P.S.A. Information:

The Clinical Value of the PSA Test for Assessing Prostate Health and Managing Cancer.

This is the transcript of a two-part program entitled "Science, Health and Healing," conducted by Majid Ali, M.D., on New York public radio on February 28, 2005, and March 1, 2005.

There Are No Controversies in Clinical Medicine, Only Levels of Understanding and Enlightenment.

Essential Points

The Spurious PSA Controversy

Here is some of what is feeding the frenzy against the PSA test. Recently, a patient brought me a copy of a consumer health letter. It declared the PSA test to be very dangerous and advised its readers not to have the test done. I do not think such health letters should be taken seriously. And I told my patient so. Then I received my copy of the January issue of the Discover magazine, which I do take seriously. The whole issue was devoted to what Discover designated as the "Top 100 Science Stories of 2004." To my surprise, it included PSA as one of its 100 top stories, and told its readers that the PSA test is a useless test. This, in a direct quote, is what the Discover magazine told its readers on page 30 of the first issue of the new year:

Millions of men over age of 50 rely on the prostate-specific antigen, or PSA, test each year in screening for prostate cancer. In October Stanford University urologist Thomas A. Stamey made headlines when he declared that the test is not a reliable predictor of cancer. Based on an analysis of more than 1,300 prostates removed over the past twenty years, Stamey reported in October issue of the Journal of Urology that the PSA test is currently predictive of cancer only in 2 percent of cases. It was not new information for me. I have known about Dr. Stamey's work for years. I consider him to be a gentleman-surgeon, who has demonstrated rare courage in admitting that he now regrets removing prostate glands based on PSA values during the past decades. Not too many surgeons are willing to admit such a thing. Prostatectomy for many persons, after all, means urinary incontinence and loss of sexual function, sometimes permanently. So, a surgeon admitting that he has caused such harm to many men, indeed, is a display of rare surgical courage.

An opposing view of the test was recently presented in the July 8, 2004, issue of The New England Journal of Medicine (page 180). Consider the following quote:

Measurement of prostate-specific antigen (PSA) has profoundly affected virtually all clinical aspects of prostate cancer. A sharp increase in both the incidence of age-adjusted prostate cancer (about 100 percent) and the proportion of patients with early stages of the disease at the time of diagnosis (stage migration) has coincided with the advent of widespread PSA testing. The Effect of Cut-Off Point on Test Sensitivity and Test Specificity. But Dr. Stamey's claim that the PSA test is currently predictive of cancer only in two percent of cases did surprise me. Actually, I was dismayed to see such words attributed to him.

People outside laboratory medicine often fail to recognize that pathologists determine the predictive function of laboratory tests. They do so by choosing where to draw the line and pick the cut-off point for test positivity. We can lower the cut-off point and increase the test sensitivity at the expense of test specificity, or we can raise the cut-off point and decrease the test sensitivity at the expense of loss of the test specificity. The test sensitivity indicates test positivity in the presence of the disease in question. The test specificity, by contrast, indicates test negativity in the absence of that disease. Let me put that in plain English. If we were to pick a cut-off point of just one ng/ml for the PSA test for the diagnosis of cancer, we will diagnose every cancer so the test sensitivity will be 100 percent, because every prostate cancer that I ever saw had a PSA value of over one. However, at a cut-off point of one, we will falsely diagnose cancer in an enormous number of persons, since most persons with a PSA value below three do not have cancer. On the other hand, if we were to pick a cut-off point of one hundred for the PSA value for the diagnosis of cancer, then the test specificity of PSA for prostate cancer will be nearly 100 percent, since nearly all men with that PSA value of over 100 will have cancer of the prostate gland. But we will pay a huge price with a high cut-off point of one hundred. At that cut-off point, we will miss most cancers, since nearly all patients with cancer show a PSA value below 100 when I first see them.

Persons without pathology background often make mistakes with the real meanings of the terms test sensitivity, test specificity, and the predictive function of the test. There is even a more important issue here. The purpose of the screening tests for cancer is to screen for, and not to diagnose, malignant tumors. If we were to accept Dr. Stamey's premise, no screening test for any cancer should ever be done. I might point out here that except when a pathologist makes an unequivocal diagnosis of cancer with a microscope, which can be validated by all other experienced pathologists who examine the microscopic slides, no test can be accepted as a true test for the diagnosis of cancer. Not MRI. Not CT scan. Not a PET scan. Not ultrasound. Experienced pathologists who spend their lifetimes studying cancer and following up those cases for years and decades know that. That, as I said earlier, is elementary laboratory medicine. That is why the whole medical profession all over the world considers the microscopic diagnosis of cancer and other diseases as the gold standard. Advances in genetics may someday change that, though I personally do not foresee that except for a small number of unusual cancers.

