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Prostate Cancer screening
Mahmoud Abdelsalam MD/PHD
Medical Oncologist, Moncton Hospital
Professor in IM dept. Dalhousie University, Canada
Director of Clinical Trial Moncton, Canada
Disclosure
• Consultancy: Merck, Novartis, Astellas, BMS, Roche,
• Ad. Board: Amgen, Pfizer, Johnson, Merck, Novartis
• Grants: Roche, Amgen, Johnson, Astellas
Objectives
• List risk factors for prostate cancer, and discuss
relative strength
• Discuss potential prevention strategies
• Discuss benefits and risks of prostate cancer
screening, including expected survival rates
• Counsel patients about primary treatment
options for local disease
• Recommend systemic therapy for advanced
cancer.
Canadian Cancer Statistics 2015
Canadian Cancer Statistics 2015
Canadian Cancer Statistics
Risk Factors for Prostate Cancer
• Age – Rare before 40; 65% over the age of 65
• Race - More common in African-American men; more likely
diagnosed at advanced stage; 2x more likely to die of the disease;
less common in Asian-American and Hispanic-American men than
non-Hispanic whites.
• Family History - 1st degree relatives, father, brother
• Nationality - North America and NW Europe vs Asia, Africa, Central
and South America
• Genetics – BRCA1 and BRCA2 increase risk, but account for very
small percentage of prostate cancer. Lynch syndrome??
• Obesity, Diet, Exercise, prostatitis, STDs, Vasectomy – not much
effect, BUT…….
Life time dying from cancer prostate
• Risk of dying from cancer
prostate is around 3 %
• Once metastatic disease
developed, there is no
cure.
• Prior to PSA screening
only 25% of prostate
cancer presented
confined to prostate vs.
91% since
Screening
• Should you screen at all?
• What age should you start and stop screening?
• Does PSA-based screening lead to decrease in risk of
death from prostate cancer?
• What are the advantages and disadvantages of
screening?
• Canadian guidelines?
Screening
• Two large trials done recently looking at survival benefit
from screening:
• PLCO screening trial (U.S.) and ERSPC screening trial
(European)
• These two RCT were largely basis for Canadian Task
Force on Preventive Health Care (CTFPHC)
recommendations.
European Randomized Study of Screening for Prostate
Cancer (ERSPC)
• Main endpoint: prostate cancer (PC) mortality
• Ages: 50-74, core age group 55-69 yrs (n=162,387)
• Screen interval 4 years (87%) or 2 years (13%)
• Sextant (lateral) biopsy recommended for PSA ≥3.0
ng/ml
or ≥4.0 ng/ml
• With ancillary tests: DRE, F/T ratio for PSA 3-4 ng/ml
Schröder. ECCO 2009; Teaching Lecture:
http://www.ecco-org.eu/Conferences-and-Events/Past-events/2009/ECCO-15-ESMO-34/Webcaptured-Sessions/page.aspx/1835#23
ERSPC screening trial (European)
• European Randomized Study of Screening for Prostate
Cancer
• 182,000 men randomized
• Ages 50-74 included
• Median f/up of 9 years there was 20% reduction in CaP
deaths in screened group
• 41 % reduction in metastases at presentation
Prostate cancer mortality –
Intention to screen analysis
• Relative risk (RR) of PC death 0.80
• (95% CI: 0.65-0.98, P=0.04), 20% relative reduction
• Absolute risk reduction: 7 per 10,000 men screened
• NNS: 1.410 (95% CI: 1.14-1.72)
• NNT: 48 (in excess of control group)
Schröder. ECCO 2009; Teaching Lecture:
http://www.ecco-org.eu/Conferences-and-Events/Past-events/2009/ECCO-15-ESMO-34/Webcaptured-Sessions/page.aspx/1835#23
Göteborg Screening Trial
• Göteborg randomized population-based prostate
screening trial
• 20,000 men randomized
• Ages 50-64 included (median 56)
• Median follow-up 14 years
• Found 44% risk reduction in CaP specific death in
screened group
• NNT analysis revealed that 293 men needed to be
screened and 12 men need to be diagnosed in order to
prevent 1 death
Hugosson et al. Mortality results from the Göteborg randomised
Population-based prostate-cancer screening trial.
