To PSA or not to PSA…that is the questio-Everything you wanted to know about PSA and not afraid to ask?

John Doe is 55 years old. He has no urinary symptoms. He goes for his annual physical exam. His prostate exam is normal, but his prostate specific antigen (PSA) blood test is 4.5, which is slightly elevated. His last PSA test was 2 years ago, and at that time it was 2.7. He is referred to a urologist and a discussion takes place regarding whether he should proceed to a prostate gland biopsy based upon this elevated PSA. What is he to do? This chapter will review the background of the PSA test. What is it’s purpose, and how it is used to make decisions regarding the diagnosis, evaluation and management of men with prostate issues and prostate cancer.

PSA is the most useful and accurate cancer marker of all the cancer “markers” used in medicine today. This statement is of almost universal agreement among physicians and researchers working in cancer treatment and research. Some of you may find that statement a bit startling in light of all the negative press that has appeared regarding the PSA test in recent history. Lets define then what is meant by a “marker.” This is different than cancer screening” which has actually been where the controversy surrounding PSA has arisen. A marker for a tumor is “A substance that can be detected in higher than normal amounts in the blood, urine, or body tissues of some patients with certain types of cancer.” (medterms.com) Other examples of tumor markers include CEA in the case of some gastrointestinal tumors, CA-125 as a marker in ovarian cancer, Beta-HCG and alpha-fetoprotein in some testicular tumors, and even abnormal cells found in a Pap smear used to detect cervical cancer in women.

But as markers go, the PSA test, in a patient diagnosed WITH prostate cancer (PCa), no marker is superior in monitoring the progress and even prognosis of a PCa patient as is the PSA test.

HISTORY OF PSA

It may seem as if we have always used the PSA test in screening for, and in evaluation and follow-up of men with prostate cancer, but its usefulness in this arena is actually of fairly recent onset. There is no question that the discovery of this tiny molecule has dramatically, and forever changed the playing field in the world of PCa.

Before the discovery of PSA the world of screening for, and of attempting to make an early and timely diagnosis of prostate cancer was entirely different. In the pre-PSA era, and this includes all the years prior to the late 1980’s and early 1990’s when PSA became clinically useful, it was very difficult for clinicians to diagnose PCa in a stage where it could be cured by the therapies of that time. Prior to the use of PSA as a screening tool, all we clinicians had at our disposal was our digital exam, our level of suspicion based upon a family history, and to some extent, a blood test called Prostatic Acid Phosphatase, or PAP. Unfortunately, in a large number of men eventually diagnosed by one of these methods, the cancer had often spread beyond the prostate, and hence, was incurable by the technologies of the time.

As strange as it may sound, the actual discovery of PSA is clouded in controversy, and it seems several scientists have been called the discoverers. PSA seems to have been first identified in he U.S., by Dr. Richard Ablin and his associates as early as 1970. A subsequent article by Dr. Ming Wang was published in 1979, and this has often has been cited, apparently incorrectly, as the first scientific article cited as the “discovery” of PSA. This 1979 publication however, was the first to advance the idea that the PSA test could purified and could be useful in detection of prostate cancer. At this point, research was then directed towards developing a commercially usable, reliable, reproducible, and reasonably priced blood test that could be made available to the public.

Some of the very early developmental research for PSA was on it’s presence in semen and to assess it’s properties and usefulness as a forensic marker for rape victims. Soon however, the usefulness of PSA as a screening tool for prostate cancer became quite evident, and as they say, “the rest is history.”

As early as 1981 research was demonstrating significant differences in the blood PSA levels in patients with benign, non-cancerous prostate enlargement (BPH) as opposed to men with prostate cancer. In addition, research in the early 1980’s was demonstrating that men with more advanced prostate cancers had higher blood levels of PSA than men with less advanced cancer.

So, as literally millions of data points were studied, what then is accepted as a “normal” PSA. The very simple answer is up to 4 nannograms per milliliter, or 4ng/ml. It’s never really that simple however. There are many nuances the physician must consider when evaluating a man and his PSA. For example a PSA of 3 in a man of 50 might be worrisome, where a PSA of 5 in a 75 year old man might not be. Change over time can be important. A man whose PSA went from 1 to 3 in one year, both “normal” numbers, might be more worrisome for cancer than a man who has had PSA’s between 5 and 7 over the past 10 years. More on this later, but for most lab reports you will see “normal” for PSA as between zero and 4.

