Rising PSA After Negative Prostate Biopsy Part II: Can PCA3 Prevent Unnecessary Biopsies?

In my last post I discussed some PSA based tools that can be used to determine whether a rising PSA is due to prostate cancer or to other causes.  Such tools are very important because repeat biopsies for men with rising PSAs are positive for cancer in only 10-30% of cases, depending on how many biopsies are performed.  The yield (chance of cancer found) is less and less for every subsequent biopsy performed.  As a result, 70-90% of men may be undergoing these biopsies unnecessarily.  The problem with performing all of these repeat biopsies, aside from the pain and discomfort, is that they are not without risk (some more information about what to expect from prostate biopsies can be found in this previous post).  Unfortunately, the PSA tools I described, while helpful, are far from perfect.  The problem with these tests stems back to the basic problem with PSA: it is not only produced by prostate cancer but by normal prostate tissue.  As a result, PSA tests can be falsely elevated by other factors like infections, large prostates, and having sex.  Due to this limitation, PSA and PSA based tools can often overestimate the risk of prostate cancer in men with previously negative biopsies.  This, in turn, can lead to many unnecessary biopsies in men without prostate cancer.  Fortunately, a new test has recently been approved that may help determine which men really need to undergo a repeat biopsy in response to a rising PSA.  This test, called PCA3, may significantly decrease the need for repeat biopsies in select men with rising PSAs.  In this post, I will explain what PCA3 is, why it may be more informative than PSA, and how it may be used to prevent unnecessary biopsies.

What is PCA3?

Lets first discuss what PCA3 actually is.  PCA3 is a gene found within the DNA of human cells.  Like other genes, PCA3 serves as a code to produce a type of protein called mRNA.  It turns out that prostate cancer cells produce over 60 times more of the PCA3 mRNA than normal prostate cells.  In addition, no other tissue type in the human body produces this mRNA either.  Identifying this very prostate cancer specific protein, scientists then developed a test to identify and quantify it in men.  Unlike PSA, the PCA3 test is actually a urine, rather than blood, based test.  The test begins with a “prostate massage” by the physician.  Basically, this is a vigorous prostate exam that lasts for a few more seconds than a routine rectal exam.  After this exam, the patient then urinates and the urine is analyzed to look for and quantify the amount of PCA3.  The idea here is that the prostate exam causes the prostate to secrete the PCA3 protein into the urine, which can then be collected for quantification.

How is PCA3 better than PSA?

As I mentioned earlier, the major flaw of PSA is that it is not specific enough for prostate cancer.  In other words, way too many other things can cause PSA elevation aside from just prostate cancer.  PCA3, in contrast, is very specific for prostate cancer.  Neither infection nor sexual intercourse elevate PCA3.  In addition, unlike PSA, PCA3 is not proportional to the size of the prostate.  In other words, larger prostates do not produce more PCA3.  Finally, even urological procedures like prostate biopsies and cystoscopies, notorious for raising PSA, have no effect on PCA3.  I am sure that you are now starting to see the beauty of this new test.  Because it is so specific for prostate cancer, it may be able to prevent the unnecessary pain and risk of repeat biopsies in men with rising PSAs.  Lets see how this theoretical advantage pans out in practice.

PCA3 and the Prostate Biopsy Decision

Numerous studies have evaluated the utility of PCA3 in predicting prostate cancer.  One study evaluated the accuracy of PCA3 in predicting the extent and significance of prostate cancer.  The study obtained PCA3 tests from men with known prostate cancer about to undergo radical prostatectomy and then correlated the PCA3 level with the pathology findings from the surgery.  The study reported some very encouraging findings.  First, the study found that men with small amounts of cancer demonstrated significantly lower PCA3 values than those with large cancer volumes (PCA3 scores of 17 versus 47, respectively).  The study similarly found that men with insignificant or low risk prostate cancer also demonstrated substantially lower PCA3 scores than their counterparts with more substantial prostate cancer (PCA3 scores of 16 versus 45, respectively).