Lancet Oncol 2010;11:725-32.
Lancet Oncology, published online July 1, 2010
Over 14 years PSA testing
increased the number of
cancers detected by 50% but
reduced the risk of dying of
prostate cancer by 44% in all
men and 56% in screened
men. The number needed to
screen to prevent one death
was 293, and number needed
to diagnose or treat was 12.
• 5 treated tp prevent one death
Caveats – ERSPC
• The 20% reduction in rate of death due to prostate
cancer underestimates true effect since some controls
were also screened (“contamination”) and some
assigned to screening did not get screened
(“noncompliance”), but …
• Model-based adjustment to correct for contamination
only indicates that screening reduces mortality by 27%,
and …
• Model-based adjustment to correct for both
contamination and noncompliance indicates that
screening reduces mortality by 31%
Roobol MJ, et al., Eur Urol 2009:56(4);584-591
More Caveats – ERSPC
• Initial data analysis indicates need to screen 1410 men
and treat 48 with cancer to save 1 life, but …
• Further modeling* indicates numbers needed to screen
(NNS) & treat (NNT) to prevent 1 prostate cancer death
decrease over time:
Definition: The number needed to screen
(NNS) is the number of people who would
need to be screened to prevent one person
from dying.
(Similarly for the number needed to treat,
abbreviated NNT.)
NNS is computed by taking the reciprocal of
the difference between the fraction of people
who die in the screening arm and the fraction
of people who die in the control arm.
* Loeb S et al., J Clin Oncol 29(4):464-467, 2011
The prostate, lung, colon, ovary cancer
screening trial (PLCO)
(Andriole et al, NEJM 2009)
RCT of screening versus “general care” control group,
to show 20% mortality reduction
n=76,693 men aged 55-74
PSA testing yearly for 6 years, DRE year 1-4
Biopsy for PSA >4.0 ng/ml or abnormal DRE
Andriole et al. New Engl J Med 2009;360:1310-1319
Schröder. ECCO 2009; Teaching Lecture:
http://www.ecco-org.eu/Conferences-and-Events/Past-events/2009/ECCO-15-ESMO-34/Webcaptured-Sessions/page.aspx/1835#23
PLCO – results
• Follow-up 7 years
• Compliance with PSA testing 85%, compliance with biopsy
indication ± 40%
• In the screen and control arm 85% and 52% of men were
PSA tested
• Cancer detection: S arm 2.86 (7.4%), C arm 2.32 (6.1%),
rate ratio 1.22
• Deaths from PC: S arm 2.0/10.000, (50 deaths), C arm
1.7/10,000 (44 deaths)
• Rate ratio 1.13, 95%CI 0.75-1.70, NS
Andriole et al. New Engl J Med 2009;360:1310-1319
Schröder. ECCO 2009; Teaching Lecture:
http://www.ecco-org.eu/Conferences-and-Events/Past-events/2009/ECCO-15-ESMO-34/Webcaptured-Sessions/page.aspx/1835#23
PLCO trial flaws
• Significant rates of screening in “control” arm
• 52% contamination (men were screened prior to study)
• Relatively low rate of biopsy in men who had “abnormal”
screening results in screen arm
• Less than 50% of men in screened arm with indication
had biopsy done
• Short follow-up (less than 10 yrs)
Does PSA Screening Reduce Prostate Cancer
Mortality?
PLCO:
No
ERSPC: Yes, but at high cost
Over 9 years, PSA screening reduced deaths
from prostate cancer by 20% but was
associated with a high risk of over diagnosis:
1410 men would need to be screened and 48
additional cases would need to be diagnosed
or treated to prevent one death from prostate
cancer.
Findings: Benefits of Screening with
PSA
Study
(country)
PLCO†
U.S. population
ERSPC‡
(Finland,
Sweden, Italy,
Netherlands,
Belgium,
Switzerland
and Spain)
Study Characteristics
PSA
Threshold
Contaminatio
n (rate of
screening in
control
group)
Prostate cancer
mortality
Relative Risk
(95% C.I.)