The PSA Test Result Is Not a License for Performing Radical Surgery So, I agree with Dr. Stamey that surgeons should not operate on prostate glands merely on the basis of PSA value, but to say that the predictive value of the test is two percent is a gross distortion. It simply means that the surgeon has utterly failed to understand how laboratory tests should be interpreted, and the test results integrated with all other available information for making the right clinical decision. That, simply stated, is elementary laboratory medicine. So, I was surprised to see that error coming from Dr. Stamey unless, of course, the reporter of the Discover magazine made that mistake. There are other more serious problems with Dr. Stamey's musings on the clinical value of PSA, which I will return to later in this program. The writer of one of the consumer health letters, which put down the PSA test, strongly urged his readers not to have the PSA test done. Then he wrote something which I am sure he did not understand himself. He told his readers that if they had to have the test done, they should have a free PSA test. Apparently, this person in the medical advice business did not know that free PSA test value is expressed as a percentage of the total. How can anyone know what ten percent of anything can be when he does not know what the hundred percent of that element is? This spurious PSA controversy continues to amuse me.

There Are No Controversies in Clinical Medicine, Only Levels of Understanding and Enlightenment.

I would have found the PSA controversy merely amusing if I did not recognize the very serious potential of hurting an enormous number of persons not well versed with the sound and basic principles of laboratory medicine. So, for you, is my commentary on the PSA controversy. Later, we will open the phone lines and you can call to disagree with me. In my commentary on the PSA test debate, First, I want to assert that there are no controversies in clinical medicine, only levels of understanding and enlightenment. I have used those words repeatedly in the various volumes of my textbook on integrative medicine when dealing with what I consider to be frivolous debates. And I use them again today because I consider the so-called PSA controversy to be frivolous. Second, today I have chosen to let my patients settle the question whether or not PSA is a useful test with their true-to-life stories. Third, there is an interesting display of cognitive disconnect among writers and physicians who have pronounced the PSA test to be useless. From personal knowledge, I know that those who pronounce the PSA test to be useless and dangerous have not stopped ordering the test, for themselves or their patients. So, I see clearly much confusion there.

How Real Is the Problem of Prostate Cancer? Now I will state in simple words seven facts concerning the clinical value of the PSA test that are crucially important to physicians in clinical trenches, like myself, who actually examine and treat persons with prostate cancer. Later, as I said earlier, I will make additional comments about the position taken by Dr. Stamey, whom, again, I admire greatly. Here are those facts:

I said earlier that in this program, I will let my patients answer the questions raised by the critics of PSA with their true-to-life accounts of their struggle with prostate problems. I present the facts. You decide for yourself whether the PSA test is useful or dangerous. Here are the voices of those patients:

Seven Illustrative Case Histories

A 71-year-old immigrant without urinary symptoms saw his cardiologist, who ordered batteries of laboratory tests but failed to order PSA test. About seven months later, he consulted me for back pain. I ordered the PSA test, which came back at a value of 71. A biopsy showed Gleason 3+4 adenocarcinoma of the prostate gland. His two physician-daughters persuaded him to elect a combination of external radiotherapy and seed insertion, following three months of androgen inhibition with Lupron injections. After eight weeks, his PSA value fell to two and hovered between two and five for several months. Then the PSA value rose sharply and within two months stood at 90. Chemotherapy was instituted at that time, but the PSA value continued to rise to 800, with evidence of extensive pelvic and bone metastases. For the last months of his life, he was bedridden, in severe pain despite heavy doses of opiate analgesics, which caused persistent nausea and vomiting. A liver biopsy done to diagnose liver metastases caused hemorrhage that proved fatal within ten hours. Some weeks before his death, he said to me: "My cardiologist did his silly cholesterol tests, but neglected to order a simple PSA test with the same blood sample. Then my cancer could have been detected earlier. Then maybe I would not have had to see these horrible days. Do you know why he did not order a PSA test for me?" He should have ordered the PSA test was my response in a low tone.

