prostate cancer screening

1. SCREENING & EARLY
DETECTION OF CA PROSTATE ..
WHERE ARE WE NOW ?
Presented By: Dr Mohammed A. Al-Saffar

2. Principles of Screening
 Disease should have a high incidence
 Biological behavior and natural history of the disease should be known
 Test should have high sensitivity, specificity, and positive predictive
value
value
 Test should be rapid, inexpensive, noninvasive, and acceptable to
patients
 Acceptable and efficacious method of treatment must exist for patients
diagnosed with disease
 Screening should lower the disease-specific morbidity and increase
survival ?

3. Prostate Cancer
 Lifetime risk of being diagnosed with prostate cancer is
15.3% but risk of dying of prostate cancer is only 2.6%
 Presentation
 Early stages usually asymptomatic
 Most cases detected by serum PSA or abnormal DRE
Campell-walsh 11th Ed

4. How common is prostate cancer?

5. Screening and early detection
 Population or mass screening is defined as the ‘systematic
examination of asymptomatic men (at risk)’ and is usually
initiated by health authorities. In contrast, early detection or
opportunistic testing consists of individual case findings,
which are initiated by the man being tested (patient) and/or
opportunistic testing consists of individual case findings,
which are initiated by the man being tested (patient) and/or
his physician.
 The co-primary objectives of both strategies are:
 reduction in mortality due to PCa;
 at least, a maintained quality of life (QoL) as expressed by QoL-
adjusted gain in life years

6. Prostate Cancer screening
 Most effective method for detection is combined use
of Prostate Specific Antigen (PSA) and Digital Rectal
Exam (DRE)
 ~15% of men with cancer have PSA <4
 PSA and DRE are complementary because they do not
always detect the same cancers

7. Major Risk Factors
 Age
 Incidence rises rapidly after age 50
 Over 60% of new cases diagnosed in men over 65
 Family history
 Family history
 1st degree relative with cancer more than doubles risk
 Brother > father
 Multiple relatives > single relative
 Multiple generations at early age > single generation at older age
 Race
 African-American men are more than twice as likely to die from prostate cancer than
Caucasian men

8. PSA facts
 Discovered in 1970
 Most widely used oncologic biomarker
 ¾ men over 50 have had a PSA
 Member of the human kallikrein family of
glycoproteins
 Produced by the glandular epithelium of the prostate
 Trace amounts in salivary, pancreatic and breast
tissue

9. PSA facts
 Found in semen, urine and blood
 Serine protease that liquefies semen to improve
sperm mobility
sperm mobility
 Found in 3 forms in serum:
 Bound to α-1-antichymotrypsin
 Bound to α-2-macroglobulin
 Free PSA

10. PSA Challenges …..
 No clear cut-point between normal and abnormal PSA . Even PSA cut-off
of 2.0ng/ml miss some prostate cancers. (The Cancer Prevention Trial - 2003)
 Positive predictive value for PSA > 4 ng/ml = 30% (about 1 in 3 men with
Positive predictive value for PSA > 4 ng/ml = 30%
elevated PSA have prostate cancer detected at time of biopsy)
 PPV increases to 45-60% for PSA > 10 ng/ml
 Nearly 75% of cancers detected in the grey zone (PSA 4-10) are organ
confined; potentially curable.
 <50% of prostate cancers organ confined if PSA >10

11. PSA is NOT Perfect
 Poor sensitivity (35–70%), specificity (60–90%) for prostate
cancer
 Sensitivity of biopsy in the screened is 60-80% at best
 The traditional PSA cut-off of 4.0 is no longer an absolute
 The traditional PSA cut-off of 4.0 is no longer an absolute
indication for biopsy
 Other factors that affect PSA:
 Infection/Inflammation/Instrumentation
 Urinary retention
 Ejaculation/Vigorous massage
 Advanced age/Benign enlargement

12. Improving Specificity of PSA
 Repeat PSA before reacting
 PSA Density
 ≥ 0.15 ng/mL/cm3 associated with CaP
PSA velocity
 PSA velocity
 A rate of change > 0.75 ng/mL/yr (4 < PSA < 10)
 A rate of change > 0.35 ng/ml/yr (PSA < 2.5)
 Rates > 2 ng/mL/year have been associated with a quicker time to death from recurrent
disease