All-Cause Mortality
Relative Risk
(95% C.I.)
Absolute
Effect
(per 1000
men
screened)
GRADE
Quality of
Evidence*
RCT
76,693 men
age 55-74, annual PSA
screening for six years
and DRE annually for four
years
14 year follow-up
4 ng/ml
52%
1.09
(0.87-1.36)
0.96 (0.93 - 1.00)
No effect
moderate
RCT
162,243 men
Age 50-74 (core group 5569)
PSA every 4 years
13 year follow-up
Most sites
3.0 ng/ml
20%
Core gp: 0.79
(0.69-0.91)
All ages:
0.83 (0.73-0.94)
Core gp: 1.00 (0.98
- 1.02)
All ages: 1.00 (0.98
– 1.02)
1.28 fewer
deaths per
1,000 men
screened
moderate
*Grading of Recommendations, Assessment, Development and Evaluation (GRADE) rates the continuum of quality of evidence in four categories of high,
moderate, low or very low – see evidence review for complete assessment of study quality
†Prostate, Lung, Colorectal and Ovarian Screening Study
‡European Randomized Study for Screening for Prostate Cancer (published online August 7, 2014)
24
Screening
Problems with both studies
• Short follow-up <10 years (mortality from CaP is very
low in first 10 years)
• Subset analysis not done for high risk men (i.e. those
with +FH, AA)
• Contamination level is high specially in PLCO trial
• Compliance was low
Findings: Harms of Screening with PSA
The main harms of screening identified were:
• Harms of biopsy
• Harms of over-diagnosis
• False positives
• Cost
Complications Following Prostate Biopsy
Loeb S, Carter HB, Berndt SI, Ricker W, Schaeffer EM. Complications after prostate biopsy: data from SEER-Medicare. J Urol 2011;186:1830-1834.
Nam RK, Saskin R, Lee Y, Liu Y, Law C, Klotz LH, Loblaw DA, Trachtenberg J, Stanimirovic A, Simor AE, Seth A, Urbach DR, Narod SA. Increasing hospital
admission rates for urological complications after transrectal ultrasound guided prostate biopsy. J Urol 2010;183:963-968.
Pinkhasov GI, Lin YK, Palmerola R, Smith P, Mahon F, Kaag MG, Dagen JE, Harpster LE, Reese CT, Raman JD. Complications following prostate needle
biopsy requiring hospital admission or emergency department visits - experience from 1000 consecutive cases. BJU Int 2012;110:369-374.
OVER DETECTION
Of all screen-detected cancers, an estimated 10-56% would not have
become apparent or caused symptoms in the patients’ lifetimes, and the
lead time for diagnosis is estimated at 5-12 years.
Risks of Screening
• Screening detects cancers that do not threaten the
patient’s life.
• Finding such cases cannot be avoided at present.
• When screening the general population for PCa by PSA,
over 50% of the PCa’s detected will be minimal cancers
(Draisma 2003).
• As immediate treatment of these has not been shown to
be beneficial, detection and diagnosis of some tumors
may be unnecessary and counter-productive, as in
some patients there will be treatment-associated
morbidity (and, rarely, even mortality).
PIVOT (Prostate cancer Intervention Versus
Observation Trial)
• Randomized men ≤75yrs old to radical prostatectomy
vs. expectant management with all-cause mortality as
primary end-point
• 731 men studied
• Median f/up 10 years
• Different than Scandinavian trial
• looked at same thing, but now in PSA screening era
Wilt et al. Radical prostatectomy versus observation for localized
prostate cancer. N Engl J Med, 367, 2012
Bill-Axelson A et al. Radical prostatectomy versus watchful
waiting in early prostate cancer. N Engl J Med, 364, 2011
PIVOT (Prostate cancer Intervention Versus
Observation Trial)
• Found 47% (171/364) men died who had surgery vs.
