In the recent press there has been much to do about the PSA now losing support. See "Widespread prostate cancer test (PSA) losing support?" in this blog. Unfortunately this publicity is negative to what we have learned in the past 10 or so years. Nothing could be further from the truth in today's medicine. However the PSA test has many variables and if these variable are understood and accounted for the PSA would be very accurate in diagnosing prostate cancer. Unfortunately the adjustments that need to be made are not fully understood or applied by the General Practitioner or even the Urologist. I will attempt to cover some of the reasons why the PSA is not accurate and what can be done to find the PSA that is created by the tumor itself.

Dr. Stamey Speaks (and maybe too loudly)

Authors comment: This paper is a discussion of PSA and how it might be effected by different things. This is not a treatise from a physician and should not be interpreted as medical advice. It is written for a patient’s consideration and for said patient to discuss its contents with the physician in order for you to better direct your treatments. An educated patient will have better results in the long run.

Dr. Stamey is a retired Urologists (at least retired from seeing patients) at Stanford University. However he has not retired from research as he has some 1300 specimen prostate glands that are sliced and diced and recorded. It is from this group of specimens that he has been developing a theory about PSA.

Basically what he has said is that with a PSA of under 10, he has no idea if there is any cancer or not from the PSA. And this is true – but more on this later. In addition he says that prostate cancer should be diagnosed from a DRE (Digital Rectal Examination). The problem is that not all DRE’s are equal. In my own case I had 5 DRE’s and only one found cancer – and guess who found something YEP! Dr. Stamey.

Now let me tell you that when Dr. Stamey does a DRE you know that he is doing it like no one else. I thought I was going to bite his finger there for awhile. He puts you on a table on your knees and elbows and digs, and digs, and digs, If every doctor did a DRE like this instead of the normal ”finger wave“ I might agree with him that this is an important way to find cancer. The truth of the matter is that most doctors do not take the time or have the skill to feel much in the gland and we see time after time a negative PSA with some significant cancer. If I had my choice of making a treatment decision based on PSA or the DRE – I believe that I would choose the PSA when consideration is given to the 6 items below. But, of course, both would be better.

THINGS THAT CHANGE THE PSA

Why is a PSA of less than 10 such a problem? Simply because PSA is not cancer specific! Lets itemize the things that have to be taken into consideration,

1. Age

As one gets older the gland gets larger. As the gland gets larger it produces more PSA. We call this condition BPH. We will also see BPH in younger men. But the growth of the gland is very small and the increase of the PSA would be minor over the short term but can be large over the long term. How to we correct the PSA for BPH.

2. Infections

In addition we develop an infection in our prostate gland that we call prostatitis. Frequently we will see PSA’s that go up and down over a period of time. I believe that this is due to prostatitis. So we need to find a way to rule out any prostatitis in the PSA result. There are some who think that any infection in the urinary tract may increase the PSA.

3. Daily Changes

It seems that the PSA when taken on a daily basis may change as much as 30% from one day to another (from 4 to 5.2 for example or 2.8). Again we have a variable that must be considered. We suspect that this is the normal rhythm of the body. But it must be taken into consideration,

4. Activities

We also know that there are certain activities that on might do that might exercise the prostate area. It seems that anything that one does that is involved in this area may increase the PSA. Things such as ejaculation, bike riding, weight lifting, prostate massage, urinary retention, race, certain medications, certain herbal supplements, may have an effect.

5. Difference in Assays

There are several different kinds of PSA tests (or assays). Each of these have a unique way to measure the PSA and each of them can be different. The difference may not be the same all along the line. Some are thought to have higher values at lower levels and others with low levels may be higher at higher levels of the PSA.

6. Lab Variance

Now that we have the above items that must be included in the consideration of the PSA between 0 and 10 (and sometimes higher) is there anything else that can make a difference.

