Screening for carcinoma prostate

Subject seminar
Topic: Screening of Carcinoma
Prostate
Chair person: Prof. C. S. Ratkal
Co chair person: Dr. M. Shivalingaiah
Presenter: Dr. Prakash. H. S.

Screening
 Definition - the search for unrecognized
disease or defect by means of rapidly applied
tests, examinations or other procedures in
apparently healthy individuals
 Three types of screening have been described
a. Mass screening ( population screening)
b. High risk or selective screening
c. Multiphasic screening

Population screening
 Is where a test is offered to all individuals in a
target group, usually defined by age, as part of
an organized programme
 Have to be high standard.
 Services are checked and monitored by
people from outside the programme.
 Everyone who takes part is offered the same
services, information and support.
 Large numbers of people are invited to take
part

Requirements for a population
screening program
 The screening program should provide more
benefit than harm to the people being
screened.
 The condition should
– be an important health problem.
– have a recognisable latent or early asymptomatic
stage.

The screening test should -
 Find the early stages of the disease (be highly
sensitive)
 Very accurate in finding the early stages of
disease (be highly specific)
 Provide consistent results from the test (be
validated)
 Safe.
 Find most disease present at the time of the
screening test (have a relatively high positive
predictive value)
 Normal when there is no disease present (have
a relatively high negative predictive value )

True positive & True negative
 True positives = number of individuals with
disease and a positive screening test (a)
 False positives = number of individuals
without disease but have a positive
screening test (b)
 False negatives = number of individuals
with disease but have a negative
screening test (c)
 True negatives = number of individuals
without disease and a negative screening

Sensitivity & Specificity
 Sensitivity is defined as the ability of the test to
detect all those with disease in the screened
population
 Specificity is defined as the ability of the
test to identify correctly those free of
disease in the screened population

PPV AND NPV…
 The positive predictive value (PPV) describes
the probability of having the disease given a
positive screening test result in the screened
population (The proportion of patients who test
positive who actually have the disease)
 The negative predictive value (NPV) describes
the probability of not having the disease given
a negative screening test result in the
screened population (The proportion of
patients who test negative who are actually
free of the disease)

The screening test should be
 Minimally invasive,
 Easily available and performed,
 Acceptable to the general population,
 Cost effective
 Significantly affect the outcome of the
disease, such as quality of life and mortality.

Population screening is associated
with 3 biases
 Detection bias – (Overdiagnosis ) refers to
identification of disease in patients in whom it
would have never become symptomatic during
their lifetime
 Lead-time bias - refers to earlier diagnosis but no
effect on mortality. It gives the appearance of
longer survival because of earlier detection with
no overall improvement in life expectancy
 Length bias - Detects less aggressive disease
due to the longer interval before it becomes
symptomatic

Epidemiology of Carcinoma
prostate
 Prostate cancer is the fifth most common
malignancy worldwide and the second most
common in men
 Makes up 11.7% of new cancer cases overall
(19% in developed countries & 5.3% in
developing countries)
 Incidence varies widely between countries and
ethnic populations (more than 100-fold)
 Lowest yearly incidence rates in Asia (1.9) &
highest in North America ( 249 per 100,000)

prostate…
 Mortality also varies widely among countries
highest in the Caribbean (28 per 100,000 per
year) & lowest in Southeast Asia, China, and
North Africa (<5 per 100,000 per year)
 Prostate cancer is rarely diagnosed in men
younger than 50 years old, accounting for only
2% of all cases
 The median age at diagnosis is 68 years, with
63% diagnosed after age 65

prostate…
 Incidence of prostate cancer in men 50 to 59
years of age has increased by 50% between
1989 &1992 due to PSA testing (age
migration)
 Also incidence of loco-regional disease has
increased, whereas the incidence of
metastatic disease has decreased (stage
migration)

Carcinoma prostate in United
States
 Is the most common visceral malignancy in
men.
 Is the second leading cause of cancer-related
deaths.
 The estimated lifetime risk of disease is
16.72%, with a lifetime risk of death at 2.57%.
 Incidence peaked in 1992 approximately 5
years after the introduction of PSA as a
screening test, declined until
1995, subsequently increased at a rate similar
to that observed in the pre-PSA era, and is
declining again in recent years

Carcinoma prostate in United
States…
 Mortality has declined since 1991 and for
whites is now lower than before PSA was
introduced
Data from American Cancer Society. Cancer facts and figures 2008

India versus United States
Age adjusted incidences (per 100,000 person
years) of prostate cancer
Countries
1973-1977 1988-1992
% change
1977-1992
2002
Total
Incidenc
e
Total Incidence Incidence
US black 2664 79.9 7129 137 71.5
US total
124.8
US white 24192 47.9 66,227 100.8 110.4
India 193 6.8 764 7.9 16.2 4.6

Screening for Carcinoma
prostate
 Two types
- Population screening
- Early detection or opportunistic screening
 Early detection or opportunistic screening
comprises individual case findings, which are
initiated by the person being screened
(patient) and/or his physician.
- Screening may not be checked or
monitored

Primary endpoint of both types of
screening
 Has two aspects:
o Reduction in mortality
o Improvement in the quality of life as
expressed by quality-of-life adjusted
gain in life years (QUALYs).

