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Table of Contents for this page.

Lets start at the beginning

Obesity, BMI and PSA

Gleason Grade

Other things that effect PSA

Labs and their Variances

Before you have a biopsy, do the following.

Prostatitis and its affect on PSA

Placebo Effect

WHAT IS UNDETECTABLE?

CONCLUSIONS

References

For a Q&A about PSA go to the National Cancer Institute and read their paper by clicking "here".

Lets start at the beginning

PSA is a protein produced by the cells of the prostate gland. The prostate-specific antigen (PSA) test measures the level of PSA in the blood. A blood sample is drawn and the amount of PSA is measured in a laboratory. When the prostate gland enlarges, PSA levels in the blood tend to rise. PSA levels can rise due to cancer or benign (not cancerous) conditions. Because PSA is produced by the body and can be used to detect disease, it is sometimes called a biological marker or tumor marker.

The PSA does not measure only prostate cancer. It is also affected by the size of the gland and any infection (bacterial or non-bacterial) in the gland (prostatitis) and other traumas. In addition, the Gleason grade, time of day, perhaps day of month, different labs, different assays used, how a lab handles a sample, what you did in the last 72 hours, etc., may all effect the PSA. In this paper, we will attempt to cover these REASONS that may cause a variation of the PSA at any one time.

Size of the gland The size of the gland is usually dependant on age. The older we get the larger the gland. This is not always true and we do see younger men with large glands and older men with small glands. But this is a good rule of thumb to remember. Therefore the older a man gets the higher the PSA - BUT THIS DOES NOT MEAN HE HAS CANCER. Nor does it necessarily mean that the cancer is growing. We call this growth BPH (Benign Prostatic Hyperplasia)

Prostatitis

Prostatitis is an infectious disease that almost all men will suffer as they get older. It is very difficult to treat and cure permanently. The infection often recurs. The treatment of choice is the antibiotic Cipro for a period of 5 to 8 weeks which attacks the bacterial type of infection along with ibuprofen (or other NSAID) to attack the non-bacterial type. The gland can and usually does have both. As prostatitis grows and subsides the PSA fluctuates up and down and often in a significant manner. THIS DOES NOT MEAN THAT SOMEONE HAS PROSTATE CANCER if the PSA is being caused by prostatitis.

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Obesity, BMI and PSA

The Associated Press Updated: 1:09 p.m. ET Jan. 24, 2005

ATLANTA - A new study suggests a man’s weight may affect the accuracy of a common test to detect prostate cancer, leading researchers to warn that doctors could be missing the dangerous cancer in obese men.

Researchers at the University of Texas Health Science Center in San Antonio studied 2,779 men without prostate cancer between 2001-04. In the study released online Monday in the journal Cancer, they reported finding that the more obese the men were, the lower their levels of prostate-specific antigen or PSA. A PSA of 4.0 or lower usually means no cancer.

Previous studies have shown that prostate cancer is more aggressive in obese men than in men of average weight. The researchers wanted to see if the cancer’s detection was somehow being delayed in obese men.

The Texas study found that men had about 30 percent lower PSA levels than men of normal weight.

"That tells us it’s likely or it’s possible that prostate cancer detection may be delayed in overweight or obese men," said Jacques Baillargeon, associate professor of epidemiology at the health science center.

The research may encourage many doctors to take a closer look at the tests of obese men.

"For sure, I will be more vigilant in my patients who are obese in evaluating their PSA," said Dr. Nelson Stone of Mount Sinai School of Medicine, who was not involved in the study. "We may be losing some of the sensitivity of the test in the obese patient in our ability to detect prostate cancer. We may have to set our sights lower."

Biopsy recommended for high PSA The antigen used in the screening test is made by normal prostate cells and is measured in blood. The higher the antigen level, the more likely the chance of prostate cancer, as the cells multiply uncontrollably, according to the American Cancer Society.

But having high PSA levels is not a definitive diagnosis of cancer, which is why the Atlanta-based society recommends men with high PSA levels have a biopsy.

The latest study builds on previous research released in May in the New England Journal of Medicine that found that men with a "normal" PSA actually had cancer 15 percent of the time and that two-thirds of those men with cancer had aggressive cases.

The Texas study did not explain why obese men have lower PSA levels. But doctors believe obese men produce more estrogen, which drives down testosterone levels and could affect cells that produce the antigen used in the test.

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Gleason Grade

We know that the Gleason Grade also is involved in this charade. The higher the Gleason grade the lower the PSA. Lets repeat this - the higher the Gleason Grade the lower the PSA. The Gleason Grade are those two figures that combine to make the Gleason score 3+4 (Gleason Grades) = 7 (Gleason Score). I have heard of a case where a man had a Gleason of 4+5=9 and a PSA of 0.8.

We know that prostate cancer caused PSA will generally move up at a very slow rate and the doubling time of the cancer caused PSA may be years. If the Gleason grade is of a high grade then the cancer tends to grow more quickly and is much less curable - but the PSA may be low.