49.9% (183/367) in observation arm
• 5.8% (21) men who had surgery died from CaP or
treatment vs. 8.4% (31) in observation arm
• Essentially NO Difference between groups
• Surgery associated with ↓ all-cause mortality in men
with PSA>10 and possibly in intermediate or high-risk
tumors
Wilt et al. Radical prostatectomy versus observation for localized
prostate cancer. N Engl J Med, 367, 2012
Bill-Axelson A et al. Radical prostatectomy versus watchful
waiting in early prostate cancer. N Engl J Med, 364, 2011
ProtecT (Prostate testing for cancer and Treatment)
• RCT of treatment effectiveness in UK
• Opened 2001 and closed 2008
• 111,000 men randomly assigned to surveillance,
radiation, or surgery
• Primary end-point will be CSS at 10yrs
• With numerous secondary end-points including QOL
analyses
Donovan et al. Prostate testing for cancer and treatment
(ProtecT) feasibility study. Health Technol Assess 2003; 7:14
Use of Watchful Waiting among U.S. Patients with Localized
Prostate Cancer
by Risk Category (1990-2006)
Low
Intermediate
High
Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate c
J Clin Oncol 2010; 28: 11117-1123.
Findings: Additional Harms of Screening
Not all men who screened above threshold had a biopsy
Some men who screen positive on the first round could be diagnosed with prostate
cancer on a subsequent round
Some men will have multiple biopsies
‡ ‡
Kilpelainen TP, Tammela TL, Roobol M, et al. False-positive screening results in the European Randomized Study of Screening for Prostate Cancer. Eur J
Cancer 2011;47:2698-705.
Causes of false positive PSA
Why Has Diagnostic Progress Not Resulted
In Greater Long-Term Survival Rates?
Death rate is comparatively low considering prevalence
• Lifetime risk of diagnosis: 1 in 6
• Lifetime risk of death: 1 in 33
• 5-year survival rate: 98%
Diagnostic and therapeutic advances have improved quality of
life, but not necessarily the years of life
• Risk is tied to age
- All ages: 17.7 cases per 100,000
- Age 75 to 84: 248 cases per 100,000
- Over 85: 591 cases per 100,000
Prostate cancer cells are generally less aggressive with
increasing age, suggesting “many prostate cancers detected in
routine practice may be clinically unimportant”
Sources: Mayo Clinic.com. Prostate Cancer Guide. Available at: http://www.mayoclinic.com/health/prostate-cancer/PC99999.
Thompson IM, Pauler DK, Goodman PJ, Tangen CM, Lucia MS, et al. Prevalence of prostate cancer among men with a prostate-specific antigen
level ≤4.0 ng per milliliter. NEJM. 2004;350:2239-2245.
Screening for Prostate Cancer with the Prostate
Specific Antigen (PSA) Test:
Recommendations 2014
• Canadian Task Force on Preventive Health Care
Summary of the Recommendations
Clinicians and Policy Makers
For men aged less than 55 years of age, we
recommend not screening for prostate cancer with the
prostate-specific antigen test.
(Strong recommendation; low quality evidence)
Basis of the recommendation
• The CTFPHC based this recommendation on the low
incidence of prostate cancer and prostate cancer
mortality, and the lack of evidence for benefit of
screening in this age group, as well as the evidence of
harms.
• The strong recommendation implies that the CTFPHC is
confident the harms of screening and subsequent
testing/treatment outweigh the benefits.
Summary of the Recommendations
Clinicians and Policy Makers
For men aged 55-69 years, we recommend not
screening for prostate cancer with the prostate
specific antigen test.
(Weak recommendation; moderate quality evidence)
Basis of the recommendation
•The CTFPHC placed a relatively low value on a small and
uncertain potential reduction in the risk of prostate cancer
mortality and a relatively higher value on the risk of harms
associated with diagnosis and treatment due to false
positive results and overdiagnosis.
•The weak recommendation against screening implies that
the harms of screening and subsequent testing/treatment
probably outweigh benefits, but uncertainty exists.
Summary of the Recommendations
Clinicians and Policy Makers
For men aged 70 years and older, we recommend not
screening for prostate cancer with the prostatespecific antigen test.
(Strong recommendation; low quality evidence)
Basis of the recommendation
• The CTFPHC based this recommendation on the lower
life expectancy and the lack of evidence for benefits of
screening in this age group, as well as the evidence of
harms.