The goals of population screening
for carcinoma prostate
Fall into three categories
 Reduction of prostate cancer mortality
 Reduction of morbidity associated with
prostate cancer
 Reduction of financial costs associated with
symptomatic prostate cancer

Modalities of Screening
 DRE
 PSA
 Prostate Biopsy
 Transrectal Ultrasound
 Magnetic Resonance Imaging

Modalities of Screening…
 The combination of DRE and serum PSA is
the most useful first-line screening test
 Prostate Biopsy is not recommended as a first-
line screening test because of low predictive
value for early prostate cancer and high cost of
examination
 TRUS has poor sensitivity (71%) & specificity
(50%)
 MRI also has poor sensitivity ( 57%) as
screening modality in Ca prostate

Digital Rectal Examination
 Before the availability of PSA, physicians
relied solely on DRE for early detection of
prostate cancer
 Has fair reproducibility
 Misses a substantial proportion of early
cancers
 PSA improves the positive predictive value of
DRE for cancer (tests are complementary and
are recommended in combination)
 DRE and PSA do not always detect the same
cancers

Digital Rectal Examination…
 The optimal role of the DRE for the early
detection of prostate cancer is unclear
 DRE performed poorest at the PSA levels at
which it was needed the most. the sensitivity
and PPV of the DRE were only 20% and 8.8%,
respectively, in men who had PSA values 3.0
ng/mL.
 With PSA values below 4.0ng/mL - only 17%
of prostate cancers were diagnosed by DRE
alone.

DRE Limitations are
 First, the sensitivity and specificity of the DRE depend
on the examiner.
 Second, although some cases are detectable in men
with low PSA levels, the lethal potential of these cancers
is uncertain
 Third, DRE may be a barrier to screening for some men.
 Finally, the capacity to detect clinically important
prostate cancers by DRE depends on the PSA
threshold used to perform a prostate biopsy.
• The lower the biopsy threshold, the less likely that DRE
will detect important prostate cancers that would be
missed by PSA.
• Conversely, as the threshold is raised, the potential
value of the DRE goes up.

Trans rectal Ultrasound
 Limitations of TRUS in prostate cancer detection
are
• Most hypoechoic lesions found on TRUS are
not cancer
• 50% of nonpalpable cancers more than 1 cm in
greatest dimension are not visualized by
ultrasonography
 Therefore, any patient with a DRE suspicious for
cancer or a PSA elevation should undergo
prostate biopsy regardless of TRUS findings if
an early diagnosis of cancer would result in a
recommendation for treatment

Trans rectal Ultrasound…
 The performance characteristics of TRUS in
populations with low prevalence of prostate
cancer are not conducive to its use for
screening.
 TRUS is an invasive test that also suffers from
operator dependent variability.
 Various modifications such as power Doppler
TRUS have not attained significant
improvement in sensitivity to justify its use as a
screening tool

Screening by PSA
 Most widely used modality for population
screening of Prostate cancer
 Approved as serum tumor marker in 1986 by
FDA
 American Cancer Society from early 1990s
advocated screening by PSA testing
 PSA is prostate specific and not cancer
specific
 Specificity improves at higher PSA thresholds
while sensitivity declines significantly

Prostate-Specific Antigen (PSA)
 PSA is a 33-kD glycoprotein, produced by the
prostatic luminal epithelial cells.
 PSA is secreted in high concentrations (0.5-
5.0 mg/mL) into seminal fluid, where it is
involved in liquefaction of the seminal
coagulum
 Found in low concentration in serum (1.0-4.0
ng/mL).
 Circulates in bound (complexed) and unbound
(free) forms - measured by assays

Arguments for screening by
PSA
 Men who had PSA testing had a 20 percent
lower chance of dying from prostate cancer
after nine years, compared to men who did not
have prostate cancer screening
 Substantial number of men die from prostate
cancer every year and many more suffer from
the complications of advanced disease
 For men with an aggressive prostate
cancer, the best chance for curing it is by
finding it at an early stage and then treating it
with surgery or radiation

Arguments for screening….
 The five-year survival for men who have
prostate cancer confined to the prostate gland
(early stage) is nearly 100 percent; this drops
to 30 percent for men whose cancer has
spread to other areas of the body.
 The available screening tests are not
perfect, but they are easy to perform and are
fairly accurate.

 Screening decreases the burden of distant-
stage disease (Stage migration)
 US Surveillance, Epidemiology and End
results (SEER) data shows incidence rates for
stage T3–4 prostate cancer were 55.5 per
100,000 in 1988–1989, 44.6 per 100,000 in
1996–1997, and decreased to 8.4 per 100,000
in 2004–2005
 PSA screening seemed to account for 80% of
the observed drop in distant-stage disease.