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Other things that effect PSA

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

The following listing of physiologic conditions and manipulations that affect PSA serum levels is 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                  ery 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 8 weeks following the biopsy would be better than the recommended 6.

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.

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Labs and their Variances

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

Other data to show the variation of the PSA

Many times the PSA variations have been brought up as a question. I think that perhaps the following best explains it.

This is an old question which was studied and discussed by Dr. Thomas Stamey, Stanford University, in a paper: "Prostate Cancer: Who should be treated?" Monographs in Urology 1995.

A table in this paper gives some PSA data for a 72 year old with untreated CaP:

1/91: - 10.8;

2/91: - 16.5;

3/91: - 14.1;

1/92: - 12.6;

7/92: - 14.1;

1/93: - 10.4;

6/93: - 13/5;

6/94: - 15.8.

He goes on to say: "..., we have thoroughly investigated the physiologic variation of PSA in volunteer men who have a second PSA a short time after the first one (about 3 weeks) without any intervening prostate manipulation. We have found that the physiologic variation is three times the methodological variation of the assay; and for 95% of men it can be as high as a 30% increase (or decrease). Therefore, changes of this magnitude should not be considered significant."

I am a patient of Dr. Stamey and when my PSA jumped from 6,2 to 8.97, he laughed and said to take it over. I did and it came back down to the 5.88. Here is the record.

05/02/95-PSA - 4.8 (Hybritech), DRE Neg 05/08/95 PSA - 3.7 (Hybritech) 04/22/97 PSA - 5.9 (Abbott) 04/30/97 PSA2- Total 6.2, free .69, %free 11, DRE Neg 07/15/97 PSA - 8.97 (Tosoh) (A 45% rise in 76 days) 08/18/97 PSA - 5.88 (Abbot) back down to where it was.

From the history of Terry:

Terry took a PSA every day for 30 days trying to keep all things equal. It is not important to see the daily changes but to understand the extent of the changes.

He had a high of 6.0 and a low of 4.5 over just 3 days). That would be an increase over the low of 33%. 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%. Interestingly, if you looked at the doubling time it would be around 7 days. The biggest up tick in one 24 hour period was from a 5 to a 6 - a rise of 20%.

I think that that this is another verification of what I have said on the possible changes of the PSA. It also shows why you can not trust any one PSA. It is not until you have a series of them that you can make any conclusions as to what is happening. These ups and downs all were around 5 or so. I believe that one can make out a 28 day cycle in what he did. However since it was only for one period it would not be valid,

I believe this study demonstrates pretty well the variability of PSA.

Figures from Roehrborn et al, "Variability of repeated prostate-specific antigen measurements within less than 90 days in a well defined patient population." Urology 1996:47:55-66.

295 men were identified who had 2 PSA readings within 90 days and who had a first reading of less than 10 ng/ml (Abbott IMx). Only 6% had 2 identical readings, 64% had a second reading with a difference between - 1.0 and + 1.0 ng/ml compared with the first. In 30% it was more than +/- 1.0. Of these 18% (53 of 295) had a PSA difference between +/- 1.0 and +/- 2.0; 7% (20 of 295) between +/- 2.0 and +/- 3.0; 5% (16 of 295)of more than +/- 3.0. The largest PSA differences recorded were -5.3 and +7.5 ng/ml. In total 46% had a increase or the same PSA on second reading, 54% a decrease. Of these 295 men 168 had normal prostates on DRE, 96 BPH and 31 suspicion of cancer. There was no variety in PSA differences among these subsets and neither age or height of the initial reading affected results. (These differences may be the result of the mixed effect of random errors, batch inequalites, so-called "physiologic variations" and transient effects of concomitant prostatitis.)<<

Many have read about my thoughts that every person should be treated for prostatitis or inflammation after their first elevated PSA and before a biopsy. Here are two studies that give the reason why.

In the first study they looked at high PSA readings due to inflammation and came to the conclusion that: "Histologically defined acute inflammation within the prostate is a significant contributor to elevated serum PSA levels, especially in patients with small prostates."

In the second study they looked at the inflammation in prostate biopsies where there was no cancer found. In these cases they found inflammation in virtually ever prostate. This is what their conclusion was: "Inflammation of the prostate is a histological finding in almost every set of prostate biopsies, even when there are no signs of clinical prostatitis. This sub-clinical inflammation can cause PSA elevation. "

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Before you have a biopsy, do the following.

1. After your first PSA take a Free PSA if your PSA is between 4 and 10. If it is out of this range - take a regular PSA.

2. Take six weeks of Cipro (an antibiotic) and at the same time take NSAID's (Ibuprofen is fine if your system can tolerate them). If Ibuprofen is a problem use Celebrex or similar prescription drug.

3. At the end of this treatment and if your PSA was between 4 and 10 take a Free PSA, if not take a regular PSA.

4. Two months later take another free PSA if your previous PSA was between 4 and 10. if not take a regular PSA.

5. You may want to continue the NSAID throughout the above time.

NOTE: If your PSA is not below 4, take a standard PSA.. If the PSA is above 10 after the first PSA following NSAID and Cipro treatment (after item 2) - go into a treatment decision mode.

