screening for carcinoma prostate
TRANSCRIPT
Subject seminar
Topic: Screening of Carcinoma Prostate
Chair person: Prof. C. S. RatkalCo chair person: Dr. M.
ShivalingaiahPresenter: 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 )
Gold standard test
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 test (d)
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
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)
Epidemiology of Carcinoma 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
Epidemiology of Carcinoma 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 Incidence Total Incidenc
eIncidenc
e
US black 2664 79.9 7129 137 71.5US 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.
Arguments for screening….
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.
Arguments for screening….
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
Arguments against screening… 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
Arguments against screening… 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 screeningPros 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
Factors Influencing PSA…
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
Factors Influencing PSA…
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)
Factors Influencing PSA…
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
Clinical use of 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
Clinical use of PSA…
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
cancerso The tests are complementaryo 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 inhibitorso 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 oro 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 group were diagnosed with prostate cancer
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
Prostate Cancer Prevention Trial ( 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)
Prostate Cancer Prevention Trial ( 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
– And the risks of finding and treating screen-
detected cancer
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
in nonelderly relatives
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 20103. EUA guidelines 20114. ACS guidelines Update 20105. UCNA volume 37, No. 1 February 20106. T. B. of Prostate biopsy by J Stephen Jones, 20117. 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
Thank you
Prostate Cancer Detection as a Functionof 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
PSA molecular derivatives
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
PSA is secreted from the prostatic luminal 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…
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 -
• 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 normalversus 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