13. Improving Specificity of PSA
 Percent free PSA: 25% cutoff: 95% sensitivity & eliminates 20% of unnecessary
biopsies
 < 15% Suspicious for cancer
 > 24% Suggests benign disease
 > 24% Suggests benign disease
 15-24% Grey area
 Age-Specific Thresholds : Age-adjusted PSA
 40 to 49 - 0.0 to 2.5
 50 to 59 - 0.0 to 3.5
 60 to 69 - 0.0 to 4.5
 70 to 79 years - 0.0 to 6.5

14.  PLCO (Prostate, Lung, Colorectal, Ovarian) Cancer Screening Trial
 US trial 76,693 men randomly assigned to annual screen with PSA & DRE or to
“usual care”; median follow-up of 11yrs
 No difference in prostate-specific mortality between the 2 groups
Prostate Cancer Screening
the evidence …..
 No difference in prostate-specific mortality between the 2 groups
 Screening and Prostate Cancer Mortality in a European RCT (ERSPC)
 162,243 men from 7 countries randomized to screening with PSA (q 4yrs) or no
screening; median follow-up of 9yrs
 20% reduction in prostate cancer mortality in the screening arm (p=0.04)
 Goteborg Prostate-Cancer Screening Trial
 20,000 men age 50-69; PSA screen(q 2yrs) or no screen, (1995>2008)
 44% reduction in prostate cancer specific mortality (p=0.002)

15. ERSPC: “The European study”
 Random assignment of men between 50 and
74 in 7 European countries
 83,000 in the screened group; 99,000 in the control
 83,000 in the screened group; 99,000 in the control
 PSA on average once every 4 years in screened cohort
 During the median follow up of 11 years, PCa
diagnosed in 9.6% of the screened group and
6.0% of controls
Schröder FH, NEJM 2012

16. ERSPC findings 2012
• Screened group was 29% less likely to die from CAP
• 1055 men would need to be screened and 37 cases of
prostate cancer treated to prevent 1 death

17. Issues with this Study
 Positive PSA defined as 3.0 ng/ml in most centers
 6-core biopsy used: prostate cancer diagnosis is up
to 20% higher with an extended biopsy scheme (10-
to 20% higher with an extended biopsy scheme (10-
18 cores)
 Localized prostate cancer more common in the
screened group
A definite benefit of avoiding metastatic disease

18. Goteborg Study
 F/U 14 years, decrease risk of death 40%
 227 screened, 12 dx to prevent 1 death

19. PLCO: “The US trial”
 38,000 men each randomly assigned to annual
screening or “usual care”
 Compliance rates for PSA and DRE were 85% and 86%,
respectively
respectively
 Usual care included up to 52% getting annual PSA and 46%
getting yearly DRE
 Follow up was for 7 to 10 years
Andriole GL, NEJM 2009; 360:1310-1319

20. PLCO results 2009
116 vs. 95 incident cases per 10,000 PY in S vs. C
2.0 vs. 1.7 deaths per 10,000 PY in S vs. C

21. Issues with this Study
 High rate of screening in the control group – diluted
results
 Follow up of 7 to 10 years not long enough to
 Follow up of 7 to 10 years not long enough to
realize a mortality advantage from screening
 Using an absolute value of 4.0 ng/ml as a “positive”
PSA may lead to under-diagnosis
 18% fewer Gleason 8-10 prostate cancers in the
screening group

22. US Preventive Services Task Force
‘USPSTF’ Considerations
 Reason for USPSTF investigation: Likely over-diagnosis and over-treatment
of prostate cancer.
 In 2012 the USPSTF recommended against PSA screening on the grounds
that there is no net benefit and that the potential harms outweigh the
that there is no net benefit and that the potential harms outweigh the
benefits. Grade D
 The harms identified by USPSTF are overestimated and relate more to
treatment than screening.
 Not all prostate cancers require treatment. The patient is entitled to know
whether he has prostate cancer and be allowed to decide if he desires
treatment. A recommendation against screening deprives him of that
autonomy.

