Pre-test Matthew R. Cooperberg, MD, MPH UCSF 40 th Annual Advances in Internal Medicine Prostate Cancer Screening 2012: Putting the PSA Controversy to Rest 1. I do not offer routine PSA screening, and the USPSTF D recommendation will not change my practice. 2. In light of the new USPSTF D recommendation I plan to reduce / stop PSA screening in my practice. 3. The USPSTF D recommendation is not strongly evidence-based, and will not change my practice. 4. I am unaware of the USPSTF D recommendation. 42% 42% 11% 5% June 28, 2012 1 2 3 4 Prostate Cancer 2012 The Good News: 40% drop in age-adjusted prostate cancer mortality since early 1990s Siegel et al. CA Cancer J Clin 2012; 62:10 Siegel et al. CA Cancer J Clin 2012; 62:10 1
So why did we end up here? This is our fault. Moyer et al. Ann Intern Med, epub 2012. Prostate cancer is heterogeneous The Changing Face of Prostate Cancer Esserman et al. JAMA 2009; 302:1685 Cooperberg et al. J Urol 2007; 178:S14 2
Risk by Age Natural history of low-risk disease Cooperberg et al. JCO 2009; 27:4306 Lu-Yao et al. JAMA 2009; 302:1202 Natural history of high-risk disease Benefits of Screening: The RCTs Lu-Yao et al. JAMA 2009; 302:1202 3
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 Up to 1995, any prior screening allowed; starting in 1995, no more than 1 PSA within past 3 years 44.1% of control group had had 1 PSA in past 3 years; 53.9% had had 1 DRE PSA >4.0 ng/ml considered abnormal Cancer incidence ascertained by questionnaire Andriole et al. NEJM 2009; 360:1310 Andriole et al. NEJM 2009; 360:1310 PLCO Compliance with screening 85% in screening arm Rate of screening in control arm 40% in first year, 52% in sixth year Rate of biopsy among those with PSA >4 fell from the 40% in study first year was to not 30% a fair by comparison third year [Grubb between al. BJU screening Int 2008; 102:1524] and no screening; instead, it was a comparison At 7 years, prostate between cancer annual diagnosed and ad hoc in screening. 2820 screening Cooperberg pts and 2322 Carroll, controls, NEJM RR 2009; 1.22 361:203 (1.16-1.29) 96.0% vs 94.3% of screened vs control tumors were stage I-II; 32% vs 39% were GS 7 At 7 years, 50 cancer-specific deaths in screening group, 44 in control group, RR 1.13 (0.75-1.70) PLCO: the contamination problem Data from surveys of the control arm of the PLCO study: Andriole et al. NEJM 2009; 360:1310 Pinsky et al. Clin Trials 2010; 7:303 4
PLCO: the contamination problem PLCO: Update Given the high level of contamination in PLCO, one way of interpreting the trial is that it is a study of an active (organized) program of screening versus passive (opportunistic) screening, that is, the current level of screening ongoing in the community a finding of no benefit implies that an organized program does not confer significantly greater mortality benefit for prostate cancer than opportunistic screening as currently carried out in the US. However, the study interpreted in this manner would not be able to answer the question of whether that level of opportunistic screening is conveying a mortality benefit over no screening. PLCO was not a trial of screening vs. no screening Pinsky et al. Clin Trials 2010; 7:303 Andriole et al. J Natl Cancer Inst 2012; 104:1 ERSPC European Randomized Study of Screening for Prostate Cancer ERSPC Population-based study at 7 European centers 182,160 men age 50-74 randomized (162,387 in core age 55-69) In 3 centers, men were randomized from population lists before informed consent; in other 4 they were identified from population lists but randomized after consent Screening interval 4 years at most centers (2 at one) Some variation in thresholds for biopsy (3.0 ng/ml vs 4.0 with ancillary tests (DRE/fPSA/TRUS) for values between 2.5 or 3.0 and 4.0. Schröder et al. NEJM 2009; 360:1320 Schröder et al. NEJM 2009; 360:1320 5
