Risk Migration ( ct2c=high)

Transcription

1 Risk Migration ( ctc=high) Prostate Cancer Over- Detection, but Selective Treatment Active Surveillance Peter R. Carroll, MD, MPH Department of Urology University of California, San Francisco February, 9 Increased Incidence of Very Low Risk Prostate Cancer The Risk of Overdetection Lead Time Bias Rates of Prostate Cancer Detected on Autopsy Decreasing* Increasing Percentage of Men Identified on Screening to Have Very Low Risk Disease Increasing Treatment of Men with Very Low Risk Disease Scheme Single 55 yrs. 4 -Yr (55-67) Annual * Lead Time (yrs) Overdetection (%) 7% 48% 5% J Urol 174: 1785 Lifetime prostate cancer risk increased by 8% (range = 69%- 116%). Extending annual or quadrennial screening to the age of 75 results in at least two cases of overdetection for every clinically relevant cancer detected J Natl Cancer Inst. 3 Jun 18;95(1):

2 Natural History of Screen Detected Cancers Radical Prostatectomy vs. Watchful Waiting Grade < 7 Lead time (years) year CS mortality (%) 1 15 year survival benefit (%) Assumes biennial PSA screening C Parker et al 6 ASCO Prostate Cancer Symposium CaP specific mortality in WW group <65 yrs highest at 19.% Only 5% men diagnosed from screening Significant number of intermediate and high risk disease Bill-Axelson, A. et al. Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer NEJM, 5 Evolution of Watchful Waiting Active Surveillance Old Less well assessed Patients well assessed Usually more advanced Early stage disease Monitoring not rigid/planned Monitored closely Treatment delayed until Treatment at first sign of clinically significant, progression symptomatic disease noted Managed with androgen deprivation New Treated based on risk; local therapy Watchful Waiting Rationale The management of clinically localized prostate cancer is controversial Retrospective epidemiological studies have shown that low grade localized cancer is associated with a limited risk of progression to symptoms or death from cancer Aggressive screening has resulted in detection of early stage lesions of uncertain biologic/clinical potential (stage migration) Ideal treatment/intensive monitoring should be directed to those patients who will progress Paucity of studies examining the variables associated with progression

3 What Predicts for Watchful Waiting? Who Undergoes Watchful Waiting? Age Insurance Status Co - morbidity Cancer risk group Not education, ethnicity or income Surveillance - Trends CaPSURE Active Surveillance How Common in Those Eligible? ELIGIBILITY FOR WW VALUE N (%) PSA <1 AT DX No 5 6 Yes NO GLEASON 4/5 PATTERN AT DX No 8 43 Yes POSITIVE BIOPSY <33% No Yes T1 OR TA AT DX No Yes PSA DENSITY <.15 AT DX No 1 63 Yes MET ALL 5 CRITERIA No Yes Yes No Low Intermediate High PSA < 1; No GS 4/5 and T1/Ta all more common with time. Eligibility predicted by age, insurance status, education and income J Urol. 8 Oct;18(4):

4 Watchful Waiting Hypotheses Surveillance - Results Surveillance in low risk patients is feasible and associated with a low risk of progression Progression can be quantitated Predictors of progression and treatment can be identified Watchful Waiting Cohort UCSF Prostate Cancer Databa Entry Criteria for WW* PSA < 1 Gleason < 6, No GG 4/5 <Tc UCSF Cohort Over 56 men enrolled All men who meet criteria are offered surveillance Mean age is 63 Mean PSA is 6.5 9% Gleason score=6 Patients on Watchful Waiti n = 56 Complete data n = 319 4

5 UCSF Active Surveillance cohort Cohort disease features Entry criteria PSA<1 Gleason sum 6, no pattern 4/5 Stage T1-T 33% cores positive, 5% any single core positive PSA Gleason Cores positive Clinical stage 1ng/ml >1ng/ml <7 7-1 <33% >33% T1 T 6 (87%) 38 (13%) 77 (9%) 4 (8%) 5 (84%) 43 (16%) (64%) 114 (36%) Risk category Low Intermediate High (81%) 7 (15%) 9 (3%) Progression Median f/u 3.6 years Progression defined as: PSA velocity >.75 ng/ml/yr Rise Gleason score Increase lesion size on ultrasound PSA DT? Not validated Type of progression 37% have evidence of progression 38% increase Gleason score 6% high PSAV PSAV does not correlate with Gleason changes US Lesion size data difficult to interpret PSA characteristics PSAV>.75 ng/ml/yr=6% PSAV> ng/ml/yr =15% Median PSADT=6.7 years 5

