PSA AND RISK OF PROSTATE CANCER
In a landmark study by Thompson et al published in 2004, 2950 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) underwent end-of-study prostate biopsies regardless of PSA and digital rectal examination (DRE) findings. For those with PSA equal to or less than 4.0 ng/mL at the time of biopsy, about 15% were diagnosed with cancer. The risk increased with PSA levels but was present at even low levels. One critical question concerns the prevalence of insignificant cancers found at biopsy and in the pathological examination of prostates surgically removed. The PCPT data has now been analyzed to examine this question.
PSA categories were 0-1.0, 1.1-2.5, 2.6-4. Tumors found at biopsy were categorized as potentially insignificant if they were stage T1c (detected by elevated PSA), negative DRE, PSA density less than 0.15 ng/mL/g, and no evidence of Gleason pattern 4 or 5 in the biopsy cores, Gleason score equal to or less than 6, tumor limited to less than 3 cores with no more than 50% involvement of any core. A second similar set of criteria were also applied. With the above definition of insignificant, the percentages of cancer meeting the criteria for the three strata of PSA were 51.7%, 33.7% and 17.8%. In the PSA range from 0 to 2.5, 39% had insignificant cancer or put another way 61% has significant cancer. The percentages of detected cancers that were significant increased with PSA level and for those with 2.6-4.0 mg/dL, the number was over 82%. These figures did not change much when the data is restricted to the placebo group with a normal DRE.
A subgroup underwent radical prostatectomy. Adverse pathology observed on the prostates removed surgically was defined as any of the following: Gleason score of equal to or greater than 7, extraprostatic extension, seminal vesicle invasion, positive surgical margin, or lymph node metastasis. In men with PSA between 1.1 and 2.5, 37.9% had one or more adverse pathologic features and this increased to 49.1% for the group between 2.6 and 4.0 mg/dL. Extraprostatic extension went up strongly with PSA, as did positive surgical margins. Even when the PSA was below 1.0, 15% had one adverse feature (in this case a Gleason equal to or greater than 7). The presence of adverse pathologic features indicates an enhanced risk of treatment failure.
These results strengthen the view that there is no cut-off value for PSA that can provide a high level of comfort if one is worried about having prostate cancer. Furthermore, the real risk of significant disease and disease with adverse features increased monotonically with PSA with no apparent threshold. These results also support the view that the only way to answer the question of the presence of prostate cancer is with a biopsy. But even this statement needs qualification since biopsies also miss cancers. The need for a simple diagnostic test for prostate cancer with a high level of sensitivity and specificity appears urgent. Those who think it is the PSA test are misguided or deceived.
Lucia MS, Darke AK, Goodman PJ et al. Pathologic characteristics of cancers detected in the prostate cancer prevention trial: implications for prostate cancer detection and chemoprevention. Cancer Prev Res 2008 August 1;1(3):167-73
Walsh PC. Re: It's time to abandon an upper limit of normal for prostate specific antigen, J Urol 2009 Mar;181(3):1499
MULTIPLE BIOPSIES EXPOSE LIMITATIONS OF PROCEDURE
The biopsy procedure can be likened to trying to answer the question—does this blueberry muffin really contain blueberries? The muffin is wrapped in opaque plastic and one proceeds to probe with hollow needles looking for blueberry pulp in the cores. The probability of getting a positive answer when there are in fact blueberries present depends upon the number of needles used or the number of cores taken, the number of blueberries and their distribution and size. In the case of prostate biopsies, only a limited number of needles are used, typically 6 to 18, and zones which statistically are favored for tumors are given more attention.
It is not uncommon that an individual will be considered at high risk, for example with a persistent elevated PSA, and yet the first biopsy is negative. A recent single center study from Spain examined the yield of positive cancer diagnosis with a third, fourth and fifth biopsy on patients who came up negative after two. Indications for performing a biopsy on this subgroup included persistent elevated PSA (greater than 4.0 ng/mL, persistent suspicious DRE, PSA velocity greater than 0.75 ng/mL/year, or the finding of precancerous pathology in prior biopsy. The results are interesting. On the third biopsy 15 cancers were found in 61 patients. The fourth biopsy found 5 cancers in 14 patients, and the fifth found 1 cancer in 2 patients. The classical six- needle biopsy was used on 25 patients and an extended 18-needle protocol was used for the balance. Thus out of 61 patients undergoing 3 to 5 biopsies, 21 were diagnosed with prostate cancer (34%). In other words, this group of 61 patients had had two negative biopsies and for those went on to have additional biopsies, over a third had prostate cancer. For those who went on to have a radical prostatectomy, examination of the prostate revealed that all had clinically significant disease. The authors comment that performance of the third, fourth and fifth biopsies were in fact unnecessary in retrospect in 29% of the patients, based on a Gleason score of equal to or less than 5 observed at biopsy. The patients undergoing the third biopsy had a range of PSA from 5.2 to 120 ng/mL. A suspicious DRE suggested the presence of only 4 out of 15 cases where tumors were found.
