11/3/2019
Julie N. Graff, M.D. Autumn 2019
Special thanks to Tomasz Beer, MD, for providing the slides!
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Prostate gland
Rectum
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Prostate cancer grading
Pattern 3 Pattern 4 Pattern 5 Gleason grade 3+3=6 Gleason grade 4+4=8 Gleason grade 5+5=10
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Gleason Grade Mortality without treatment
Grade Mortality
2 - 4 4-7%
< 5 6-11%
6 18-30%
7 42-70%
8 -10 60-87%
Albersten, JAMA; 1998 4
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Prostate cancer staging
T . N . M
Incidental (TUR/PSA) T1 A, T1 B, T1 C
Localized T2 A, T2 B , T2 C
T3 , T3 , T3 Locally-advanced A B C and T4
N(0) vs N(+) Metastatic M(0) vs M(+)
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Background- PSA • 32 kDa serine protease produced by prostate epithelial cells • Increased in cases of prostate cancer • PSA also used for disease monitoring after treatment
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Factors Affecting PSA Secretion
• Increased • Decreased – Cancer – Finasteride – BPH – Antiandrogenic therapy – UTI – Phytoestrogens? – Prostatitis – Exercise – Ejaculation – Urologic procedures
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Prostate Cancer is Common
NEW DIAGNOSES DEATHS
ACS Cancer Facts & Figures 2015 8
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Prostate Cancer is More Common in the Deceased than in People Who are Still Alive
Prevalance of cancer (at autopsy) Wayne State Univ: Dr. Wael Sakr
80 70 60 50 40 30 20 Percentmen of 10 0 20-29 30-29 40-49 50-59 60-69 70-79
Age (by decade)
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Prostate Cancer Death Rates are Declining United States, 1930-2009
US deaths from prostate cancer have declined 51% between 1993 and 2014
CA: A Cancer Journal for Clinicians Volume 63, Issue 1, pages 11-30, 17 JAN 2013 DOI: 10.3322/caac.21166 http://onlinelibrary.wiley.com/doi/10.3322/caac.21166/full#fig4 10
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Risk Factors for PCA
• Family history
– Hereditary disease accounts for 5-10%
– Single relative: 2.2-fold • Race: African American – 50% increase in incidence – 100% increase in PCA mortality
• BMI - increased rate of advanced PCA • BRCA-1/2 - Increased risk of PCA. BRCA-2 associated with high-grade disease • Agent Orange
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A man’s lifetime risk of cancer
Prostate 17%
No Cancer 55% Lung 8%
Colorectal 6%
All others 14%
American Cancer Society, 1999 12
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Prostate Cancer Risk Family History
10.9 12 10 8 4.9 6
Odds Ratio Odds 4 2.2 2 0 1 2 3 Number of 1st degree relatives
Steinberg et al, Prostate; 17:337-47, 1990 13
Screening
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TMB1 JG1 Prostate Cancer Screening Guidelines
USPSTF Shared decision making for men 55-69 years of age AAFP Shared decision making for men 55-69 years of age ACP Shared decision making for men 55-69 years of age and who have 10+ years life expectancy ASCO In men with a life expectancy>10 years, it is recommended that physicians discuss with their patients whether PSA testing for prostate cancer screening is appropriate for them. ACS Starting at age 50, men should talk to a doctor about the pros and cons of testing so they can decide if testing is the right choice for them. If they are African American or have a father or brother who had prostate cancer before age 65, men should have this talk with a doctor starting at age 45.
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TMB1 Need to update Tom Beer, 1/11/2018 JG1 https://www.cancer.net/sites/cancer.net/files/asco_answers_guide_prostate.pdf Julie Graff, 10/31/2019 11/3/2019
Does treatment of localized prostate cancer make a difference?
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Bill-Axelson et al, NEJM 352:1977-84, 2005 18
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Stacked Cumulative Incidence of Death from Any Cause, Death from Prostate Cancer, and the Development of Metastasis, According to Study Group, Age, and Risk Group
Bill-Axelson A et al. N Engl J Med 2014;370:932-942 19
Prevalence of Metastases and Use of Palliative Treatment in Men Alive at Various Time Points since Randomization
Bill-Axelson A et al. N Engl J Med 2014;370:932-942 20
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PIVOT Trial of Intervention Versus Observation (Active surveillance)
• 731 men randomized to Surgery vs. Observation • 70% Gleason 6 or less • 44% had significant health issues – 50% dead at end of study (10 years). • Median PSA = 7.7 ng/ml • Non-compliance common: – Surgery arm: 23% – Observation arm: 31% • Study stopped at 10 years.
