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Post subject: Understanding Prostate Cancer  PostPosted: Nov 20, 2005 - 06:17 PM

Q I am 64 years old. At a recent routine physical examination by my internist, my PSA was 6.3 ng/ml. I then saw a urologist who biopsied my prostate gland and later told me I had Gleason score 6 prostate cancer, stage T1c. My wife and I have never been more scared. The urologist wants to do a radical prostatectomy. Another urologist said I should have my prostate gland frozen by cryosurgery. A radiation doctor (radiation oncologist) said I should be treated with accelerator irradiation using IMRT and not surgery, while still another radiation doctor said I should have a seed implant. A third radiation oncologist said that everybody else was wrong and I should have high dose rate radiation (HDR). Each of these doctors claims he is an expert and his treatment method is the best. I am now more scared and confused about the best treatment for my prostate cancer. What should I do?

A Your experience is fairly typical of what men find when they are newly diagnosed with prostate cancer. Doctors typically recommend only the treatment they themselves give. A urologist will talk about surgery and a radiation oncologist about radiation. It can be like buying a car. If you go to a Chevrolet dealer, the talk will be about Chevrolets, and a Ford dealer will talk only about Fords.

The most important advice I can give you is for you to learn about prostate cancer yourself and then make your own decision about treatment and doctor. It is easy to understand and learn about prostate cancer and about doctors, and it is very important that you do. With few exceptions, you will get only one chance to be treated for cure of prostate cancer.

Q Should I be treated with surgery or irradiation for my prostate cancer?

A Most men who have prostate cancer immediately focus on treatment. That is a big mistake. Right now, forget about treatment. First, understand prostate cancer - about the meaning of PSA, Gleason score, stage, PSA nadir, microscopic capsule penetration and how to determine cure and cure rates for prostate cancer. Learn about the disease first and then let treatment outcome (cure and complication rates) determine your treatment decision and decision on a doctor.

Q Okay, so to begin with, where is the prostate gland located, and what does it do?

A The prostate is located behind the pubic bones in a man's pelvis and is sandwiched between the bladder on top and the rectum underneath. A normal-sized prostate is about 20-25cc, about the size of a walnut, and is covered by a capsule similar to a shell around an egg. A tube, called the urethra, runs through the middle of the prostate and drains urine from the bladder out the penis.

Smaller tubes, called the ejaculatory ducts, run from each testicle into the prostate and empty into the urethra in the middle of the gland. Two sex nerves for erection of the penis, one on the right side and one on the left side, run next to and along the side of the prostate. About two-thirds of the prostate gland is made up of normal prostate cells and the remaining one-third is made up of the urethra, muscles in the prostate that encircle the urethra, fibrous tissue that holds the prostate together, blood vessels and the ejaculatory ducts. The purpose of the prostate cells are to produce seminal fluid, which, when mixed with the sperm from the testicles, is called semen. Semen is the white fluid seen when men ejaculate. Prostate cells also secrete various proteins into the bloodstream, one of which is called prostate specific antigen or PSA.

Q What is PSA?

PSA is an enzyme that is produced only by prostate cells, either normal cells or cancer cells, and secreted into the seminal fluid to keep it liquefied. More importantly, a small amount of PSA is continually leaked into the bloodstream by prostate cells, which can be measured by the PSA blood test.

Q How much PSA from the normal prostate leaks into the bloodstream?

A For men aged 60 or less, the normal level is up to 2.5 ng/ml. The normal range is up to 4.0 ng/ml for older men, since the prostate usually enlarges and makes more PSA as men age.

Q How much PSA is produced when men have prostate cancer?

A When a normal prostate cell undergoes malignant change to a cancer cell, it leaks a lot more PSA into the bloodstream. On average, one prostate cancer cell will produce 10 times more PSA than one normal prostate cell. Consequently, when prostate cancer cells multiply, more PSA spills into the blood and when you measure the PSA in a man with cancer, the PSA level is usually (but not always) above the normal of 4.0 ng/ml overall or 2.5 ng/ml for men aged 60 or less.