The answer to that is – YES. The test itself, how the blood might be handled and how often the equipment is calibrated, the age of the assay serum, - all play a role. There is a national testing lab that send out some 2500 identical samples to the labs on a quarterly basis and asks that they return their results of testing. For example on one sample sent to 2689 labs the following was found:

Low 5.3

Median 7.3

High 12.8

Mean 7.36

SD 0.79

95% Confidence Level

Range 5.78-8.94

7. Gleason/PSA CONSIDERATIONS

We know that the higher the Gleason Score the lower the PSA. For example I have seen a Gleason of 4+5=9 show a PSA of only 0.8. Yet another consideration that has to be taken into mix.

ADJUSTMENTS TO BE MADE

Now that we have established that there are many things, not including the tumor load, that can change the PSA – how do we adjust for each one of the 7. Following is a discussion of things that might be done to get a reading of the tumor caused PSA.

First let us agree to one thing. No biopsy decision should be made on the basis of one PSA. PSA’s must be taken over a period of time to see what the trend is and also to check what we might do below to adjust the PSA. No treatment decision should ever be made on the basis on one PSA for the same reasons.

For this paper I am referring to PSA’s that lead one into the decision making process of getting a biopsy and trying better to understand Dr. Stamey’s findings. Since most of the 6 items above are involved in the original diagnosis they must be looked at and adjusted for in any diagnosis until be get at a PSA that we believe may represent the actual tumor load. If we do thins we can probably throw Dr. Stamey’s theories out the window.

With that in mind lets look at each of the items and see how we might adjust.

1. Age

"As one gets older the gland gets larger. As the gland gets larger it produces more PSA. We call this condition BPH."

This is indeed true and it is this BPH that Dr. Stamey says is the cause for most of the PSA in the glands in men these days. This would be more true the older you get. Actually we have what is called "Age Adjusted PSA" which allows for the PSA to adjust upwards the older you get. This is also one of Stamey’s papers some years ago. There has been several papers presented since that time looking to see what would happen to some patients who never got to the "Age Adjusted PSA". Dr. Catalona, a well know Urologist Surgeon, in looking at the overall picture found that one should look at a PSA of anything 2.6 and over as having a possibility of cancer. He gave statistics on how many cancers would be missed if we used a standard PSA of 4.0 before we did a biopsy.

So we have some well known Urologists who are at odds with each other in terms of when the PSA becomes important. This is no surprise in this disease. If you looked at 10 equally great Urologists you would probably get 10 different answers.

But, as so many times happens, the doctors do not go far enough!

We all know that the larger the gland the higher the PSA. Would it not make sense that one might be able to come up with some kind of a formula that would be able to estimate what a gland of a certain size might produce in PSA. And this has been done but there are few medical professionals out there who would ever apply the formula.

Simply speaking it is estimated that if you take the size of the prostate gland and multiply it by 0.066 you will get some idea of how much PSA is being caused by the enlarged gland. For example lets say that you have a 40cc gland. Take 40 x 0.066 and you arrive at a figure of 2.64. This would be the estimated PSA from a 40cc gland. So we can subtract this from the total PSA and we get closer to the PSA caused by things other than the gland size.

Now I believe that this is somewhat too high and in large glands may be higher than the reported PSA. You have to take into consideration as to how the Gland is measured. To begin with it is measured by the DRE and the doctors finger playing a guessing game. It would not be unusual to see an error of 25% in this method of blindly measuring a gland. We really need to apply a correction figure low and high when we are doing our calculations. This is therefore not a hard and fast rule but one that gives us a ball park figure to look at. This is also involved in item 7 above.

2. Infections

"In addition we develop an infection in our prostate gland that we call prostatitis."

Prostatitis is a common ailment that increases with age and likewise it increases the PSA. There are two kinds of prostatitis, one caused by bacteria and one whose cause is non-bacterial. They each take different treatments.

It seems that once we get prostatitis we can never get rid of it. It keeps returning to old men (and sometimes younger men). It is treated and a few months later it is back again. It seems to rise and fall almost on a daily basis and makes the PSA go up and down. It is extremely difficult to rid the gland of this condition. It seems that what we might do for other bacterial infections will simply not work for prostatitis.