NEJM 367: 203-213, 2012
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Effect of Surgery on Overall and Cancer Survival
Authors conclusion: “..prostatectomy did not improve survival or prostate cancer survival as compared to observation…”
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Prostate cancer mortality: PSA < = 10 ng/mL
NEJM 367: 203-213, 2012
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Prostate cancer mortality: PSA >10 ng/mL
NEJM 367: 203-213, 2012
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Prostate cancer mortality: high-risk disease
NEJM 367: 203-213, 2012
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Table 2. Improvement in Clinical outcome over observation in patients treated with surgery in randomized controlled trials.
SPCG-4 PIVOT study
Outcome PSA < 10 ng/ml PSA ≥ 10 ng/ml
Overall survival 25% ns 21%
Prostate cancer survival 38% ns 57%
Metastases-free survival 41% ns 72%
Local control 67% ns NA
Abbreviations: SPCG = Swedish Prostate Cancer Group, PIVOT = Prostate Cancer Intervention Versus Observation Trial, ns = non-significant, NA = not available. All numerical outcomes statistically significant (P<0.05).
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Radical prostatectomy reduces risk of: • Local progression • Metastases • Need for hormonal therapy • Death from prostate cancer • Death from any cause • Extended follow-up confirmed a substantial reduction in mortality after radical prostatectomy; the number needed to treat to prevent one death continued to decrease when the treatment was modified according to age at diagnosis and tumor risk • Little difference in the first 4 to 6 years
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Why must we be careful about screening for prostate cancer? 1. Overdetection: with screening (only 55% of men are routinely screened), there is an 17% lifetime risk of diagnosis in the U.S 2. In U.S., since statistics were first kept in the 1980’s, the lifetime risk of death from prostate cancer remains 3% 3. Of men who die of prostate cancer, 2/3 have Gleason 8-10 at diagnosis 4. Harms of treatment of clinically insignificant cancers are a significant concern
Brawley, ASCO ; 2009 (education session) 28
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Chou R, et al, Ann Intern Med 2011;155:762-771 29
USPSTF Recommendations
Screening for Prostate Cancer: U.S. Preventive Services Task Force Recommendation Statement DRAFT
Summary of Recommendation and Evidence The U.S. Preventive Services Task Force (USPSTF) recommends against prostate-specific antigen (PSA)-based screening for prostate cancer. This is a grade D recommendation. Changed in 2018 to Category C.
This recommendation applies to men in the U.S. population that do not have symptoms that are highly suspicious for prostate cancer, regardless of age, race, or family history. The Task Force did not evaluate the use of the PSA test as part of a diagnostic strategy in men with symptoms that are highly suspicious for prostate cancer. This recommendation also does not consider the use of the PSA test for surveillance after diagnosis and/or treatment of prostate cancer.
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US SEER database (NCI): • 75% decrease in metastatic disease • 40% decrease in age-adjusted PC mortality rate • 20K fewer men died of PC in 2008 than in 1992
http://www.seer.cancer.gov 31
Brawley, ASCO ; 2009 (education session) Andriole, N Engl J Med ; 360:13, 2009 32
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The PLCO Trial
• Randomized 76,693 men aged 55 to 74 years to screening or usual care • Annual PSA screening for 6 years with concomitant DRE for 4 • PSA cutoff 4.0 ng/ml • Diagnostic follow-up for positive screening tests was left to participants
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Prostate Cancer Diagnoses and Deaths in the PLCO Screening Trial
Andriole G, et al, N Engl J Med 2009; 360:1310-9. 34
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PLCO (US) Trial of Screening Follow-up 11.5 years from enrollment
Screening (38K) Control (38K)
Prior biopsy 4.3% 4.3%
Prior PSA testing 44% 44%
Prior DRE 55% 54%
PSA screening on trial 85% 52% (compliance)
Cancer detection 9% 8%
PCA deaths 0.13% 0.12%
Andriole G, et al, N Engl J Med 2009; 360:1310-9.