A limitation with this study is that not all those with a negative first biopsy went on to have additional procedures until either cancer is detected or four or five have been performed. In this study, out of 2457 first biopsies, 810 were positive but of the remaining 1647, only 306 went on to the second biopsy which incidentally had a 29% yield of positive diagnosis. Those encouraged having repeat biopsies presented with risk patterns suggesting that cancer had been missed. This pattern repeated with the majority of individuals having negative results not having additional biopsies. On the third round, only 61 out of 220 had biopsies, with 15 positive results. For the fourth round, only 14 out 146 had biopsies, with 5 positive results, and finally in the fifth round, only 2 had biopsies with one positive result. No information was provided on the prevalence of strong indications in those with a negative biopsy at each stage in the series. Nevertheless, the results are suggestive of large numbers of cancers being missed even in repeat biopsies. The design of this study is quite different from a study reported in 2001, where all participants had agreed to up to 4 biopsies if no cancer was found after the first. The first biopsy yielded 22% positives, the second 10%, the third 5% and the fourth 4%. This study used an 8-needle protocol. Thus in the Spanish study, presumably there was some selection for high-risk candidates for each additional biopsy since they found much higher percentages of positive results.
Presumably, when a patient is told that his first biopsy is negative, he is also told that while it is unlikely that he has cancer, the probability is still significant. When a second biopsy is suggested, it is because there are clinical indications that there is a high probability cancer is present, frequently because of a persistently elevated PSA. It is nevertheless interesting that it can be missed in multiple biopsies. Thus what is held up as the gold standard in prostate cancer diagnosis is not quite 24-caret. We all, including the urology community, eagerly await both screening and diagnosis protocols that come closer to perfection. What is unfortunate is that so many individuals think that perfection has already been attained.
Bahilo Mateu MP, Ramirez BM, Trassierra VM, Di Capua SC, Arlandis GS, Cruz Jimenez JF. [Clinical features and histopathology of prostate cancer diagnosed from the third biopsy]. Actas Urol Esp 2008 November;32(10):961-7
Djavan B, Ravery V, Zlotta A et al. Prospective evaluation of prostate cancer detected on biopsies 1, 2, 3 and 4: when should we stop? J Urol 2001 November;166(5):1679-83
PROSTATE GROWTH AND PSA VELOCITY—A SOURCE OF CONFOUNDING?
PSA velocity is used to increase the power of PSA screening. But PSA also tends to increase with prostate size, and an increasing prostate size accompanies benign prostatic hyperplasia (BPH). Thus the question of potential confounding. A study by Loeb et al just published in The Journal of Urology addresses this concern. The researchers identified 242 men without prostate cancer from the Baltimore Longitudinal Study of Aging who had 2 or more serial pelvic MRI studies and contemporaneous PSA tests. Prostate volume was estimated from MRI images and the median PSA was 0.9 ng/mL with a mean of 1.3 ng/mL. During the 4.2 years median follow-up, the median rate of prostate volume change was 0.6 cc/year whereas the median PSA change was 0.03 ng/mL per year. Prostate growth rates as high as 10 cc per year were encountered, and yet PSA velocity was less that 0.1 ng/mL per year in most men and showed no correlation with prostate volume. The authors point out that the National Comprehensive Cancer Network now recommends that a prostate biopsy would be considered for men with PSA equal to or less than 2.5 ng/mL if the PSA velocity were greater than 0.35 ng/mL per year. The results of the study by Loeb et al suggest that PSA changes greater than 0.35 ng/mL per year are unlikely to be due to prostate volume changes. These results suggest that progressing BPH is not a confounding factor when PSA velocity is used to indicate a probability of prostate cancer high enough to warrant a recommendation of a biopsy.
An editorial by Westphalen which is at the end of the paper by Loeb et al points out that in addition, there is a study in which PSA velocity correlated with MRI findings of malignancy but not BPH which also supports the use of PSA kinetics as a tumor marker. Westphalen suggests that the study of Loeb et al adds to others to provide added evidence for the use of PSA velocity not only in determining prostate cancer aggressiveness but also to aid in biopsy decisions.
Loeb S, Kettermann A, Carter HB, Ferrucci L, Metter EJ, Walsh PC. Does prostate growth confound prostate specific antigen velocity? Data from the Baltimore longitudinal study of aging. J Urol 2008 October;180(4):1314-7
% FREE PSA AND RISK OF PROSTATE CANCER IN MEN WITH A PSA EQUAL TO OR LESS THAN 2.5 ng/L
The famous Prostate Cancer Prevention Trial (PCPT) found that 17% of patients with a total PSA between 1.1 and 2.0 ng/mL and 23.9% with total PSA between 2.1 and 3 ng/mL had prostate cancer as detected by biopsy. This prompted the suggestion that the threshold for biopsy be reduced, but the counter argument is always that this will result in a large number of biopsies which in retrospect will turn out to have been unnecessary. This is the inevitable result of having a marker, i.e. PSA, the level of which is associated with a continuously increasing risk of prostate cancer. In fact, there is no safe total PSA level below which prostate cancer does not exist. Since the publication of the PCPT there has been renewed interest in improving the selection process among men with PSA equal to or less than 2.5 ng/mL in order to reduce the number of unnecessary biopsies. If a patient with PSA equal to or less than 2.5 ng/mL has a suspicious digital rectal examination (DRE) then this is generally considered sufficient reason for recommending a biopsy, but when the DRE is unremarkable, there is obviously a problem and the need for novel biomarkers for this subgroup.