A 52-year-old man had a PSA value of 2.9 in 1999. It rose to 3.1 in 2000, then to 4.1 in 2001 when a biopsy revealed a Gleason 7 cancer. He was offered surgery and radiotherapy. He refused both options and elected to pursue a completely natural program for cancer control. Initially, his PSA continued to rise and peaked at 4.8. Next year it dropped to 2.5. At the last review, about four years after the initial diagnosis of cancer, he was free of prostatic symptoms and his PSA stood at 2.8 ng/ml. "I have a belief system. I did Silva mind control 30 years ago. Ever since, my belief in natural healing has been becoming stronger," he told me. "What sustains you?" I asked. "Once you waver in your belief, you go down," he replied, then added, "It's all spiritual. It's not about words or analysis. You can't do this in just one specific way. I thank God every day for little things." "Why do you get PSA done every three to four months?" I asked. "Knowledge and understanding strengthens me. PSA is just one piece of that knowledge."

A 63-year-old man had a digital prostate examination. The gland was normal in size, regular in contour, movable, and without any nodules. His PSA value was 7 ng/ml. A prostate biopsy revealed Gleason 3+3 cancer. "Why did my urologist not pick up that cancer when he examined me?" he asked. I told him that microscopic prostate cancers often do not form tumor nodules that can be palpated by urologists. This case does not require any further comment. Every urologist sees such cases in dozens, if not hundreds, in her or his career.

A 71-year-old man had a PSA value of nine. His ultrasound report included the sentence: No evidence of tumor seen. A biopsy revealed a Gleason 7 prostate cancer. "Why did the ultrasound miss my cancer?" he asked. "That has not been very uncommon with early cancers in my experience ," I replied. It is true that the newer power Doppler technology has substantially increased the diagnostic yield of prostate cancer. But I saw this man only months ago. That is the reality as of today. Even when the latest power Doppler technology becomes available for everyone, I believe ultrasound scans will continue to miss early cancers at microscopic stages. It is important to remember that ultrasound detects cancer only when it has created a tumor with abnormal blood vessels.

A man in his late sixties consulted me for rising PSA and increasing symptoms of prostatic obstruction three years after receiving radiotherapy for prostatic cancer. His PSA value was 341 ng/ml. His blood creatinine level was 1.4, clearly indicating kidney failure. The CAT scan showed marked dilatation of the collecting system of the kidneys. He showed an unusually gratifying response to our treatment plan. After about three months, his urinary symptoms cleared. The PSA value fell to a five to seven range. The blood creatinine level returned to normal range, indicating complete recovery of kidney function. A repeat CAT scan showed normal appearance of kidneys. I did not see that man for the next six months. He returned with a PSA value of 81 ng/ml and progressive prostatic symptoms. "There have been severe family stresses. I have been traveling and have been off my program. But I have heard the PSA test is not reliable. What do you think?" he asked. "I think we need to pay much more attention to the problem. It can get out of hand. To begin with, when cancer returns after radiotherapy, it is very difficult to control," I replied. In this case study, there was a perfect correlation between clinical symptomatology, the PSA values, blood creatinine levels, and CAT scan during the course of several months when he was able to follow the Oxygen Protocol, as well as during the several months when circumstances did not allow him to closely follow the program.

Here are the rising values of the PSA test of an 80-year-old man: 2 ng/ml in 1996; 7.5 in 1997, 14 in 1999. He declined prostate biopsy advised by his urologist at that time. Instead, he accepted the Oxygen Protocol for prostate cancer with us at the Institute. PSA rose initially, peaking at 15 three months later, then the values began falling, such that the PSA number was 0.5 five years later. His night urination now ranges from zero to two. He has no other urinary symptoms. "Why do you want to get a PSA test?" I asked him during one visit. "Why shouldn't I? It gives me a sense of where I stand. When it was 15, I knew I needed to do more to control the problem. Now that it is 0.5, I can do less," he replied. Here is the lesson in this case: The rising PSA values provide us a reason not for surgery, or radiotherapy, or chemotherapy, but for doing more to address the real issues in prostate cancer, which are the matters of oxygen homeostasis, redox equilibrium, and acid-base balance. And that is exactly what that gentleman chose.