The treatment of choice for bacterial prostatitis is the antibiotic Cipro for a length of 4 to 6 weeks. The more severe cases may even take longer - maybe two 4 to 6 week sessions. But prostatitis caused by bacteria is not the most common but it is the most common one that the Urologist looks for and if he does not get a positive he simply rules out prostatitis.

By far the most common prostatitis in the non-bacterial type. Here Cipro has very little effect. This is what we think of as being an inflammation and a swelling by other unknown causes. The treatment of choice here is a class of drugs called NSAID’s These drugs include aspirin, ibuprofen (Advil) and prescription drugs like Celebrex and Vioxx. In terms if fighting the infection these dugs are far more effective and work much quicker but they do not touch the bacterial prostatitis.

And sometimes you may have a combination of both. I would say that if you have a bacterial caused prostatitis you will also have inflammation and swelling caused by other things. However, I do not believe that this works the other way. You can have non-bacterial caused prostatitis without having prostatitis caused by bacteria.

What I think would be the proper route to take with any elevated PSA is if you have been treated before with a antibiotic for prostatitis, take Cipro for 6 weeks along with your NSAID of choice at the same time and for the same period. Than retake your PSA.

If you have never been diagnosed with bacterial caused prostatitis you might be able to just take 2 to 6 weeks of a NSAID depending on the drug and the amount taken. Retake your PSA and if there is no change - treat with Cipro and retake your PSA.

Now we have a way to get even closer to tumor caused PSA.

3. Daily Changes

It seems that the PSA when taken on a daily basis may change as much as 30% from one day to another (from 4 to 5.2 for example or 2.8)." I also believe it may change within a day by the same amount. For example we had one man who decided to run a test for 30 days. He tried to make everything equal, test at the same time at the same lab, etc. He found:

a. He had a high of 6.0 and a low of 4.5 (and actually over just 3 days). That would be an increase over the low of 33%.

b. A decrease from that 6.0 to a 4.6 (and over just 3 days). That would be a decrease from the high of 23%.

c. The biggest up tick in one 24 hour period was from a 5 to a 6 - a rise of 20%.

One might therefore say that any PSA could be off by as much as 30%. In the examining of the actual daily test results, I found a 28 day rhythm. Unfortunately since I could only look at 30 days I could not see if it was indeed a 28 rhythm or just a fluke in this instance.

When you are getting ready to take a PSA let me recommend that you avoid any caffeine, alcohol or spicy foods for a couple days prior to taking the PSA. Take the PSA the first thing in the morning before you eat. If you do this ever time you will get more consistent results. It is little know and seldom discussed but I was told this my a doctor who heads a national testing laboratory who tests some 2500 labs on a quarterly basis for PSA standardizing. I have made this a practice actually for all blood tests.

4. Activities

We also know that there are certain activities that on might do that might exercise the prostate area. It seems that anything that one does that is involved in this area may increase the PSA. Things such as ejaculation, bike riding, weight lifting, prostate massage, urinary retention, race, certain medications, certain herbal supplements, may have an effect.

The following listing of physiologic conditions and manipulations that affect PSA serum levels is a from S Yox: "To Screen or Not to Screen? The Controversy Over Prostate Cancer." Laboratory Medicine V29, No 8. Aug/98.

Condition           Manipulation Increase Effect on PSA Level Persists Up To

Acute bacterial prostatitis   5-7 fold        6 weeks

Acute urinary retention       5-7 fold        6 weeks

Digital Rectal Exam (DRE)   Variable        3 days

Exercise - bicycle                 0-3 fold        1 week

Prostate biopsy            Very Variable      6 weeks

Prostate massage              Variable        6 weeks

Ejaculation                         Variable        3 days

TURP                            Very Variable      6 weeks

I added the DRE to the above. I also believe that at least 8 weeks following the biopsy would be better.

MY COMMENTS: In addition bike riding, weight lifting, horse back riding or any activity that may put a strain on the prostate area should be avoided for at least 48 hours before the blood draw. Stress is also thought to be a contributing factor.