ERSPC 82% compliance with screening in screening arm (better in consent-first countries) 85.8% compliance with biopsy recommendations Incidence 4.8% in control, 8.2% in screening arm 27.8% vs 45.2% of screened vs. control tumors were Gleason 7 Adjusted mortality rate ratio 0.8 (0.67-0.95) in favor of screening. Mortality rates begin diverging at 7 years. Other findings from ERSPC No substantial heterogeneity among different centers in Europe (mortality reduction varies from 16-26%) Absolute mortality risk reduction 7 per 10,000 men screened NNS: 1,410 NNT: 48 in excess of control group at 9 years NNT to prevent metastasis: 24 Schröder et al. NEJM 2009; 360:1320 Schröder et al. NEJM 2009; 360:1320 ERSPC: Adjusting for compliance ERSPC: Update 21% risk reduction for cancer-specific mortality with screening (up to 38% in years 10-11) 29% risk reduction with adjustment for noncompliance Number needed to diagnose=33 Roobol et al. Eur Urol 2009; 56:584 Schröder et al. NEJM 2012; 366:981 6
The Göteborg trial (the best prostate cancer screening RCT you ve never heard of) Men 50-64 (median 56) in a single Swedish city randomized without consent in 1994 to biannual screening until age 69 vs. no screening 9952 men in each arm Referral to urologist at PSA 3.4, later reduced to 2.9 then to 2.5 ng/ml. Biopsies used sextant template 76% of men in screening arm were screened at least once; 93% of men with elevated PSA had at least one biopsy The Göteborg randomized trial Hugosson J. Lancet Oncol 2010; 11:725 Hugosson J. Lancet Oncol 2010; 11:725 The Göteborg randomized trial The Göteborg randomized trial RR 0.56 (0.39-0.82, p=0.002) RR 0.56 (0.39-0.82, p=0.002) NNS: 293, NNT: 12 Hugosson J. Lancet Oncol 2010; 11:725 Hugosson J. Lancet Oncol 2010; 11:725 7
The Göteborg randomized trial Absolute vs. relative benefit? Göteborg vs. PLCO & ERSPC Younger mean age at start of screening Lower PSA threshold for referral Q2 year interval Higher rate of biopsy among those with high PSA Lower rate of pre- and intra-study PSA contamination Longer followup (though still relatively short) At 14 years followup not lifetime Hugosson J. Lancet Oncol 2010; 11:725 Carroll et al. J Clin Oncol 2011; 29:345 Short-term Perspective Distorts Harms as Well As Benefits 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! 58% of screen detections ERSPC after 9 years 28% of screen detections US population over lifetime (annual screening) The harms of screening: overtreatment Overdiagnoses/Lives saved 48 7 Courtesy of Ruth Etzioni 8
Fair assessment of harms? Adequate evidence shows that up to 5 in 1000 men will die within 1 month of prostate cancer surgery and between 10 and 70 men will have serious complications but survive. Radiotherapy and surgery result in long-term adverse effects, including urinary incontinence and erectile dysfunction in at least 200 to 300 of 1000 men treated with these therapies. Radiotherapy is also associated with bowel dysfunction Moyer et al. Ann Intern Med, epub 2012. The real problem: overtreatment Treatment by risk and age Cooperberg et al. J Clin Oncol 2010; 28:1117 Bechis et al. J Clin Oncol 2011; 29:235 9
What do PCPs do? Do PCPs care about the USPSTF? Walter et al. JAMA 2006; 296:2336 Tasian et al. Urol Oncol 30:155, 2012 Do PCPs care about the USPSTF? So what now? Prasad et al. JAMA 307:1692, 2012 10
One approach Establishing a baseline PSA at 60 predicts long-term prostate cancer mortality Analysis of 1167 samples from 1981-2 matched to Malmö registry data 11.4% diagnosed, 2.7% died of prostate cancer If PSA <1.0 at age 60, likelihood of prostate cancer death <0.3% 90% of prostate cancer deaths occurred in men with PSA >2.0 (top quartile) or we can screen smarter Vickers et al. BMJ 341, 2010 Rationale for earlier screening (AUA) An interesting perspective A baseline PSA level above the median for age 40 is a strong predictor of prostate cancer The age adjusted mortality rate for prostate cancer between ages 55 and 64 is significant. Such men may have been cured by earlier diagnosis and treatment Younger men are more likely to have curable cancer PSA is a more specific test for cancer in younger men Earlier and less frequent testing might reduce mortality and costs compared to annual testing beginning later Patients at risk for, but who do not have cancer may be candidates for chemoprevention Greene et al. J Urol 2009; 182:2232 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. Detsky et al. JAMA 307:1035, 2012 11
Multivariable risk assessment Targeting the right populations 35 30 25 26.2 28.6 29.2 25.6 CaPSURE 20 15 14.1 15.6 10 5 0 11.0 9.2 6.8 6.4 6.8 5.1 4.3 3.1 1.0 1.6 1.3 1.7 1.4 0.8 0.2 0.3 0 1 2 3 4 5 6 7 8 9 Adv CAPRA Score http://tinyurl.com/caprisk Porten et al. J Urol 2010; 184:1931 Targeting the right populations 35 30 25 20 15 10 5 0 CaPSURE SFGH 28.6 29.2 26.2 25.6 17.5 15.9 15.9 15.6 14.1 11.2 11.0 9.2 7.3 7.6 6.8 7.3 6.4 5.1 3.1 2.9 1.6 1.3 1.7 1.0 1.4 1.0 0.8 0.2 0.3 12.4 6.8 4.3 0 1 2 3 4 5 6 7 8 9 Adv CAPRA Score Porten et al. J Urol 2010; 184:1931 Risk Assessment and Risk- Adapted Management Diagnosis Treatment 12