Q What is the average PSA of men with prostate cancer?

A The average is 7.2 ng/ml, but there is wide variation. We have treated men for prostate cancer with a PSA as high as 430 ng/ml and as low as 0.3 ng/ml. Fifteen percent of men with prostate cancer have a PSA below 4.0 ng/ml, in the normal range. Based on a man's PSA, we classify men with prostate cancer into four PSA groups:

Q My PSA is 6.3 ng/ml. What does this mean?

A The amount of PSA usually indicates the amount of prostate cancer in a man. More PSA typically means more cancer. Your PSA of 6.3 ng/ml places you in the PSA group of 4.1-10.0 ng/ml and also suggests that you have slightly less cancer than the average patient with this disease.

Q Does the amount of PSA always measure how much prostate cancer you have?

A No. Some prostate cancers will not make very much PSA and are called low-PSA producing cancers>. Low-PSA producing cancers can be very advanced and fool doctors. For example, the worst cancer we have treated at RCOG in the past 10 years was in a man whose highest PSA was only 0.5 ng/ml. However, he had a Gleason score of 10 and the cancer had already spread (metastasized) into his bones and he was incurable. The PSA is usually a good indication of the amount of cancer you have, but it is far from foolproof.

Q Does PSA tell you where prostate cancer cells are located?

A No. PSA is produced by prostate cancer cells no matter where they are located in a man's body. Prostate cancer cells that have spread through the prostate capsule into the areas around the prostate or to other areas in a man's body, such as lymph nodes, bone, lungs or liver, still make PSA just as well as prostate cancer cells located in the prostate.

To illustrate, let's say that with your PSA of 6.3 ng/ml, you have a total of 100 cancer cells. If all 100 cancer cells are contained inside the prostate capsule (step one of cancer growth), your PSA would be 6.3 ng/ml.

On the other hand, if you had 75 cancer cells in the prostate and 25 had penetrated the prostate capsule and spread outside, but around the gland (step two of cancer growth), your PSA would still be 6.3 ng/ml.

If five of those capsule penetration cancer cells had spread into your lymph nodes or bones (step three of cancer growth), your PSA would still be 6.3 ng/ml. PSA measures the amount of prostate cancer in a man from head to toe, but does not tell you where the cancer is located.

Q Can you have PSA above 4.0 ng/ml and not have prostate cancer?

A Yes. Half of men aged 60 or more have an enlarged prostate produced by a separate disease called BPH (benign prostate hyperplasia), which can elevate the PSA above 4.0 ng/ml. Incidentally, BPH is the reason men have difficulty with urination, such as a weak, slow urine stream because the urethra tube is squeezed by an enlarged prostate. Inflammation of the prostate gland, called prostatitis, can also elevate the PSA by leaking more PSA into the bloodstream.

Q My Gleason score is 6. What does this mean?

A Gleason score indicates how fast the cancer is growing. When you had your prostate biopsy (needle sticks into the gland by your urologist), the tissue removed in the needle was sent to a pathologist who examined each of your prostate biopsy needle specimens under a microscope. If prostate cancer is detected, the pathologist gives us a number between 2 and10 to show how fast the cancer is growing. This number is called the Gleason Score. Table 1 below gives the percent of all men in the three different Gleason score groups and rate of cancer growth.

Q Since my biopsy is Gleason score 6, does this guarantee I just have Gleason 6 cancer?