During this same timeframe it was becoming apparent that men who had undergone curative treatment for prostate cancer had PSA levels close to zero, and that if the cancer reappeared, the PSA levels began to climb, making the test very useful in following, or monitoring patients to detect failure or success of treatment. In addition, it became clear that a rise in PSA could be seen usually long before the location of the recurrence could be detected by other means.

Despite all this favorable research data accumulating in the early 1980’s, PSA was originally approved by the FDA in 1986 to monitor the progression of prostate cancer in men who were diagnosed with the cancer. It may surprise you that it was not until 1994 that the FDA approved the PSA blood test , along with a digital rectal exam (DRE), to screen men without symptoms, for prostate cancer. Clearly, over this two decade period, screening for cancer with PSA and DRE has become commonplace in medicine.

Things have now gone backwards in the eyes of many clinicians, in that NOW, another governmental agency, the U.S. Preventive Task Force (USPSTF) recommends AGAINST prostate cancer screening. More on this controversial move, to follow.

Since PSA has dramatically changed our approach to screening for, diagnosing, and monitoring prostate cancer, what has changed in the two decades since this approach has been in full swing? The incidence rates for PCa took a significant upturn at the same time PSA test was approved by the FDA, and even before it was FDA-approved for screening of asymptomatic men. Clearly, clinicians recognized its utility for screening before it was “officially” approved for this particular use. The incidence rates of prostate cancer remain much higher than it was in the pre-PSA era. This is a reflection of our ability to diagnose the disease much earlier now, and not due to an actual increase in the true incidence of the disease in our society. One of the arguments of proponents of “non-screening” with PSA is that many more men are being diagnosed with cancer that might never have impacted their lives had it never been detected. More on this later.

Along with improved early detection brought on by the advent of PSA, the death rates have also begun to fall. This would certainly be anticipated. If we can diagnose cancer, or for that matter, almost any medical condition, before it is far advanced, our chances of cure or survival are enhanced. Death rates, calculated as rates per 100,000 males was rising slowly from about 1940 until about 1985 when the death rate took a spike through about 1995, and has fallen steadily over the past 20 years or so.

The number of men dying in the U.S. yearly from PCa is a little over 30,000. Many clinicians involved in studying this disease feel that if these men who die of the disease had been seeing a physician yearly, and had been undergoing appropriate screening we might be able to drop this number of deaths perhaps as much as 90%. Even with appropriate screening, and let’s say even if 100% of men over the age of 50, could be screened yearly for PCa, there would still be some deaths from the disease. Some men, albeit a small percentage, will develop a form of prostate cancer that is so aggressive and virulent, that even with the best treatments available to us today, we still cannot cure them.

Since it is intuitively clear to all of us, that early diagnosis of disease is good, and we all now know the wonderful utility of the PSA test in early detection of PCa, why has the test gotten so much negative publicity? In fact, if you have been watching, there has been almost no positive publicity in the past few years, but there has been an onslaught of negative. We physicians are asked daily now by our patients as to why there is this negativity, and then whether they should be doing the test. More about how to make the decision to test, or screen, for prostate cancer. Some guidelines to help you in this decision will follow in soon in this chapter.

We will look into the science, and some would call it “junk science” behind the recommendations of the U.S. Preventive Services Task Force recommendations against screening for prostate cancer, but let’s first take a look at some of the “politics” if you will, of cancer screening in general, as this puts a lot of it into a perspective we can all understand. A lot of this seems to be driven by finances on both a private, federal, and state level. Since a large portion of the costs of cancer screening is borne by governmental agencies, and most of the rest, by private insurance, the costs have to be taken into consideration. Now, for the thousands, or millions of Americans whose lives have been saved by early detection, and cure of their own bout with cancer, these cost issues seem quite secondary to them, and to their loved ones. They know cancer screening saves lives. They are living proof.

To actuaries looking from under their green eye shades at the numbers, screening for cancer, regardless of the lives saved, does not make good policy or financial sense. And, they would say arguably, the costs are not sustainable. We all know Medicare is going broke, despite the fact that any of us who have a job, and are receiving a paycheck, are paying not only for the private insurance we are using now, but also Medicare premiums are being taken out of every paycheck. So where does screening for cancer fit in this financial mileu?

