Localized prostate cancer

Prostate Cancer 2014 Localized prostate cancer Progress toward personalized care Matthew R. Cooperberg, MD,MPH Departments of Urology and Epidemiology & Biostatistics UCSF Mini Medical School July 22, 2014 Siegel et al. CA Cancer J Clin 2014; 64:9 Meet the prostate CaPSURE Disease Registry 1

The Changing Face of Prostate Cancer Prostate Cancer Worldwide: 2011 Cooperberg et al. J Urol 2007; 178:S14 Jemal et al. CA Cancer J Clin 2011; 61:69 CaP Risk Among Low SES Men CaP Risk Among Low SES Men CaPSURE CaPSURE SFGH CAPRA Score Porten et al. J Urol 2010; 184:1931 CAPRA Score Porten et al. J Urol 2010; 184:1931 2

The good news: So why did we end up here? >40% drop in age-adjusted prostate cancer mortality since early 1990s Siegel et al. CA Cancer J Clin 2013; 63:11 Moyer et al. Ann Intern Med, epub 2012. Prostate cancer is heterogeneous This is (partly) our fault. Esserman et al. JAMA 2009; 302:1685 3

Treatment options Active surveillance (watchful waiting) Surgery (radical prostatectomy) Radiation (external-beam) Brachytherapy Hormonal therapy Chemotherapy Treatment options (localized) Active surveillance (watchful waiting) Surgery (radical prostatectomy) Open, laparoscopic, robotic Radiation (external-beam) 3DCRT, IMRT, CyberKnife, proton beam, ±hormonal therapy Brachytherapy Permanent vs. HDR, I vs Pd, ±EBRT, ±hormonal tx Hormonal therapy alone Cryotherapy (focal therapy?) (HIFU, interstitial laser, eye-of-newt, etc) Who gets screened? Who gets treated? Walter et al. JAMA 2006; 296:2336 Cooperberg et al. J Clin Oncol 2010; 28:1117 4

Older men have worse tumors Treatment driven by age, not risk Bechis et al. J Clin Oncol 2011; 29:235 Bechis et al. J Clin Oncol 2011; 29:235 Treatment Variation Prostate cancer treatment by site Dartmouth Atlas of Health Care, 1999. www.dartmouthatlas.org Cooperberg et al. J Clin Oncol 2010; 28:1117 5

Recent rays of hope So is the USPSTF right?? PLCO Prostate, Lung, Cancer, & Ovarian Cancer Screening Trial PLCO 76,693 men aged 55-74 randomly assigned to annual PSA screening for 6 years vs. usual care at 10 U.S. centers 1993-2001 the 79% of study men was in the not usual a fair comparison care group between had at screening least one and PSA no test screening; drawn instead, it was a comparison between annual and ad hoc screening. Only Cooperberg 30-40% and of men Carroll, with NEJM high 2009; PSAs had 361:203 biopsies Virtually no difference between types of tumors seen in screening vs. usual care groups Andriole et al. NEJM 2009; 360:1310 Andriole et al. NEJM 2009; 360:1310 6

PLCO: Update ERSPC European Randomized Study of Screening for Prostate Cancer PLCO was not a trial of screening vs. no screening Andriole et al. J Natl Cancer Inst 2012; 104:1 Schröder et al. NEJM 2009; 360:1320 ERSPC Population-based study at 7 European centers Number needed to diagnose=33 182,160 men age 50-74 randomized (162,387 in core age 55-69) Screening interval 4 years at most centers (2 at one) 21% risk reduction for cancer-specific mortality with screening (up to 38% in years 10-11) 29% risk reduction with adjustment for noncompliance Schröder et al. NEJM 2009; 360:1320 The Göteborg randomized trial Göteborg vs. PLCO & ERSPC Younger mean at start of screening Lower PSA threshold for referral Q2 year interval Higher rate of biopsy among those with high PSA Lower rate of PSA contamination Longer followup (though still relatively short) 44% of men were managed with initial surveillance Hugosson J. Lancet Oncol 2010; 11:725 7

The Göteborg randomized trial Taking the long view on screening RR 0.56 (0.39 0.82, p=0.002) NNS: 293, NNT: 12 Short-Term Long-Term Lives saved 0.7 6 Overdiagnoses 34 42 A guideline based on outcomes at 8 or 10 years is completely meaningless! Overdiagnoses/Liv es saved 48 7 Hugosson J. Lancet Oncol 2010; 11:725 Gulati et al. J Clin Epidemiol 64:1412, 2011 What about reassurance? Risk Assessment and Risk Adapted Management What seems to be missing from most of the PSA discussion is that the majority of men will have a normal PSA value and they will be reassured A normal PSA level offers peace of mind, a valued commodity in a world that is frequently full of troubling news. Diagnosis Treatment Detsky et al. JAMA 307:1035, 2012 8

