ACTIVE SURVEILLANCE FOR PROSTATE CANCER

ACTIVE SURVEILLANCE FOR PROSTATE CANCER Dr. Michael J Metcalfe PGY-2 Department of Urological Sciences April 25, 2012 CASE RM 65 year old active Caucasian male, married. PSA= 7.0 T2a Gleason 3+3=6 2/6 cores positive 2mm total core involvement No LVI IPSS= 7 (1) SHIM = 29 Hx: Left Knee Surgery, Asthma Med s: Symbicort Father died at 86, Cardiovascular causes. 1

CASE RM Treatment Options Low Risk Prostate Cancer AUA 2007, NCCN 2012, EAU 2007 Guidelines: Radical prostatectomy External Beam Radiation Therapy Brachytherapy Active surveillance CASE RM Treatment Options Low Risk Prostate Cancer AUA 2007, NCCN 2012, EAU 2007 Guidelines: Radical prostatectomy External Beam Radiation Therapy Brachytherapy ACTIVE SURVEILLANCE (Treatment of choice, NICE 2011) 2

Date Stage PSA Path Grade Positive cores Size* Feb. '07 ct2a 7.24 6 core 3+3=6 2/6 2mm May '07 7 12 core 3+3=6 2/12 4mm Dec. '07 3.92 Jan. '08 3.87 Apr. '08 3.92 Dec. '08 3.62 10 core 3+4=7 2/10 2mm Apr. '09 4.75 June '09 pt2a Rpx 4+4=8 1 cm nodule -ve SV, -Margins June 09- Apr. 2012: PSA < 0.02 Prostate Volume= 35 cc on TRUS *Size=Total Core Involvement OBJECTIVES Review current use and acceptance of AS in low risk prostate cancer. Review appropriate patients for AS Review markers for disease progression for patients on AS. Review safety of AS based on PIII trials and registration trials. Review benefit of secondary chemoprevention in patients on surveillance. 3

WHAT IS ACTIVE SURVEILLANCE? NOT active surveillance of prostate cancer as defined in the pre PSA era. Involved waiting until clinical progression the palliation NOT watchful waiting Reserved for patients who are not candidates for radical therapy on the basis of life expectancy and aims to delay treatment until palliation. IS an ACTIVE decision to monitor a patient with prostate cancer who has a low risk of progressing and there is intent to curatively treat the cancer if it progresses. 4

RISK OF PROSTATE CANCER MORTALITY FROM MODERATELY DIFFERENTIATED PROSTATE CA Albertson PC, JAMA 2009, 293, 2095-2101 T- STAGE SHIFTS IN BC SINCE PSA TESTING 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% T4 T3 T2 T1 2000 1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 1989 1988 PSA TESTING INITIATED BCCA referred patients only 5

STAGE SHIFT IN BC: PROPORTION OF PATIENTS REFERRED TO BCCA WITH N+ OR M+ DISEASE 16.0 14.0 12.0 10.0 8.0 6.0 4.0 PSA TESTING 2.0 0.0 2000 1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 1989 1988 SCREENING FOR PROSTATE CANCER- ERSPC AT 11 YEARS FOLLOW UP NNTS= 1055 NNT= 37 6

SCREENING IN PROSTATE CANCER PLCO (USA) 40 % reduction in mortality reduction. ERSPC (EUROPE) 20% mortality reduction 25% reduction in metastatic disease 50% more cancers found NNTS-1410 NNTT-48 US PREVENTATIVE TASK FORCE Recommends against screening for Prostate cancer. PREVALENCE OF AS AT MSK FROM 2000-2009. Cancer Volume 117, Issue 21, pages 4855-4860, 11 APR 2011 DOI: 10.1002/cncr.26132 http://onlinelibrary.wiley.com/doi/10.1002/cncr.26132/full#fig5 7

LONGEVITY QUALITY OF LIFE A FINE BALANCE HOW MANY PEOPLE ARE CHOOSING AS? In a large series of almost 800 US men, from 7 centers 40% chose surgery, 31% conformal beam radiotherapy, 21% chose brachytherapy 8% chose AS. Anandas CN, et al. BJU International, 2010 Of 1,886 men with all 5 criteria documented: 16.4% (310 of 1,886) met all 5 surveillance criteria and 9.0% (28 of 310) chose surveillance. Older age was the only demographic predictor of surveillance. Barocas, D. A. et al. J. Urol. 180,(2008) 8