Several cancers have taken a hit lately. Screening mammograms for early detection of breast cancer in women came under fire recently. Women rose up, and the government and insurance companies backed off. Screening for cervical cancer has come under fire, and the recommendation for screening for colon cancer, largely under the radar, has changed too. Will lives be lost? Will failure to detect early cost us in suffering and early demise of untold Americans? Of course. But in a dollars and cents world, screening for cancer is just too expensive. Let’s take a somewhat imaginary look at the numbers before we look at the USPSTF recommendations in detail.

Let us imagine a million men being screened annually for prostate cancer. Since the numbers used here are estimates, they are going to be off a little from what might be absolutely correct, but since the actual numbers are not obtainable, the numbers we use here at least give us a reasonably accurate framework. And this is done, only to try and put the costs of cancer screening into perspective.

So, back to our one million men being screening annually for PCa. Let’s suppose that this could be done for about $75.00 to include a doctor visit, the exam, and the blood test. Right away we have consumed 75 million dollars. Let’s say that of those million men, everything is normal for 800,000 of them-probably a reasonable estimate. We are through with them for this year. Now of the remaining men something in the exam, the blood test, or the medical history is concerning. The doctor has a concern that these men might have cancer. For those being screened by their primary provider, a consult with a urologist will be needed. Some of these men will be seeing a urologist for their yearly screening, but the others will have to be referred. Let’s say conservatively that of these 200,000 men, 50,000 will need a new and initial consultation with a urologist, and the cost could be around $100.00 for this initial consultation. $5,000,000 there. Some will go to immediate biopsy, but let’s say the doctors decide not to do a biopsy on half of the men, but simply to recheck them, and obtain another blood test in couple months. These would be the men for whom the urologist is not highly suspicious for cancer, but they still will need to be followed appropriately. Another couple million for the second visit and testing of blood for PSA. Now let’s suppose that out of the one million men being screened, only 1% are ultimately thought to need a biopsy. That would be 10,000 men times a conservative cost for biopsy of $1,000.00. Another $ 10,000,000 dollars for the biopsies. Now if 1 in 4 had a positive biopsy, probably 3 in 4 with cancer would need treatment. Millions and millions have been spent before treatment has even started.

So, using these numbers, which are reasonable, the screening costs for 1 million men is easily in the neighborhood of $100,000,000. Now, what if we are trying to screen 5 million men, or 10 million men, or more, yearly? You can see how this adds up to astronomical numbers. And this is only for one cancer. We have not even looked at screening for breast, colon and lung cancers which make up the rest of the “big four.”

With this financial meltdown facing health insurance providers one can see why screening for cancer has become such an issue, and perhaps these numbers factor into some of the decision making processes.

Let us now take a look at the Draft Recommendation Statement from the USPSTF. First, at this time, it is a draft. More will come. If you care to review it in detail, it is available at http://www.uspreventiveservicestaskforce.org/prostate/prostateart.htm.

However, the salient points will be reviewed for you here. Quoting, “The USPSTF makes recommendations about the effectiveness of specific clinical preventive services without related signs or symptoms.” Keeping in mind here, by the time a man has symptoms or signs of PCa, the cancer has spread beyond the prostate and is no longer curable.

Quoting: “Summary of Recommendation and Evidence. The U.S. Preventive Services Task force (USPSTF) recommends against prostate-specific-antigen(PSA)-based screening for prostate cancer. This is a grade D recommendation.”

What is a grade D recommendation? If you ever got a grade of D in school, you know it is not good! Specifically, the definition is: The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that harms outweigh the benefits. Their “Suggestions for Practice” here regarding screening for prostate cancer with the D rating, “Discourage the use of this service.”

Quoting further from the draft document:

“Prostate cancer is the most commonly diagnosed nonskin cancer in men in the the United States, with a lifetime risk of diagnosis currently estimated at 15.9%. Most cases of prostate cancer have a good prognosis, but some are aggressive; the lifetime risk of dying from prostate cancer is 2.8%. Prostate cancer is rare before age 50 years and very few men die of prostate cancer before age 60 years. The majority of deaths due to prostate cancer occur after age 75 years.”

Let’s take a quick look at this 2.8% risk of dying from prostate cancer. About 238,590 new cases will be diagnosed in the U.S. in 2013, and about 29,720 men die of this cancer in 2013 according to the National Cancer Institute estimates. It would appear from these numbers that the risk of dying from prostate cancer easily exceeds 10%.