 Grade migration in the PSA era has generated
considerable controversy
 Incidence of Gleason score 8–10 prostate
cancer on biopsy has decreased from 47.5 per
100,000 in 1988–1989 to 38.3 per 100,000 in
2004–2005
 Screening finds lower grade cancers than
would be found in the absence of
screening, but when cancers are found they
are assigned a higher Gleason score than they
would have received in the pre-PSA era

Arguments against screening
 Only one man in every 1400 benefited from
PSA testing
 75 percent of men with an abnormal PSA who
had a prostate biopsy did not have prostate
cancer
 A large American study did not find that
prostate cancer screening reduced the chance
of dying from prostate cancer
 Many prostate cancers detected with
screening are unlikely to cause death or
disability

Arguments against screening…
 Population screening initiatives carry a
significant risk of overdiagnosis
 Overdiagnosis refers to identification of latent
disease that would not have otherwise caused
symptoms or been identified during the
patient‘s lifetime (In US it is upto 23% to 42%)
 Overtreatment leads to unnecessary costs to
the health care system, and significant
morbidity and possible mortality to some
patients exposed to curative treatment

 Earlier detection of prostate cancer introduces
the problem of detection and treatment of
indolent tumors
 Indolent tumors are generally defined as small
tumors (<0.5 cm3), that are well differentiated
(Gleason grade 1 or 2) or noninvasive, and
lack the propensity to penetrate beyond the
prostatic capsule
 Up to 30% of all cases of PSA-detected (stage
T1c) prostate cancer are indolent tumors

 Most patients experience some deterioration in
the QOL as measured by sexual function,
urinary incontinence, urinary irritation or
obstruction, bowel or rectal function, and
vitality
 Considering the morbidity of treatment as
evidenced by deterioration of QOL for patients
and their spouses and the significant
overtreatment associated with prostate cancer,
the overall benefit of PSA screening is
uncertain

Pros and Cons of PSA
screening
Pros Cons
Stage migration: more
localized disease, and less
advanced/metastatic
disease
Incidence of indolent tumors
Earlier at diagnosis Problems associated with
overdiagnosis and treatment
Lower PSA at diagnosis Lead-time and length-time
biases in survival rates in
PSA era
Improved survival in the
PSA era
Ideal PSA cut off for
screening unknown

Effect on mortality
 From 1993 to 2003 after the onset of
widespread PSA testing, the mortality rate
from prostate cancer declined by 32.5%
(Surveillance, Epidemiology, and End Results
[SEER] Program), along with a 75% reduction
in the proportion of advanced-stage disease at
diagnosis
 PSA screening is accounted for 45% to 70% of
this reduction in prostate cancer mortality in
the United States

Factors Influencing PSA
 PSA levels vary with age, race & prostate
volume
 Blacks without prostate cancer have higher
PSA values than whites
 PSA increases 4% per milliliter of prostate
volume
 30% and 5% of the variance in PSA can be
accounted for by prostate volume and
age, respectively
 PSA expression is strongly influenced by
androgens

Factors Influencing PSA…
 The presence of prostate disease (prostate
cancer, benign prostatic hyperplasia
[BPH], and prostatitis) is the most important
factor affecting serum PSA levels
 Not all men with prostate disease have
elevated PSA levels, and PSA elevations are
not specific for cancer
 PSA elevations occur from disruption of the
normal prostatic architecture, allowing PSA to
gain access to the circulation

 PSA is elevated in the setting of prostate
disease (BPH, prostatitis, prostate cancer) and
with prostate manipulation (e.g., prostate
massage, prostate biopsy, transurethral
resection)
 DRE can lead to slight increases in serum
PSA, the resultant change in PSA falls within
the error of the assay and rarely causes false-
positive tests

 Prostate-directed treatments (for BPH or
prostate cancer) can lower serum PSA by
decreasing the volume of prostatic epithelium
available for PSA production and by
decreasing the amount of PSA produced per
cell
 5α-Reductase inhibitors that are used for BPH
treatment have been shown to lower PSA
levels, including both type 2 isoenzyme
inhibitors (finasteride) and dual type 1 and 2
isoenzyme inhibitors (dutasteride)

 Prostate cancer treatments (medical or
surgical), such as manipulation of the
hormonal axis (e.g., luteinizing hormone
releasing hormone (LHRH) agonists,
orchiectomy), radiation therapy, and radical
prostatectomy lead to reductions in PSA
 The interpretation of PSA values should
always take into account age, the presence of
urinary tract infection or prostate disease,
recent diagnostic procedures, and prostate-
directed treatments

Clinical use of PSA
Distribution(%) of PSA levels in men age 50
years and older in an invitational screening
study

Clinical use of PSA…
 Measurement of free and complexed PSA by
assays is referred to as the serum PSA level
 Use of PSA increases the detection of prostate
cancers that are more likely to be organ-
confined when compared with detection
without PSA
 Observational studies and randomized trials
have shown that both the future risk of
prostate cancer and the chance of finding
cancer on a prostate biopsy increase
incrementally with the serum PSA level

Relative Risk of Subsequent Prostate Cancer
Diagnosis after an Initial Baseline PSA

 PSA is directly associated with the present risk
of prostate cancer
 Predicts the future risk
 The probability of detecting prostate cancer on
biopsy increases directly with PSA across the
full spectrum of PSA levels
 When a PSA cutoff of 4 ng/mL and an
abnormal DRE were used together as
screening criteria for prostate
cancer, pathologically organ-confined disease
was found in 71% of men who underwent
surgery for prostate cancer