While PCA3 has, thus, been demonstrated to be a good predictor of significant prostate cancer, can this new test help predict the presence of prostate cancer and the need for prostate biopsy in men with a rising PSA after a previously negative biopsy?  Several studies have done just that.  A small study of 51 men, for example, performed a PCA3 test on men with a negative prostate biopsy who then underwent  a repeat biopsy for a further rising PSA.  The study reported that men with a positive repeat biopsy demonstrated substantially higher PCA3 values (median 50) as compared to those men with negative repeat biopsy (median 28).  A substantially larger study of over 1100 men undergoing repeat biopsies demonstrated a similar discrepancy of PCA3 values of 34 versus 17 for men with positive versus negative repeat biopsies, respectively.  This large study also reported that men with a PCA3 level greater than 35 had twice the risk of a positive biopsy as compared to those men with PCA3 less than 35.  Given this ability of PCA3 to differentiate prostate cancer from other causes of rising PSA, another study of 127 men reported that the PCA3 test can help avoid up to 73% of unnecessary repeat biopsies. 

Is there a downside to PCA3?

The main downside to PCA3 appears to be the lack of an accepted, definitive cutoff point above which the presence of prostate cancer is nearly certain.  While higher values of PCA3 are certainly more indicative of prostate cancer than lower values, there is no single magic number that can serve as a cutoff.  Numerous studies have used 35 as such a cutoff but with mixed results.  For example, one study evaluated using 35 as the PCA3 cutoff.  The study demonstrated that if only men with PCA3 over 35 were biopsied, 85% of previously undiagnosed prostate cancers would be detected while avoiding 50% of unnecessary, repeat negative biopsies in men without cancer present.  The study demonstrated that if a PCA3 cutoff of 44 is used to trigger a repeat biopsy, in contrast, only 75% of previously undiagnosed cancers would be detected while avoiding 73% of unnecessary, repeat negative biopsies. Still other studies have argued for lower cutoffs (such as 15 or 25), which identify larger percentages of previously undiagnosed cancers (95%) for the tradeoff of substantially more unnecessary biopsies.  So what is the magic number?  Is it more important to identify more cancers or prevent more unnecessary biopsies?  That is the million dollar question that is still being debated.  That is also a drawback of the test.

Take Home Message

For many years, urologists have been looking for a noninvasive test that can reliably predict the presence of prostate cancer in men with a rising PSA and a negative previous prostate biopsy. A rising PSA can often be misleading as its rise can be triggered by factors not related to prostate cancer such as an enlarging prostate, urinary tract infection, or even sexual intercourse.  A test was needed that can eliminate such extrinsic factors to determine if a man really does need a repeat biopsy or if he can safely avoid the risks and discomfort of this procedure. 

In many respects, PCA3 seems to be just such a test. It is only produced by prostate cancer and, so, is not affected by extrinsic factors.  It is fairly easy to obtain if you discount the discomfort of a “vigorous” rectal exam.  It appears to differentiate significant from relatively innocuous prostate cancer.  And it has been demonstrated through numerous studies to significantly reduce the number of unnecessary prostate biopsies while not substantially decreasing the ability to identify prostate cancer.  Is PCA3 the holy grail of prostate cancer diagnosis?  Of course not.  Is it without its limitations?  No.  However, it appears to be a valuable tool to be used in conjunction with the PSA tools I previously discussed to reliably determine which men really need a repeat prostate biopsy and which can avoid the risk and discomfort of a repeat procedure.

Check out my new Book: 

   Prostate Doc’s Guide to Life After Prostatectomy

This blog is not a medical practice and cannot provide specific medical advice. This information should never be used to replace or discount the medical advice you receive from your physician

Rising PSA After A Negative Prostate Biopsy Part I: Crunching The Numbers

One of the most pleasant phone calls I can make is to tell one of my patients that their prostate biopsy was negative…no cancer.  I can often hear the sigh of relief on the other end of the line after several days of anticipation end in the best possible news.  After allowing the patient to rejoice for a while, however, I proceed to explain that a negative biopsy is not a guarantee of the absence of cancer.  I explain that while a prostate biopsy is undertaken through ultrasound guidance and in a systematic fashion, it is not 100% accurate. After all, a biopsy entails removing 12 tiny slivers of tissue from a gland that can vary in size from that of a walnut to that of a grapefruit.  You can imagine how possible it can be to miss some prostate cancer, particularly in men with very large prostates and small amounts of cancer.  As a result, I counsel these patients that, while the news is great, we still have to be cautious by checking the PSA every 6 months (some urologists advocate yearly tests) as well as performing a rectal exam at the same time intervals.  Most of my patients agree to this follow up protocol.