The draft document goes on further to elaborate on harms of detection and early intervention to include risks associated with biopsy itself, the adverse effects of treatments be they surgery or radiation or hormone deprivation. Another risk is “overdiagnosis.” This, the panel seems to believe, results in many men being treated for cancer that never would impact their lives. Now since urologists and oncologists treating prostate cancer make every effort not to overtreat the insignificant cancers, we have to wonder what exactly is meant by this? As they were quoted above, “some of these cancers are aggressive,” is there a way to know which type (aggressive vs. non-aggressive) without a diagnosis? Do we as physicians owe it to our patients to help them make decisions for treatment based upon the best evidence we can provide? In most cases, one would answer yes to that question.

There is no doubt this panel put a monumental amount of time and effort into this document, and the conclusions they came to were based upon the evidence they felt was significant. They reviewed at least three large trials regarding prostate cancer, one called the PLCO, another, from Europe. The ERSPC trial, and the preliminary results from the PIVOT trial.

The USPSTF estimates that for every 1,000 men ages 55 to 69 who are screened every one to four years for a ten year period that only a maximum of one death from prostate cancer would be avoided. Using our estimated numbers above, this means it would cost about $1,000,000.00 to save one life. If this is true. There are other ways to run these numbers, and you mathematicians can have a field day with them, but you can see again, screening for cancer is very costly. Now we as physicians don’t see 1,000 men at a time, we see individual men just like you, and together you and I have to try and make our best decisions for your individual health. More on that decision making process later on.

On May 21, 2012, the USPSTF released it’s Final Recommendations of PSA Screening, and the final document confirmed what was said in the draft.

Urologists are at the forefront of being tasked with diagnosing, and in most cases, treating men with prostate cancer. We work closely with our oncology colleagues in men with very advanced cancer. The American Urological Association (AUA) has spoken out against the USPSTF recommendations.

The AUA’s position is one of outrage regarding the USPSTF position and takes the position that the Task Force “is doing men a great disservice by disparaging what is now the only widely available test for prostate cancer, a potentially devastating disease. We hold true to our current position s supported by the AUA’s Prostate Specific Antigen Best Practices Statement that, when interpreted appropriately, the PSA test provides important information in the diagnosis, pre-treatment staging or risk assessment and monitoring of prostate cancer patients.”

(Further 2013 position to be presented in May-will be elaborated here)

So, how are we, as men, to make decisions regarding PSA screening as it fits into our own individual lifestyle, expectations, and plans for our own medical futures?

In simplest terms, if you and your physician feel that if you are screened for PCa it would help you make decisions about the direction you would want to take if you were in fact diagnosed with prostate cancer, then screening is probably a wise step to take.

Let’s keep in mind a few facts. It is clear that PSA screening does reduce mortality from prostate cancer compared to men who are not screened. It is also true that screening has led to a diagnosis of PCa in men in whom the disease might never had caused problems. Many of these men were nonetheless, treated, hence “overtreatment.” It is also true that we as clinicians have gotten much better at helping to cull out those insignificant cancers and counseling our patients accordingly. It is also true that biopsy does carry some risk, albeit small, of serious infection. A small number of men, in our experience, less than 1% will require extended antibiotic therapy after a biopsy, and a few may even end up spending a few days in the hospital for post-biopsy fever and infection. It is also true that some men who are treated for prostate cancer will suffer adverse effects including incontinence, erectile dysfunction and bladder dysfunction. It is also true, that nearly all men who may have these effects can be adequately treated for these adverse consequences.

So, who should be screened? A life expectancy of 10 years is often used as a guideline. Clearly we don’t know how long we will live at any given time, but a very healthy 75 year old man might benefit from screening far more than a 60 year old man who has had a heart attack, bypass surgery, diabetes, high blood pressure and obesity. Now that 60 year old might live to a ripe old age, and that “healthy” 75 year old might have that fatal heart attack tomorrow. Hence, the dilemma we all face-patients and physicians alike. But we try to be as practical here as we can. But if you as a male patient feel that you would want to be in a position to make decisions regarding prostate cancer treatment if you were to be diagnosed, then the decision to screen is likely in your best interest. Our advice is to have this discussion with your physician before screening for prostate cancer.

HOW CAN WE IMPROVE SCREENING FOR PROSTATE CANCER?

With regards to PSA screening, what is on the horizon, and what do we have now to further refine and tighten our accuracy of screening for PCa?

Now that so much progress has been made with DNA and in clarifying the human genome, it seems likely that in the not to distant future, genetic identification of those either at high risk, or that in fact WILL develop prostate cancer seems plausible. We are not there yet.

From the National Cancer Institute, here are some ways that scientists and researchers are looking to improve PSA screening.