 When DRE and PSA are used as screening
tests for prostate cancer detection, detection
rates are higher with PSA than with DRE and
highest with a combination of the two tests
 This is because
o They do not always detect the same cancers
o The tests are complementary
o And are therefore recommended in
combination

PSA increases lead time
 With the widespread use of PSA, a stage shift
favouring localized disease occurred because
PSA increases the lead time for prostate
cancer detection
 Lead time is the time by which the diagnosis of
prostate cancer is advanced by screening
 Estimates of lead time based on screened
populations, are in the range of 10 years

PSA limitations
 It is organ specific and not disease specific
 There is an overlap in the serum PSA levels
among men with cancer and those with benign
disease
 Because PSA elevations are associated with
both false-negative and false-positive results,
a great deal of effort has been devoted to
improving the performance characteristics of
the test

Approaches for Improving PSA
Test Performance
 The use of PSA thresholds depending on age
and ethnicity
 The PSA density and PSA transition zone
volume index
 PSA velocity

PSA threshold for prostate
biopsy
 Data from the PCPT clearly show that the risk
of prostate cancer is continuous as PSA
increases
 The use of higher PSA thresholds risks
missing important cancers during the window
for cure, whereas the use of lower thresholds
increases the proportion of unnecessary
biopsies & overdiagnosis
 Many clinicians now use lower thresholds (2.5
to 3 ng/mL) to do a biopsy

PSA threshold…
 PSA cutoff -
o 4.0 ng/mL for men age 50 to 70 years (the
target population for screening at present) &
o 2.5 ng/mL for men age 40 to 50 years has
sensitivity of 95%
 The use of a PSA threshold of 4.0 ng/mL for
men older than 50 years has been accepted
by most clinicians as striking a reasonable
balance

PSA threshold…
 Regardless of the threshold chosen, an
isolated PSA elevation should be
remeasured before performing a prostate
biopsy because of fluctuations in PSA that
could represent a false-positive elevation
in the test

Volume Based PSA parameters
 Distinguishing between men who have PSA
elevations driven by BPH or cancer is difficult
because PSA is not specific for cancer and the
prevalence of BPH in the population is high
compared with prostate cancer

Volume Based PSA
parameters…
 Volume-based PSA parameters (with prostate
volume determined by ultra-sonography)
includes
o PSA density (PSA divided by prostate volume),
o complexed PSA density (complexed PSA
divided by prostate volume), and
o PSA transition zone index (PSA divided by
transition zone volume)- have been evaluated
as methods for excluding men with PSA
elevations related to BPH

Volume Based PSA
parameters…
 PSA density of 0.15 or greater was proposed
as a threshold for recommending prostate
biopsy in men with PSA levels between 4 and
10 ng/mL and no suspicion of cancer on DRE
or TRUS
 The major determinant of serum PSA in men
without prostate cancer is the transition zone
epithelium

Volume Based PSA
parameters…
 Because BPH represents an enlargement of
the transition zone, adjusting PSA for transition
zone volume has been evaluated as a method
to help distinguish between BPH and prostate
cancer
 Recommended cutoffs of 0.23 ng/mL/cm3
when transition zone volume was above 20
cm3 and 0.38 ng/mL/cm3 when transition zone
volume was below 20 cm3 as a threshold
above which prostate cancer was more likely

PSA velocity
 Substantial changes or variability in serum
PSA can occur between measurements in the
presence or absence of prostate cancer
 The changes in serum PSA can be adjusted
(corrected) for the elapsed time between the
measurements, a concept known as PSA
velocity or rate of change in PSA

PSA velocity - Baltimore Longitudinal
Study of Aging (BLSA) -1992 by Carter
 There was a gradual and slow increase in PSA
over time in most men.
 PSA increased more rapidly among men with
prostate cancer
 The rate of increase was the greatest, in men
with the most aggressive tumors
 A rate of increase in PSA 0.75 ng/mL per year
was associated with a higher risk of prostate
cancer

PSA velocity…
 The minimal length of follow-up—time over
which changes in PSA should be adjusted—for
PSA velocity to be useful in cancer detection
has been calculated in separate studies to be
18 months
 Evaluation of three repeated PSA
measurements, to determine an average rate
of change in PSA, would appear to optimize
the accuracy of PSA velocity for cancer
detection

Free PSA
 Men with prostate cancer have a -
o Greater fraction of serum PSA that is
complexed to protease inhibitors
o Lower percentage of total PSA that is free
 A free/total PSA cutoff of 0.18 (18% free/total
PSA) significantly improved the ability to
distinguish between cancer and noncancer
subjects as compared with use of total PSA
alone

Complexed PSA
 There is general agreement that at high
sensitivity, complex PSA provides
• Higher specificity compared with total PSA and
• Comparable specificity to the percentage of
free PSA in prostate cancer detection.
 The potential advantage of complex PSA as a
screening modality is the requirement for one
assay

pPSA & truncated pPSA
 PSA is secreted from the prostatic luminal
epithelium in a precursor or zymogen form
(pPSA or proPSA) with a 7-amino-acid leader
sequence and then either -
o Cleaved by hK2 to active free PSA or
o Partially cleaved into isoforms of free PSA
with 2- or 4-amino-acid leader sequences

pPSA & truncated pPSA…
 The native form of pPSA and the truncated or
clipped forms of pPSA are elevated in the
tissue and blood of patients with prostate
cancer compared with those without the
disease.
 These novel markers have the potential to
improve the accurate identification of men with
cancer and the identification of those with
more aggressive disease