SPCG-4 trial: RP vs. WW 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) Bill-Axelson et al. New Engl J Med 2011; 364:1708 Wilt T. AUA 2011 Plenary Presentation. PIVOT Trial PIVOT Trial Wilt T. AUA 2011 Plenary Presentation. Wilt T. AUA 2011 Plenary Presentation. 13
Prostate Cancer Risk Assessment The UCSF-CAPRA Variable Level Points Variable Level Points Goal: inform physician-patient decisions about optimal initial treatment approach and timing Active surveillance Early local therapy Multimodal therapy Systemic therapy PSA 6 0 T-stage T1/T2 0 Gleason (primary/ secondary) 6.1-10 1 T3a 1 10.1-20 2 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 CAPRA: Cancer-specific survival Surveillance: Recent Experiences HR C-index 1.39 (1.31-1.48) = 0.80 # at risk 4892 1430 350 Institution (PI) Total (n) Strict* (n) Median age Inclusion criteria Royal Marsden (Parker) 326 326 67 Gleason 3+4, PSA 15 ng/ml, ct stage 2a, 50% of cores positive University of Miami (Soloway) 230 230 64 Gleason 6, PSA 10 ng/ml, ct stage 2, 2 cores, 20% of any core positive Johns Hopkins (Carter) 769 633 66 UCSF (Carroll) 640 376 62 Gleason 3+3, PSAD 0.15 ng/ml/ml, ct stage 1, 2 cores positive, 50% of any core positive Gleason 3+3, PSA 10 ng/ml, ct stage 2, 33% of cores positive, 50% of any core positive University of Toronto (Klotz) 453 453 70 Gleason 6, PSA 10 ng/ml (until Jan 2000, for men >70: Gleason 3+4, PSA 15 ng/ml) ERSPC sites (Schröder) 988 616 66 Gleason 3+3, PSA 10 ng/ml, PSAD 0.2 ng/ml/ml, ct stage 1c-2, 2 cores positive Memorial-Sloan Kettering (Eastham) 238 238 64 Gleason 3+3, PSA 10 ng/ml, ct stage 2a, 3 cores positive, 50% of any core positive TOTAL 3644 2872 67 Cooperberg et al. JNCI 2009; 101:878 Cooperberg et al. J Clin Oncol 29:3669, 2012. 14
Surveillance: Recent Experiences Active Surveillance: UCSF Institution Median followup (months) Progress by grade / volume (%) Progress by PSA / PSA kinetics (%) Treatment without progression (%) OS (%) CSS (%) PFS (%) Royal Marsden 22 13 18 2 98 100 73 University of Miami 32 10 NR NR 100 100 86 Johns Hopkins 32 14 NR* 9 98 100 54 UCSF 47 35 5/11 8 97 100 54 University of Toronto 82 9 14 3 68 97 70 ERSPC sites 52 NR 13 18 91 99 68 Memorial- Sloan Kettering We need better biomarkers, imaging tests, and psychosocial interventions 22 13 14 11 n/a n/a n/a Cooperberg et al. J Clin Oncol 29:3669, 2012 Dall Era et al. Cancer 2008; 112:2664 So what explains this graph? Treatment Changes Explain Only a Fraction of the Mortality Decline 40% drop in age-adjusted prostate cancer mortality since early 1990s No treatment Treatment Cases diagnosed since 1975 Siegel et al. CA Cancer J Clin 2012; 62:10 Cancer, in press. Courtesy of Ruth Etzioni 15
Mortality Trends Suggest a Clear Role for PSA Screening What if we listened to the USPSTF? No treatment Treatment Treatment and screening ERSPC benefit Cases diagnosed since 1975 Cancer, in press. Courtesy of Ruth Etzioni A Decision Aid for the Task Force How to save the baby: screen smarter Start earlier (e.g., 40) Screen less frequently if baseline is low Focus on populations at highest risk Screen for high-risk prostate cancer, don t over-treat low-risk disease Embrace active surveillance Fix incentives Refer early and wisely Change nomenclature Continue to develop novel biomarkers 16
Conclusions Screening saves lives, period. The USPSTF analysis downplays benefits, overestimates harms, and is predicated on far too short of a time horizon. D is the wrong conclusion. Overtreatment is without question a major public health problem. But the answers lie in smarter screening and better treatment decisions, not in wholesale cessation of screening. Post-test? 1. I will not offer PSA screening to any men 2. I will only offer PSA screening to men who specifically ask for it 3. I will discuss screening with men with long life expectancy, and individualize the decision to screen 4. I will screen most men over 40 in good health 5. I am more confused than I was an hour ago! 0% 6% 70% 12% 12% 1 2 3 4 5 17