Unfortunately, at a later point in time, some of these men demonstrate a rise in their PSA.  This leads to a much less festive phone call.  Instead of a sigh of relief, I often hear anxiety and fear.  I also invariably hear the same question: “ Doc, what do we do now?”  This is actually a very important question with a complicated answer.  For some men, it means a repeat biopsy.  For others, in contrast, it means just repeating the PSA again in a few more months.  So how do you determine how to deal with a rising PSA after a negative prostate biopsy?  There are many tools that help urologists to figure out who needs a repeat biopsy in this setting.  In this post, I will cover how a more detailed look at the PSA can help determine whether a PSA rise after a negative biopsy is a sign of missed cancer or simply of benign growth of the prostate.

What Causes the PSA to Rise?

Before delving into the details of PSA rises, lets first explore why the PSA rises in men:

1) Artificial Rises: As I described in a previous post, at least 50% of elevated PSA tests are actually elevated in error.  PSA can be falsely elevated due to sexual intercourse within 2-3 days of the test, urinary tract infections, motorcycle riding, and even lab errors.  As a result, as with a single elevated PSA in new patients, I always recommend a repeat PSA test for those men who demonstrate a rise in PSA after a negative prostate biopsy.

2) Benign Prostatic Hypertrophy (BPH):  PSA is not only produced by prostate cancer cells.  It is also produced by normal prostate cells.  As a result, when benign prostate tissue grows in the form of BPH (the condition that gives you a slow stream and makes you urinate multiple times at night), the PSA naturally rises as a result.

3) Prostate Cancer:  Of course, in some men, a rising PSA is actually a sign of growing prostate cancer.  Most prostate cancer cells produce PSA and as the cells reproduce and grow, more and more PSA is produced.

Dissecting PSA Further

So how do we differentiate among these three potential causes of a rising PSA in a man after a prostate biopsy?  As I just mentioned, artificial rises in PSA can simply be differentiated from the other two through a repeat test after refraining from activities such as sexual intercourse while simultaneously checking a urine culture.  Determining whether a true rise in PSA is due to BPH versus prostate cancer is a much more complicated task after a negative prostate biopsy.  However, this determination can be made by taking a more detailed look at some specific aspects of PSA:

1) PSA Velocity:  Studies have demonstrated that a “normal” rise in PSA can be as high as about 0.7-1 per year.  This rise in PSA can safely be ascribed to BPH.  A yearly rise in PSA higher than this amount is a warning sign that cancer may be present and often triggers a repeat biopsy in men with a previously negative biopsy.

2) PSA Density:  Another aspect of PSA that can be valuable in distinguishing between BPH and prostate cancer is the PSA density.  During a biopsy, the urologist usually obtains an accurate measurement of the prostate volume by means of the ultrasound.  This size is usually described in grams or cubic centimeters (cc).  This measurement can be very helpful in evaluating future PSA elevations after the biopsy by allowing for the determination of the PSA density.  This calculation is carried out by dividing the PSA by the prostate volume.  For example, a man with a PSA of 5 and a prostate volume of 50 grams has a PSA density of 0.1.  Because BPH can also produce PSA, men with very large prostates should be expected to have higher PSA values than men with small prostates.  The PSA density allows you to compare apples to apples by determining the PSA in men per gram of prostate tissue.  Studies demonstrate that a PSA density of greater than 0.15 is suspicious for prostate cancer.