A study by Waltz et al has just been published in the journal Cancer which examines the ability of the % free PSA to stratify patients with PSA equal to or less than 2.5ng/mL in order to aid in the decision regarding the recommendation of a biopsy. Since the probability of prostate cancer in this group is about 17%, the objective was to find a way of identifying those most likely to actually have the disease. Between 1999 and 2006, 7880 consecutive men underwent an initial biopsy at two European centers (Hamburg and Milan). Of the total cohort, 1036 had total PSA equal to or less than 2.5 ng/mL. For patients in this subgroup with an unremarkable DRE, 19% had prostate cancer at biopsy whereas overall the rate in the subgroup was 23%. The researchers comment that this is somewhat higher than would be predicted from the PCPT and that this may be due to the nature of the cohort which was referred on the basis of abnormal or suggestive PSA behaviour. The present study also used more biopsy cores as compared to the PCPT study.
The % free PSA was found to provide considerable discrimination. For men with an unremarkable DRE, those with % free PSA equal to or less than 14%, 49% had prostate cancer, whereas for those with %free PSA equal to or greater than 28%, only 9% had prostate cancer. This unfortunately leaves a grey area of greater than 14% to less than 28% free PSA. For the entire group which included men with suspicious DRE, these same two cut-offs found 59% and 13% with prostate cancer. The authors point out that the finding that the % free PSA was highly useful in identifying patients with prostate cancer was also observed in a study by Catalona et al in a group with total PSA between 2.5 and 4.0 ng/mL. Also in studies that examined the performance of free PSA at initial biopsy, repeat biopsy and saturation biopsy, % free PSA was the strongest predictor of prostate cancer. However, a Korean study found that for men 50 to 65 years of age with an unremarkable DRE and PSA between 4.0 and 10.0, % free PSA did not add diagnostic advantage.
Walz et al also examined the fraction of cancers detected in the equal to or less than 2.5 ng/mL group that were deemed clinically significant among the patients undergoing a radical prostatectomy. Despite the favourable total PSA range of this cohort, 16% of the cancers had established extracapsular extension or seminal vesicle invasion and 35.6% had a pathological Gleason score of 3 + 4. It was thought that this subgroup undergoing surgery was representative of the total cohort. The authors comment that the surprisingly elevated proportion of unfavourable pathologic characteristics indicates that low total PSA values are neither indicative of nonexistent cancer nor a favourable pathology. Obviously, the need to replace PSA and even its variants with a definitive yes or no marker for prostate cancer is urgent, but it must be recognized that even the biopsy misses a significant number of cancers. We have come a long way in this field, but we appear to have a long way to go.
Walz J, Haese A, Scattoni V et al. Percent free prostate-specific antigen (PSA) is an accurate predictor of prostate cancer risk in men with serum PSA 2.5 ng/mL and lower. Cancer 2008 Nov 15; 113(10):2695-703
Catalona WJ, Smith DS, Ornstein DK. Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng/mL and benign prostate examination. Enhancement of specificity with free PSA measurements. JAMA 1997 May 14;277(18):1452-5
Jeong IG, Lee KH. Percent free prostate specific antigen does not enhance the specificity of total prostate specific antigen for the detection of prostate cancer in Korean men 50 to 65 years old: a prospective multicenter study. The Journal of Urology 2008 January;179(1):111-6
Prostate cancer screening in men over 75 years
DURHAM, NC. Recent evidence shows that men older than 75 years are frequently screened for prostate cancer, despite current guidelines suggesting they are unlikely to benefit from treatment as the disease develops slowly in this age group. Rates of prostate specific antigen (PSA) testing in the US were examined by researchers from Duke University Medical Center. The team took data from national surveys of physician-reported information carried out from 1999 to 2002. They found that 14.1 per cent of all PSA tests during this time involved men over 75 years. Among men of this age, 27.8 per cent underwent PSA testing - a greater proportion than in any other age group. Urologists were more likely to initiate the tests than non-urologists. This confirms patient-reported data; say the team, adding that the presence of a testing laboratory on-site is significantly linked to the likelihood of testing. Excessive PSA testing has direct and indirect costs, and reflects an inefficient allocation of resources, they conclude.
Scales, C. D. et al. Prostate specific antigen testing in men older than 75 years in the United States. The Journal of Urology, Vol. 176, August 2006, pp. 511-14
A rational approach to prostate cancer treatment
TORONTO, CANADA. Dr. Laurence Klotz of the University of Toronto believes that localized
prostate cancer is
overtreated and that many men with "good risk" prostate cancer can avoid radical intervention
prostate removal) and still live long enough to die of causes other than prostate cancer. Dr. Klotz
reported on an ongoing study involving 299 men over the age of 70 years with prostate cancer. At
the start of
the study in 1995 the men had a PSA (prostate specific antigen) value below 15 ng/mL, a Gleason
score of 7 or
less, and their cancer rated as stage 2b or less. The men were all placed under active surveillance,
included frequent PSA measurements and a repeat biopsy at 12-18 months after initial diagnosis.