Free versus total PSA: The lower the free PSA is a percentage of total PSA the more likelihood of finding cancer, and a very low free PSA may be associated with more aggressive cancer. We like to see a free PSA greater than 25% of total. For example, a man with a total PSA of 5, and a free PSA of 2.5 has a 50% ratio. His likelihood of PCa is low (not zero though) Whereas the man with a total PSA of 5, and a free of 0.4 has a ratio of 8%, and his risk for having PCa right now is high. This is useful test, but not perfect.

PSA density of the transitional zone: To gather this information requires ultrasound measurements of the prostate, and though perhaps more accurate than PSA alone, this approach has not been fully validated.

Age-specific PSA reference ranges: Unless a man is taking medication to shrink the prostate, dutasteride or finasteride, the prostate grows a little each year. Hence there are more prostate cells to produce PSA. As a result, a “normal” PSA in a man of 70 may be different that “normal” at age 50. This approach lacks general acceptance in the urological community however, since its use may delay a diagnosis of PCa.

PSA velocity and PSA doubling time: You will recall earlier in this chapter we discussed the man whose PSA went from 1 to 3, as being perhaps more worrisome than a man with a PSA between 5 and 7 while being followed for a decade. Quoting from the National Cancer Institute, “Some evidence suggests that the rate of increase in a man’s PSA level may be helpful in predicting whether he has prostate cancer.”

Pro-PSA: There is quite a lot of work being done looking at these different inactive precursors of PSA, and there is some evidence that pro-PSA may be a better predictor, and hence a better screening methodology than PSA as we are using it today. This is not yet ready for “primetime” yet.

PCa3: This test is readily available for clinical use today, and has a place in our screening toolbox. PCa3 is a chemical produced in the prostate gland. In order to do the test, the physician must put a little pressure on the prostate while doing the digital rectal exam. This pushes a little prostate fluid into the urethra. The patient is then asked to urinate, and the first ounce or so of urine will contain that prostate fluid. This sample is then sent to a specialized lab capable of doing the test. If PCa3 is present in this urine sample, depending upon the degree, the risk of prostate cancer can be further elucidated. The nee for a biopsy can be refined depending upon the result of the PCa3.

One other approach that is receiving increased incidence we will mention only briefly here since this chapter is about PSA, but is being looked at as a screening tool for prostate cancer. This is not a blood test, but an imaging study. Prostate MRI with a powerful 3 tesla MRI machine has shown usefulness in imaging cancer with considerable accuracy within the prostate gland itself.

DEFINITIVELY DIAGNOSING PROSTATE CANCER:

As the science of prostate cancer diagnosis stands today, biopsy remains the only definitive way to make the diagnosis. There are a couple caveats here-a man with a PSA over 100 probably does not need a biopsy. A man who has on X-Ray definitive evidence of cancer in his bones, and a high PSA many not need a biopsy. However, this chapter is about screening, and especially screening in the man with no symptoms. In that man, biopsy of the prostate remains the final diagnostic test. The use of PSA and the other modalities mentioned above serve mostly to help the physician and the patient decide as to whether proceeding on to biopsy is indicated. We are trying to refine screening so that we will be able to avoid biopsy in many men because, as a result of screening tests, we can reasonably believe our patient does NOT have prostate cancer.

As is clear to all of you now, having read these pages, PSA remains an extremely valuable tool in our cancer screening toolbox. How it can be useful in the case of each individual patient remains just that, individual. With the information we hope you have gained in this chapter, you will hopefully be in a better position to understand the usefulness as well as the limitations of PSA screening. Hopefully the decision making process will be clearer to you as you have discussions with your physician regarding PSA screening for prostate cancer. For many of you, it will be quite simple. If for example, you are a healthy man between 50 and 70 years of age, and you already know that whether you have PCa matters to you so that you can make proper decisions, doing the test is a slam-dunk. This would include a wide swath of men. For some, it will not be so simple, and many factors will have to be considered prior to screening. We hope this chapter has helped.

Let’s go back to our patient described at the beginning of the blog: He is 55 years old, having no urinary symptoms and is in for his physical. His prostate exam is normal, but his PSA is slightly elevated at 4.5. Last year he did not have an exam, but two years ago it was 2.7. He is referred to a urologist and a discussion takes place regarding whether he should proceed to prostate gland biopsy. What should he do? What would you want to do it this was your data? Hopefully, you now have some parameters to help you make the decision in your own individual situation.

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