3) PSA Doubling Time: The PSA doubling time appears pretty self explanatory.  The term refers to the time it takes for the PSA to double in value.  To calculate this number you need a few PSA values spread at least 3 months apart.  You also need to use a fairly complex formula to get the exact value.  For our purposes, a rough, eyeball assessment will do just fine.  For example, by looking at a series of PSA values we can roughly estimate if the PSA is doubling every month, every 6 months, or every year, etc... Studies have demonstrated that PSA doubling time is one of the most important prognostic factors used to evaluate a rising PSA after a negative biopsy.  A PSA that doubles in 3-6 months is substantially more worrisome with regards to potential underlying prostate cancer as compared to a PSA that doubles in 1-2 years.

4) Free PSA:  Believe it or not, the PSA test actually represents a combination of two different types of PSA that are found in the blood stream: free and complexed.  While free PSA floats freely through the bloodstream, complexed PSA floats through the bloodstream attached to a specific protein. Why do we care about these two PSA subtypes?  Free and complexed PSA are sort of like good and bad cholesterol.  A higher free PSA is actually associated with a lower prostate cancer risk.  In contrast, a higher complexed PSA is associated with a higher prostate cancer risk.  While there is no great commercially available complexed PSA tests, a free PSA test is available.  The free PSA is reported as a percentage of the overall PSA test.  A I mentioned , the higher the free PSA, the less likely prostate cancer is present.  Studies have demonstrated that a free PSA of greater than 15-18% represents a low risk for prostate cancer as opposed to a free PSA less than 8% which represents a high risk for malignancy of the prostate.  Using such parameters, free PSA can help predict the likelihood of prostate cancer being present in men with a rising after a negative prostate biopsy.

Take Home Message

A rising PSA can be a stressful and worrisome finding in men following a negative prostate biopsy.  In this situation, the PSA needs to be further examined in terms of PSA velocity, doubling time, density as well as free PSA.  These various PSA based tests are used in combination to gauge the risk of prostate cancer in men with a rising PSA after a negative prostate biopsy.  Because prostate biopsies are not without risks, not every PSA rise in men necessitates a repeat biopsy.  Prudent use of these PSA tests can help determine which men with rising PSA after a negative prostate biopsy really need a repeat biopsy and which simply need to be followed with serial PSA tests and digital rectal exams.  In future posts, I will discuss other tests that can help to determine when a PSA rise after prostate biopsy truly indicates the presence of cancer.

Check out my new Book: 

  Prostate Doc’s Guide to Life After Prostatectomy

This blog is not a medical practice and cannot provide specific medical advice. This information should never be used to replace or discount the medical advice you receive from your physician

The Prostate Biopsy: What to Expect

Whenever I tell one of my patients that he needs a prostate biopsy, the same look of fear usually comes over his face.  Fortunately, a prostate biopsy no longer has to be the painful, embarrassing procedure that it has been known for in the past.  In this post I want to provide the answers to common questions I hear from my patients about prostate biopsies:

1)      Why do I need a prostate biopsy?

A prostate biopsy needs to be performed when there is a suspicion that you may have prostate cancer.  That suspicion may be from an elevated PSA blood test (see previous post) or an abnormality of the prostate felt during a rectal exam.  It is the most definitive way to determine whether there is cancer in your prostate.

2)      Do I need any preparation for the biopsy?

Yes.  You will need to take oral antibiotics and some enemas around the time of your biopsy.  Every Urologist has a different preparation but most will involve 1-2 days of oral antibiotics around the time of the biopsy.  Most will also have you do an enema the night before and the morning of the biopsy.  An important aspect of preparation is to avoid any blood thinners like Aspirin, Motrin, Aleve, Ibuprofen, Plavix, or Coumadin for 7-10 days prior to the biopsy.  If you take any of these medicines, make sure that you let your Urologist know well in advance of the biopsy.  Something not well known is that some vitamins and supplements such as Vitamin E, Fish Oil, and Glucosamine also have blood thinning properties and should also be stopped prior to a biopsy.

3)      What are the risks of a biopsy?