Dr. Klotz believes that the time it takes for the PSA level to double is a good indicator of the
the cancer. If the PSA level doubles in less than 2 years or progression is noted on repeat biopsy or
rectal examination, then the patient should be offered radical intervention. The PSA doubling time
based on 3 separate measurements during a minimum of 6 months and the final value should be
greater than 8
ng/mL before radical intervention is considered.
The median PSA doubling time (DT) among the 299 patients was 7 years and 42% of the men had
a DT of
greater than 10 years. Only 21% had a DT less than 3 years. Only 2 patients died from prostate
the first 5 years and after 8 years of follow-up the prostate cancer specific mortality in the group
was only 1%.
About 60% of the patients remained on active surveillance after 55 months, with the remaining
opting for radical
therapy either because of diagnosed progression or by personal preference. Dr. Klotz concludes
surveillance with selective delayed intervention in patients whose PSA DT is less than 3 years may
be a practical
compromise between across-the-board radical therapy for all patients with localized prostate cancer
watchful waiting with palliative therapy only.
Klotz L. Active surveillance with selective delayed intervention: using natural history to guide
treatment in good risk prostate
cancer. Journal of Urology, Vol. 172, November 2004, pp. S48-S51
Hand-held scanner for cancer.
Researchers at the University of Bologna have developed
a hand-held scanner, similar to those used in airports, which can be used to detect cancer. Apparently
cancer tumours create a strong interference at 400 mega hertz when exposed to a weak microwave field
emitted by the scanner. Preliminary trials have shown that the scanner can detect prostate cancer with
an accuracy of 93% and breast cancer with an accuracy of 66%. Trials for lung, stomach, liver, and
colorectal cancers are underway and it is hoped that the scanner can be made commercially available
later this year.
New Scientist, June 14, 2003, p. 15
New test predicts the risk of prostate cancer
SEATTLE, WASHINGTON. Researchers at the Pacific Northwest Research Institute and Baylor College
of Medicine report the development of a promising new method for determining prostate cancer risk and
the risk of metastasis. The researchers compared the DNA spectra (Fourier transform-IR spectra) of
prostate tissue taken from younger men (aged 16 to 36 years) and older men (aged 55 to 80 years) as
well as prostate tissue spectra from older men with prostate cancer and older men without prostate
cancer. They found that there was a highly significant increase in DNA damage (8-hydroxypurine lesions)
with advancing age. This damage could be estimated by measuring the concentration of 8-
hydroxyguanine in prostate tissue from young and older men. It is known that 8-hydroxyguanine is
formed when DNA is attacked by free radicals, specifically hydroxyl radicals.
The researchers also found that they could easily distinguish DNA spectra from older men without
prostate cancer from those of older men with prostate cancer. They speculate that the new test may be
able to predict the risk of a man developing prostate cancer by determining the extent of free radical
damage at any particular point in time. Perhaps the most exciting discovery was the ability of DNA
spectra analysis to determine whether the cancer had metastasized well before any damage to other
organs actually had occurred.
The researchers conclude that prostate cancer is largely caused by free radical attacks on both the base
and backbone structure of DNA. They suggest that an increase in the intake of such dietary antioxidants
as vitamin E, lycopene and polyphenols may inhibit the development of prostate cancer.
Malins, Donald C., et al. Cancer-related changes in prostate DNA as men age and early identification of metastasis
in primary prostate tumors. Proceedings of the National Academy of Sciences, Vol. 100, No. 9, April 29, 2003,
Editor's comment: Vitamin-C (ascorbic acid) is also an effective scavenger of hydroxyl radicals
and helps prevent the formation of 8-hydroxyguanine.
Thyroid hormone and prostate cancer
NEW YORK, NY. Prostate cancer usually progresses very slowly and in many cases, especially among
older men, requires no other treatment than "watchful waiting". The problem, of course, is to identify
those cases that do require aggressive treatment (surgery and radiation) in order to prevent metastasis.
Researchers at Mount Sinai School of Medicine now report that the thyroid hormone, triiodothyronine
(T3), may be a useful marker for prostate cancer aggressiveness. It is well established that T3 is required
for the growth of prostate cancer cells in vitro. The researchers measured T3 levels in 208 men aged 46
to 96 years. Twenty of the men had an enlarged prostate (benign prostatic hyperplasia or BPH), 161 had
localized prostate cancer, and 27 controls had neither BPH nor prostate cancer. The researchers found
that men with BPH had significantly higher levels of T3 than did the controls and the prostate cancer
patients. Prostate cancer patients also had significantly higher levels than the controls, but lower levels
than the men with BPH.