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Limitations of the PLCO Trial • Pre-screening – 44% of men in each arm had undergone PSA testing at least once before randomization – Pre-screened patients had a lower risk of prostate cancer than unscreened patients • Contamination: 52% of control patients screened versus 85% in the screened arm • Neither the pre-screening not contamination were likely to be random – They reflect choices of individual men – These choices were likely influenced by knowledge and perceptions of cancer risk – People at higher risk (i.e. family history) would be expected to choose PSA testing more often, further diluting the power of the study • Poor adherence with biopsy when indicated – About 40% of men referred for biopsy were biopsied within a year • Short follow-up time (7 years from diagnosis) – Likely insufficient to detect a mortality difference
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Consequences of PLCO trial limitations
• An early screening effect was not observed – Minimal increase in cases diagnosed • 17% increase in new cases (ERSPC – 71%) – Expected down-staging not seen • Large reduction in advanced cases seen in ERSPC • Dramatic loss of power to detect an impact of screening – Design assumed a 20% reduction detectable with 90% compliance of the screened group and 20% in the control group – Actual power with the observed contamination rates and lower than expected rates was 15% • A power of 15% means that if a true difference between the two groups existed, there is an 85% probability that the study would miss it!
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Prostate cancer-related mortality
Absolute risk reduction of 0.71 PCA death per 1000 men after 8.8 years, translating into a 20% reduction in risk of cancer death. Compliance rate of 82% for screening.
Schröder et al, N Engl J Med ; 360:13, 2009 38
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Schröder et al, N Engl J Med ; 360:13, 2009 39
The ERSPC Trial • Randomized 182,000 men aged 50-74 from seven countries to screening or no screening • Testing every 2-7 years; PSA triggers ranged from 2.5 to 4.0 ng/ml – Sweden (Goteborg): testing every 2 years with a cutoff of 3.0 ng/ml – Finland: testing every 4 years with a cutoff of 4.0 ng/ml • Generally excellent compliance with screening assignment and biopsy referral – 82.2% men on the screening arm screened at least once – On average 85.8% of men referred to biopsy had one done • Results published after median 8.8 years follow-up
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Cumulative prostate cancer mortality 13-year follow-up
NNI of 781 (95% CI 490–1929) NND of 27 (17–66)
Follow-up from randomization was 13 years Follow-up from diagnosis of prostate cancer was only 6·4 years in the intervention group and 4·3 years in the control group
The Lancet, 2014
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Estimates of cumulative prostate cancer mortality in both groups by 4-year periods
The Lancet, 2014 42
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ERSPC (European Trial) Trial of Screening Follow up of 11.0 years from enrollment
Screening (89K) Control (73K)
Age 61.5 61.3
Prior PSA/DRE or NA NA Biopsy PSA screening on trial 83% NA
Cancer detection 9.6% 6.0%
Prostate Cancer deaths 299 (0.3%) 462 (0.6%)
O/E PCA deaths 10% 20%
N Engl J Med 2012; 366:981-990, 2012.
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Prostate Cancer Mortality Reduced in Screening Arm by 21%
38% reduction in PCA death
Prostate cancer survival improved by 29% after adjustment for non-compliance
N Engl J Med 2012; 366:981-990, 2012.
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ERSPC Results Adjusted for Nonattendance and Contamination • Definitions: – Nonattendance = not participating in the initial screening round – Estimate of contamination based on PSA use in controls in ERSPC Rotterdam • Adjustment for nonattendance by itself resulted in RR of 0.73 (27% reduction) • Additional adjustment for contamination led to estimates of RR 0.69 -0.71 (31% reduction)
Roobol MJ, et al, Eur Urol 2009; 56:584-591. 45
ERSPC Results – 11 Years of Follow-up
. Continues to show a 21% reduction in prostate- cancer mortality in the screening group, 31% after adjustment for noncompliance . The NNS declined from 1410 in the initial analysis to 1055 in the current analysis (USPSTF 1 life saved per 100 screened) . The NNT declined from 48 to 37 . The relative risk reduction during year 10 and 11 of follow-up was 38% (more than 1/3 of risk reduction after 9 years)
Schröder F, et al, N Engl J Med 2012; 366:981-90
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Göteborg Population-Based Randomized Screening Trial (Sweden) • Population-based, 20K men (50-64 yrs) • Contamination rate only 3% vs 15% (ERSPC) and 52% (PLCO) • Screened every 2 yrs, used progressively lower PSA thresholds for biopsy: – 1995-1998 3.4 ng/ml – 1999-2003 2.9 ng/ml – 2004-end 2.5 ng/ml • 93% complied with biopsy (vs 40% PLCO) • 77% had 14 years follow-up
Hugosson J, et al, Lancet Oncol 2010; 11:725-732 47
Göteborg Screening Trial Prostate Cancer-Specific Mortality
44% PC mortality HR 0.56 p=0.002
Hugosson J, et al, Lancet Oncol 2010; 11:725-732 48
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Göteborg Trial Results
• 41% decrease in advanced disease – >66% lower in men actually screened • 44% decrease in prostate cancer mortality – 56% lower in men actually screened • NNT at 14 years – 12. Compares favorably with well-established screening programs for breast CA (NNT at 10 years = 10) • As yet, no difference in overall survival which takes the longest to demonstrate
Hugosson J, et al, Lancet Oncol 2010; 11:725-732 49
ERSPC – 2 additional years of follow-up • The European Randomized Study of Screening for Prostate Cancer continues to show a 21% reduction in prostate- cancer mortality in the screening group, after 11 years of follow-up. • The number of needed to screen has declined from 1410 in the initial analysis to 936 in the current analysis • The number of cancers that would need to be detected to prevent one prostate-cancer death has declined from 48 to 33 • The relative risk reduction during year 10 and 11 of follow- up was 38% • Screening does not affect all-cause mortality
N Engl J Med 2012; 366(11):981-990 50
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Cumulative Hazard of Death from Prostate Cancer among Men 55 to 69 Years of Age
Schröder FH et al. N Engl J Med 2012;366:981-990 51
Survival improved in Screening arm for Gleason 6 and higher.