HOW MANY ARE ON ACTIVE SURVEILLANCE LOW RISK HIGH RISK RESULTS FROM CAPSURE DATABASE Cooperberg, JCO 2010 REASONS BEHIND TREATMENT CHOICE Reasons for AS: 1. Unknown 2. Other- didn t want active or invasive treatment. 3. More Convenient 4. Fear of Side Effects 5. Fear of Other Options BJU International NOV 2010 9

BARRIERS TO ACTIVE SURVEILLANCE Predicting clinically insignificant Prostate Cancer Lack of defined optimal monitoring patients on Active Surveillance Potential need for multiple Prostate Biopsies Effect on Delayed Therapy Secondary preventative measures QOL on Active Surveillance PREDICTING CLINICALLY INSIGNIFICANT PROSTATE CA: Risk Stratification: PSA (Absolute, velocity, density ) Gleason Grade ct stage Volume of Disease PCA 3 MRI 10

CURRENT PUBLISHED ACTIVE SURVEILLANCE PROTOCOLS Clinical Stage PSA (ng/ml) Gleason Score on Biopsy PSA Density Number of pos. Cores U of T EPSTEIN* PRIAS UCSF CANARY BCCA T1c T1c T1c or T2 T1 or T2 ct1-t2 < T2b <10 N/A < 10 <10 - < 10 <3+3=6 <3+3=6 <3+3=6 < 3+3=6 - < 3+3=6 - < 0.15 < 0.2 - - - - <2 2 of (8-12) < 33% min. 10 core - No level 1 evidence to support any surveillance protocol * Epstein- Very low risk criteria PSA IS A USEFUL PREDICTOR OF INSIGNIFICANT PROSTATE CANCER A Single entry PSA is a useful predictor of Clinically Insignificant Disease Elevated PSA at or before 50 is a risk factor for advanced prostate cancer Scardino, BMC Med 2008 PSA at baseline > 10 is a useful predictor of patients on AS who undergo definitive intervention. Klotz, JCO 2011 PSA and PSA Density at Diagnosis is a significant predictor of future intervention in patients on Active Surveillance. Tosoian, JCO 2011 PSA < 10 is an independent predictor of no overall benefit in 10 year survival with RP. PiVOT, 2011 11

PIVOT TRIAL- OBSERVATION VS RP 731 men randomized to: Observation (n= 367) RP (n-364) Mean age of 66.8 Median 10 years follow No difference in Prostate Cancer Mortality between radical treatment and observation for: PSA < 10 D Amico Low Risk (Intention to treat analysis) Wilt, GU ASCO 2011 12

612 patients who had RP in Germany met A.S. protocols. 2 Groups: AS-A- < T2a, < Gleason 7, PSA < 10 AS-B < T2a, < Gleason 7, PSA < 15 >25% of patients had pathological upgrading in their RP Specimen, independent of which group. Addressed by 12-core re-biopsy which demonstrated upgrade in 17% of biopsies PCA - 3 AS A MARKER FOR PROGRESSION PCA 3 has a direct correlation with: Tumour volume, Margins at time of RP and positive biopsy percentage. Durand, BJUI 2012 Can discriminate between low volume / low grade cancers. Nakanashi, J Urol 2008 PCA3 > 25 associated with Significant disease (OR 12.74, P=0.003) in 106 men. Ploussard et al, Eur Urol 2011 PCA3 score predicts extracapsular extension and tumor volume. Whiman et al, J Urol 2008 13

PCA 3 IN PREDICTING ADVERSE PATHOLOGY Haese et al, Eur Urol 2011 ROLE OF MRI New techniques improve incremental diagnostic accuracy and improves assessment of disease volume. Klowkowicz et al 2010 Endorectal coil prostate MRI added to Epstein criteria in the ability to predict low risk disease prior to radical prostatectomy. Margolis, J Clin Oncol 2012 PRIAS found that T2 DW and DCE MRI found more aggressive disease in 27% of patients in their active surveillance group. Somford, GU ASCO 2011 114 patients with a lesion suggestive of malignancy on MRI had an increased risk of gleason score upgrading on subsequent biopsy. Fradet, Radiology 2010 14