The researchers conclude that T3 may be a useful biomarker for prostate cancer, but that more work is
required to definitely establish this. They also suggest that new therapies for BPH and prostate cancer
could perhaps be directed towards inhibiting the mitogenic (cell dividing) effects of T3.
Lehrer, Steven, et al. Serum triiodothyronine is increased in men with prostate cancer and benign
prostatic hyperplasia. Journal of Urology, Vol. 168, December 2002, pp. 2431-33
Prostate biopsies often unnecessary
SHREVEPORT, LOUISIANA. It is common practice to perform a biopsy of the prostate on men whose
PSA (prostate specific antigen) level exceeds 4.0 ng/mL. The results of the biopsy, which is expensive,
uncomfortable and anxiety-provoking, are negative in most cases (65 to 85 per cent negative) indicating
that no cancer is present. Urologists at the Louisiana State University point out that acute prostatitis
(inflammation of the prostate gland) and benign prostatic hypertrophy (enlarged prostate) can also give
high PSA readings. They now report on a just completed trial designed to determine if men with chronic
prostatitis also have high readings and if so, how often these abnormal readings actually are an indication
of prostate cancer.
Their trial involved 95 men who had been diagnosed with chronic prostatitis and who had an elevated
PSA level (average of 8.48 ng/mL), but no abnormalities in digital rectal examination. The men were all
assigned to a four-week course of antibiotics (fluoroquinolones or doxycycline) and anti-inflammatories
(ibuprofen or celecoxib). At the end of the four weeks 44 of the men (46.3 per cent) had a PSA level of
less than 4 ng/mL (mean of 2.48 ng/mL) and were deemed to be free of prostate cancer. The remaining
51 men underwent double sextant transrectal ultrasound guided biopsy. Thirteen patients (25.5 per cent)
were found to have prostate cancer, 37 (72.5 per cent) had chronic inflammation, and one patient had an
enlarged prostate. The researchers conclude that treatment of chronic prostatitis in men with high PSA
levels can substantially reduce the need for biopsies. It is of interest to note that the PSA levels in the
men eventually diagnosed with prostate cancer only declined from an average of 8.32 to 7.92 ng/mL after
four weeks of antibiotic therapy. Editor's Note: The moral of this story is that one should always
ensure that one does not have acute or chronic prostatitis before submitting to a prostate
Bozeman, Caleb B., et al. Treatment of chronic prostatitis lowers serum prostate specific
antigen, Journal of Urology, Vol. 167, April 2002, pp. 1723-26
PSA Screening revisited
BOSTON, MASSACHUSETTS. Dr. Michael Barry of the Harvard Medical School and the Massachusetts
General Hospital provides an excellent review of the current status of PSA screening for prostate cancer.
Dr. Barry starts out by posing the question "Should a 65-year-old man with no risk factors for prostate
cancer except his age and with a normal digital rectal examination undergo a PSA (prostate-specific-
antigen) test?" Dr. Barry points out that whether or not to have a PSA test is controversial because of the
- No randomized clinical trials have ever demonstrated that early detection and aggressive treatment of
prostate cancer reduce mortality;
- The treatments usually mobilized after a positive PSA test and biopsy (radical prostatectomy,
radiation therapy or castration) are associated with severe side effects including impotence and
He also emphasizes that the PSA test is not that accurate. A recent large-scale trial showed that using a
cut-off point of 4.0 ng/mL would pick up 46 per cent of cancers that would occur within the next ten years
with an accuracy of 91 per cent. The average age of the test group was 63 years. Among older men with
benign prostatic hyperplasia (enlarged prostate) the accuracy may be as low as 54 per cent leading to
many unneeded biopsies and much unwarranted anxiety. It is estimated that 75 per cent of men
undergoing a prostate biopsy because they have PSA levels between 4 and 10 ng/mL do not have
cancer. On the other hand, there is also a 10 per cent chance of harbouring cancer even though the
biopsy shows nothing.
There are currently at least two large-scale trials underway to determine whether PSA screening is
beneficial or harmful overall. However, the results of these trials are not expected until the year 2009. In
the meantime Dr. Barry recommends that men aged 50 to 75 years of age (with no established risk
factors) should be made aware of the availability of the PSA test and its potential harms and benefits so
that they can make an informed choice about having the test. They should receive information on the
- the likelihood that prostate cancer will be diagnosed;
- the possibilities of false negative and false positive results;
- the anxiety associated with a positive test;
- the uncertainty regarding whether screening reduces the risk of death from prostate cancer.
Several studies have shown that providing this information significantly reduces the proportion of men
who decide to be tested.
Barry, Michael J. Prostate-specific-antigen testing for early diagnosis of prostate cancer. New England
Journal of Medicine, Vol. 344, May 3, 2001, pp. 1373-77
Should men be screened for prostate cancer?