Summary - Improving PSA test
performance
 PSA-D > 0.15 ng/mL/cc3 considered
suspicious for Carcinoma prostate
 Cutoff of 0.23ng/ml/cm3 when transition zone
above 20cm3 & 0.38ng/ml/cm3 when below
20cm3
 PSA-V >0.75ng/mL per year – seen in
Carcinoma
 Proportion of ―complexed‖ PSA (PSA-ACT) to
―free‖ PSA (F-PSA) is higher in Carcinoma
Prostate patients ( free/total PSA cutoff of
0.18)

hK2.
 hK2 is a closely related serine protease in the
PSA/kallikrein gene family that has also been
evaluated for prostate cancer detection
 Expression of hK2 is higher in more poorly
differentiated cancer tissues than in normal
and benign tissues
 hK2 does appear to correlate directly with
grade and cancer volume and could be useful
in patient assessment after diagnosis

Prostate cancer gene 3 (PCA-3)
 PCA-3 is a noncoding prostate-specific mRNA
overexpressed in prostate cancer tissue
compared with benign tissue
 Urine assays have been developed to
measure PCA-3 mRNA, which is associated
with the likelihood of a positive initial or repeat
prostate biopsy

Future of biomarkers
 In the future, it is likely that panels of
biomarkers will be used in combination with
standard measures of risk (age, family
history, race) to selectively identify men who
should undergo further evaluation for the
presence of prostate cancer

Randomized trails
Two large-scale randomized trials are -
 The Prostate, Lung, Colorectal, and Ovary
(PLCO) cancer trial of the National Cancer
Institute (NCI)
 The European Randomized Screening for
Prostate Cancer (ERSPC) trial

Other RCT‘s are
 Prostate cancer prevention trail (PCPT)
 Norrkoping trial (with 20 years follow up)
 Quebec trial (with 11 years follow up)
 Stockholm trial (with 15 years follow up)

Randomized trails…
 Designed to evaluate the effectiveness of
screening for prostate cancer by comparing
individuals assigned to a screened arm with
those in a control arm who are not screened
 Both the PLCO and ERSPC have a common
endpoint - ‗prostate cancer specific mortality‘
for assessing effectiveness of screening

PLCO
• Inclusion criteria
– Age 55–74 (76,693)
– Multi-institutional trial (across 10 study centres in
USA)
• Exclusion criteria
– History of prostate, lung, colon or ovarian cancer
– More than 1 PSA test in the previous 3 year

PLCO – Study design
 Enrollment 1993–2001
 Annual PSA for 6 years; DRE for 4 years -
intervention arm
 Community standard of care or no screening for
control group
 PSA >4 ng/mL- cutoff value
 Primary care physicians notified of the screening
test (PSA and DRE) results
 Management based on community standard of
care. No protocol for biopsy or treatment of
prostate cancer -community standard of care

PLCO - Results
 The incidence of prostate cancer per 10,000
person-years was 116 (2,820 cancers) in the
screening group & 95 (2,322 cancers) in the
control group
 No reduction in incidence of advanced cancer
 The incidence of death attributed to prostate
cancer per 10,000 person-years was 2.0 (50
deaths) in the screening group and 1.7 (44
deaths) in the control group
 No difference in survival between screened
and non-screened arms at 7–10 years

PLCO - Limitations
 Rate of compliance in the screening arm was
85% for PSA testing and 86% for DRE.
 Rate of contamination in the control arm was
as high as 40% in the first year and increased
to 52% in the sixth year for PSA testing &
ranged from 41% to 46% for DRE
 Biopsy compliance was only 40-52% versus
86% in the ERSPC.
 Thus, the PLCO trial will probably never be
able to answer whether or not screening can
influence prostate cancer mortality

ERSPC
 Inclusion criteria
– Age 55–69 yrs (162243)
– Collection of 7 European trials with different
screening protocols, different ages of entry,
controls (Across 9 countries - Netherlands, Belgium,
Sweden, Finland, Italy, Spain, Switzerland, Portugal &
France)
 Exclusion criteria
– History of prostate cancer

ERSPC - Study design
 Enrollment 1991–2003
 PSA screening once every 4 years -
intervention arm
 Control - no screening
 PSA >3 ng/mL cutoff value
 No protocol for treatment of prostate cancer -
community standard of care

ERSPC - Results
 20% reduction in prostate cancer specific death in
the screened group at 9 years of follow-up. No
overall survival difference between the screened
& control
 Reduction in incidence of advanced cancer by
screening
 1410 men screened and 48 men treated to
prevent 1 mortality from prostate cancer
 False-positive PSA accounted for 75.9% of
biopsies. PPV of biopsy was 24.1%
 8.2% in the screening group and 4.8% in control

ERSPC - Limitations
 Suboptimal treatment with low dose RT
 Screened men were 2.77 times more likely to
undergo RP vs controls
 No information on possible control group
contamination.
 Possible differences in management protocols
between groups make it difficult to separate
benefit from screening vs subsequent
management