SUMMARY: ELIGIBILITY FOR ACTIVE SURVEILLANCE No eligibility criteria has been identified as being optimal for Active Surveillance. It is a spectrum of disease and stratification must take this continuum into consideration. PSA < 10 and prostate biopsy with D Amico risk cliassification are reliable predictor at 10 years for clinically insignificant disease. If Biopsy is performed, a confirmation biopsy is recommended. PCA3 and MRI are appearing to provide additive information to risk stratification of Prostate Cancer and may be used in nomograms/ risk criteria in future. Patient factors are equally important as prostate cancer factors. SURVEILLANCE PROTOCOLS PSA University of Toronto John's Hopkins PRIAS UCSF CANARY / UBC 3 monthly for 2 years; 6 monthly 6 monthly 3 monthly 3 monthly 3 monthly PSA DRE 6 monthly DRE 6 monthly 6 monthly 3 monthly 6 monthly DRE Re-biopsy Indica9on for re- biopsy 6-12 months in the first year, then q 3-4 Annually 1,2 and 7 years, PSA DT < 3 year None, no PSA kine9cs ct3, PSADT< 10 years TRUS- q 6-12 mo. Bx.- 1-2 years PSA DT< 3 years 0, 6-12 months, q2 years. Physician Discretion PSA DT< 3 years 15

REASONS FOR LEAVING ACTIVE SURVEILLANCE A multiinstitutional cohort of 262 men from 4 institutions < 75 years old with: PSA< 10, ct1-t2a, Gleason < 6, < 3 + cores. Repeat Biopsy at diagnosis, T=0 at rebiopsy date. Surveillance: DRE and PSA q 6-12 months Biopsy before 18 months then q 1-3 years or for cause MRI intermittent, q 1-3 years, concerning features= Bx Median Follow up= 29 months 43 patients received Treatment: 2 year probability of being on AS= 91% 5 year probability of being on AS= 75% PREDICTORS OF DISCONTINUING AS Eggener, J of Urol 2009 16

TORONTO- ACTIVE SURVEILLANCE EXPERIENCE 450 patients, Median age 70 6.8 years Median Follow up Inclusion for < 70 years old: Gleason < 6 PSA < 10 > 70 years Gleason < 7 PSA < 15 Triggers for intervention: PSA DT< 3 yr (originally < 2 years) Clinical progression Pathological Upgrade 65% Gleason < 7 & PSA < 10 TORONTO- ACTIVE SURVEILLANCE EXPERIENCE 450 patients, Median age 70 6.8 years Median Follow up Inclusion for < 70 years old: Gleason < 6 PSA < 10 > 70 years Gleason < 7 PSA < 15 Triggers for intervention: PSA DT< 3 yr (originally < 2 years) Clinical progression Pathological Upgrade 65% Gleason < 7 & PSA < 10 17

TORONTO SERIES- AS DROP OUT RATES 60% of patients Spared radical therapy at 10 years TORONTO OUTCOMES 10 year OS = 68% 10 year CSS = 97.2 % Klotz JCO 2011 18

PSA IS NOT AN ADEQUATE MARKER OF PROGRESSION 305 pt. s offered treatment based on PSA DT, at 5 years, not one pt. developed symptoms or died from prostate Cancer. False trigger for treatment fanged from 42-80% based on PSA DT. Use of PSA triggers (PDA DT<3 yr, PSAv > 2 ng/ml and PSA T>10) would have led to unacceptably high treatment rates Klotz GU ASCO 2011 EPSTEIN very low risk inclusion criteria Median Survival free progression 6.5 years after Diagnosis Median intervention at 2.2 years. 235/ 418 (30.6%) men s biopsies progressed in risk stratification. 106/235 (45.1%) Gleason Score Upgrading 129/ 235 (54.9%) had an increased number of cores Tosian, JCO 2011 19

JOHNS HOPKINS EXPERIENCE WITH SURVEILLANCE BX Of patients on AS, risk factors for eventual therapy included: PSA at diagnosis PSAD at diagnosis Year of cancer diagnosis Tosian et al JCO 2011 PSA Velocity PSA Doubing Time BIOPSY Specimen P=0.06 PSAV on Bx AUC= 0.61 P=0.83 PSA DT on BAUC = 0.57 Radical Prostatectomy PSAV on RP AUC = 0.56 PSADT on RP AUC = 0.51 PSA V or PSADT was not significantly associated with subsequent adverse biopsy findings. Ross et al JCO 2010 20