MONTREAL, CANADA. Physicians in North America are becoming increasingly
enthusiastic about screening men for prostate cancer. Prostate cancer is now
the second most common cancer among Canadian men and is second only to lung
cancer in cancer mortality. The two screening tests commonly used are the
digital rectal examination (DRE) and the prostate-specific antigen (PSA)
blood test. Recently some doctors have been warning against the wholesale
use of screening tests. Dr. Kenneth Marshall of the Queen Elizabeth Hospital
in Montreal emphasizes that obtaining the patient's informed consent prior to
testing is essential. This is because the PSA test in particular often gives
a false reading. This can lead to dangerous, invasive biopsies, and
subsequent even more dangerous surgery and radiation treatment. It is
estimated that 30 per cent of men undergoing radical prostate surgery become
impotent, five to six per cent become incontinent and about one per cent die
of the operation. Dr. Marshall concludes there is, as yet, no evidence that
screening for prostate cancer actually saves lives - a view supported by many
European urologists. He also points out that screening and biopsies may
actually do more harm than good in cases where the tumor might have remained
dormant or only grown very slowly.
Marshall, Kenneth G. Screening for prostate cancer. Canadian Family
Physician, Vol. 39, November 1993, pp. 2385-90
Prostate cancer reaching epidemic proportions
LONDON, ENGLAND. More than 100,000 new cases of prostate cancer are now
detected in the U.S.A. and about 33,000 American men die from this disease
each year. In the U.K. prostate cancer claimed 9,400 lives in 1992. The
cause of the rise in cases is unknown. Alcohol and smoking are not
implicated, but diet may well be. Thus the incidence amongst men eating a
typical western diet is about 100 per 100,000 as compared to 6 per 100,000 in
the Far East. Many men are unaware that they have a prostate tumour. As a
matter of fact, latent prostate cancers are found in more than 70% of men
over the age of 80, but are not the cause of their death. Recent publicity
in the U.S.A., fuelled by the treatment of Senator Robert Dole for prostate
cancer, has heightened the awareness of the disease. The total research
budget for prostate cancer in the U.S.A. has been increased from $10 million
to $24 million annually and all men are now advised to have a rectal
examination and a PSA (prostate specific antigen) test every year. While
this is expected to detect about 30 to 40% more cancers some medical doctors
are sounding a warning: many men have no complications from their prostate
tumour and go on to die of unrelated causes - is it right to affect the
quality of their lives by telling them that they have prostate cancer?
Siddall, Rhonda. Time to screen for prostate cancer? New Scientist,
February 6, 1993, pp. 27-30
Is screening for prostate cancer worthwhile ?
TORONTO, CANADA. The controversy over the benefits of screening for prostate
cancer rages on. Now researchers at the University of Toronto have concluded
that testing men with no overt symptoms of prostate cancer is inadvisable.
They found that screening often precipitates invasive procedures and that the
overall effect on quality of life is negative. Specifically, they found that
a one-time screening with prostate-specific antigen (PSA) or transrectal
ultrasound (TRUS) resulted in only a very small increase in life expectancy
in randomly selected men between 50 and 70 years of age. The increase in
life expectancy was far outweighed by a net loss in the quality of life due
to complications (impotence, incontinence, rectal injuries) occurring during
invasive testing procedures and surgery. Screening with a digital rectal
examination (DRE) produced no reduction at all in mortality from prostate
Krahn, Murray D., et al. Screening for prostate cancer: a decision analytic
view. Journal of the American Medical Association, Vol. 272, No. 10,
September 14, 1994, pp. 773-80
Are prostate cancer rates really growing?
DETROIT, MICHIGAN. The incidence of prostate cancer has seemingly grown
rapidly in recent years. In the Detroit area an increase in invasive
prostate cancer of 72 per cent has been observed between 1988 and 1991.
Researchers at the Michigan Cancer Foundation now believe that the observed
increase is due not to the fact that more men get prostate cancer, but rather
to a much more widespread use of the prostate-specific antigen (PSA) test.
They point out that the use of the PSA test almost quadrupled in the period
1990 to 1992. This rise in test volume is paralleled by a dramatic increase
in the rate of radical prostate surgery (prostatectomy) which also quadrupled
in the Detroit area between 1987 and 1991. The researchers believe that the
"rise" in prostate cancer with the advent of the PSA test is analogous to the
"rise" in breast cancer coinciding with the widespread use of mammography.
They also point out that the benefit of aggressive local therapy such as
prostatectomy as a cure for prostate cancer remains uncertain.
Demers, Raymond Y., et al. Increasing incidence of cancer of the prostate.
Archives of Internal Medicine, Vol. 154, June 13, 1994, pp. 1211-16
Screening for prostate cancer not recommended
HOUSTON, TEXAS. Over 165,000 new cases of prostate cancer were diagnosed
among men in the United States in 1993 and 35,000 died from the disease. The
increased use of screening tests has long been advocated by the medical
community as a means of lowering the death toll. Now researchers at the
University of Texas have reached the clear conclusion that periodic screening
of men with no other symptoms of prostate cancer is not recommended. They
base their conclusion on the fact that there have never been any medical
trials which showed that early diagnosis increases length of survival or
quality of life. Early detection of microscopic cancers may lead to invasive
biopsies and treatments which in turn can result in impotence, incontinence
and even death. A recent study found that even with the "best possible"
treatment (radical prostatectomy and radiation) a patient with a nodule
identified by DRE (digital rectal examination) would have been better off if
the nodule had been left alone. Other studies have shown that watchful
waiting is a reasonable clinical management strategy if a prostate nodule is
found. The researchers conclude that when quality-of-life factors are
considered, screening men for prostate cancer is not indicated.