The main risks of a biopsy are bleeding and infection.  After a biopsy, you may notice blood in your urine or your stool for several days.  This blood usually goes away on its own if you drink lots of water.  If you have severe bleeding, make sure to let your doctor know or go the Emergency Room right away.  Blood in the semen is also a very common side effect of a biopsy that is rarely discussed.  Because semen is produced in the prostate, a prostate biopsy almost always leads to blood in the semen for several weeks.  It usually starts off red and then becomes a rust color.  It is absolutely nothing to worry about but you may want to wear a condom for a week or two during sex as it may be a little disturbing to you and your partner.

A fever is always concerning after a biopsy as it could mean that there is an infection of the prostate.  This infection can spread into the bloodstream and make you feel very sick.  If you have a fever after a biopsy, it is very important that you go to the Emergency Room right away as you may need intravenous antibiotics.  Fortunately, this complication is seen very rarely after a prostate biopsy.

4)      What should I expect during my biopsy?

The whole process should take about 20-30 minutes.  You will first be checked in by a nurse who will take your blood pressure and have you sign a consent form for the biopsy.  The nurse will also probably make sure that you have taken the preparation discussed above.

After you are checked in you will be asked to change into a gown and empty your bladder.  You will then be asked to lie down on a table.  The position you are in during the procedure depends on your doctor. Some Urologists(including myself) will have you lie on your side with your knees bent towards your chest while others will have you lie on your back and place your legs in stirrups(less common).  The doctor will then perform a rectal exam like you received in the clinic during your initial visit.  He will apply some topical anesthetic cream to your anus and prostate.  Once the cream has been applied, the doctor will then place an ultrasound probe inside the rectum.  This is a little bigger than a finger and may feel like a little more pressure in the rectum.  The doctor will then measure your prostate with the ultrasound.  While he is able to see the prostate during the procedure, the doctor will not be able to really see any cancer within the prostate unless it is very obvious.  After the measurements are taken, your doctor will give you some local anesthetic to numb the prostate.  This will feel like pinching and burning in your prostate not unlike when you get anesthetic at the dentist’s office.  After a minute or two, your doctor will start the biopsy.  You will hear some loud clicks as the biopsy gun deploys.  You may feel a slight pinch with each biopsy.  A total of 12 biopsies are done.  The whole process usually lasts between two and five minutes.  After the procedure is completed the ultrasound will be removed from the rectum and you will be asked to get dressed.

5)      What should I expect after the biopsy?

After the biopsy, most people say that they feel a little sore in their rectum.  Usually some Tylenol will help relieve the discomfort.  Make sure not to take Aspirin, Ibuprofen, or other blood thinners as this will cause bleeding.  As mentioned above, some blood in the urine or stool is normal after the procedure.  It may look frightening at first, but it should go away fairly soon.  You should try to take it easy for the next day or so to let everything settle down.  I would recommend that you avoid any sexual activity for at least a week after the biopsy.

As I mentioned before, fever after a biopsy is NOT NORMAL.  If you have a fever, make sure that you get medical attention right away.

6)      When do I find out the results?

Your doctor will generally call you within a week with the results of your biopsy.

I hope that this post was helpful for those of you about to undergo a prostate biopsy.  Although any kind of biopsy can be stressful, a prostate biopsy does not need to be a horrible experience.  Most of my patients tolerate the biopsy very well.  In fact, most tell me the same thing after the procedure is finished: the anticipation was the worst part.

Check out my new Book: 

   Prostate Doc’s Guide to Life After Prostatectomy

PSA: Not Perfect But Vital

Three letters that many men fear are PSA.  These letters stand for Prostate Specific Antigen, a chemical produced by the prostate which is checked via a blood test to look for prostate cancer.  PSA has been an extremely important tool for doctors in identifying early prostate cancer.  Before PSA, prostate cancer could only be identified by means of a yearly rectal exam.  As prostate cancer is often advanced by the time it can be felt on an exam as a mass, many men at that time were diagnosed with prostate cancer after it had already spread outside of the prostate and could no longer be cured.  As a result, Urology wards in hospitals were often filled with men suffering from painful bone metastases that had no hope of cure.  After the advent of PSA, prostate cancer became a much more manageable disease.  Today, men are often diagnosed when just a few cells of prostate cancer are found in the prostate, making the cancer very curable and avoiding the unnecessary pain and suffering of metastatic disease.