• The strong recommendation implies that the CTFPHC is
confident the harms of screening and subsequent
testing/treatment outweigh the benefits.
USPSTF To Downgrade PSA Screening
From "I" to "D" — As In "Don't Do It"
• U.S. Preventative Service Task Force recommended
NOT to use PSA to screen for prostate cancer
• Based on meta-analysis of available literature
ABSTRACT Background: Prostate specific antigen-based screening can detect prostate cancer in earlier, asymptomatic stages,
when treatments might be more effective.
Purpose: To update the 2002 and 2008 U.S. Preventive Services Task Force evidence reviews on screening and treatments for
prostate cancer.
Data Sources: MEDLINE (2002 to July 2011), the Cochrane Library Database (through the 2nd quarter of 2011) and reference lists.
Study Selection: Randomized trials of PSA-based screening; randomized trials and cohort studies of prostatectomy or radiation
therapy versus watchful waiting for localized prostate cancer; and large (n>1000), uncontrolled observational studies of
perioperative harms.
Data Extraction: Investigators abstracted details about the patient population, study design, data analysis, and results and assessed
quality using predefined criteria.
Conclusions: After about 10 years, PSA-based screening results
in small or no reduction in prostate cancer-specific mortality and
is associated with harms related to subsequent evaluation and
treatments, some of which may be unnecessary.
The Cancer Letter, Oct. 7, 2011
Current Screening Guidelines
from Major U.S. Organizations
• American Urological Assoc Best Practice Statement
– Individual decision for those with 10yr life expectancy
– Baseline PSA at 40
– PSA at subsequent intervals based on PSA level and risk factors
• American Cancer Society
– Advises against routine screening
– PSA should be offered as option
• Age 45 in those with risk factors (FH, AA)
• Age 40 in those at highest risk (multiple family members or a family
member diagnosed at a young age)
• US Preventive Services Task Force
– Do not screen routinely over age 75
– Inadequate evidence regarding younger ages
– Current (October 2011) recommendation against PSA-based
screening of any asymptomatic men
© Stanley H. Weiss, 2011
Slide 44
Presented By Mark Stein at 2014 ASCO Annual Meeting
Prostate Cancer—Indolent vs. Aggressive?
• Low Risk
– PSA < 10
– Gleason score ≤6
•
Intermediate Risk
– PSA 10-20, Gleason 7 or Gleason 6 with PSA >10
• High Risk
– PSA > 20, Gleason 8-10
TREATMENT OPTIONS FOR PROSTATE
CANCER
Watch +/hormones
Curable
At Diagnosis
NonCurable
Watch +/treat for cure
later
TREAT NOW
for cure
Active Surveillance
• Watch, and if need be treat for cure later
• Means watching PSA and re-biopsy of prostate every 12 years
• Go on to curative Rx if PSA jumps quickly, urinary
symptoms, or biopsy shows worsening cancer
• Best for men with very slow growing cancers whose life
expectancy is less than 15 years.
Low-risk prostate cancer
• Cancer is VERY LIKELY restricted to the prostate gland
• Must have T2 (or less) and PSA <10 and Gleason Score
6 (or less)
• Expect 80-95% chance of cure with treatment
• Active surveillance is good option for many
Low-risk prostate cancer
T1/T2 and PSA<10 and GS<7
Surgery
Therapy
Low risk
Surveillance
Seed
implant
External
Radiotherapy
Treatments of Localized Prostate Cancer
•
•
•
•
•
The primary treatments reviewed:
Radical Prostatectomy
Radiation Therapy
Androgen Deprivation Therapy (ADT)
Combination Therapy
Treatment for cure: operation
• Radical prostatectomy – removes the prostate and
seminal vesicles
• Has a specific side effects
–
–
–
–
Related to major operation
Urinary incontinence 5-10%
Erectile dysfunction 30-70%
Bladder neck stricture 10%
• Is an excellent option in a situation where prostate
cancer cells are likely restricted to the prostate gland
• Removing the prostate gland provides much more
information about the aggressiveness and extent of
cancer
• Radiotherapy can be used after surgery if it looks like
cancer is likely left behind in the surgical bed or if PSA
begins to rise in follow up
Treatment of cure:
Radioactive seeds in prostate
• Also called Low Dose Rate or Seed
Brachytherapy
• Best for men with early disease when cancer
cells likely in prostate gland of just beyond
capsule
• Very high cure rates similar to operation when
done by an experienced specialist
• “Simple” outpatient procedure
– General anaesthetic
– Rapid return to normal activity
– Men appear happy with this treatment
Findings: Benefits of Treatment
• Some treatments were found to reduce the risk of prostate
cancer-specific mortality, although the quality of evidence
was variable.