Cantor, Scott, B., et al. Prostate cancer screening: a decision analysis.
The Journal of Family Practice, Vol. 41, No. 1, July 1995, pp. 33-41
Cancer screening comes under increasing scrutiny
BOSTON, MASSACHUSETTS. Many cancer researchers are becoming concerned about
the development of more and more sophisticated screening tests. Professor
Suzanne Fletcher, MD of the Harvard Medical School says "Our tests and
technology may have outstripped our ability to distinguish lesions that look
like cancer under the microscope but don't act like it." Other researchers
point out that 50 per cent of men have signs of prostate cancer, but
nevertheless die from other causes. Similarly, 20 to 30 per cent of women
have signs of breast cancer when autopsied but only 3 to 4 per cent of all
women actually die of breast cancer. The criticism is particularly heavy
when it comes to the prostate-specific antigen (PSA) test. Dr. Barnett
Kramer, MD of the National Cancer Institute points out that the rate of
prostate cancer diagnosis is going up faster than any other cancer on record
and the rate of prostate surgery (prostatectomy) is following right along.
Complications of impotence, incontinence, and bowel dysfunction after surgery
"are on the order of tens of percents" says Dr. Robert Nease of the
Washington University Medical School in St. Louis. Dr. Nease concludes
"That's a pretty steep price to pay for unproven benefits."
Holzman, David. Screening tests pick up too many indolent cancers. Journal
of the National Cancer Institute, Vol. 87, No. 20, October 18, 1995, pp.
Accuracy of PSA test questioned
DALLAS, TEXAS. The PSA (prostate-specific antigen) test is commonly used to
screen men for prostate cancer. A PSA level of greater than 4.0 ng/mL is
generally considered indicative of possible prostate cancer and often
triggers an invasive and potentially dangerous biopsy (transrectal
ultrasound-guided prostate biopsy). Now researchers at the Dallas Veterans
Affairs Medical Center report that a single PSA test may not be reliable
enough to serve as a basis for the biopsy decision. Their study involved 295
men who had had a PSA test twice within a period of 90 days. The reseachers
found that 30 per cent of the patients tested had a PSA difference of more
than 1 ng/mL between the two measurements. They conclude that 10 per cent of
all patients having a single PSA test would be told either that everything
was OK when in fact they might have cancer or be subjected to an unnecessary
biopsy. The researchers recommend that physicians make up their own mind as
to the level of error they are comfortable with and then repeat the test
accordingly. For instance, if a doctor is only willing to accept a 20 per
cent or lower probability of being wrong he would repeat the test if the
first PSA test gave a value between 2.3 and 8.6 ng/mL. If however, he was
willing to accept a 50 per cent risk of being wrong he would only need to
repeat tests with values between 3.5 and 4.9 ng/mL. Further statistical
evaluation of the data collected by the researchers confirmed that PSA values
tend to increase with age from a mean of 1.4 ng/mL between 40 and 50 years of
age to a mean of 3.6 ng/mL for men aged 70 to 80 years. The researchers also
found that a standard digital rectal examination (DRE) correlates quite well
with the PSA test. Men with a normal prostate according to the DRE test had
a mean PSA level of 2.44 ng/mL while men with a suspected cancerous tumor on
the prostate (according to the DRE test) had a mean PSA level of 3.73 ng/mL.
The researchers question the validity of using one standard value (4.0 ng/mL)
as a cutoff point to determine if a biopsy is needed. They suggest that the
cutoff point should depend on the patient's age with 2.5 ng/mL being the
cutoff point for men 40 to 50 years old rising to 6.5 ng/mL for men 70 to 80
Roehrborn, Claus G., et al. Variability of repeated serum prostate-specific
antigen (PSA) measurements within less than 90 days in a well-defined patient
population. Urology, Vol. 47, No. 1, January 1996, pp. 59-66
More tests lead to more surgery
PORTLAND, MAINE. Physicians have long been puzzled why some areas of the New
England states have very high rates of heart surgery while others have
relatively low rates. Now researchers at the Maine Medical Center report
that the amount of heart surgery (bypass surgery and angioplasty) done in an
area is almost entirely dependent upon how much diagnostic testing is done in
that area. In other words, it bears little or no relation to the actual
prevalence of heart disease. The researchers found a strong linear
relationship between the number of stress tests done in a certain
geographical area and the number of subsequent angiography examinations and
surgical interventions. This relationship could only be explained by
concluding that more testing leads to more surgery. Other New England
researchers have arrived at a similar conclusion and have also discovered
that more mammography leads to more biopsies and more breast surgery, that
more spine x-rays lead to more back surgery, and that more prostate biopsies
and most likely more PSA tests lead to more radical prostatectomies. The
researchers conclude that "how much disease is diagnosed depends on how hard
one looks." They also suggest that physicians should recognize that just as
more therapy may be harmful so may more diagnostic tests. The total Medicare
billings by American physicians in 1993 for diagnosis and treatment of
coronary heart disease exceeded one billion dollars. Medical researchers
estimate that 80 per cent of all angiographic procedures are inappropriate
and that half of all bypass operations performed in the United States are
unneccessary or of no benefit.