Prostate Cancer Risk Assessment Risk Assessment: D Amico / AUA Goal: inform physician-patient decisions about optimal initial treatment approach and timing Active surveillance Early local therapy Multimodal therapy Systemic therapy Low PSA 10, GS 6, and stage T1-2a Intermediate PSA 10-20, GS 7, or stage T2b Numerous existing instruments D Amico Kattan UCSF-CAPRA High PSA >20, GS 8, or stage T2c / T3a D Amico et al. JAMA 1998; 280:969 The UCSF CAPRA The UCSF CAPRA: brfs Variable Level Points Variable Level Points PSA 6 0 T-stage T1/T2 0 6.1-10 1 T3a 1 10.1-20 2 Gleason (primary/ secondary) 20.1-30 3 % of biopsy <34% 0 cores >30 4 positive >34% 1 1-3/1-3 0 1-3/4-5 1 Age <50 0 4-5/1-5 3 >50 1 Sum points from each variable for 0-10 score Cooperberg et al. J Urol 2005; 173:1938 Cooperberg et al. Cancer 2006; 107:2384 9

CAPRA: Cancer specific survival The Myriad Prolaris Assay HR C-index 1.39 (1.31-1.48) = 0.80 # at risk 4892 1430 350 31 cell cycle progression (CCP) genes, normalized to 15 housekeeper genes Score is expressed as average centered expression of CCP genes relative to housekeeper genes; negative scores = less active CCP, positive scores = more active CCP Cooperberg et al. JNCI 2009; 101:878 Cuzick J et al. Lancet Oncol 2011; 12:245 Biomarkers vs. clinical parameters 10 year PGP predictions Cooperberg et al, JCO 31:1428, 2013 Cooperberg et al, JCO 31:1428, 2013 10

Oncotype DX Genomic Prostate Score (GPS) Multivariable Performance of GPS Quantitative 17-gene RT- PCR assay on manually microdissected tumor tissue from needle biopsy Genes and biological pathways predictive of multiple endpoints, with emphasis on clinical recurrence Optimized for very small tissue input: six 5 micron sections of single needle biopsy block with as little as 1 mm tumor length Androgen Signaling AZGP1 FAM13C KLK2 SRD5A2 Stromal Response BGN COL1A1 SFRP4 Proliferation TPX2 Cellular Organization FLNC GSN GSTM2 TPM2 Reference ARF1 ATP5E CLTC GPS1 PGK1 GPS = 0.735*Stromal Response group -0.352*Androgen Signaling group +0.095*Proliferation group -0.368*Cellular Organization group Scaled between 0 and 100 Model Variable Odds Ratio 95% CI P-value 1 GPS (per 20 units) 1.85 (1.23, 2.81) 0.003 Age (continuous) 1.05 (1.01, 1.09) 0.004 PSA (continuous) 1.11 (1.04, 1.18) 0.002 Clinical Stage T2 vs. T1 1.57 (0.98, 2.51) 0.059 Biopsy Gleason Score (7 v. 6) 1.70 (1.00, 2.88) 0.050 2 GPS (per 20 units) 2.13 (1.44, 3.16) <0.001 CAPRA 1.58 (1.24, 2.02) <0.001 Cooperberg et al, AUA 2013 Improved Risk Discrimination with Addition of GPS to CAPRA CAPRA 0 = 86% CAPRA 1 = 78% CAPRA 2 = 67% CAPRA 3 = 55% CAPRA 4 = 43% % patients in this range increases from 5% to 24% 49% of pts have 5% change in predicted risk 26% to more favorable 23% to less favorable 5% 5% 36% 38% 16% Cooperberg et al, AUA 2013 GenomeDx and Decipher Decipher is a 22-gene genomic classifier, with genes chosen purely by statistical selection to predict metastasis among high-risk RP patients at Mayo, no pathway analysis (includes noncoding genes, 3 unknowns) Rather than RT-PCR on established gene set, clinical assay is run using Affy Human Exon 1.0ST GeneChip (1.4M probe sets interrogating 5.5M features of whole exome) Decipher score is calculated, but an enormous trove of data is kept in the databank for ongoing / future discovery Erho et al., PLoS ONE 8:e66855, 2013 11

Genomic reclassification But will this change practice? The state of the art isn t bad Will Precision Medicine be enough? 12

It s more complicated How do you prove a better decision? 2012 DOD Transformative Impact Award Transforming prostate cancer care (in 3 years) CaPSURE Better Information, Better Understanding, Better Outcomes UCSF Patient Advocates Smoking and PC mortality Watchful wai ng Ac ve surveillance Leveraging models and infrastructure from two industry leaders Stan Rosenfeld John Nidecker UCSF Decision Support Services Active Surveillance to reduce overtreatment 13

NIH Consensus Conference Surveillance: Recent Experiences Cooperberg et al. J Clin Oncol 29; 2669: 2011 Active surveillance: challenges Who is eligible? Very low risk only? What about intermediate risk? Is PSA a reliable outcome measure? Is Gleason score a reliable outcome measure? Does upgrading = progression or re-sampling? Interobserver variability What is the role for biomarkers? Can active surveillance be less active? Watchful waiting for IDLE tumors? Outcomes of Surveillance Cooperberg et al. J Clin Oncol 2011; 29:228 14