N Engl J Med 2012; 366:981-990, 2012.
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Conclusions from the randomized trials
• PLCO is flawed • Because the problems with PLCO occurred at enrollment and during the active portion of the study, longer follow-up is unlikely to be helpful – The absence of the early screening effect (increased diagnosis, down-staging) set “in stone” the flaws that are reflected in the results • PLCO showed that somewhat more frequent screening was not better than standard of care screening – it did not show that screening had no effect when compared to no screening • Over-diagnosis and over-treatment remain a major concern • Efforts to reduce over-diagnosis and especially overtreatment are critically important
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• PLCO trial is flawed • In the ERSPC trial, prostate cancer screening reduced prostate cancer mortality with an NND of 27 at 13 years median follow-up • Overdiagnosis and overtreatment are significant concerns • Net benefit vs. harm of screening is uncertain • Population-based screening is probably not appropriate • Screening may be considered for individuals who receive well balanced information, preferably on the basis of validated decision aids.
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Comparative Effectiveness of Alternative PSA Screening Strategies Risk PCa Risk Screening Strategy death overdiagnosis Other (%) (%)
No screening 2.86 NA NA
Annual screening, age 50-74 years, with PSA threshold 4 2.15 3.3 NA ng/ml Annual screening, age 50-74 years, higher PSA threshold in 2.23 2.3 older men Reduces total tests Biennial screening, longer by 59%, false inter-screen intervals for low 2.27 2.4 positive tests by PSA levels 50%
Gulati R, et al, Ann Intern Med 2013; 158(3):145-53 55
Problems Areas in Prostate Cancer
• PSA Specificity (4-10) : 25 – 35% • PSA Sensitivity > 4.0 cutoff: 85% • Complications from biopsy ( 7% hospitalized) • Overtreatment: 3% overall death rate from PCA • Current models do not discriminate well
https://www.aacc.org/publications/cln/articles/2013/june/prostate-cancer Clin Chem 2008:54:e11–79 National Academy of Clinical Biochemistry (NACB) Laboratory Medicine Practice Guidelines
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The way forward for prostate cancer screening
• Decoupling screening and diagnosis from treatment is essential to reduce over-treatment • To radically improve the situation: – We must understand the difference between lethal and non-lethal cancer – We need to use this understanding the develop markers for detection of lethal cancer – It is likely that a multi-marker panel that might include both biologic and clinical information will prove to be the best way to do this
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Predicting Outcomes
• Low risk: PSA <10 ng/ml; Gleason 6 or less; less than ½ of one lobe involved by DRE • Intermediate risk: PSA 10-20 ng/ml; Gleason 7; more than ½ of one lobe or bilateral • High risk: PSA > 20 ng/ml; Gleason 8-10; tumor involving other structures
JAMA 2005; 293 (17): 2095-2101.
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ProtecT Study: 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer • UK Study that recruited men 50-69 years of age • 1999-2009 • 82,429 had a PSA test • 2664 received a diagnosis of localized prostate cancer • 1643 agreed to be randomized between AS, RP, and RT • Stratified by age, Gleason score, PSA
NEJM 2016;375:1415-24.
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Baseline Characteristics
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Outcomes
Development of Metastatic Disease
Active Monitoring: 33 Surgery: 13 Radiation: 16
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Trends in Active Surveillance
JAMA 2015; 314:80-82
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Thank You!!
We don’t take crap from just anyone. Only the responders.
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