ANo. When a biopsy is performed, only a tiny amount of material is removed from the prostate. The biopsy Gleason score applies only to the reading from that tiny amount of tissue. Medical studies have compared biopsy Gleason score with the Gleason score of men who later had a radical prostatectomy and the pathologist can then determine Gleason score from the entire prostate, the prostatectomy specimen Gleason score. One-third of men with a biopsy Gleason score of 2-6 actually have a Gleason score of 7-10 when the whole radical prostatectomy specimen is examined under the microscope. Why? You could have a large area of Gleason 6 cancer in your prostate, which is easily hit with the tiny needle biopsy, but also have a small area of Gleason 8 that could be missed. Therefore, your biopsy Gleason score 6 does not guarantee that you only have Gleason 6 cancer. You have a one-third chance of a Gleason score between 7 and10, which means a more aggressive cancer with a greater chance of microscopic capsule penetration.

Q Are there other problems with the Gleason score?

A Yes. The Gleason score is determined by the pathologist, which, of course, is based on his experience and training. Most pathologists who read prostate biopsies have had limited experience in interpreting these specimens. Consequently, at RCOG, we always have the biopsy slides reviewed by an expert pathologist, because the Gleason score influences how we treat a man. Not infrequently, our expert pathologist changes the Gleason score. For example, we recently treated a 50-year-old man whose original biopsy report showed Gleason 5, but he actually had Gleason score 9 when reviewed by our expert pathologist. The Gleason 9 reading made us completely change our treatment plans.

Q How do you determine location of prostate cancer?

A Cancer location is determined by what is called cancer stage. So that all doctors determine stage by the same method, stage is determined only by finger examination of the prostate gland, the digital rectal examination (DRE). Table 2 below lists the various stages, what they mean and the percent of men found in each stage (the prostate has two sides or lobes, right and left.). Most men (64%) have stage T1c cancer.

Q How accurate is staging of prostate cancer?

A Often inaccurate. In fact, compared to the PSA and Gleason score, staging of prostate cancer is the most inaccurate measure of the extent of cancer. The biggest area of inaccuracy concerns stage T1 and T2 disease, the stage that most men have. In reality, one-third to one-half or more of men with stage T1 or T2 prostate cancer actually have stage T3 prostate cancer, cancer outside the prostate, due to microscopic capsule penetration of cancer cells, which cannot be detected before treatment.

Q Why are stages T1 and T2 cancer so inaccurate?

A Microscopic capsule penetration. Prostate cancer is typically located on the back side of the prostate next to the capsule. In this location, prostate cancer often invades into and destroys part of the capsule, creating a hole through which cancer cells leave the prostate and invade into the area around the prostate, such as the rectum, bladder, sex nerves or muscles that control urination. (To picture this, take an egg with its shell intact, then punch a small hole in the shell, analogous to cancer eating a hole in the prostate capsule. The yolk will leak through the hole in the shell similar to cancer extending or leaking outside the prostate.) More importantly, a doctor cannot detect this small amount of capsule penetration cancer with his examining finger (DRE) nor can you reliably find this capsule penetration cancer with any test, including MRI scans or color Doppler ultrasound scans. Microscopic capsule penetration can be determined only by a pathologist with the microscope when examining a radical prostatectomy specimen.

Q I still do not understand microscopic capsule penetration. Will you explain it further?

A Microscopic capsule penetration is one of the most important concepts to understand about prostate cancer and has been extensively studied at Johns Hopkins University. Based on DRE, men were staged before radical prostatectomy as having stage T1 or T2 disease. Then radical prostatectomies were performed on these men and the whole prostate given to the pathologist for examination under the microscope. On microscopic examination a few days after surgery, 36% of stage T1 and T2 men were found to have cancer cells that extended through the capsule and were outside the prostate. This is called microscopic capsule penetration, which means that men are really stage T3. The chance of microscopic capsule penetration was then correlated with the four PSA groups and compiled in tables called the Partin Tables. Table 3 below lists the chance of microscopic capsule penetration based on PSA group.

