(treatment intensification) or Gleason score 6 and organ-confined (active surveillance)confined (active surveillance)

Donovan et al. Donovan et al. J Clin OncolJ Clin Oncol 2008; Eggener et al. 2008; Eggener et al. CancerCancer 2009 2009

SummarySummary

• Robust prognostic information contained within radical Robust prognostic information contained within radical prostatectomy specimenprostatectomy specimen

• PCSM can be predicted with near-perfect accuracy once the PCSM can be predicted with near-perfect accuracy once the pathological features of prostate cancer are knownpathological features of prostate cancer are known

• Issues going forward……Issues going forward……

• ““Tweaking” of the Gleason grading system (2005 ISUP)Tweaking” of the Gleason grading system (2005 ISUP)Epstein et al. Epstein et al. Am J Surg PatholAm J Surg Pathol 2005 2005

• Difficulty adjusting for the use of secondary therapy when Difficulty adjusting for the use of secondary therapy when making predictionsmaking predictions– E.g. All patients who die from prostate cancer receive ADTE.g. All patients who die from prostate cancer receive ADT

NY Prostate Cancer Conference - A. Stephenson - Session 4: Predicting clinical and biochemical...

Health & Medicine

Transcript of NY Prostate Cancer Conference - A. Stephenson - Session 4: Predicting clinical and biochemical...