Preparation for a PSA test

Let me recommend that you avoid any caffeine, alcohol or spicy foods for a couple days prior to taking the PSA. Take the PSA the first thing in the morning before you eat. If you do this ever time you will get more consistent results. It is little know and seldom discussed but I was told this my a doctor who heads a national testing laboratory who tests some 2500 labs on a quarterly basis for PSA standardizing.

5. Difference in Assays

There are several different kinds of PSA tests (or assays). Each of these have a unique way to measure the PSA and each of them can be different.

There is no study evidence on this as to which are low and which are high. We know from experience that this is true. It seems that some assays give higher low readings and lower high readings or the other way around. If you took the same blood and sent it to different labs with different assays you would get different answers. Actually you may well get different answers from different labs using the same assay.

I have continuously looked for some way that I can adjust the different assays to a common number but have been unable to do so. All we can do is suggest that you get the blood drawn for the PSA from the same lab using the same assay.

6. Lab Variance

Now that we have the above items that must be included in the consideration of the PSA between 0 and 10 (and sometimes higher) is there anything else that can make a difference. PSA results vary considerably due to several factors. The first is random lab error which is always present because nothing can be measured with 100% accuracy.

The second factor is called systematic error. These are errors that result because one lab may use a different analytical technique (assay) for reading the PSA, or the labs may calibrate differently. The one factor we cannot control is random lab error. Periodically a survey is taken of thousands of labs to detect their random error in measuring PSA. Identical blood samples are sent to all labs for a PSA reading. In the study available to us at this time, six samples were sent to over 2500 labs. Each sample contained a blood sample with a different PSA level from about 0.2 to 19.4.

The results reported by each lab are analyzed to obtain the mean reading, the standard deviation from the mean for each lab and for each PSA level (of the six different samples sent to each lab). This allowed for the determination of a 95% confidence range -- a range around the mean value reported that there is a 95% chance the real PSA value falls within (hence, 1 in 20 reported readings will be out of this range). The actual data, combined for all labs, even though they used different assays, are gathered. This random error range is higher then it would be if each lab were considered separately.

Various labs use different brand instruments with different precision (random errors and detection limits). Various labs use different calibration standards and from different batches and some may not always do calibration as required. This leads to a systematic relative error for each lab. These systematic errors, when pooled from 2600 labs, behave like random errors in the study. This is why all errors (systematic and random) can be combined. Thus, so-called standard deviations (SD) can be calculated, SD's only applying to random errors, not systematic errors.

For a given lab, any systematic error (due to inaccurate calibration) does not show up when doing repeated analysis on one blood sample. We would only see the random errors. Constant relative systematic errors are not a problem when we are interested in the PSA trend and this is the case when we always use the same lab. (I am ignoring here that within one lab, the relative systematic error may change when a switch is made to a different batch of calibration standards.) The results give the so-called 95% confidence intervals. For example, the first sample has a Mean PSA of 19.67 ng/ml and a Standard Deviation of 2.14 ng/ml. The true PSA remains unknown, but there is a 95% chance (probability) that is lies between 15.39 and 23.95. The latter "from-to" values are calculated from Mean - 2 SD and Mean + 2 SD respectively. At higher PSA values, we see that relative errors (%relSD or CV) are fairly constant, about 11%, whereas at low values, the absolute errors (SD in ng/ml) are fairly constant, about 0.10. (This behavior is quite normal in many analytical techniques). For a Mean of 0 ng/ml, the SD is more like 0.08. This implies that the detection limit is 0.16 (2 times SD at 0 PSA). The meaning of this is best given by examples:

Suppose that your blood sample is measured by one of the 2600 labs and you do NOT know which lab that is.

EXAMPLE FOR HIGH PSA

Your PSA is reported as 15.0 ng/ml

Because this is a relatively high value, you must consider RELATIVE errors (in %). Taking 2 relative standards deviations (%relSD) both ways, you get a 95% chance that the TRUE PSA is between 15.0 - 22% and 15.0 + 22%, that is between 11.7 and 18.3 ng/ml.