A man in his seventies had a prostate cancer diagnosed more than fifteen years previously. He managed his tumor very successfully for that period with natural therapies. Then he developed prostate discomfort and urinary difficulties, and also experienced pain in his rib cage. A bone scan showed troublesome areas. The PSA value was over 350. With a vigorous application of the Oxygen Protocol, his PSA fell to less than ten. His urinary and prostate symptoms cleared up. Then the PSA values began to rise again after there were lapses in the program and reached a value of 120. An ultrasound was done at that time. The ultrasonographer assured the patient that there was no tumor in the prostate. I asked the ultrasonographer if the high levels of PSA could be coming from the tumor outside the prostate region that had been examined with the power Doppler technology. He admitted that that could be the case. Again, I do not see how one can rule out the presence of microscopic clusters of cancer cells by ultrasound in such a case. With a closer attention to the oxygen program, the PSA value in that patient fell down to 60. The PSA test in this case study clearly served as the laboratory metric of central importance. The Doppler study did not provide clear, reliable information concerning the status of the tumor. Now, I return to the issues raised by professor Stamey of Stanford University as presented by the Discover magazine. Rising Total PSA and Falling Free PSA Levels in the Presence of Strong Family History of Prostate Cancer.

The essential point in all of the above case studies is that the real value of the PSA test, as is the case with nearly all other laboratory tests, is in close examination of the trend in changing values. The combination of rising total PSA and falling free PSA values is a clear indication for a diligent evaluation of all clinical, laboratory, and imaging information of the case, since this combination indicates a much higher likelihood of the presence of cancer. Again, it is noteworthy that free PSA is expressed as a percentage of the total. Do individuals who insist that PSA is "a misleading, even dangerous test" realize that? This pattern of diverging total and free PSA values is especially disconcerting in the presence of a strong family history of prostate cancer, because that makes the probability of cancer even higher.

Prostate Cancer Test Questioned / 100 Top Science Stories of 2004

Discover magazine, January 2005, page 30—here is a quote from that article: "Studies have shown that 80 percent or more of men over age 70 die with—but not from—prostate cancer." What does the writer mean by those words?, I wondered when I read those words in the Discover magazine. What is he teaching us? He seems to want to make two points:

Discover is a good magazine. I subscribe to it and read it. But in writing this story about the PSA test, the writer was clearly out of his depth. He does not have any personal perspective on the problem. To him, the PSA story is just another story, to be written and forgotten. He does not even understand the problem, let alone think clearly about the solution. Let's go on with the Discover story. Here is another quote: "'First of all, it is not known how often PSA test saves lives,' says Howard Parnes, an oncologist at the National Cancer Institute." That quote from NCI is very revealing. Laboratory tests do not save any lives. What saves lives is the treatment prescribed based on the diagnosis established by a given test. So the number of saved lives is a indicator of the efficiency of the treatment plans. In essence, the NCI oncologist admits that the Institute does not know how many lives they saved. That is a refreshingly honest statement from NCI, a government agency not known for excessive honesty. At least this time, the agency admits it has no clear sense of how well its therapies work for prostate cancer. One hopes that such an open admission will be sobering for those at the helms of the National Cancer Institute. Perhaps NCI's admission about their poor results with prostate cancer will keep it from making irresponsible statements against natural therapies that are helping an ever-growing number of persons with prostate cancer. Might such a change in attitude at NCI pave the way for a change in the insurance industry concerning reimbursement for natural therapies that the American society so sorely needs? Courage of a Few, Guiding Light for Many.

In the last few months, we have been fortunate to have three strong, enlightened, and generous individuals who have openly shared their personal experiences with prostate cancer. We had Mr. Edward van Overloop from Ridgewood, New Jersey, who has kept his own prostate cancer under control with all natural therapies for over 16 years, without surgery, without radiotherapy, and without synthetic hormone therapies. That experience put him on his spiritual journey and his inspiring work in organizing his CARE support group for persons with various types of cancer. We had Dr. Jerry Mittelman who, like Mr. van Overloop, has controlled his cancer for nearly 14 years, again with all natural therapies, without surgery, without radiotherapy, and without synthetic hormone therapies. Dr. Mittelman has been on his spiritual path along with his wife, Beverly, who was here in the studio with him and shared with us her view of that spiritual quest. And yesterday, we had Mr. Gordon Voorhees who, like Mr. van Overloop and Dr. Jerry Mittelman, has controlled his cancer for nearly eight years, again with all natural therapies, without surgery, without radiotherapy, and without synthetic hormone therapies. Mr. Voorhees presented to our tribe his insights into the nature of healing, as well as the crucial issues of breaking through the fear brought on by what he called the big C word. Some weeks ago, Bernard White had Mr. Larry Clapp, the author of a very useful book on prostate cancer. He described some of his extensive experience with many effective natural therapies for prostate cancer.