• Prostatectomy was the only treatment with high QoE
• Hormone therapy alone was found to produce an increased
risk of prostate cancer-specific mortality.
• Very limited and low QoE to support a reduction in the risk of
all-cause mortality for the following treatments:
• Prostatectomy
• Radiation Therapy
• Combination Therapy (Radiation and Hormone Therapy)
Management of CRPC
How to Improve screening benefits
•
•
•
•
•
•
High Risk
Family History
Age
PSA velocity
PSA Density
PCA 3 (non-coding mRNA molecule that is believed to
be prostate specific)
• Risk Score
Considerations for High Risk Populations
High risk populations include men of black ethnicity or men
with a family history of prostate cancer.
• Men of black ethnicity were included in the USA studies,
however, the results are not broken down by risk level
or risk factor. Instead, the studies provide results for the
male population as a whole.
• Therefore, there is currently no trial data to suggest that
men at high risk should be screened differently from
men in the general population.
• Clinicians may wish to discuss the benefits and harms
of screening in men at high risk, with explicit
consideration of their values and preferences.
Screening Smarter:
How to Increase the Benefits and Reduce the Risks
of Screening for Prostate Cancer
• Risk-adjust screening by age and PSA (reduce false
positives)
• Reduce false positive PSA results by repeating (verifing)
positives and by adding additional markers (4 kallikrein
panel or -2(pro)PSA) (reduce indications for biopsy)
• Active surveillance for low-risk cancers (reduce harms
of unnecessary therapy)
• Refer patients who need treatment to high-volume
physicians or centers (reduce harm of necessary
therapy)
Memorial Sloan-Kettering Cancer Center 2010
Guidelines
Risk-adjusted Screening for Prostate Cancer
• Begin PSA testing at age 45
• For men age 45 - 59
• PSA ≥ 3 ng/ml : consider biopsy
• PSA > 1 but < 3 ng/ml : return for PSA every 2-4 years
• PSA <1 ng/ml : return for PSA in 5 years or at age 50 or 60,
whichever comes first
• For men age 60 – 70
• PSA ≥ 3 ng/ml : consider biopsy
• PSA > 1 but < 3 ng/ml : return for PSA every two years
• PSA < 1 ng/ml : no further screening
• For men age 71 or higher
•
No further screening
© Stanley H. Weiss, 2011
Example:
2011-Oct-29
© Stanley H. Weiss, 2011
A Novel Urine Exosome Gene Expression Assay to
Predict High-grade Prostate Cancer at Initial Biopsy
•
we compared the urine exosome gene expression
assay with biopsy outcomes in 499 patients with
prostate-specific antigen (PSA) levels of 2 to20 ng/mL.
• the urine exosome gene expression assay plus SOC
was associated with improved discrimination between
GS7 or greater and GS6 and benign disease: AUC 0.77
(95% CI, 0.71-0.83) vs SOC AUC 0.66 (95% CI, 0.580.72) (P < .001).
• Independent validation in 519 patients Urine exosome
gene expression assay plus SOC AUC 0.73 (95% CI,
0.68-0.77) was superior to SOC AUC 0.63 (95% CI,
0.58-0.68), (P < .001).
JAMA Oncol March 31st, 2016 online
Conclusions
 Prostate Cancer screening using PSA is controversial
with evidence of ?? Reduced mortality.
 Long term follow-up is needed to prove mortality
reduction.
 Harms related to screening, biopsy, treatment and cost
should be considered.
 Guidelines do not encourage routine screening.
Conclusions (continued)
 High Risk Group Screening?????
 Smarter screening??????
 Other screening tests??????
 Risk adjusted models??????