Free PSA

"There is an additional test that can be given that will help make a decision for a biopsy. This is called a PSA II sometimes called a "Free PSA". That will give some indication of cancer unless there is an infection (Prostatitis) involved. If there is Prostatitis, then some doctors recommend one to two months of Cipro (See Higher PSA's Caused by Inflammation and NSAID's and Prostate Cancer. Another condition that will cause a high PSA is called BPH. The PSA II will rule this out. In the PSA II you are looking for a number called "%free PSA". The lower the number is the more likely you are to have prostate cancer. Some docs use a 20 as the high limit with little chance of cancer. In the use of the PSA II your initial PSA should be between 4 and 10.

Still another page demonstrating how much error there can be in the PSA at any one time. http://www.prostate.help.org/capsava.htm .

As you now know, an elevated PSA does not automatically mean cancer. There are several steps that one should take before even a biopsy.

To make sure that this imperfect test (the best we have to measure cancer) is correct - one must take more than one test and preferably, a series for three or more to verify a rise or fall. In addition anytime a PSA is high at the time of the first PSA test, (or anytime one sees a sharp jump or fall) one needs to rule out the effect on any infection or inflammation and BPH that may be present. This can be done by taking 5 or 6 weeks of Cipro along with a NSAID and then having a free PSA to find out the true PSA from the cancer and the percent free PSA.

When do you repeat a PSA

The answer to this is easy - anytime you have a PSA that is out of line with previous PSA's - either low or high. Why - because there may be errors as indicated above.

What have we learned so far:

1. Q. If the PSA is going up does that mean that my cancer is growing?

A. Not necessarily!

2. Q. If the PSA is going down does that mean that my cancer is shrinking?

A. Not Necessarily!

3. Q. Is PSA a marker for prostate cancer?

A. Not necessarily!

4. Q. Does any one PSA tell you anything

A. Not necessarily

5. Q. Is it important to keep track of the PSA

A. Yes!

6. Is there a wide variance in any one PSA

A. Yes

7. Can I find my true tumor caused PSA

A. Yes - continue to find out how you can get close to it.

A Deeper Understanding Of The Above

How do I find my true cancer caused PSA

It is not easy but it can be worked at and gotten some kind of an estimate. Lets look at BPH, prostatitis and activity that makes the PSA vary.

BPH (Benign Prostatic Hyperplasia)

We know that BPH (Benign Prostatic Hyperplasia) makes the gland become larger. In the process it produces more and more PSA. If we can somehow estimate how much PSA the BPH produces we can come up with a formula. This is not easy to do and it seems that each man may have many differences and they may be wide. There are more than one estimate out there by various doctors and in my looking at them I have tried to come up with something that combines a little of all of them. Mine may be no more right or wrong than the next one but it is a starting point. But lets compare.

We have had the formula presented by some in the industry that 0.066 times the prostate volume would give us benign PSA attributed to the BPH. (However not all agree to this figure.) This has always worried me as sometimes with large glands we get negative numbers. I believe other doctors even use larger numbers. Perhaps this small diviation will help us with out figures.

If we assume that the PSA has a beginning of 2.0 at 30ml and increases at the rate of 0.5/10 ml for anything above that we could use the following formula:

For the first 30 ml use 2.0 For each ml above multiply it by 0.05.

Therefore a prostate gland volume of 70 ml would be (70 - 30) x 0.05 = 2.0 plus 2.0 gives 4.0 of PSA being caused by BPH.

By the industry's formula we would if had 0.066 x 70 = 4.62. This is certainly not a large difference but something to think about - especially on large glands. Either one has built in errors and as you use them they give some unusual results. Sometimes the findings by using this formula may give you higher PSA's then one actually has. They are not perfect - just another tool.

This assumes that their "ml" would be the same as our "cc" or "grams" - which technically it is not but for the prostate gland we assume they are the same. Confusing!!

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Prostatitis and its affect on PSA

As we noted earlier the PSA may cause the PSA to go up and down over time. I have seen a PSA of 64, treated for prostatitis and the PSA was reduced to 7. A treatment decision based on a PSA of 64 would probably be a lot different than a treatment decision based on a PSA of 7.

Remember above we mentioned bacterial and non bacterial prostatitis. There are some tests that a Urologist can do to discover if it is bacterial. However I find that few will do this and it seems to me that the results are inconclusive. Actually there is not a lot known about prostatitis and what is known is also kind of inconclusive.

Prostatitis is very difficult to treat, it seems to be in a position that it takes a long time for an antibiotic to work. Often times the Urologist will treat with a few days of an antibiotic and the patient finds that nothing changed. This simply is not enough time to be on an antibiotic to treat prostatitis.

It seems that those doctors who have been very much involved in prostatitis choose to treat it with from 6 to 8 weeks of the drug Cipro. In addition I believe that a NSAID, such as ibuprofen, should be added at the same time. I believe that the level of ibuprofen should be at a prescription level as recommended by the doctor.