ERSPC - Benefit
 Real benefit will only be evident after 10-15
years of follow-up, especially because the
41% reduction of metastasis in the screening
arm will have an impact
 With longer follow-up, the Goteborg
randomized population-based screening trial
reported a greater mortality benefit with
screening

PLCO versus ERSPC
 PLCO compares PSA screening in a
community practice setting versus an
organized screening program
 ERSPC investigates the use of PSA screening
in a best practice model (no screening versus
screening)
 PLCO study shows that more versus less
screening makes little difference to
mortality, whereas the ERSPC shows that
screening versus not screening reduces
prostate cancer mortality, albeit with a potential
risk of overdiagnosis

Prostate Cancer Prevention Trial (
PCPT)
 Only trial that conducted a prostate biopsy for
all participants at the end of the trial period and
allows the reporting of true sensitivity of PSA
at different cutoff values
 114 Men who had PSA levels 3.0 ng/mL and
normal DRE results were included at baseline
 The men underwent annual PSA and DRE and
were recommended for a prostate biopsy if the
PSA level was above 4.0 ng/mL or if their DRE
was abnormal

PCPT)
 At the end of the 7-year follow-up period, all
men without a diagnosis of prostate cancer
underwent a prostate biopsy
 Relatively low prostate cancer detection
sensitivities of 20.5% and 32.2% were
reported for PSA cutoff values of 4.0 ng/mL
and 3.0 ng/mL, respectively
 However, the sensitivity of PSA for aggressive
prostate cancer (Gleason grade8 or higher)
was greater (51% and 68% for PSA values 4.0
ng/mL and 3.0 ng/mL, respectively)

PCPT)

PCPT…
 Lowering the PSA test cutoff to 3.0 ng/mL -
results in higher estimates for test positivity
and prostate cancer detection rates but at a
cost of lower specificity and PPV
 Resulting in increases in false-positive screen
results, prostate biopsies, and diagnosis of
cancers that would never have become
important clinically if they were left undetected

GUIDELINES FOR EARLY DETECTION
OF PROSTATE CANCER
 Detection guidelines determine the burden of
screening of the population in terms of
• Unnecessary tests,
• False-positive tests
• Downstream effects of false-positive testing

GUIDELINES FOR EARLY DETECTION
OF PROSTATE CANCER…
 The age at which screening should begin
 Rescreening intervals
 The age at which screening should be
discontinued are important in designing a cost-
effective screening strategy

U.S. Preventive Services Task
Force
 Routine screening for prostate cancer using
PSA testing or digital rectal examination (DRE)
was not recommended for men over 75 and
that the evidence was insufficient to
recommend for or against screening for men
under 75 years old

National Comprehensive Cancer Network
(NCCN)
 Baseline PSA test and DRE at ages 40 and 45
 Annual PSA testing and DRE beginning at age
50 through age 80, along with information on
the risks and benefits of screening
 At age 40 for African-American men, men with
a family history of prostate cancer & men with
a PSA ≥ 0.6 ng/mL (at age 45 if PSA <
0.6 ng/mL)

NCCN…
 Biopsy is recommended
- if DRE is positive or PSA ≥ 4 ng/mL
 Biopsy considered
- if PSA > 2.5 ng/mL
- or PSA velocity ≥ 0.35 ng/mL/year when
PSA ≤ 2.5 ng/mL

AUA
 PSA test should be offered to well-informed
men aged 40 yrs or older who have a life
expectancy of at least 10 yrs
 AUA does not recommend a single PSA
threshold at which a biopsy should be
obtained.
 The decision to biopsy should take into
account additional factors, including free and
total PSA, PSA velocity and density, patient
age, family history, race/ethnicity, previous
biopsy history and co-morbidities

EUA
 A baseline PSA determination at age 40 years
has been suggested upon which the
subsequent screening interval may then be
based
 A screening interval of 8 years might be
enough in men with initial PSA levels ≤ 1
ng/mL
 PSA testing is not necessary in men older
than 75 years and a baseline PSA ≤ 3 ng/mL
because of their very low risk of dying from
prostatic carcinoma

American Cancer Society
(ACS)
 Asymptomatic men who have at least a 10-
year life expectancy have an opportunity to
make an informed decision , after receiving
information about
• The uncertainties
• Risks &
• Potential benefits associated with prostate
cancer screening
 Prostate cancer screening should not occur
without an informed decision-making process

ACS…
 Men at average risk should receive this
information beginning at age 50 years
 Men at higher risk, including African American
men and men who have a first-degree relative
(father or brother) diagnosed with prostate
cancer before age 65 years, should receive
this information beginning at age 45 years
 Men at appreciably higher risk (multiple family
members diagnosed with prostate cancer
before age 65 years) should receive this
information beginning at age 40 years

ACS…
For men who choose to be screened-
 Screening is recommended with PSA with or
without DRE
 Screening should be conducted yearly for
men whose PSA level is 2.5 ng/mL or greater
 For men whose PSA is less than 2.5 ng/mL,
screening intervals can be extended to every 2
years.

