Prostate Cancer Screening: Who Is Right And Who Is Wrong? Part II

I bring you the concluding part of this article.Although In the 1970, Dr. Ablin and colleagues were trying to identify an antigen that was specific to prostate cancer. For you to understand this concept very well an Antigen is a substance that the immune system perceives as being foreign or dangerous. The body combats an antigen with the production of an antibody. Antibodies on the other hand are our molecular watchdogs, waiting and watching for viruses, bacteria and other unwelcome visitors. Antibodies circulate in the blood, scrutinizing every object that they touch. When they find an unfamiliar, foreign object, they bind tightly to its surface.

So what Dr. Ablin identified instead was that PSA was present not only in malignant prostates but also in benign prostates. He did agree, however, that elevated levels of PSA might be useful in predicting a recurrence of prostate cancer in men who were thought to be in remission.

It was much to Dr. Ablin's dismay that more than 2 decades later, in the mid-1990s, the US Food and Drug Administration (FDA) approved the use of PSA not only to test for recurrence of cancer, but also as a possible predictor of cancer. Since then, Dr. Ablin maintains, the United States spends billions each year administering a preventive prostate cancer screening test to men, using PSA that produces false positives in the majority of cases. In his interview with Dr. Topol, Dr. Ablin explains why physicians and patients should proceed with caution when using PSA as a marker for preventive screening.

Here is an in an interview with EricJ. Topol, MD I chance upon it while researching

“ PSA Discoverer Says Antigen Test Is Misused, Unreliable “www.medscape.com/viewarticle/828854 Aug 8, 2014

Dr. Topol: Let's talk about your background. You were at Lake Forest College, and then at SUNY in Buffalo. You worked at the well-known cancer center at Roswell Park. You were in Chicago at Cook County for a while, and now you are at the University of Arizona.

Let's go back to 1970, around the time that you first came across what is now called PSA. What were your thoughts about it at that time?

Dr. Ablin: To be as brief as possible, in 1967 I had joined 2 urologists in Buffalo at a teaching hospital there (my background is immunology) who were working on an alternative treatment for prostate cancer called cryosurgery -- freezing instead of cutting. In the course of our studies, when we were freezing the prostates of experimental animals -- rabbits, dogs, baboons, rhesus monkeys -- we were observing an immune response similar to that seen following a vaccine. When we froze more than once, we saw a characteristic booster response.

When we were following up some of our clinical studies by looking at x-rays, we saw in a patient an initial remission of metastasis in his lungs. This patient had stage IV lung cancer and metastatic prostate cancer, but he still had his prostate. On the basis of our experimental studies, we wondered whether the remission of these metastases had something to do with an immune response, which I subsequently characterized as cryoimmunotherapy.

We subsequently treated more patients by multiple cryotherapy of their prostates, and observed that several of these patients underwent remission of their metastases at distant sites. There was a lot of press and questions from the medical and lay communities about what was happening. Why is there an immune response? Is there a tumor-specific or cancer-specific antigen? To answer that question, I started to look at the immunologic complexity, or the antigenicity, of the normal benign and malignant prostate. I hoped to find a cancer-specific antigen.

Dr. Topol: Immunotherapy is one of the newest dimensions of cancer. That was your early work where you observed the PSA, but at that point did you think it was specific for cancer?

Dr. Ablin: To my dismay and disappointment, the tissue-specific antigen that I found -- PSA -- was the same protein found in the normal (benign) as well as the malignant prostate. It wasn't what I was looking for. We didn't have monoclonal antibodies in 1970, but with available techniques, we could see a spike in the area where PSA would have occurred, from a molecular standpoint. After treatment, if we followed this level, we saw a reduction of that peak. That was the forerunner of the test approved by the FDA in 1986 -- the PSA test that was the harbinger of the recurrence of the disease.

Dr. Topol: Yourbook reviews 40-plus years of the PSA test and what happened. One of the first things you discuss is how the PSA was commercialized by a San Diego company called Hybritech. This was the first company to manufacture a commercial PSA test. Was that commercialization of the PSA ill-founded?

Dr. Ablin: The difficulty is that the 1986 approval by the FDA was to use the protein as a harbinger of the recurrence of the disease, and that is what it is used for today. This is a very important observation. Because of the tissue specificity of the protein, it allows us to follow a patient after treatment. When you remove the prostate, for example, you remove the source of the protein.