For this paper it is enough to know that prostatitis causes the PSA to go up and down and that a high PSA may be caused by prostatitis and have nothing to do with the cancer. There is an excellent web site for prostatitis and has a lot of information. That site is at http://www.prostatitis.org/index.html .

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Placebo Effect

In medicine the "Placebo Effect" consists of a drug containing no active ingredients given to a patient participating in a clinical trial in order to assess the performance of a new drug. The "Placebo Effect" comes into play in many different ways in everything we do.

History has shown us often times we do something and have a result but the result may or may not be from what we did. For example we frequently take herbal products, change diets, etc. and we see this has a desired effect - in this case reducing the PSA. But when we put this to a test we find that the "Placebo Effect" will actually help in 25% to 50% of the time.

For example if we gave simple aspirin to 100 patients who had a headache and gave a placebo (sugar pill) to another hundred men who have a head ache and told them both that these were headache pills. We would find that some of both groups got rid of their headaches. If in the aspirin group 75% got rid of their headaches and in the sugar pill group 50% got rid of their headaches (not unusual) - that 50% is the "placebo effect".

Often times we see men who will have PSA's that change when taking a herbal product, change of diet, etc. and all we may be seeing is the placebo effect.

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 this was presented in the JAMA 279:1543, 1998

PSA's and Biopsy

Ok - when should I get a biopsy. I have a series of PSA's that have been adjusted as per above.  Some ask what is the prostate PSA scale.  Although the PSA can rise in to the thousands (the highest I have seen is 7000) it is the lower end of the scale that we are concerned with in the diagnosis.

Anytime a PSA gets over 2.5 there is a chance of you having prostate cancer. But there is also a chance that your PSA may be 20 and you do not have prostate cancer. How can we tell.

First we need to establish a pattern of PSA's. One should NEVER make a decision to have a biopsy based on a single PSA. It is important that you have several taken over the years that show a steady increase in the PSA. Only one PSA may be only prostatitis or BPH - neither one would you want to do a biopsy.

As you read from the beginning there are a number of things that will increase the PSA - some over the long haul and some only temporary. These have to be somehow ruled out until we get to the place that we are fairly confident that the PSA that is reported is caused by a prostate cancer tumor.

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WHAT IS UNDETECTABLE?

We frequently use this word "undetectable" and have no idea what we really are talking about. Is it anything below 0.0, 0.003, 0.03, 0.05, 0.07, 0.1, 0.2, 0.3, 0.4? The answer to all of these is a YES. It depends on the assay you are using and the established nadir that a doctor or clinic might have established.

Lets start with 0.2. In this case this was established by Pat Walsh at John's Hopkins because 0.2 was the lowest level that could be measured at the time with the assay he was using. Since they could not measure anything less than 0.2 - anything below that was considered undetectable. Does that mean the assay at the time had only exactly 0.2 as a threshold. If one was 0.19 - it was undetectable or was there a rounding and everything over 0.15 was 0.2 and below 0.15 was undetectable. What does it mean?   In most cases anything under 0.2 is considered undetectable.

If we look at the numbers above 0.2 above there is no "undetectable" involved because all of the assays they used would get below those higher numbers.

What about below 0.2 - like 0.1, 0.07? These were also assays minimums that came along and anything below those could be undetectable. With the same questions of rounding as above.

Now we go into the triple digits to the right of the decimal and we can go all the way down to below 0.003 to be undetectable. Does it really make any difference if your PSA is in the thousandths.

To further confuse the issue, I have seen reports that said 0.0 for any assay, some use 0.0 minimum and I have seen some use 0.1 when in fact it was 0.05. So not only do we have the assay differences but the reporting differences.

What good is the ultrasensitive assay. It depends on when you want to get started on salvage treatment. Actually does it do you an good to know that your PSA is up to 0.004 from 0.003. Are you going to get treated at 0.005 - probably not. Most doctors will not consider salvage treatment following a confirmed failure until the PSA is over 0.2. If we get a treatment we should have some idea in our own mind when is failure and when would you start back on treatment. That is really the most important PSA that we need to know. Anything below that has only the value to the fact that the PSA is rising. Certainly if I have decided that I want to get salvage treatment at 0.2, I would like to know what the record has been below that. Any of the assays that give hundreds would probably tell me that.

I have seen some suggest three rises in the PSA before they get treatment. Does this mean 0.003, 0.004 and 0.005? Or maybe 0.01, 0.02, 0.03? How about 1, 5 and 10. A very unreliable test of failure is three consecutive failures and the third one may be to late.

To further compound this whole issue is that different assays give different results from the same blood - see http://www.prostate-help.org/capsava.htm .

In reporting undetectable PSA's one needs to do a little digging. We need to know the name of the assay the lowest measurement that the assay measures, the lowest number the assay reports and then what does the doctor tell you.

An undetectable of 0.19 might be a mite different that a undetectable of 0.002.