The specter of undersampling Is upgrading trustworthy? N=1097 RP patients at UCSF 1996-2007 Percent 40 30 20 10 0 31 14 4 Toronto 21 19 8 Royal Marsden Upgrade ECE SVI 23 10 21 19 Progression vs. undersampling? 2 8 35 10 JHH MSKCC UCSF Conti et al. J Urol 2009; 181:1628 3 N=17 easy cases: =0.76 (0.59-0.90) N=17 controversial cases: =0.27 (0.15-0.42) McKenney et al. J Urol 2011; 186:465 Quantitative Gleason Grading Active Surveillance: Anxiety Treatment decision driven by PSA velocity and anxiety velocity Change nomenclature? PUNLUMP IDLE Reese A et al. Cancer 118:6046, 2012 Latini et al. J Urol 2007; 178:826 15

Comparative Effectiveness Research Who should be treated, and how? the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care. The purpose of CER is to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and population levels. Institute of Medicine, 2009 CER: What matters? Cancer control (PSA endpoints, survival) Urinary function (continence vs. irritation) Bowel function Sexual function (potency) PIVOT Trial 52 centers over 7 years screened 13,022 pts to find 5023 eligible and accrue 731 (14.5% of eligible, more likely Af-Am, low grade) Complications blood loss, pain Length of stay, time off work Cost (who pays?) Inappropriate care is never high-quality Wilt T et al. NEJM 2012; 367:203 16

PIVOT Trial: low risk PIVOT Trial: high risk Wilt T et al. NEJM 2012; 367:203 Wilt T et al. NEJM 2012; 367:203 Contemporary trials of RP vs. RT RP vs RT BCR definitions are not comparable! (stay tuned for ProtecT) Nielsen et al. Urology 2008; 72:389 17

Unadjusted cancer specific survival Results: Cancer specific mortality Predictors of Cancer-Specific Mortality Variable HR p 95% CI Age 0.98 0.046 0.97 1.00 CAPRA 1.35 <0.001 1.28 1.43 RP Ref EBRT 1.96 <0.001 1.28 2.78 PADT 3.26 <0.001 2.27 4.67 PADT:EBRT HR 1.7 (1.3 2.1) Cooperberg et al. Cancer 116:5226, 2010 Predicted 15 year cancer specific mortality Results from MSKCC and Baylor 1318 RP and 1062 EBRT patients All EBRT was IMRT 81 Gy Short-course NADT in 56% Predictor for metastasis HR 95% CI P value Age 0.98 0.95 1.02 0.3 Year of treatment 0.97 0.87 1.07 0.5 NCCN risk (high vs low/int) 6.37 3.89 10.5 <0.001 Surgery vs. EBRT 0.35 0.19 0.63 0.001 Zelefsky et al. J Clin Oncol 2010; 28:1508 18

Results from MSKCC and Baylor Zelefsky et al. J Clin Oncol 2010; 28:1508 Quality of life: RP vs. RT? Multiple well-done non-randomized studies (CaPSURE, PROSTQA, Spanish Multicentric Study, PCOS, etc) Specific rates vary, but minimal controversy: Surgery causes more incontinence, but less urinary irritation symptoms (and may improve obstructive symptoms compared to baseline) Radiation causes more irritative symptoms and bowel symptoms Both can cause erection problems surgery has more of an early impact ADT increases QOL impact Open vs. robot assisted surgery? Radiation details De facto nearly all EBRT in the U.S. is now IMRT Increasing the radiation dose improves PSA outcomes; inconsistent findings re: mortality Adding ADT improves outcomes for intermediate- and high-risk disease Brachy likely offers small benefits over IMRT in terms of PSA oucomes and some QOL domains Brachy + EBRT may be better than EBRT alone for high-risk disease, but increases QOL risks 19

What about costs? A cost effectiveness model Nguyen et al. J Clin Oncol 2011; 29:1517 Cooperberg et al. BJU Int 2013; 111:437 Results: low risk Results: high risk Proton beam therapy shouldn t even be considered! Cooperberg et al. BJU Int 2013; 111:437 Cooperberg et al. BJU Int 2013; 111:437 20

Protons: If you build it they will come We are building it Adjusted OR for receiving proton beam therapy for pts residing in San Bernadino: 5.5 Aaronson et al. Arch Intern Med 172:280, 2012. http://www.proton-therapy.org Prostate cancer treatment variation But what if we do listen to the USPSTF? Willet F. Whitmore, Jr 21

Conclusions UCSF Urologic Oncology Don t trust the NY Times to interpret complex literature! Screening saves lives, period. But screening must be done better. Coming soon: AQUA Cancer management must be risk-adapted. If diagnosis does not lead inevitably to treatment then overdiagnosis (AUA Quality will be Registry) less of a problem. Decisions should be driven by health and risk, not age. Biomarkers and imaging may help, but we don t need to wait Peter Carroll Katsuto Shinohara Max Meng Kirsten Greene Sima Porten Nannette Perez Janet Cowan Shoujun Zhao Niloufar Ameli June Chan Stacey Kenfield Jenny Broering Jeff Simko Mark Bridge Imelda Tenggara Sarah Joost 22