“Did you come in here sick or are they going to make you sick?”
(Overheard at a hospital entrance years ago when one friend greeted another. It still rings true today.)
A Government panel-The United States Preventative Task Force-recently issued a statement that men should no longer get screened for prostate cancer as they found the PSA blood test did not save lives, but instead resulted in needless medical procedures that left tens of thousands of men impotent, incontinent or both.
I have no argument on the latter. However, ruling out all PSA testing is tantamount to tossing the baby out with the bathwater. Can PSAs be helpful? My 30 years of experience says maybe, carefully and selectively.
Sweeping generalizations rarely reflect reality and the same probably holds true for the inference that the tPSA testing holds no clinically important impact. For any disease screening process to be effective the marker used should be able to identify some 80% or so of afflicted, but asymptomatic people, and who would have benefited from early intervention. Therefore, such a screening should be relatively specific for a disease, and associated with a low incidence of false positives while treatment of the disease diagnosed results in significant life extension.
Prostate cancer screening with a total PSA (prostatic specific antigen or tPSA) presents a dilemma. Why? Simply because the tPSA is a non-specific marker for prostate cancer.
Elevated tPSA usually means BPH
The usefulness of the tPSA as a prostate cancer screening agent has been of some concern to urologists for many years as its arbitrary normal, between 0-4 ng/ml, has a low specificity for prostate cancer. The tPSA is about as accurate as a coin toss (similar to the accuracy of the prostate exam or DRE) and the evaluation of a man based on one abnormal tPSA is associated with a lot of unecessary biopsies and “false positives” as this marker commonly reflects the benign enlargement component of the prostate or BPH and/or associated asymptomatic inflammation called prostatitis. That is, 70% of all men who undergo a prostate biopsy because of a tPSA elevated between 4-10 ng/ml (somewhat above normal) have no cancer but benign prostatic hypertrophy (BPH).
Furthermore, in many men where some cancer was found in association with an elevated tPSA, it was not the small amount of cancer that caused the tPSA elevation but the harmless benign enlargement or BPH component of the prostate. For tPSAs greater than 10 ng/ml, however, the positive predictive value for the existence of prostate cancer is better at about 42-72%.
The tPSA under 10 ng/ml does not correlate well with prostate cancer presence or amount. As well, the tPSA is unable to distinguish common (non-killer) from uncommon (killer) cancer.
On the other hand, some 15-20% of all men with a normal tPSA (4 ng/ml or less) are believed to have significant prostate cancer that may require treatment.
Adding further insult to the inaccuracy of tPSA screening is that high risk or aggressive prostate cancers with Gleason scores of 8 or more often have little, if any, rise in the tPSA at presentation or with cancer progression. In addition, after some treatments such as radiation, there can be an upgrading (from the original Gleason score) to these higher Gleason scores of residual or recurrent prostate cancer and with cancer progression that is not reflected in a rising tPSA.
Furthermore, there are several medicines that artificially lower the tPSA giving one a false sense of security. The spurious lowering of the tPSA in this way is probably without protective benefit. The medicines that commonly lower the tPSA are the Statins, NSAIDS, Thiazides and the
5 alpha reductase inhibitors like Proscar and Avodart.
Slow Growth- the prostate cancer cell takes one year to divide!
An important reason as to why we are still without adequate data on the results of the various prostate cancer treatment options is because the prostate cancer cell is generally very slow growing. On average, the prostate cancer cell divides every 475 days or so (between 380-570 days). This means that in some men the cancer cell can take close to 2 years to divide (mitoses are rarely, if ever, seen).Therefore, clinical studies reviewing prostate cancer treatment results and success would only be meaningful if these studies were taken out 20-30 years or so. Clearly, medical publications regarding radical surgery/robotics or radiation clinical studies have not taken account of this very slow cell division as prostate cancer recurrences can take 20 years or so to manifest, making 5-10 year clinical data meaningless. This slow rate of cell growth is also the reason why radiation is not always effective and why most men die with their prostate cancer rather than from it.
Does tPSA Screening Result in Life Extension?
Prostate cancer screening with the tPSA has never provided any significant scientific evidence for life extension after treatment of the cancer with radical surgery/robotics or radiation. Whether this finding is because most studies were loaded with non-threatening slow growing cancers and skewing the results in favor of inaction, is not clear.