PCA3 AS A MARKER OF PROGRESSION - Gleason > 7 - Unfavourable, Gleason 6 - Favourable 294 men in the Johns Hopkins AS program provided PCA3. 38 patients had progression on biopsy, 16 had progression in gleason grade 7. PCA 3 could not be used to identify men with progression. Elevated PCA3 > 35 not associated with progression (p=0.15) Tosoain, et al J of Urol 2010 MRI IN MEN WITH UNTREATED LOCALIZED PROSTATE CANCER ON ACTIVE SURVEILLANCE 80 men enrolled in Active surveillance: T1/T2a, PSA < 15 Gleason < 7 <50% positive cores Median age 66 Apparent Diffusion Coeffieint was significant predictor of : Adverse repeat biopsy findings P<0.0001; HR 1.3 (95% CI 1.1-1.86), AUC= 0.7 Time to Radical Treatment; P< 0.0001, HR 1.5 (95% CI 1.2-1.8), AUC= 0.7. Eur Urol 2008 21

SUMMARY OF TRIGGERS FOR INTERVENTION PSA, PSA DT or PSA kinetics not adequate to monitor for progression Re-Biopsy is required. PCA 3 has no role so far in monitoring patients on AS protocols. MRI may play a significant role in monitoring tumor progression and guiding surveillance biopsies. OUTCOMES ON AS Primary Outcome- Survival Secondary Outcome- Pathology at time of RP Biochemial Free Recurrence post RP Quality of Life 22

Prostate-Cancer Mortality in the RP and WW of the Scandanavian SPCG- 4 vs UofT Active Surveillance Cohort. NEJM Klotz 2011 23

PATHOLOGICAL RESULTS FROM RP IN 6 ACTIVE SURVEILLANCE PROTOCOLS AUA 2012 BIOCHEMICAL FREE SURVIVAL POST DEFINITIVE THERAPY UCSF- 100% at 3 years (n=74) University of Miami- BFS 100% at 3 years (n=12) Johns Hopkins- 96% at 3 years (n=96) ERSPC- 91 % at 3 years (n=81) Toronto- 50% at 5 year (n=130) Cooperberg et al, JCO 2011 Soloway et al, Eur Urol 2010 Tosoian et al, JCO 2011 Van den Bergh et al, Eur Urol 2009 Klotz et al, JCO 2011 24

CLINICAL SIGNIFICANCE OF BIOCHEMICAL RECURRENCE Post Radical Prostatectomy Median 8 years from PSA recurrence to metastatic disease. Median 5 years from metastatic disease to death from prostate cancer. Post Radiation Therapy Median Time to castration resistant prostate cancer is 9.8-10 years. 7 year disease specific mortality 15-18 years 1. PR-7 Data, J Clin Oncol 29: 2011 2. Pound. JAMA 1999, Vol 281, No. 17 SECONDARY CHEMOPREVENTION Retrospective Study on 288 Men on AS for low-risk Disease, Rate of progression significantly lower in dutasteride(18.6 vs. 36.7%). Rate of withdrawal significantly lower (20 vs 37.6%). The absence of 5-ARI was associated with a nearly three fold likelihood of pathologic progression. Follow up to short to comment on survival. 5-ARI initiated in 47 ARI naïve patients, Finelli. Eur. Urol. 2011 Reclassification occurred in 17% vs. 31% of non-users. Multivariable model showed no-significant risk reduction Ross AE et al, BJUI 2012 25

302 men with Low grade, Low D Amico risk, Gleason < 6 Prostate Cancer N= 155 Placebo N= 147 Dutasteride 0.5mg 10 core Biopsy at initiation, 12 core at 1.5 years and 3 years. 65 Academic Centers Men aged 48-82, life expectancy > 5 years. ct1c-ct2a, Gleason 5-6, PSA < 11 REDEEM- ESTIMATE OF TIME TO PROGRESSION (PATHOLOGICAL OR THERAPEUTIC) Placebo: 70/145 (48%) progressed at 3 years. Dutasteride: 54/144 (38%) progressed at 3 years. HR= 0.62 (95% CI 0 43 0 89). Gleason 8 detected in 2 men in Dutasteride group, and 3 men in control on follow up Bx. Dutasteride had more ejaculation disorders. No difference in anxiety levels. Time to progression Placebo Dutasteride 26