My point here is this: There are many truthful and enlightened persons in this field who are not only living thoughtful, full, and healthy lives with their cancers, they are also beacons of light, love, and hope for others with cancer. I hope to invite many others to do the same for the listeners. People at the National Institute of Cancer need to listen to them. Let's hope there will be a change. Mr. Gordon Voorhees also made another important point. The natural therapies may not be for everybody, since a program of cancer control with natural therapies requires highly motivated persons who have done considerable spiritual work to rid themselves of fear that the word cancer always brings initially.

Let's go to another quote from Discover magazine:

Millions of men over age of 50 rely on the prostate-specific antigen, or PSA, test each year in screening for prostate cancer. In October Stanford University urologist Thomas A. Stamey made headlines when he declared that the test is not a reliable predictor of cancer. . . . Based on an analysis of more than 1,300 prostates removed over the past twenty years, Stamey reported in October issue of the Journal of Urology that the PSA test is currently predictive of cancer only in 2 percent of cases. Dr. Stamey is a preeminent professor of urology who has been an outspoken critic of some of the prevailing notions of the benefits of prostate cancer surgery. There again is a refreshing breeze of honesty from a urologic surgeon with vast true-to-life experience with the results of prostate surgery. I agree with his opinion that surgery is not a good treatment choice for most persons with prostate cancer. As I said earlier, I greatly admire Dr. Stamey, but here I strongly disagree with him. In the September/October 2002 issue of AUA News (AUA stands for American Urologic Association), Dr. Stamey ended his commentary on the PSA test with the following two astounding questions:

But Who Should Be Treated With Such a Small Death Rate From Cancer? Even More Importantly, Who Should Be Diagnosed? Amazing questions! I will take the second of those two questions first: Even more importantly, who should be diagnosed?

Shall we say we will diagnose prostate cancer only in Republicans? Or those who have dark eyes? Or those between 65 and 69 inches in height? Should I want to get the prostate cancer of my brother diagnosed? Or should I ask him to chill out, heeding Dr. Stamey's advice? Now the first question: But who should be treated with such a small death rate from cancer? That is an easier question to answer. Since we are told that one cannot know whose cancer should be diagnosed, obviously it follows that one cannot know whether a cancer should be treated or not.

What Dr. Stamey is really saying—in my view—is this: Radical prostate surgery generally gives poor results with high potential of serious long-term complication, especially urinary incontinence and the loss of sexual function. One cannot ignore those complications. And, of course, there is the disturbing issue of cancer returning after prostate surgery, an event that is not uncommon. Such recurrent tumors are usually hard to control because surgery evidently destroys the local anatomy.

An Unfortunate Inconsistency

Unfortunately some of Dr. Stamey's statements can be easily misconstrued—and, indeed, have been. Consider the following two quotes from an article he published in the British Journal of Urology in 2004 (94:963-870). The first of the two quotes is actually the title of his article: " The era of serum prostate specific antigen as a marker for biopsy of the prostate and detecting prostate cancer is now over in the USA." Having stated his position on the PSA test in the title of the article, he wrote the following words in the opening paragraph: "[B]iologic variables . . . might determine failure after RP (radical prostatectomy), as measured by a rising PSA." So, it is not surprising that Dr. Stamey's words have caused so much confusion and fueled a spurious controversy.