ACS…
 A PSA level of 4.0 ng/mL or greater - used to
recommend referral for further evaluation or
biopsy, which remains a reasonable approach
for men at average risk for prostate cancer
 For PSA levels between 2.5 ng/mL and 4.0
ng/mL, health care providers should consider
an individualized risk assessment that
incorporates other risk factors for prostate
cancer, particularly for high-grade cancer, that
may be used to recommend a biopsy

ACS…
 Factors that increase the risk of prostate
cancer include African American race, family
history of prostate cancer, increasing age, and
abnormal DRE
 A previous negative biopsy lowers the risk

Rescreening intervals
 Rescreening intervals can influence the
effectiveness of a screening program
 Long rescreening intervals could miss
detecting curable disease for those with fast-
growing cancers
 Short intervals could lead to unnecessary
testing, overdiagnosis, and overtreatment with
no impact on disease mortality for those with
slowly growing cancers

Rescreening intervals…
 Annual screening is recommended for all men
older than 50 years regardless of risk by -
• American Cancer Society
• American Urological Association
• NCCN ( National Comprehensive Cancer
Network)
 Extending the screening interval in men with
initially low PSA levels would delay diagnosis
for only a very few cases and would be
unlikely to have a significant impact on
prostate cancer mortality

Rescreening intervals…
 Men with PSA levels below 2.5 ng/mL form a
significant portion of the screened population;
thus, extending the screening interval for these
men could lead to considerable reductions in
PSA tests, biopsies, overdiagnosis, and costs
 Therefore, the ACS recommends that men
whose initial PSA level is below 2.5 ng/mL can
reduce their screening frequency to every 2
years. Men with higher PSA values should be
tested annually

Summary of ‗Current
Guidelines‘
 AUA recommends routine PSA screening
 EAU & JUA (Japanese) – No routine screening
 ACS - No routine screening but offers to make
an informed decision
 American College of Preventive Medicine also
offers no recommendation for screening
 NHS (UK) – No organised screening
programme
 US Preventative services task Force – No
recommendation for screening

Future Advances
 PSA based screening - Finasteride improved
the ability of PSA to diagnose aggressive
cancers (PCPT)
 Another means to improve PSA -based
screening is through the use of urinary
markers. In this regard, DNA, RNA and protein
markers are all under investigation
 Of these potential tests, only the PCA3 test is
commercially available now

Future Advances…
 Because of controversy regarding the benefit
of current screening strategies, better methods
for the detection and treatment of early stage
prostate cancer are needed urgently
 Innovations and new understanding in the field
of molecular oncology have provided a host of
potential prostate cancer tumor markers

Future Advances…
 Identification of hyper methylated regions such
as GSTP1 and overexpressed proteins such
as DD3 and NMP48 provides greater
diagnostic and prognostic potential to improve
detection of prostate cancer
 Novel urinary diagnostic tests are potentially
interesting screening tools for this disease. For
example, uPM3 is a recently developed urine-
based test for detecting prostate cancer. It
detects DD3 - cancer gene & is effective for
diagnosing prostate cancer of all stages

Future Advances…
 Development of these markers from research
into clinically applicable tools will improve
detection and management of prostate cancer.
 Hopeful that future advances in the early
detection of prostate cancer will lead to the
ability to distinguish accurately between
indolent and aggressive cancers and that the
adverse effects of prostate cancer treatment
will be reduced sufficiently to tip the balance
clearly in favor of screening

Future Advances…
 The ideal screening test would be very
sensitive and specific for prostate cancer, and
not only specific, but specific for the tumor with
a poor prognosis
 Serum protein profiling using surface-
enhanced laser desorption/ionization time-of-
flight mass spectrometry(SELDI-TOF-MF) in
the detection of prostate cancer is on second
phase of validation now. It has incorporated
prognosis also by analyzing high & low risk
disease

Conclusion
 Two decades into the PSA era of prostate
cancer screening, the overall value of early
detection in reducing the morbidity and
mortality remains unclear
 Emerging evidence that early detection may
reduce the likelihood of dying from prostate
cancer must be weighed against the serious
risks incurred by early detection and
subsequent treatment

Conclusion …
 PSA testing cannot distinguish nonaggressive
from aggressive cancers and cannot resolve,
on its own, issues of overdiagnosis and
overtreatment
 By using strategies such as active
surveillance, we can separate detection of
prostate cancer from treatment among patients
with low-risk and very low-risk disease, and
thereby achieve a reduction in overtreatment

Conclusion …
 Important to involve men in the screening
decision
 Men have to understand
– The importance of prostate cancer
– The potential benefits of early detection
– The strengths and limitations of PSA
testing

Conclusion …
 Life expectancy ≤ 10 years- No need for
screening
 Men at risk for developing cancer at early age
should be provided the opportunity for
informed decision making at a younger
age, like in
– African Americans
– Men with a family history of prostate cancer

Conclusion …
 There is no true PSA cut-off point that
distinguishes cancer from non-cancer
 Lowering the PSA threshold for biopsy will
increase the rate of over-diagnosis
 PSA level of 4.0 ng/ml - reasonable threshold
for further evaluation.
 PSA levels between 2.5-4.0 ng/ml -
Individualized decision making ( particularly in
men who are at increased risk)