EXAMPLE FOR LOW PSA

Your PSA is reported as 0.30 ng/ml

Because this is a relatively low value, you must consider ABSOLUTE errors (in ng/ml). Taking 2 standard deviations both ways, you get a 95% chance that the TRUE PSA is between 0.30 - 0.16 and 0.30 + 0.16, that is between 0.14 and 0.46 ng/ml. This is better explained at http://www.prostate-help.org/capsava.htm

7. Gleason/PSA CONSIDERATIONS

We know that the higher the Gleason Score the lower the PSA. For example I have seen a Gleason of 4+5=9 show a PSA of only 0.8. Yet another consideration that has to be taken into mix.

This is a fairly well known fact among doctors who specialize in prostate cancer - but little known outside of these circles. A GP or a Urologist takes your PSA and finds it is 1.8. He tells you that you are OK come back in a year. But the fact is you may not be alright. The incidence of this is very small but it does happen with very aggressive cancers that have not yet spread and even some that have spread.

If you have a positive DRE with a low PSA then you need to think about having a biopsy. If you have family history I would suggest a biopsy at any PSA over maybe 1.5. No hard and fast rules but just be warned.

Additional Notes

The moral to this story is that any one PSA can easily vary as much as 25% and sometimes more. We saw one sample of the raw data from the chart on the web page that varied from 0.1 to 0.8 (a 800% change in the same sample - although a low number). Most of the variances in the laboratory tests were around 200% to 300% from low to high with the same standardized sample. These would be extremely rare but they obviously happen.

The PSA is not a reliable report of your tumor load except when. one has metastatic cancer and we follow it closely. In this case we can be talking about PSA's in the hundreds and sometimes thousands. A reduction from 167 to 75 may be a very significant occurrence.

If you do not have metastatic cancer, the PSA may be very unreliable to measure the progress of the disease. It is possible to maintain a low PSA and have a metastatic spread of the disease. It is also possible to have very high PSA's and have little or no prostate cancer. I have seen a PSA of 64 treated with Cipro and it was reduced to 7.

Another kind of PSA - the Free PSA

Is there other tests that we can look at that might better tell us if out PSA is caused by cancer? The simple answer to that is yes there is if the PSA is between 4.0 and 10.0. Sometimes this can be pushed down to a PSA of 2.5 and still be an effective measurement.

The PSA II or free-PSA ratio test is actually two tests. One measures the amount of free-PSA in the blood. The second test is a total PSA test (this is the "normal" PSA test). The result of the free-PSA ratio test is obtained by dividing one result by the other.

% Free-PSA ratio = free-PSA in blood sample/total PSA X 100

The result of this test is not an absolute for PCa. The higher the free-PSA ratio the lower the probability of PCa. All of this is based on the fact that patients with prostate cancer have significantly lower amounts of free-PSA circulating in their bloods. The two forms of PSA measured in blood are free-PSA and bound-PSA (bound to alpha-antichymotrysin) The two forms are immunoreactive and when measured in blood produce the result of the current PSA assays commercially available. In other words: Total PSA = free-PSA + bound PSA (PSA-ACT).

One of the problems with the Free PSA test is that although it allows for BPH in the gland, it does not allow for prostatitis. Therefore when prostatitis is involved the %fPSA (percent free PSA) will be lower and would indicate that one would have a higher chance of prostate cancer.

For additional information on PSA and Free PSA see http://www.marinurology.com/articles/cap/learning/psa.htm .

Here is how you read the %fPSA findings.

Free PSA and PSA chance of disease

Probability of Cancer based on PSA and % FPSA (Free PSA) results (men with non-suspicious DRE results, any age): % FPSA can stratify risk for men with PSA between 4 and 10 ng/ml.

PSA_ Probability of Cancer

0-2 ng/ml______1%

2-4 ng/ml______15%

4-10 ng/ml_____25%

>10 ng/ml_____>50%

%FPSA Probability of Cancer

0-10%_________56%

10-15%________28%

15-20%________20%

20-25%________16%

>25%__________8%

The original of the above Probability figures was presented in JAMA 279:1543, 1998.

Page Reviewed and/or Updated:

September 21, 2008