More Risk than Reward
The prostate biopsy which is necessary to establish the diagnosis of a prostate cancer is associated with several possible significant complications. Furthermore, most of the prostate cancers that are diagnosed are slow growing and would never have impacted the patient’s survival. Despite this knowledge, most men with localized prostate cancer are still pushed towards treatment with radiation or radical surgery/robotics. For most men with a slow growing prostate cancer, these treatment options are overly aggressive as well as being responsible for several common complications making the treatment often worse than the prostate cancer disease itself. For example, the radical surgery/robotics option is non-FDA (Food and Drug Administration) trialed (simply rubber-stamped, FDA approved) and associated with some very significant complications including urinary leakage, loss of erections (or if maintained, has urine leakage during orgasm), shortening of the penis by 1-2 cms and psychological issues. Clearly, this operation is like no other and was faulty by design when first performed over 100 years ago and remains so today. Even without the all important FDA scrutiny, history will eventually conclude that this one operation produced so much harm for such little patient benefit.
Even so, some ardent proponents of radical surgery/robotics gloat about the numbers of surgeries they perform inferring that the more cases done lowers their complication rate. Unfortunately, these surgeons exhibit an obvious lack of comprehension between numbers done and whether or not these men underwent treatment appropriately.
Radiation, in addition to this treatment option not being tested through FDA controlled trials, has its own treatment complications.
In the final analysis for many men, the sum of the risks associated with prostate cancer evaluation, coupled with the complications of treatment, far outweighs any possible benefits. Especially so, when there is no significant scientific evidence documenting life extension.
Over-diagnosing and Over-treating Insignificant Prostate Cancer is an Epidemic
Since the majority of prostate cancers diagnosed and treated do not appear to impact the survival of the patient, it is important to bear in mind that the harder we look for prostate cancer (with ultra-sensitive PSAs, special MRI imagery, color doppler sonography, extended and multiple biopsies as well as special tissue stains), the more likely we are going to diagnose insignificant prostate cancer. This intensified hunt for the common insignificant early prostate cancer only puts more men at risk from the potential complications associated with evaluation as well as the increased “limp and leaking” from misguided treatment that fails to produce life extension. Over-diagnosing and over-treating insignificant prostate cancer is an epidemic.
Let’s Look at the Numbers
Although prostate cancer can strike 1 in 6 men (but is found more commonly in autopsy studies as an insignificant association, 70% in 80 year old men) and prostate cancer is the second leading cause of death in men after lung cancer, these numbers need to be put into perspective. Only one man in 380 over 50 years of age with a prostate cancer picked up on an abnormal tPSA will die from his cancer. Viewed from a different perspective, a recent European trial found that 50 men had to be treated for their prostate cancer (that was never going to affect them) in order to reduce one death.
In other words, most prostate cancers are insignificant non-killer cancers and their numbers outweigh by far the few killer prostate cancers. Many men with these non-killer cancers are encouraged by overzealous physicians to undergo aggressive complication ridden treatments like the radical surgery/robotics for their low risk prostate cancer. This scenario represents a classic example of over-treatment and can be likened to removing your arm for a little skin cancer on the hand.
The big dilemma for urologists is trying to minimize all of the complications associated with evaluation and treatment of prostate cancer while trying to identify those cancers that should be treated from those that do not. Calculating prostate cancer tumor volume may be meaningful and a tumor volume about 0.5 mls may be significant and treatment may be warranted.On the other hand, treating only higher Gleason scores (as in 7 or above) may not be reliable as similar Gleason 6 tumors can have differing malignant potential. Not all prostate cancers are the same and not all treatment options are suitable for every cancer. However, if a treatment is indicated, consideration of a less aggressive minimally invasive option such as hifu or cryoablation may be more appropriate.
How Can We do Better?
We can try to improve our focus on specificity for prostate cancer by measuring PSA components other than just the tPSA as well as instituting other forms of monitoring.
The following criteria may narrow the screening boundaries and improve the specificity for prostate cancer detection a little and help to decrease the incidence of complications associated with the prostate biopsy:
1) minimize tPSA testing of those men over 75 and/or those not likely to live another 15-20 years.