Conclusion …
 Future advances in the early detection of
prostate cancer will lead to the ability to
distinguish accurately between indolent and
aggressive cancers and that the adverse
effects of prostate cancer treatment will be
reduced sufficiently to tip the balance clearly in
favour of screening

References
1. Campbell-Walsh Urology, 10th ed.
2. AUA guidelines 2010
3. EUA guidelines 2011
4. ACS guidelines Update 2010
5. UCNA volume 37, No. 1 February 2010
6. T. B. of Prostate biopsy by J Stephen
Jones, 2011
7. Prostate-specific Antigen Testing and Prostate
Cancer Screening, Primary Care: Clinics in
Office Practice - Volume 37, Issue 3 (September
2010)
8. Randomised prostate cancer screening trial: 20
years follow up BMJ 2011: 342, March 2011

Prostate Cancer Detection as a
Function
of Serum PSA and DRE

PSA Derivatives and Molecular
Forms
 Numerous variations on PSA-based screening
have been proposed to improve test
performance -
• PSA level for total prostate volume (PSA
density)
• PSA Transition zone density
• Evaluation of rate of change in PSA (PSA
velocity)
• Complexed and free PSA assays

Volume-Based PSA Parameters
 Volume-based PSA parameters have been
evaluated to reduce confounding from BPH
 These include - PSA density
(PSAD), complexed PSA density and PSA
transition zone density
 PSAD of 0.15 or greater was proposed for
recommending prostate biopsy in men with
PSA levels between 4 and 10 ng/mL and
normal DRE

Prostate Specific Antigen
Velocity
 Rate of change in PSA (PSA velocity, or
PSAV) - PSA corrected for the elapsed time
between measurements is associated with the
risk of prostate cancer
 PSAV more than 0.75 ng/mL per year is a
specific marker for the presence of prostate
cancer in men with PSA levels between 4 and
10 ng/mL
 PSAV may play a role in the prediction of life-
threatening prostate cancer

Free Prostate Specific Antigen
 Men with prostate cancer generally have a
greater fraction of serum PSA that is
complexed and therefore a lower percentage
of total PSA circulating in the free (unbound)
form than men without prostate cancer
 This difference is thought to be due to
differential expression of PSA isoforms by
transition zone (zone of origin of BPH) tissue
compared with peripheral zone tissue(where
most prostate cancers arise)

Free PSA ( fPSA)…
 %fPSA appears to be most useful in
distinguishing between those with and without
prostate cancer at intermediate total PSA
levels
 In men with PSA levels of 4 to 10 ng/mL and
palpably benign prostate glands, a %fPSA
cutoff of 25% detected 95% of cancers while
avoiding 20% of unnecessary biopsies
 The percentage of free PSA (%fPSA) does not
appear to be significantly altered by race or
5α-reductase inhibitors

Complexed Prostate Specific
Antigen
 Because men with prostate cancer have a
greater fraction of total PSA that is complexed
to protease inhibitors than men without
prostate cancer, measurement of complexed
PSA (cPSA) has been studied as a marker for
detection
 At a high sensitivity, cPSA provides higher
specificity compared with total PSA and
comparable specificity to %fPSA in prostate
cancer detection

PSA Isoforms
epithelium in a precursor form (pPSA or
proPSA)
 Active free PSA can be further cleaved to
BPSA or intact PSA (iPSA) that is inactive and
not complexed
 BPSA is found preferentially in nodular BPH
tissue from the transition zone and can be
considered a marker for BPH
 Larger relative proportion of proPSA has been
associated with prostate cancer

Differential cleavage and activation of pro
prostate-specific antigen (PSA)

PSA Isoforms…
epithelium in a precursor or zymogen form
(pPSA or proPSA) with a 7-amino-acid leader
sequence and then either -
• Cleaved by hK2 to active free PSA or
• Partially cleaved into isoforms of free PSA
with 2- or 4-amino-acid leader sequences

PSA Isoforms…
 The native form of pPSA and the truncated or
clipped forms of pPSA are elevated in the
tissue and blood of patients with prostate
cancer compared with those without the
disease.
 These novel markers have the potential to
improve the accurate identification of men with
cancer and the identification of those with
more aggressive disease

Prostate-specific antigen (PSA) synthesis in
normal
versus cancer tissue

Active surveillance
 Active surveillance refers to the process of
regularly monitoring disease activity through
clinical parameters (PSA, DRE) and possibly
periodic re-biopsy, with active treatment
(surgery, radiation, brachytherapy) offered to men
whose disease appears to be progressing
 Benefit of active surveillance is its capacity to
reduce overtreatment, that is, the treatment of
disease that would not have become apparent
clinically during the patient‘s lifetime, which is
particularly problematic for less aggressive tumors

Watchful waiting
 Generally implies less aggressive surveillance
and no treatment until progressive symptoms
or evidence of metastatic disease develop.
 Active surveillance generally is offered to men
whose cancers are Gleason grade 6 or less. It
usually includes regular clinical re-evaluation
with PSA and DRE as well as biopsy every 1
to 4 years, depending on the protocol

Screening for carcinoma prostate

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