PSA Velocity

I mentioned earlier that in laboratory medicine, a study of trend in the changing values with sequential performance of a given laboratory test is the standard approach to resolving common problems in interpretation of tests. In the case of the PSA test, such trending is designated PSA velocity—specifically, the rate of change in the PSA value at suitable results. In my own clinical work, I consider it a critically important step in evaluating the full case characteristics of a given person. In this context, I include the following quote from the July 8 issue of The New England Journal of Medicine (page 125): As compared with an annual velocity of 2.0 ng per milliliter or less, an annual PSA velocity of more than 2.0 ng per milliliter was associated with a significantly shorter time to death from prostate cancer (P<0.001) and death from any cause (P=0.01). In the integrative model, one has choice in using the information furnished by The New England Journal of Medicine in the above quote: We can consider radical surgery (with substantial risk of urinary incontinence and the loss of sexual function) and accept substantial loss of life because of the failure of cancer to completely excise the tumor; or We can use a rapid PSA velocity as a motivational signal to follow a more vigorous program of restoration of oxygen homeostasis, redox equilibrium, and acid-base balance.

Laboratory Tests Are Wonderful Servants, But Very Dangerous Masters So, there I have presented the voices of my patients about the so-called PSA controversy. I have also explained my difficulty with the advice of Dr. Stamey concerning the clinical value of the PSA test. Now you decide whether the PSA test is a valuable test or not. Or whether you should have that test yourself or not. In closing this discussion of the PSA test, I return to the words with which I opened the program: There are no controversies in clinical medicine, only levels of understanding and enlightenment. I am a surgeon- turned-pathologist-turned integrative physician. I will continue to order PSA test for my patients and integrate the results of the test with the larger, holistic clinical perspective of the case for best possible clinical results. Laboratory tests, to me, are wonderful servants but very dangerous masters. I do not accept any lab test as my master.

The Cancerization/De-Cancerization Hypothesis

The prostate-specific antigen is an enzyme belonging to a family of serine kinases. I hypothesize that a prostate cancer cell uses this enzyme as a potent defense against the oxygen weapon of healthy cells in its vicinity. A prostate cancer cell also employs this enzyme, I also hypothesize, to open up new territories for it to invade and conquer.

To explain my hypothesis, I first need to explain two terms I introduced some time ago: (1) cancerization of a noncancer; and (2) de-cancerization of a cancer cell. I introduced the term cancerization for a phenomenon in which a cancer cell alters the metabolic conditions of a noncancer, such that cell metabolically behaves as a cancer cell—a noncancer cell shows a respiratory-to- fermentative shift in its ATP production. I introduced the term de-cancerization for a phenomenon in which the opposite of that occurs—a healthy cell alters, partially or completely, the metabolic conditions of a cancer cell, such that the cancer cell metabolically behaves as a non-cancer cell—a cancer cell shows a fermentative-to-respiratory shift in its ATP production.

that A cancer cell is forever busy cancerizing noncancer cells in its vicinity. A noncancer cell strives to de- cancerize a cancer cell. To date, I can support my cancerization/de- cancerization hypothesis only with indirect evidence obtained with demonstration of increased urinary excretion of Krebs' cycle metabolites. But I consider it safe to predict that when this hypothesis is put to experimental test, it will be borne out. Prostate-specific antigen is an enzyme, belonging to the family of serine kinase proteolytic enzymes. In discussion of prostate-specific antigen, the issue of important metabolic roles of this enzyme are nearly always ignored. In the context of my cancerization/de-cancerization hypothesis, the proteolytic enzymatic role of PSA may have significant roles on the spread of cancer. Specifically, a cancer cell is an oxyphobe, and one mechanism it employs to shield itself from tumoricidal effects of oxygen involves building a protective cocoon of precipitated proteins around it (usually through its prodigious hydrogen peroxide and acid production). But a cancer cell also has another goal: to multiply and spread. To do that, it must also have a second mechanism of dissolving that protein coat. In the context of the cancerization/de-cancerization hypothesis, it seems to me that PSA serves that role (most likely in association with other proteolytic enzymes).It is not uncommon for the PSA values to begin to drop incrementally in the presence of rapidly spreading metastases. Clinically, this has not been a problem for me. I have observed this phenomenon in evidently advanced cases of widely disseminated prostate cancer in which the PSA test value was of purely academic interest. But does this phenomenon have anything to do with the serine kinase function of PSA? Possibly yes. A rapidly spreading prostate cancer is likely to use up most of the PSA it produces for its proteolytic function—leaving little of it behind to escape into the circulating blood and be measured in the PSA testing.

Concluding Comments

In closing this article, I repeat my earlier words to summarize my sense of the clinical value of the PSA test as follows: