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PROSTATE CANCER SCREENING PROGRAM BASED ON PROSTATE

SPECIFIC ANTIGEN TEST OR ANY OTHER TEST-TO DO OR NOT TO DO?
DR.PRATIK MUKHERJEE

MBBS( IND), MPH (AUS)

PREVENTION IS BETTER THAN CURE

The issue of prostate cancer is a burning question in today’s world of medical practice
and the major hurdle faced by the medical fraternity is to judge whom to screen and
treat. Prostate cancer is a very elusive disease and the tools available to screen it are
very limited. Prostate cancer is the most common malignancy in American men,
accounting for >29% of all diagnosed cancers and approximately 13% of all cancer
death. Nearly 1 of every 6 men will be diagnosed with the disease at some time of
their life . Although the prevalence of prostate cancer in autopsy specimens around the
world varies little there is significant difference in clinical incidence which seems to
bear association with environmental and dietary differences between populations.

Before the PSA era, digital rectal examination (DRE) was practised for years. But
with the advent of PSA 20 years back, the topic of prostate cancer screening has
become a heatedly debated issue. When an effective screening tool is introduced
certain events should occur. There should be a transient increase in the incidence, the
cancers should be diagnosed in patients of younger age, at earlier stages and there
should be an apparent increase in disease-specific survival. As of 2003, PSA testing
has arguably fulfilled all these criteria, and many clinicians practice screening. With
the popularity of screening and public awareness, more young men between the age of
40 and 49 years are seeking evaluation.

As regards the change in the incidence of the disease, the surveillance, epidemiology
and end results (SEER) program of National Cancer Institute data, as well as Mayo
clinic, support the change. The data from early 1989 to 1992 exemplify the “cull
effect”- that is with the introduction of a new screening tool there is an increase
followed by decrease of the incidence of the disease following depletion of the
prevalent pool of undiagnosed cases. The mean and median age of diagnosis has
decreased significantly in the PSA era. The decrease in age at time of diagnosis from
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72 to 69.4 has been shown by SEER data and a lead time of 3-5 years has been
derived which is significant.

In a major case control study, it was found that screening of asymptomatic men with
PSA was associated with a significantly reduced risk of metastatic prostate cancer. In
another study on whether to combine the free PSA and total PSA to improve the
screening properties it was found to show modest improvements over total PSA vis-à-
vis their ratio . However, utilization of percent free PSA below a certain threshold of
4ng/ml could translate into a practically important reduction in unnecessary biopsies
without sacrificing cancers detected. In another study on the use of percent free PSA
as an indication for biopsy in men at increased risk of developing prostate cancer
with a normal DRE and total PSA level between 2 and 4 ng/ml showed that a percent
free PSA of less than 27% was useful for detecting early-stage but clinically
significant cancers in these men. Another major study, an appraisal on the diagnostic
properties of serum PSA in screening prostate cancer in Thai population, showed on
meta-analysis of 1321 cases that the overall diagnostic property with regard to
sensitivity, specificity, false positive and false negative rates were
95.8%,66.2%,33.8% and 4.2% respectively. Therefore, the test has a good sensitivity
and potent enough for screening purposes as compared to DRE but pathological
confirmation is also required . A comparative meta-analysis on the use of PSA and
DRE for screening showed a pooled sensitivity, specificity and positive predictive
value(PPV) for PSA of 72.1%,93.2% and 25.1% for PSA and for DRE 53.2%,83.6%
and 17.8% respectively. The inference from this study was that the potential for
detecting early-stage prostate cancer with these screening tests were good as 83.4%
cancers were localized. Secondly, the overall usefulness of PSA as a screening tool
was better than DRE. The following table will summarize the test performance of the
tools that are commonly used for screening.