2) identify factors that may increase risk of significant disease such as:
family history of prostate cancer
men of African heritage
3) improve specificity of PSA testing by
a. measuring the tPSA as well as the free PSA (fPSA) to determine the %free PSA (comes with a table giving estimated probability of prostate cancer).
b. PSA density or dPSA (tPSA divided by prostate volume in ccs) and should be below 0.15
c. tPSA velocity, through serial tPSA measurements and can be meaningful if the tPSA rises to greater than 0.75ng/ml/year.
d. finasteride (proscar) suppression test by administering daily finasteride for 3 months and rechecking the tPSA. Failure for the tPSA to drop by 50% suggests a cancer may be present.
e. PCa3 test which involves a prostate massage and prostatic fluid assay.
Still too Many False Positives
Despite these somewhat more reliable tests listed above, all must be interpreted with caution as none of these markers exhibit a high specificity for prostate cancer. Presently, however, this is the best screening approach we have.
The evaluation of a man based upon a solitary abnormal tPSA should never be considered. Men who have one or more of these consistently abnormal values should be counseled about the possible benefits of a prostate biopsy and the options for definitive treatment if a significant cancer is detected. However, most men evaluated with a tPSA of between 4-10 ng/ml will not have prostate cancer (false positive). If a cancer is present, most men will have the common non-killer prostate cancers and not the less common killer prostate cancers. The patient needs to be clear about this as well as the potential complications (such as sepsis) associated with the needle biopsy of the prostate before considering an evaluation based upon abnormal tPSAs or their components.
Emotions and Quality of Life Issues
The word cancer carries quite an emotional charge and some men may elect to have their abnormal tPSAs evaluated through a prostate biopsy simply to prove to themselves that they have no cancer.
However, because prostate cancer is generally a very slow growing cancer in most men and most men will die with their cancer rather than from their cancer, and the treatments such as radiation and radical surgery/robotics are associated with severe complications that negatively impact their quality of life (QoL), afflicted men and their wives would do well to take charge and, with a very slow hand, empower themselves with knowledge before submitting to anything.
Many of these low volume, low risk prostate cancers do not need treatment and can be followed with active surveillance (AS).
This AS program is usually offered to those men who have a life expectancy of less than 20 years or so, have a normal prostate exam, a tPSA under 10ng/ml and/or PSA density under 0.15 and with at least a 12 core prostate biopsy showing two or less cores of prostate cancer (each less than 50% involvement) and with Gleason scores 6 or less (low volume low risk cancer).
Most of these men are reevaluated every 6 months or so with a tPSA test and undergo a biopsy on an annual basis. About 25% of men in an AS program may have progression of their prostate cancer while 75% do not.
Those men with a microfocus of prostate cancer (5% or less of a Gleason 6 prostate cancer in one core only) have even less chance of disease progression. In most, I will never detect another microfocus in a future biopsy and it is possible that the body’s own surveillance and defense mechanisms have disposed of it. The definitive treatment of any man with a solitary microfocus of prostate cancer also represents over-treatment.
Coexisting with Non-killer Prostate Cancer
Some men are uncomfortable living with untreated low volume low risk prostate cancer and some are only willing to undergo AS for a small number of years before they seek a more definitive treatment and resolution of their situation. However, trying to identify those prostate cancers that really need treatment from those in men who can coexist with their prostate cancer is a quandary for both patients and true physician patient advocates. Other men with localized high risk and/or high volume prostate cancer may benefit from a definitive treatment. Although there are four definitive treatment options for localized prostate cancer (hifu, cryoablation, radiation and surgery) and each with similar survival benefits, none have had their worth proven in scientifically run FDA trials. Self serving clinical trials, as well as philosophies of treatment, abound but they can never take the place of rigorous, blinded, long-term FDA studies. Rather than resolving this dilemma of what is the best treatment option, the prostate cancer industry along with a few arrogant physicians continue to make a mockery of honesty and truthfulness in data collection by falsely endorsing these clinical studies in place of real, scientifically undertaken FDA controlled trials.These FDA trials are fundamental to determining not only the worthiness of a treatment but the all important issue of which prostate cancers deserve treatment and which can be left untreated.
The current enthusiasm for prostate cancer screening with the tPSA alone is clearly not specific enough to justify its continued routine use in men over 50 and the push for testing of these men through the annual prostate cancer awareness program (September or “Blue” prostate cancer awareness month), may be doing more harm than good. Routine tPSA screening does not reduce the number of deaths from prostate cancer and each man needs to decide for himself whether to get his tPSA measured and if abnormal, whether to undergo a prostate biopsy. Testing and screening for prostate cancer with the tPSA needs to be considered carefully and selectively.
Bert Vorstman MD MS FAAP FRACS FACS
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