MORBIDITY OF ACTIVE SURVEILLANCE Repeat biopsies: Increased risk of biopsy related sepsis, 4% risk in 2009 (Fujita, J Urol 2009) Increased risk of erectile dysfunction (Nam RK, J Urol 2010) Anxiety 55% of men are anxious of progression on AS. Increased risk of disease on delayed therapy Lower Urinary Tract Symptoms Glass J Urology, 2012 HOW SATISFIED ARE MEN WITH THEIR TREATMENT? BJU International Volume 107, Issue 11, pages 1762-1768, 17 NOV 2010 DOI: 10.1111/j.1464-410X.2010.09833.x http://onlinelibrary.wiley.com/doi/10.1111/j.1464-410x.2010.09833.x/full#f4 27

400 men randomised to RP or WW with 281 extra men as population controls. Survey follow up at 3.7 and 13.4 years. 19% in RP group were on ADT, 28% in WW. Physical Symptoms similar, RP had a greater increase in physical symptoms in longitudinal data. ED 84% in RP, 80% in WW HIGH QUALITY OF LIFE IN RP VS WW PATIENTS. Radical Prostatectomy Watchful Waiting R. P. W.W. 4 years 12 years 28

OUTCOMES OF ACTIVE SURVEILLANCE Good 10 year data for low risk prostate cancer patients that are observed when compared to radical prostatectomy. (PiVOT) Active Surveillance MAY have improved survival over observation trials There is an incrased risk of high risk pathology and biochemical recurrence at the time of RP. There is minimal, but real, morbidity associated with AS through anxiety, ED and sepsis. HRQOL outcomes between WW and RP groups are both poorer when associated with a healthy population. WW is associated with reduced physical symptoms affecting quality of Life. 29

SUMMARY Active Surveillance is a safe option for Very Low Risk Prostate Cancer with no difference in 10 year mortality. There is no proven optimal surveillance Protocol for Active Surveillance. A multifactorial approach weighting patient values, comorbidities and life expectancy must be taken into consideration with measures of prostate cancer risk such as PSA, Biopsy, PCA 3 and MRI to decide risks and benefits of Active surveillance. Clinical trials on risk stratification, tumor markers and imaging in Active Surveillance patients will reveal significant amounts of information on the natural course of low risk prostate cancer. QUESTIONS? 30

ACTIVE SURVEILLANCE RISKS Risk of understaging biopsy result No concrete predictor of progression Increased PSA recurrence Increase positive margin rate Anxiety and quality of life still affected BENEFITS Relieves ~ 50% of patients with low risk prostate cancer treatment related morbidity. No reduction in mortality at 10 years Decreased early physical symptoms Another, safe option for patients WHAT WE KNOW ABOUT GOOD RISK PROSTATE CANCER 30% or more of men harbor prostate cancer (Sakr) before age 50 Systematic prostate biopsy results in a 25% prostate cancer detection rate (PCPT) in men with PSA < 3.0 Screening increases the incidence to mortality ratio from 2.5:1 to 15:1 (Schroeder) Need to treat 48 men in screened population to prevent one prostate cancer death Mortality rates have fallen in both screened and unscreened populations (Lu-Yao; Albertsen) 31

???? WHERE IS THIS FROM PROBABILITY OF BEING PROGRESSION FREE 96% at 1 year 79% at 2 years 65% at 5 years J Urol 2004 Inclusion Criteria (EPSTEIN): T1c disease, PSAD < 0.15 ng/ml, Gleason score <6, <2 biopsy cores with cancer maximum of 50% core involvement Surveillance protocol includes: PSA and DRE q 6 mo. Annual 12- to 14-core surveillance biopsy (recently routine transition zone biopsies) Curative therapy was recommended based on Disease reclassification from upgrade to Gleason score >6, two cores with cancer, >50% cancer involvement of any core NOT PSA concentration or kinetics Tosian, Trock, Lansi, Feng, Epstein, Partin, Walsh, Carter JCO 2011 32

UCSF- CANCER OF THE PROSTATE RISK ASSESSMENT SCORE (CAPRA) http://urology.ucsf.edu/patientguides/urooncpt_assess.html#capra 33