TEST SENSITIVITY SPECIFICITY POSITIVE PREDICTIVE

VALUE
ABNORMAL PSA 0.67 0.97 0.43
(> 4ng/ml)
ABNORMAL DRE 0.50 0.94 0.24
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ABNORMAL PSA OR 0.84 0.92 0.28

DRE
ABNORMAL PSA AND 0.34 0.995 0.49
DRE
Source: - -CMDT 2005

The goal of a screening effort should be to detect and effectively treat only those
prostate carcinomas most likely to cause mortality or morbidity if left untreated.
Detection of latent, non progressive cancers would expose patients to unnecessary
treatment and its attendant costs and complications. A study on the effect of false-
positive prostate cancer screening results on subsequent screening behaviour in
African American men showed that having a previous false-positive prostate cancer
screening result(p< 0.001), were predictive of not returning for prostate screening in
subsequent trial year . Here lies the importance of shared decision making between
patients and clinicians regarding risks and benefits of screening and follow-ups of
abnormal screening results.

Need of the hour?

What is needed is a reliable coding system for inference from the screening results
and their diagnostic value from patient’s charts. A study reviewed the chart
abstraction of a group of cases and evaluated the reliability of Tran rectal
ultrasound(TRUS), DRE and PSA and developed a coding system for them. Inter
observer reliability (kappa) was considered. Other screening studies by Labrie et al
and Bartsh et al also suggest a benefit for screening. The Bartsh study particularly,
showed a 42% decrease in disease-specific mortality rate for prostate cancer when
PSA screening was offered aggressively to all men in the Tyrolean state of Austria
between 1993 and 1997 as compared to the rest of the country were it wasn’t done
commonly.

Although randomized clinical trials have yet to definitely prove or disprove the
efficacy of population-based screening, emerging data from various studies in the
PSA era arguably support PSA testing in the early diagnosis of prostate cancer. Even
though the lead-time benefit may not extend to a long-term improvement these
changes are surely comforting. Use of age and race specific reference ranges based on
sensitivity or maximal cancer detection is the most favoured approach. The use of an
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annual PSA blood test and DRE for men over 40 years sounds promising. The
following table summarises the threshold values on age and race specific basis.
-CMDT 2005.

AGE SPECIFIC REFERENCE RANGES (MEN)

AGE GROUPS(IN YEARS) PSA RANGE (IN ng/ml)
40-49 <2.5

50-59 <3.5

60-69 <4.5

70-79 <6.5

AGE SPECIFIC REFERENCE RANGES FOR BLACK MEN

AGE GROUPS(YEARS) PSA RANGE (ng/ml)
40-49 <2
50-59 <4
60-69 <4.5

70-79 <5.5

Other factors like PSA velocity (<20% /year), percent free PSA (<18%-25%) and
complex PSA can be used to determine risk, but more studies are needed in young
men. Several RCT’s are going on, whose results are awaited. One study showed that
there is significantly higher intra-individual variation of complex PSA (cPSA)
(25.4%) and lower intra-individual variation of ratio of cPSA to t PSA (total PSA)
(13.1%) compared to other individual PSA iso-forms and ratio of f PSA(free PSA) to t
PSA. The minimum change was ratio of c PSA to t PSA(36.2%). These results have
significance in diagnosing and monitoring of patients with prostate cancer .

RECOMMENDATIONS FOR PROSTATE CANCER SCREENING POLICY

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Prostate cancer screening has become synonymous with the PSA era and though PSA
is the most powerful tool we have, there is a lack of specificity. Although the
arguments against screening are many like potential side effects from over treatment,
some men been treated unnecessarily, economic burden on health care system and
lack of definitive scientific evidence favouring screening and its benefits in reducing
overall disease-specific mortality, a human life can’t be weighed against such protests
ethically.

Most recent studies and some feedbacks from the ongoing RCT’s tilt the balance in
favour of screening of prostate cancer with PSA. PSA level at baseline itself appears
to be a risk factor for future prostate cancer development in population-based studies.
A study by Gann et al found that a single PSA measurement had a relatively high
sensitivity and specificity of 73% and 91% respectively for cancer detection in a
4year follow-up. Other researches reproduced similar results.