Table 3

Chance of Microscopic Capsule Penetration

Up to 4.0 ng/ml
10 - 72%
4.1 - 10.0 ng/ml
20 - 87%
10.1 - 20.0 ng/ml
38 - 94%

Since your PSA is 6.3 ng/ml, you would be in the 4.1-10.0 PSA group and your chance of microscopic capsule penetration would be 25%. In other words, although you are stage T1c based on the DRE, you actually have a 25% chance of having microscopic capsule penetration and, thus, stage T3 cancer.

Q if I understand this correctly, with my PSA of 6.3 ng/ml, Gleason score of 6 and stage T1c disease, I could have microscopic capsule penetration and a lot more advanced cancer than I know about.

A That's correct. Your PSA of 6.3 ng/ml could be from a low-PSA producing cancer. With Gleason score 6, you have a one-third chance of having a Gleason score of 7-10 and you have a 25% chance of microscopic capsule penetration or stage T3 disease. In other words, when doctors evaluate a man's PSA, Gleason score and stage before treatment, they make an educated guess about the extent of his cancer. You will never hear a doctor say, "I guarantee you all the cancer is inside the prostate." Typically, you will hear doctors say, "As far as I can determine," or, "As best we know," or "I think." One of the most important things that you should learn is that before any treatment of prostate cancer, you never really know just how extensive a man's cancer is in any individual patient.

Q Are there other tests I should know about?

A Yes. You should know about the PSA nadir test, which is determined after treatment. The PSA nadir is the single most important measurement of any man who has been treated for prostate cancer. PSA nadir is far more important than your PSA before treatment, Gleason score, stage or anything else.

Q What is PSA nadir?

A As you know, we use the PSA test to search for prostate cancer in men. For example, you had a PSA of 6.3 ng/ml, which led to prostate biopsy and finding of your prostate cancer. An equally important role for PSA is to determine whether or not we get rid of prostate cancer, whether we cure you of this disease. We determine cure by measuring how low the PSA falls after treatment of prostate cancer. The lowest PSA measured after any treatment for prostate cancer is called the PSA nadir and the PSA nadir achieved determines whether or not you will be cured.

Q What PSA nadir is needed for me to be cured of prostate cancer?

A PSA nadir 0.2 ng/ml or lower, which is also called an undetectable PSA. The reason we use PSA 0.2 ng/ml is that PSA tests cannot reliably measure PSA below 0.2 ng/ml. In other words, PSA 0.2 ng/ml essentially means that you have zero

Q I still do not understand. Please tell me more about PSA nadir.

A The best way to understand PSA nadir and also microscopic capsule penetration is to discuss treatment with radical prostatectomy, surgical removal of the prostate, which is where we first learned about both of these issues.
First, remember that your PSA of 6.3 ng/ml is produced only by your normal prostate cells and prostate cancer cells. Now, of the 100 prostate cancer cells we used in an earlier example, let's assume all those cells are inside the prostate gland and you have no microscopic capsule penetration. If you had a radical prostatectomy, the entire prostate gland would be cut out. Consequently, all your normal prostate cells as well as all of the 100 prostate cancer cells would be removed. You would no longer have any prostate cells in your body. Your PSA would then fall from 6.3 ng/ml to 0.2 ng/ml. PSA nadir of 0.2 ng/ml after your radical prostatectomy would mean that you had been potentially cured of prostate cancer. Having your PSA fall to 0.2 ng/ml or lower is the first PSA step (of two steps) for you to be cured of prostate cancer (Figure 7).

Q If my PSA nadir reaches 0.2 ng/ml, why do you say potentially cured instead of cured? What is the second PSA step for cure?