One has to establish in his own mind what is the maximum that I will allow my PSA to go before I will do salvage treatment - and then get the PSA assay that will give you ample warning. In most cases I believe that PSA's measuring in the hundreds (which most all do today, I believe) is ample enough warning for making treatment decisions. Anything below that is of little use - except to worry.

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CONCLUSIONS

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.

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References

Instead of giving just the referenced journal, I have chosen to give the complete abstract below. If one wants to read the complete study, go to a medical library and see if they have the referenced journal. For additional research and reading go to Prostate-Help Quick Clicks - Searching, click on number 2. Prostate-Help Information Database (PHID) and you can search for the very latest of studies, papers, websites on prostate cancer. You can also search many places from this page.

What to Do with an Abnormal PSA Test

The Oncologist, Vol. 13, No. 3, 299-305, March 2008; doi:10.1634/theoncologist.2007-0139

© 2008 AlphaMed Press

Stacy Loeba, William J. Catalonab

aDepartment of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA; bThe Northwestern Feinberg School of Medicine, Chicago, Illinois, USA

Key Words. Prostate cancer • Prostate-specific antigen • PSA • Screening • Detection • Prognosis

Correspondence: William J. Catalona, M.D., 675 N. Saint Clair Street, Suite 20-150, Chicago, Illinois 60611, USA. Telephone: 312-695-4471; Fax: 312-695-1482; e-mail: wcatalona@nmff.org

Disclosure: W.C. has received PSA kits at cost and participated in scientific studies with Beckman Coulter (Fullerton, CA). No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

For more than a decade, prostate-specific antigen (PSA) has been used for prostate cancer screening. Over the years, this screening has been continually refined, including investigation into the use of lower total PSA thresholds, PSA isoforms, and PSA kinetics. This review describes the evolution of prostate cancer screening and provides clinical insights into the informed use of PSA and its adjunctive measurements.

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Prostatitis 

Urology 2000 Jun 1;55(6):892-898

Correlation of histological inflammation in needle biopsy specimens with serum prostate- specific antigen levels in men with negative biopsy for prostate cancer.

Okada K, Kojima M, Naya Y, Kamoi K, Yokoyama K, Takamatsu T, Miki T Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan

Objectives. To reveal the possible contribution of histological inflammation within the prostate to the abnormal elevation of serum prostate-specific antigen (PSA) levels in patients with needle biopsy negative for prostate cancer. Methods. We reviewed negative needle biopsy specimens obtained in 93 patients. The degree of acute and chronic inflammation as evaluated histologically was compared with serum PSA levels in conjunction with age and prostate volume.Results. Both age (P <0.01) and prostate volume (P <0.0001) correlated significantly with serum PSA levels and were significantly greater in patients with abnormal serum PSA levels (greater than 4.0 ng/mL) than in those with normal serum PSA levels (4.0 ng/mL or less) (P <0.01). The presence of histological inflammation within the prostate also correlated significantly with serum PSA levels. Multiple regression analysis demonstrated prostate volume to be the only independent determinant of serum PSA levels (P <0.01). In patients with a prostate volume larger than 25 mL, only prostate volume correlated significantly with serum PSA levels (P <0.05). On the other hand, the degree of acute inflammation as represented by polymorphonuclear leukocyte infiltration was the only parameter correlating significantly with serum PSA levels (P <0.05) in patients with a prostate volume smaller than 25 mL.

Conclusions. Histologically defined acute inflammation within the prostate is a significant contributor to elevated serum PSA levels, especially in patients with small prostates. In the assessment of needle biopsy results negative for prostate cancer, it might be helpful to evaluate the degree of histological inflammation, especially in terms of the necessity of subsequent repeated biopsies.

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Eur Urol 2000 Apr;37(4):404-12

Inflammation in prostate biopsies of men without prostatic malignancy or clinical prostatitis: correlation with total serum PSA and PSA density.

Schatteman PH, Hoekx L, Wyndaele JJ, Jeuris W, Van Marck E Department of Urology, University Hospital of Antwerp, Belgium.

OBJECTIVE: Inflammation is a frequent histological finding in prostate biopsies, performed on men without prostatic malignancy or clinical prostatitis. We investigated the relationship between morphological parameters of inflammation in prostatic tissue and total serum prostate-specific antigen (PSA) and prostate-specific antigen density (PSAD) levels to determine if subclinical inflammation can cause elevation of PSA and PSAD.

METHODS: We reviewed 268 prostate biopsies, performed on 238 men with elevated PSA and/or abnormal digital rectal examination of the prostate. All premalignant and malignant biopsies and cases of clinical prostatitis were excluded. The inflammation in the remaining 145 prostate biopsies was scored for extent of inflammation and aggressiveness of inflammation, using the four-point scale designed by Irani and co-workers. In this prostatic inflammation scoring system, extent of inflammation is graded from 0 up to 3 according to the degree of invasion of inflammatory cells in prostatic tissue. Aggressiveness of inflammation is graded from 0 up to 3 according to the degree of contact or disruption of prostatic glandular epithelium by inflammatory cells.

RESULTS: Each of the studied biopsies showed inflammatory cells. Median PSA levels in grades 1, 2 and 3 of extent of inflammation were, respectively, 5.7, 6.8 and 13. 0. Median PSAD levels in these groups were 0.13, 0.16 and 0.33. There was no significant difference between these grades for PSA nor for PSAD. Median PSA levels in grades 0, 1 and 2 of aggressiveness of inflammation were, respectively, 3.9, 5.9 and 8.9. Median PSAD levels in these groups were 0.12, 0.18 and 0.17. For both parameters, there was a significant difference between grades (respectively, p = 0.0028 and p = 0.0330).

CONCLUSION: Inflammation of the prostate is a histological finding in almost every set of prostate biopsies, even when there are no signs of clinical prostatitis. This subclinical inflammation can cause PSA elevation. Not the extent of inflammation is of importance, but the disruption of epithelial integrity caused by the inflammatory infiltrate. When confronted with a patient with an elevated PSA level whose prostate biopsies reveal no malignancy but only inflammation, this concept can help in determining the need for quick repeat biopsies.

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Prostatitis Screening Reduces Unnecessary Biopsies in Men With Elevated PSA

WESTPORT, CT (Reuters Health) Oct 31 - Nearly half of all asymptomatic men with an elevated prostate specific antigen (PSA) level have laboratory signs of prostatitis.

Screening for prostatitis in this population is "safe and effective, and may decrease the number of potentially unnecessary biopsies," Dr. Jeannette M. Potts, of the Cleveland Clinic Foundation, in Ohio, suggests in the November issue of the Journal of Urology.

This is the first prevalence study of the National Institutes of Health category IV prostatitis in asymptomatic in men with an elevated PSA level, according to Dr. Potts. Her team initiated a screening protocol for prostatitis that consisted of two tests: expressed prostatic secretion and post-prostate massage urine, also known as the voiding bottle 3, or VB3 test. Screening was performed for 122 men with PSA of 4.1 ng/mL to 29 ng/mL and no evidence of acute urinary tract infection.

Forty-two percent of the men had positive laboratory results for prostatitis, although most had negative VB3 cultures. These men received antibiotics for 4 weeks followed by reassessment, while men with negative laboratory tests underwent biopsy. After treatment, 22 of the 51 men with signs of prostatitis had normalized PSA levels, while the PSA remained elevated in 29. Of these 29 men, follow-up biopsy revealed cancer in 9 patients.

Overall, the screening protocol reduced the number of biopsies performed by 18%, and increased the positive predictive value of PSA for prostate cancer "substantially," from 37% to 51%. Moreover, all of the men who did not undergo biopsy after treatment for prostatitis had "continued normal or stable PSA" at last follow-up.

J Urol 2000;184:1550-1553.

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FreePSA

Clin Chem 2000 Jan;46(1):55-62

Ratio of Free or Complexed Prostate-specific Antigen (PSA) to Total PSA: Which Ratio Improves Differentiation between Benign Prostatic Hyperplasia and Prostate Cancer?

Jung K, Elgeti U, Lein M, Brux B, Sinha P, Rudolph B, Hauptmann S, Schnorr D, Loening SA

Departments of Urology, Laboratory Medicine and Pathobiochemistry, and Pathology, University Hospital Charite, Humboldt University, Schumannstrasse 20/21, D-10098 Berlin, Germany. Author for correspondence. Fax 49-30-2802-1402.

BACKGROUND: The aim of this study was to compare the diagnostic utility of a new assay that measures all forms of prostate-specific antigen complexed (cPSA) to serum proteins except alpha(2)-macroglobulin with the assay of free PSA (fPSA) and the corresponding ratios to total PSA (tPSA) to improve the differentiation between benign prostatic hyperplasia (BPH) and prostate cancer (PCa). METHODS: Serum samples were collected from 91 men without prostate disease and with normal digital rectal examination (controls), 144 untreated patients with PCa, and 89 patients with BPH. tPSA and cPSA were measured using the Bayer Immuno 1 system; fPSA and the additional tPSA were measured with the Roche Elecsys system. RESULTS: The median cPSA/tPSA, fPSA/tPSA, and fPSA/cPSA ratios were significantly different between patients with BPH and PCa (78.7% vs 90.7%, 25.5% vs 12.1%, and 36.8% vs 14.3%, respectively; P <0.001). No correlations of cPSA and its ratios to tumor stage and grade were found. ROC analysis showed that cPSA was not different from tPSA (areas under the curve, 0.632 vs 0.568), whereas the cPSA/tPSA ratio was similar to the fPSA/tPSA ratio in increasing discrimination between BPH and PCa patients with tPSA concentrations in the tPSA gray zone between 2 and 10 mug/L (areas under the curve, 0.851 vs 0.838). CONCLUSIONS: Compared with tPSA, the fPSA/tPSA and cPSA/tPSA ratios both improve the differentiation between BPH and PCa comparably and are similarly effective in reducing the rate of unnecessary biopsies, whereas cPSA alone does not have any effect.