While very beneficial, however, PSA is far from perfect.  First, PSA is not specific for prostate cancer.  As I previously mentioned PSA is a functional enzyme NORMALLY produced by the prostate.  In other words, PSA is not JUST produced by prostate cancer.  As a result, many factors can cause an elevation in the PSA test.  The most common cause of an elevated PSA that is NOT caused by prostate cancer is sexual intercourse.  Men who have any type of sex that results in ejaculation within 2-3 days of giving a blood sample usually demonstrate an elevated PSA.  This elevation of  PSA is caused by natural production and secretion of PSA by the prostate for sex rather than by prostate cancer.  Other causes of an elevated PSA  include a urinary tract infection (that may be asymptomatic), retention of urine, and even riding a motorcycle.  As a Urologist I have countless patients referred to me by their primary doctors for an elevated PSA test. Unless I feel an abnormality of the prostate during a rectal exam, I almost always repeat the PSA test, making sure that the patient does not have sex for 2-3 days prior to the test.  I also have the patient give a urine test at the same time to make sure that there is no infection.  In at least 50% of my patients, a repeat PSA test comes back as normal.  Multiple academic studies have demonstrated the same likelihood of what is called a false positive PSA test.  This means that over half of men with a single elevated PSA could avoid unnecessary procedures and worry by simply repeating the test in the right way!

Another problem with PSA is that sometimes it is too sensitive, meaning that it does too good a job in finding prostate cancer.  Studies have shown that 80% of men over the age of eighty have prostate cancer.  Because prostate cancer is usually slow growing, most of these men will never be symptomatically affected by the disease and so will die with it rather than from it.  They will die from more aggressive diseases such as heart disease or stroke.  To some extent, the same situation can be applied to younger men as well.  For example, a 70 year old man found to have a tiny amount of moderately aggressive prostate cancer may live into his 80s or 90s before that prostate cancer grows to any significant extent.  Many studies both conducted in the United States and in Europe have recently demonstrated that many men are diagnosed and treated for prostate cancer as a result of an elevated PSA test that would otherwise never have been significantly affected by prostate cancer within their lifetimes.

So what do all of these problems with the PSA test mean?  Should we get rid of it altogether?  I definitely think not.  While PSA is not a perfect test, it is vitally important if used the right way.  As I mentioned before, prior to PSA, many more men were needlessly dying of metastatic prostate cancer.  In addition, while identifying prostate cancer in 80 year old men MAY not be useful, finding any prostate cancer in healthy, 50 or 60  year old men while the cancer is still contained is VITAL.  PSA can help doctors identify CLINICALLY SIGNIFICANT prostate cancer that WILL affect and possibly shorten the lives of men who suffer from it. 

The real question then is how do we use PSA appropriately and for the most benefit.  First, as I mentioned previously, care must be taken to make sure that the PSA reading is actually real.  Elevated PSA tests should be repeated while minimizing the effects of other factors causing elevation of the test such as sexual intercourse.  In addition, current recommendations are for men over the age of 75 to stop getting PSA tests altogether.  The thinking behind this recommendation is that, because prostate cancer grows slowly, men in their mid to late seventies are unlikely to live long enough for a small amount of prostate cancer to grow enough to significantly affect them.  I don’t completely agree with this thinking because I treat many men in their 70s who are very healthy and will most likely live for at least 20 years.  As a result, I think the decision of whether to do  PSA testing should be tailored to the individual health and wishes of each patient and should entail a detailed discussion between men and their doctors.  I think that this approach should be applied to all patients who undergo PSA tests.  You and your doctor should take many factors into account when deciding whether to get a PSA test and how to interpret the results of that PSA test including your age, health, and desires.  If used in this patient specific manner rather than a “knee-jerk” fashion the PSA test can help save many lives while avoiding unnecessary procedures, pain, and worry. 

Check out my new Book: 

   Prostate Doc’s Guide to Life After Prostatectomy