23. Impact of the United States Preventive Services Task Force 'D'
recommendation on prostate cancer screening and staging
 Recent findings: Following the USPSTF recommendation, a substantial
decline in PSA screening was noted for all age groups. Similarly, overall
rates of prostate biopsy and prostate cancer incidence have significantly
decreased with a shift toward higher grade and stage disease upon
decreased with a shift toward higher grade and stage disease upon
diagnosis.
 Concurrently, the incidence of metastatic prostate cancer has significantly
risen in the United States. These trends are concerning particularly for
the younger men with occult high-grade disease who are expected to
benefit the most from early detection and definitive prostate cancer
treatment.

24. 2017 USPSTF Screening Update
 The decision about whether to be screened for prostate cancer should be an individual one.
 The USPSTF recommends that clinicians inform men ages 55 to 69 years about the potential
benefits and harms of prostate-specific antigen (PSA)–based screening for prostate cancer.
 Screening offers a small potential benefit of reducing the chance of dying of prostate cancer.
However, many men will experience potential harms of screening, including false-positive
However, many men will experience potential harms of screening, including false-positive
results that require additional workup, over-diagnosis and overtreatment, and
treatment complications such as incontinence and impotence.
 The USPSTF recommends individualized decision-making about screening for prostate
cancer after discussion with a clinician, so that each man has an opportunity to understand
the potential benefits and harms of screening and to incorporate his values and preferences
into his decision.
 Recommendation Grade C (Offer or provide this service for selected patients depending on
individual circumstances)

25. 2017 USPSTF Screening Update
 Men age 70 and older
 The USPSTF recommends against PSA-based screening for
prostate cancer in men age 70 years and older.
prostate cancer in men age 70 years and older.
 Recommendation Grade D (Discourage the use of this
service)

27. Screening for Prostate Cancer:
CTF Recommendations
27
 For men aged less than 55 years, we recommend not
screening for prostate cancer with the prostate-specific
antigen test. (Strong; low quality evidence)
 For men aged 55–69 years, we recommend not screening
 For men aged 55–69 years, we recommend not screening
for prostate cancer with the prostate-specific antigen test.
(Weak; moderate quality evidence)
 For men 70 years of age and older, we recommend not
screening for prostate cancer with the prostate-specific
antigen test. (Strong; low quality evidence)
Canadian Task Force, 2014

28. EAU 2018
 Cochrane review published in 2013 , which has been updated since presents the main
overview of the date. The findings of the updated publication (based on a literature search
until April 3, 2013) are almost identical to the 2009 review:
 Screening is associated with an increased diagnosis of PCa (RR: 1.3; 95% CI: 1.02-1.65).
 Screening is associated with detection of more localised disease (RR: 1.79; 95% CI: 1.19-2.70) and
less advanced PCa (T3-4, N1, M1) (RR: 0.80; 95% CI: 0.73-0.87).
less advanced PCa (T3-4, N1, M1) (RR: 0.80; 95% CI: 0.73-0.87).
 From the results of five RCTs, randomising more than 341,000 men, no PCa-specific survival benefit
was observed (RR: 1.00; 95% CI: 0.86-1.17). This was the main endpoint in all trials.
 From the results of four available RCTs, no overall survival (OS) benefit was observed (RR: 1.00;
95% CI: 0.96-1.03).
 Moreover, screening was associated with minor and major harms such as over-diagnosis and
over-treatment.
 Surprisingly, the diagnostic tool (i.e. biopsy) was not associated with any mortality in the
selected papers

29.  The reduced mortality rate seen recently in the USA is
considered to be partly due to a widely adopted
aggressive PCa screening policy. However, there is still
aggressive PCa screening policy. However, there is still
no level 1 evidence that PSA mass screening is cost-
effective in reducing PCa mortality
 Currently, screening for PCa is one of the most
controversial topics in the urological literature