A Your PSA must not only fall to 0.2 ng/ml (step 1), but must stay there forever (step 2). In other words, go to PSA 0.2 ng/ml; stay at PSA 0.2 ng/ml. To illustrate, let's assume microscopic capsule was found after radical prostatectomy. With your stage T1c disease, you have a one-third chance of microscopic capsule penetration. Now, let's still assume you have 100 prostate cancer cells with 95 of the cancer cells inside the prostate capsule, but the cancer has eaten a hole in the capsule and five cancer cells have escaped into the surrounding area around the rectum, bladder, sex nerves or muscles that control urination. With a radical prostatectomy, you would again remove the entire prostate gland, which means all normal prostate cells and the 95 cancer cells inside the prostate. You would also remove some of the five microscopic capsule penetration cancer cells, but most of the time you cannot remove all of these cells because you do not want to cut out your normal adjacent organs. You are not going to cut out your rectum or bladder, nor do you want to cut out the muscles that control urination or the sex nerves where microscopic cancer cells can spread. Let's assume that you are able to cut out four of the five microscopic capsule penetration cancer cells, but one would be left behind. This one cancer cell would not make enough PSA by itself to be detectable. Consequently, your PSA would still fall from 6.3 to 0.2 ng/ml after surgery. That is why we say you have been potentially cured.

Q What would happen with the one cancer cell left behind?

A Over time, this one cancer cell would multiply and make more cancer cells. Eventually, the increasing number of cancer cells would produce enough PSA to make your PSA level rise above 0.2 ng/ml. Any rise in PSA above 0.2 ng/ml after radical prostatectomy guarantees that you were not cured and your cancer is regrowing because the only other cells that make PSA are normal prostate cells, but they were all removed at the time of surgery. (Figure 8)

Q So is that what you mean when you say to be cured of prostate cancer, my PSA has to stay at 0.2 ng/ml forever?

A Yes. Remember, there are two PSA steps to cure: 1) you must not only achieve PSA nadir 0.2 ng/ml, but 2) you must stay at 0.2 ng/ml forever. From a practical standpoint, almost all prostate cancer that is going to grow back will do so within 10 years, or certainly 15 years after treatment. This is why cure rates must be calculated 10 years after treatment.

Q Are you guaranteed to be cured with radical prostatectomy if the pathologist cannot find any microscopic capsule penetration?

A No. Even when the pathologist can find no microscopic capsule penetration after examining the radical prostatectomy specimen, approximately 15% of men still fail to be cured with surgery. Apparently, microscopic capsule penetration cancer cells can be missed even by the pathologist or these cells can spread through lymph channels or tiny blood vessels and not be detectable under the microscope.

Q What would it mean if I had radical prostatectomy and my PSA nadir was more than 0.2 ng/ml, for example 0.6 ng/ml?

A A PSA nadir after radical prostatectomy of more than 0.2 ng/ml guarantees that you have not been cured (you did not achieve step 1). Let's revisit our example of 100 cancer cells.

This time let's assume 90 cancer cells are inside the prostate and 10 are microscopic capsule penetration cancer cells. With surgery, you would remove the 90 cancer cells in the prostate, plus all the normal prostate cells. And let's assume seven out of the 10 microscopic capsule penetration cancer cells are removed, for a total of 97 of the 100 cancer cells (three cancer cells were left behind). Let's also assume these three cancer cells produce a total PSA of 0.6 ng/ml. Therefore, when you remove the normal prostate and the 97 cancer cells, your PSA would fall, but the three cancer cells left behind will stop the PSA fall at 0.6 ng/ml. You did not achieve PSA nadir 0.2 ng/ml (step 1 for cure), which means you still have cancer.

Q Why is it important that I learn about PSA nadir 0.2 ng/ml?

A Because an understanding of PSA nadir 0.2 ng/ml is the key to understanding how prostate cancer works. With this understanding, it is easy to learn how to calculate cure rates so you can compare different doctors, and different treatment methods for prostate cancer and decide yourself on how you wish to be treated. In fact, the cornerstone to understanding treatment and cure of prostate cancer is this: after any treatment, your PSA must fall to PSA nadir 0.2 ng/ml or lower and remain at 0.2 ng/ml. A PSA nadir of 0.3 ng/ml or more, or a later rise to this level, means you have not been cured. It's as simple as that.


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