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J Urol 1999 Oct;162(4):1346-51

Prediction of post-radical prostatectomy pathological outcome for stage T1c prostate cancer with percent free prostate specific antigen: a prospective multicenter clinical trial.

Southwick PC, Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, Richie JP, Walsh PC, Scardino PT, Lange PH, Gasior GH, Parson RE, Loveland KG

Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.

PURPOSE: Prostate specific antigen (PSA) exists in bound (complexed) and unbound (free) forms in serum. The percentage of free PSA enhances the specificity of PSA testing for prostate cancer detection. We evaluated the use of percent free PSA preoperatively to predict pathological stage. MATERIALS AND METHODS: A total of 379 men with prostate cancer and 394 with benign prostatic disease 50 to 75 years old were enrolled in this prospective study at 7 medical centers. All subjects had a palpably benign prostate gland, serum PSA 4.0 to 10.0 ng./ml. and a histologically confirmed diagnosis. The Hybritech Tandem PSA and free PSA assays were used. Of the 379 cancer patients 268 (71%) underwent radical prostatectomy. RESULTS: Higher percent free PSA levels were associated with more favorable histopathological findings in prostatectomy specimens. A value of 15% free PSA provided the greatest discrimination in predicting favorable pathological outcome. Organ confined cancer, Gleason sum less than 7 and small tumors (10% or less involvement of the prostate) were noted in 75% of patients with greater than 15% and only 34% with 15% or less free PSA (p<0.001). Multivariate logistic regression analysis revealed percent free PSA to be the strongest predictor of postoperative pathological outcome (odds ratio 2.25), followed by biopsy Gleason sum (2.06) and patient age (1.35). Total PSA was not predictive in this cohort but has been shown in prior studies to be predictive of outcome when a broader range of PSA values is evaluated. CONCLUSIONS: Percent free PSA may be used for risk assessment of the presence (diagnosis) and stage of prostate cancer in men with PSA between 4 and 10 ng./ml. Percent free PSA may be combined with PSA, digital rectal examination and biopsy findings to help predict postoperative pathological stage and grade, and may assist the patient and physician in making more informed treatment decisions.

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Eur Urol 1999 Aug;36(2):111-5

Intraindividual variations of total and percent free serum prostatic-specific antigen levels in patients with normal digital rectal examination.

Morote J, Raventos CX, Lorente JA, Enbabo G, Lopez M, de Torres I Department of Urology, Vall d'Hebron Hospital, Autonoma University, Barcelona, Spain.

PURPOSE: To analyze intraindividual variations of total and percent free serum prostate-specific antigen (PSA) in patients with normal digital rectal examination. MATERIAL AND METHODS: Total and free serum PSA were determined in two blood samples corresponding to 107 nonconsecutive patients. The period between both determinations ranged from 23 to 60 days. Prostatic biopsy was done after both determinations in all except 17 patients because the two serum PSA concentrations were <4 ng/ml. Total and free PSA were determined using double monoclonal antibody immunoassay Tandem and Tandem free (Hybritech Inc.). The diagnosis was benign prostatic hyperplasia (BPH) in 63 patients and prostate cancer (PCA) in 44. RESULTS: The variations of PSA ranged between -6.8 and +3.2 ng/ml in BPH patients and between -2.8 and +9.0 in patients with PCA. The median coefficients of variation were 15.4 and 15.7% respectively. The variations in the percent free PSA were between -30.7 and +40.9 in the BPH group and between -17.9 and +15.8 in the PCA group. The median coefficients of variation were 32.2 and 32.3% respectively. If prostatic biopsy had been indicated when percent free PSA had been less than or equal to 25 in the PSA range of 4.1-10 ng/ml, we would have found discrepancies in 15% of all the patients. The sensitivity for the first determination would have been 100 and 94.4% for the second. The rate of negative biopsies would have been reduced by 16.6 and 19. 4% respectively. CONCLUSIONS: Intraindividual variations in serum PSA concentration and percent free PSA could have clinical implications in the decision to perform prostatic biopsy.

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Prostate 1999 Jun 15;40(1):56-61 Related Articles, Books

Correlation between preoperative predictors and pathologic features in radical prostatectomy specimens in PSA-based screening.

Horninger W, Rogatsch H, Reissigl A, Volgger H, Klocker H, Hobisch A, Bartsch G

Department of Urology, University of Innsbruck, Austria.