6 Active Treatment Time to Active Treatment 4% received secondary treatment Median time to treatment: 3 years (range 1-17 years) 71% of treated men had evidence of clinical progression 8% of cohort treated with no evidence of clinical progression Time to Active Treatment Study Comparisons Author Year Median FU (months) Patients % progr. Current study % De Vries (Rotterdam) % Choo/Klotz (Toronto) % Carter (JHU) % Hardie (RMH) % El-Geneidy (OHSU) % Carter (CPDR) % Patel (MSKCC) % 6

7 Predictors of Treatment p value HR 95% CI Can we determine predictors of receiving treatment at baseline and over time for men on active surveillance? Rise Gleason score PSAD>.15 Increase lesion size.1. ns ns ns Grade progression is strongest driver of treatment (HR %CI.-7.7) Results OR 95% CI Can we determine predictors of Gleason score increase for men on active surveillance undergoing serial biopsy? Age (continuous) Age ( ( 63) Interval dx to last biopsy ( years vs. 1 1 year) # biopsies # cores diagnosis # cores re-biopsy #pos cores re-biopsy 1.6*.4* 3.1* * Neg biospy before dx *p<.5 7

8 Radical Prostatectomy after Active Surveillance: Pathologic Outcomes Can we determine the risk of untimely progression while on active surveillance (i.e.miss a window of opportunity)? 46 men Median time to RP is 16.4 months Ta Tb Tc T3a T3b N+ Overall n % Met all inclusion Criteria T T3a T3b n 18 3 % Gleason Grade Change at RP N % Risk of Under - staging and/or Grading Up - grading/staging No change Gleason 7 to 6 Gleason 8 to 7 Gleason 6 to 7 Gleason 7 to 9 Of 9 men with at least 1 surveillance bx, 6 (%) were upgraded after RP vs. 5 of 17 (9%) with no surveillance bx Percent Toronto Royal Marsden Upgrade ECE SVI JHH MSKCC UCSF 3 8

9 Impact of upgrading or staging Active Surveillance Best Candidates Based on Extended - Pattern Biopsy Low grade (no pattern 4 or 5) Low volume (< 33% of core); < 33% of total core Non - palpable (T1C) Serum PSA < 1 ng/ml; Stable, Free - Fraction Elevated, PSAD <.15 Older Age and/or Significant Co - Morbidity Available for Follow - up A well - performed biopsy essential CaP Diagnosis Eligibility PSA <1 Gleason sum <7 (no pattern 4/5) Clinical stage Ta 33% of biopsy cores involved 5% of any single core involved Criteria for study withdrawal PSA doubling < 1 months Evidence of clinical progression Adverse pathological finding (grade progression, 1/3 of cores positive or >5% of any core involved Patient preference THE FUTURE Accession Re-biopsy (extended pattern) mrna microarray analysis Randomization to dietary intervention Serum markers (PSA, %fpsa, T, E, etc) Baseline HRQOL assessment No progression Q3 months: PSA, %fpsa, DRE At 1 months, and q1 months: HRQOL assessment TRUS/biopsy At 3 months Re-biopsy for diagnosis, mrna analysis DRE Serum markers (PSA, %fpsa, T, E, etc) Formal dietary intervention ends Progression Standard treatment per physician, patient preferences 9

10 Effect of Lifestyle Intervention Conclusions The molecular mechanisms by which improvements in diet and lifestyle might affect the prostate microenvironment are poorly understood. A pilot study to examine changes in prostate gene expression Secondary an intensive nutrition and lifestyle intervention. 48 upregulated and 453 downregulated transcripts after the intervention. Pathway analysis identified significant modulation of biological processes that have critical roles in tumorigenesis. Active surveillance appears feasible 4% of men treated a median of 3 years after diagnosis Small percentage of men come off of surveillance despite no evidence of disease progression Overall median f/u remains short Change in Gleason grade is greatest driver of treatment Proc Natl Acad Sci U S A. 8 Jun 17;15(4): Acknowledgements Nannette Perez, RN, NP Kirsten Greene, MD. MS Katsuto Shinohara, MD Janet Cowan Matt Cooperberg, MD, MPH Badri Konety, MD, MBA Max Meng, MD June Chan, PhD Chris Haqq, MD, PhD Dean Ornish, MD - PMRI Vincent Fradet, MD Simon Conti, MD Marc Dallera, MD UCSF Prostate SPORE 1