30. GR
LE
2018 EUA Recommendations for screening and early Detection
B
3
Do not subject men to prostate-specific antigen (PSA) testing without counseling them on the
potential risks and benefits.
B
3
Offer an individualized risk-adapted strategy for early detection to a well-informed man with a
good performance status and a life-expectancy of at least ten to fifteen years.
A
2b
Offer early PSA testing in well-informed men at elevated risk of having PCa:
• men > 50 years of age;
• men > 45 years of age and a family history of PCa;
• African-Americans > 45 years of age;
• African-Americans > 45 years of age;
• men with a PSA level of > 1 ng/mL at 40 years of age;
• men with a PSA level of > 2 ng/mL at 60 years of age.
C
3
Offer a risk-adapted strategy (based on initial PSA level), with follow-up intervals of two years
for those initially at risk:
• men with a PSA level of > 1 ng/mL at 40 years of age;
• men with a PSA level of > 2 ng/mL at 60 years of age;
Postpone follow-up to eight years in those not at risk.
C
3
Decide on the age at which early diagnosis of PCa should be stopped based on life expectancy
and performance status; men who have a life-expectancy of < 15-years are unlikely to benefit.

31. Biomarkers

32.  Developed an algorithm to
combine serum PSA and
urine TMPRSS2:ERG fusion
urine TMPRSS2:ERG fusion
and PCA3 to predict prostate
cancer on subsequent biopsy
 Improved cancer prediction
(AUC=0.88; specificity 90%;
sensitivity 80%)

33. Imaging

34. Multi-parametric Prostate MRI
 Technique and sequences are crucial – 3 phases obtained
1. T2: peripheral zone exhibits high signal intensity
• Peripheral zone cancers have low T2 signal intensity – the lower the intensity the higher grade the
disease
• Cancer more difficult to discern in the transition zone due to signal heterogeneity in this region
2. Diffusion weighted MR measures random motion of water molecules – DWI can help
identify high-risk disease
3. Dynamic contrast enhanced (gadolinium) MR allows evaluation of contrast kinetics –
cancer enhances quickly, more intensely and with a faster washout
MP-MRI sensitivity is 80% for detecting 0.2cm3 disease ≥ Gleason 4+3 or 0.5cm3 Gleason
3+4.

35.  170 patients with negative biopsy but persistent suspicion of prostate
cancer
 Blinded standard systematic prostate biopsy performed
 Blinded standard systematic prostate biopsy performed
 Receiver Operating Characteristic (ROC) analysis showed that MP-
MRI contributed most to the prediction model (AUC 0.936)
 MP-MRI only significant independent predictor of prostate cancer
diagnosis
 Can a MP-MRI without lesion negate the need for repeat prostate
biopsy?

36. Prostate Biopsy

37. Prostate Biopsy
 > 1.2 million prostate biopsies are performed yearly
in the US
 Elevated PSA most frequently triggers biopsy
 Elevated PSA most frequently triggers biopsy
 30% of men referred for biopsy are diagnosed with
prostate cancer
 Relies on random sampling

38. Shortcomings of Standard Systematic Prostate
Biopsy
 False-negative rate
 Incorrect risk stratification (up to 45%)
 Detection of clinically insignificant disease
 Need for repeat biopsy
Need for repeat biopsy
 Disease overtreatment
Increasing the core number (saturation or repeat biopsy) does not significantly
reduce the risk of under sampling and incorrect risk stratification
More biopsy episodes increases the risk of detecting indolent cancers
Goal: Detect high-grade disease while avoiding low risk disease

40.  Patients with low,
intermediate and high
suspicion lesions had
cancer diagnosed 28%,
67% and 90% of the time
 Fusion biopsy detected
more cancer per core than
12-core biopsy

41.  195 men with previous negative biopsy with targets on
MP-MRI underwent MR/US fusion and 12-core biopsy
 37% were found to have cancer
 11% had high-grade (Gleason 8+) – 55% of these were
missed with standard biopsy
 39% were upgraded on fusion biopsy vs standard biopsy

44. HomeMessage
 Offer PCa screening on individual basis according to risks.
 Not all prostate cancers require treatment. The patient is entitled to know whether
he has prostate cancer and be allowed to decide if he desires treatment
 Prostate cancer screening is worthwhile, as evidenced by negative repercussions of
 Prostate cancer screening is worthwhile, as evidenced by negative repercussions of
the USPSTF recommendations
 Prostate cancer screening should include PSA and DRE.
 Obtain a confirmatory test prior to proceeding with biopsy to help refine risk
 Serious prostate biopsy complications are very rare and should not discourage
screening.
 Obtain MRI to help improve the yield of biopsy
 Promote active surveillance as front line treatment in appropriate patients

45. THANK
YOU
YOU