Wennberg, David E., et al. The association between local diagnostic testing
intensity and invasive cardiac procedures. Journal of the American Medical
Association, Vol. 275, No. 15, April 17, 1996, pp. 1161-64
Verrilli, Diana and Welch, H. Gilbert. The impact of diagnostic testing on
therapeutic interventions. Journal of the American Medical Association, Vol.
275, No. 15, April 17, 1996, pp. 1189-91
Screening for prostate cancer comes under fire - again!
BRISBANE, AUSTRALIA. The controversy over the routine screening of healthy
men for prostate cancer using the PSA (prostate specific antigen) test
continues. Now Australian medical doctors and researchers have come out
strongly against the practice. The Australian team estimates that if 100,000
men over 50 years of age are screened with the PSA test, about 15,000 will
show a positive result, i.e. possible cancer. These 15,000 men will likely
have a biopsy which, in itself, is by no means without danger. Of the 15,000
about 4,500 will have a positive biopsy result and will presumably be exposed
to further treatment in order to "cure" the cancer. The remaining 10,500
will suffer considerable anxiety while waiting for their biopsy results. The
researchers point out that there has been no scientifically valid studies
which prove that treatment is more beneficial than no treatment or that
screening can extend or improve quality of life. The preferred treatments,
however, have very serious side effects. It is estimated that 60 to 90 per
cent of men undergoing radical prostatectomy become impotent while 30 to 40
per cent develop some degree of incontinence. Between 40 and 70 per cent of
men exposed to radiotherapy also develop impotence. The researchers suggest
that routine screening for prostate cancer is comparable to screening for
lung cancer. Even though lung cancer kills five times more men than does
prostate cancer nobody advocates a routine screening program for lung cancer
- for the simple reason that no effective treatment is available for this
disease. The researchers conclude that screening men with no other symptoms
of prostate cancer is inadvisable.
In a separate research paper Dr. Brian Cox of the Otago Medical School in New
Zealand echoes the Australians' recommendation and points out that no proper
trials have ever shown that screening has an effect on prostate cancer
mortality. He concludes that recommending asymptomatic patients have a PSA
test is unethical.
Hirst, Geoffrey H.L., et al. Screening for prostate cancer: the case
against. Medical Journal of Australia, Vol. 164, March 4, 1996, pp. 285-
Cox, Brian. Prostate cancer screening is experimental. New Zealand Medical
Journal, Vol. 109, March 8, 1996, pp. 63-4
New early warning signal for prostate cancer
BOSTON, MASSACHUSETTS. Researchers at the Harvard Medical School report that
they have discovered a new diagnostic test which will predict men's risk of
prostate cancer years before the cancer actually develops. Their discovery
is part of the ongoing Physicians' Health Study which was started in 1982 and
involves almost 15,000 physicians. By March 1992 520 cases of prostate
cancer had occurred among the physicians. In 152 of these cases enough blood
plasma had been collected in 1982 to perform analyses for the content of IGF-
I (insulin-like growth factor-I). These analyses were done in 1997 and the
results compared to analyses done on 152 plasma samples from 1982 obtained
from physicians without prostate cancer. The researchers found that survey
participants who later developed prostate cancer tended to have higher levels
of IGF-I in their blood than did the controls. Men with IGF-I levels in the
upper quartile (25 per cent) were found to have a 4.3 times greater risk of
developing prostate cancer than did men with levels in the lower quartile of
results. On average, there was a seven-year lag between the appearance of a
high IGF-I level in the blood samples and the actual diagnosis of prostate
cancer. The importance of high IGF-I levels was found to be particularly
significant for men over 60 years of age. In this age group men with IGF-I
levels in the highest quartile were almost eight times more likely to later
develop prostate cancer than were men with levels in the lowest quartile. It
is interesting to note that many of the men with elevated IGF-I levels who
later developed prostate cancer had normal PSA levels (less than or equal to
4 ng/ml) when the blood samples were collected. The researchers conclude
that IGF-I levels may serve as an early warning signal for prostate cancer in
much the same way as high cholesterol levels serve as an early warning for
atherosclerosis and heart disease. They also raise concern that
administration of growth hormone and specifically IGF-I to delay the effects
of aging in older men may increase the risk of prostate cancer. Other
researchers (data still unpublished) have found an equally strong link
between IGF-I levels and the risk of breast cancer and are currently
investigating an association with colon cancer.
Chan, June M., et al. Plasma insulin-like growth factor-I and prostate
cancer risk: a prospective study. Science, Vol. 279, January 23, 1998, pp.
Barinaga, Marcia. Study suggests new way to gauge prostate cancer risk.
Science, Vol. 279, January 23, 1998, p. 475