BACKGROUND: Measurement of percent free prostate-specific antigen (PSA), PSA density, and PSA-transition zone density (PSA-TZ density) in addition to total PSA is known to improve the specificity of PSA-based prostate cancer screening. We evaluated the ability of total PSA, percent free PSA, PSA density, and PSA-TZ density to predict pathologic features in radical prostatectomy specimens. METHODS: The levels of total PSA, percent free PSA, PSA density, and PSA-TZ density assessed prior to the diagnosis of prostate cancer were correlated with the pathologic findings in 102 prostate glands with cancer obtained at radical prostatectomy. The entire organs were examined histologically; Pearson correlation coefficients were used for statistical analysis. RESULTS: High levels of total PSA, PSA density, and PSA-TZ density correlated significantly with capsular penetration, high Gleason scores, and large cancer volumes in the prostatectomy specimens. Free PSA was found to correlate well with high Gleason scores, high percentages of cancer, and large cancer volumes, but not with capsular penetration. The four parameters were evaluated by means of logistic regression, which showed that only percent free PSA and total PSA were significant predictors of Gleason scores > or =7 and cancer volumes > or =0.5 cc. With regard to clinically insignificant cancers, only percent free PSA and the Gleason score obtained at biopsy were significant predictors. CONCLUSIONS: In men whose prostate cancers are detected by PSA-based screening, high total PSA levels in combination with low percent free PSA levels are suggestive of a potentially more aggressive type of prostate cancer. This may help both patient and clinician in selecting the most appropriate therapeutic approach

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Urology 1999 May;53(5):945-50 Related Articles, Books

Diagnostic value of percent free prostate-specific antigen: retrospective analysis of a population-based screening study with emphasis on men with PSA levels less than 3.0 ng/mL.

Tornblom M, Norming U, Adolfsson J, Becker C, Abrahamsson PA, Lilja H, Gustafsson O

Department of Urology, Huddinge Hospital, Karolinska Institute, Stockholm, Sweden.

OBJECTIVES: To retrospectively investigate the use of percent free prostate-specific antigen (PSA) compared with total PSA in serum as predictor of prostate cancer in men selected randomly from the general population who underwent biopsy on the basis of abnormal findings on digital rectal examination (DRE) or transrectal ultrasound (TRUS) and/or serum PSA levels greater than 10 ng/mL. METHODS: A single intervention, population-based screening study was undertaken in 1988 and 1989. Of the 2400 men aged 55 to 70 years invited to participate, 1782 men responded and were examined with DRE, TRUS, and PSA testing (Tandem-Hybritech). In 1995, frozen serum samples from 1748 men were analyzed for percent free PSA (Prostatus, Wallac OY). Five-year follow-up data on new cancers in the screened population were obtained from the Swedish Cancer Registry (SCR). RESULTS: Of the 1748 men, 367 underwent TRUS-guided biopsies because of abnormal findings on either DRE or TRUS or serum PSA levels of greater than 10 ng/mL. This resulted in the diagnosis of 64 cases of prostate cancer (3.7%). PSA levels of 3.0 ng/mL or greater were found in 55 (86%) of 64 cancer cases and in 399 (24%) of the 1684 benign cases. Among the 1294 men with PSA less than 3.0 ng/mL, 9 prostate cancers were diagnosed (14% of all prostate cancers). All 9 patients with cancer and with PSA less than 3.0 ng/mL had a percent free PSA of 18% or less. In the group of 1109 patients with PSA less than 3.0 ng/mL and a percent free PSA greater than 18%, 159 biopsies were performed because of abnormal DRE or TRUS. However, no prostate cancer was diagnosed in this category of patients. Five years after the screening intervention, 7 more cases of prostate cancer were clinically diagnosed in the screened population according to the SCR. CONCLUSIONS: The combination of PSA levels less than 3.0 ng/mL and percent free PSA greater than 18% defines a large part of the population at a very low risk of cancer of the prostate both at the time of screening and during the following 5 years. Men in this group may be spared DRE, and longer screening intervals may be considered. However, the risk of having prostate cancer is not negligible in men with PSA less than 3.0 ng/mL and percent free PSA of 18% or less. The results of this study indicate that biopsy should be recommended to men fulfilling these criteria, although these results should be confirmed in larger prospective studies because of the limited number of patients with prostate cancer in the present series.

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J Surg Oncol 1999 Feb;70(2):91-4 Related Articles, Books Free-to-total prostate-specific antigen ratios 18-24 months following external beam radiation for adenocarcinoma of the prostate. Ward JF, Johnstone PA, Kane CJ

Department of Urology, Naval Medical Center, San Diego, California 92134-5000, USA. jfward@snd10.med.navy.mil

BACKGROUND AND OBJECTIVES: The purpose of this study was to evaluate free-to-total prostate-specific antigen (PSA) ratios after definitive external beam radiation therapy for men with adenocarcinoma of the prostate (CaP). METHODS: A prospective evaluation of percent free PSA in men following definitive external beam radiation therapy for CaP was compared to men with untreated CaP and men at very low risk for CaP. Statistical comparison of clinical and pathologic parameters was performed. RESULTS: There was no statistically significant difference in free-to-total PSA ratios for men with newly diagnosed CaP and men with detectable PSA who were treated with external beam radiation therapy. CONCLUSIONS: Free-to-total PSA ratios after definitive external beam radiation therapy for CaP are consistent with percent free PSA in patients with newly diagnosed CaP. This supports the theory that PSA from in situ prostate tissue following external beam radiation therapy is produced by malignant cells.

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September 21, 2008