There has been considerable research in the utility of combining the iso-forms of PSA
in analysis, like ratio of free to total PSA and c PSA. PSA velocity and PSA density
studies have been contributory but have failed to decrease the number of negative
prostate biopsies. This has led to search for better tumour marker which is more
specific while maintaining their sensitivity.

Today in the world of molecular science there have been quite a few developments in
the field of cancer screening. Following are some of them:-

• Prostate specific membrane antigen (PSM )– expressed more in cancer

cells than in benign cells. PSM as a marker has shown 58% and 47%
sensitivity and specificity respectively. The main drawbacks are that in
conjunction with PSA it hasn’t increased specificity.

• Alpha-methylacyl coenzyme a racemase (AMACR) – expressed more by

cancer cells and found in prostatic secretion and urine after biopsy which
turned out to be a drawback for this marker. But one potential use is to stratify
patients with initial negative biopsy in the face of rising PSA .
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• Artificial intelligence and neuronal network in screening – in a study

investigators analysed serum proteomic streams generated by high resolution
mass spectroscopy by using a pattern recognition algorithm. The result
yielded 100% sensitivity and 67% specificity.

The most promising novel approach seems to be based on detection of prostate cancer
cells in urine. In a study, uPM3 assay was used which is based on amplification of
specific target RNA using nucleic acid sequence based amplification(NASBA)
technology. In a large multi-centre study, the overall sensitivity, specificity and
positive predictive value (PPV) were 66%, 89% and 75% respectively compared to
PPV of 38% for serum PSA cut-off of 4ng/ml resulting in a two-fold accuracy of this
method in diagnosing clinical disease. This seems to be answer to the problem in the
near future.

SUMMARY

Men more than 75 years old and men with less than 10 year life expectancy should
not be screened.
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A percent free PSA <27% has been found to be useful in detecting early-stage but
clinically significant cancers in men with a total PSA value between 2 and 4 ng/ml
and normal DRE findings.

Focus should be on improving sensitivity and specificity of screening methods by

using tools like age-specific cut-off values for PSA, determining free and bound
forms of PSA, correcting PSA for BPH and standardizing DRE. A greater benefit
would result from a screening program with regular screening intervals. More studies
in different population groups using variety of approaches need to be done. While
reduction in mortality and metastatic cancer are important, issues like quality of life &
men’s preferences need to be evaluated. All men over 45 years with an estimated life
expectancy of more than 10 years should be informed of the potential benefits and
drawbacks of PSA screening so that they can make an informed decision on whether
to have the test. If a man wants to minimize risk of prostate cancer and maximize his
chance of living as long as possible, PSA screening might be advisable. On the
contrary, if a man wants to maximize his quality of life and not take risks (impotence
and incontinence) arising from surgery and only avail of the medical options, then
PSA screening is of no value to him. So a cafeteria approach is what should be
advocated to men when it comes to go for screening or not.

Screening policy:- Prostate cancer is a disease with a long natural course, so men
should be screened only if they have a 10 year life expectancy and are at appreciable
risk of cancer. Most sources suggest offering screening to population group between
40 & 70 years. Optimum screening could depend on PSA velocity and absolute level.
Suggested intervals are at age 40 & 45 to establish a baseline, and then at 50. After the
age of 50, men should be screened every two years unless otherwise advised. If PSA
is <1ng/ml then testing every 5 years and if between 1-2 ng/ml, then every 2 years
seems to be the favoured approach.

….the future:- Results from the ongoing randomised control trials which will take
another 5-10 years to publish results, show that men with screening have their cancers
detected at an earlier and less deadly stage as compared to men who didn’t have
screening. So it’s best to offer men the cafeteria approach of choosing till something
more substantial and promising comes out.
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Future efforts in redefining the role of PSA in benign and malignant disease, use of
newer markers and use of intelligent technology will decrease the number of
unnecessary biopsies and controversy surrounding screening. Research should be
done in developing risk-stratified approach using molecular biomarkers like upm3 and
proteomics in young men. Till the next era comes, PSA remains the backbone of
screening prostate cancer and is here to stay and clinicians should use this tool
effectively and judiciously to save lives.

BIBLIOGRAPHY