Dr. Topol: That is a legitimate use of the PSA -- to track the prostate gland after surgery. So you didn't have a problem with the commercialization or initial FDA approval?

Dr. Ablin: One problem with the FDA approval was that when Paul Lange presented data to the advisory committee meeting in 1985, Hybritech was really after detection. They had in mind developing some sort of blockbuster drug or form of immunotherapy. There was some disappointment on their part when they went to the FDA, because they didn't have prospective data. They had only retrospective data, and a lot of questions were raised. They didn't get what they wanted to get in 1986

Dr. Topol: In 1994 (8 years later), the FDA approved the PSA test for routine use in men aged 50 years and older. That is what the company was initially after. What created the big problem?

Dr. Ablin: The calamity was that right after its approval in 1986, people started to use the PSA test off-label. The only company that was permitted to produce the test kit was Hybritech, but several other biotech companies began producing it shortly after the approval. A tsunami began in the urology community when clinicians started to use the PSA test off-label between 1986 and 1994. This was a crime, because they were using a test that was approved as a harbinger of the recurrence of the disease for the detection of prostate cancer 8 years before it was approved for that indication.

Furthermore, it should have never been approved for that purpose, because at the advisory committee hearing in 1993 (before the 1994 approval), many members of the committee opposed it. For example, Alexander Baumgarten made the statement that because of the results that Bill Catalona was presenting, it was like Pontius Pilate; you won't be able to wash the blood (the guilt) off your hands because of the 78% false-positive rate.

How is a test with a 78% false-positive rate approved?

Dr. Topol: How is a test with a 78% false-positive rate approved? As you wrote in the book, the PSA is wrong 80% of the time.

Dr. Ablin: Through the Freedom of Information Act, we obtained the transcripts of the 1985 and the 1993 meetings. A portion of the transcripts are reprinted in the book. The meeting had a circus atmosphere. Prostate cancer patient support groups were there. Lobbyists were there. Bill Catalona was saying that every few minutes, a man is dying of prostate cancer. The irony is that even Dr. Catalona said that the PSA test doesn't detect prostate cancer. It is a measure of risk. By his own admission, it wasn't a test for prostate cancer, but to determine the risk of developing prostate cancer. There was chaos.

We talked to some of the people who were present at the 1993 advisory board meeting and people from the prostate cancer advocacy groups. There was screaming and yelling: "Men are dying; you have to approve this test!" With the 78% false-positive rate, and being wrong 80% of the time, I don't know how the test was approved.

In the book, we also cover what it costs to go to the FDA. It costs a million dollars. Does that mean anything? I don't know. I can't say anything because I can't prove it, but something went on to lead to this approval.

Dr. Topol: Are you suggesting that there was a pay-off?

Dr. Ablin: How would they have approved a test with an 80% false-positive rate?

Dr. Topol: It seems outlandish, and you cover this in the book. We then go from 1994, when the FDA approves the PSA for mass screening, to today. I was presenting at the American Urological Association (AUA) in May 2013, the day after the professional society said that we should no longer use the PSA routinely. Why did it go on for almost 20 years?

Dr. Ablin: Fear and money, because other than melanoma, prostate cancer is the most prominent cancer in men. It went on because of the continual proselytizing of fear and the money that was being generated by the screenings.

"Patients and doctors believe that lives have been saved by the PSA test. This is offset by all of the men who have developed urinary incontinence or who have lost sexual function -- all of the travesties that have occurred

For example, in 1989, which was 5 years before the test was approved by the FDA for detection; Schering-Plough paid $1.2 million to a marketing firm during September, which is Prostate Cancer Awareness Month, to promote PSA screening. Primary care physicians were brainwashed that they needed to do a PSA test. If you don't do a PSA test and a man is subsequently diagnosed with prostate cancer, you could be sued.

Dr. Topol: Urologists who have incorporated the PSA test into their practice are still very tied to it , even after the May 2013 backing off from the AUA initial recommendations. This happens because patients and doctors believe that lives have been saved by the PSA test. This is offset by all of the men who have developed urinary incontinence or who have lost sexual function -- all of the travesties that have occurred.

We know from the analyses that net benefit isn't there -- but there is striking net harm. In 2010, you wrote a New York Times op-ed calling this is a public health disaster, and stating that several billion dollars a year could be saved by eliminating the PSA test as a screening test. That was back in 2010, and then you published this book. You said that you were working on it for several years. What were you trying to accomplish in the book?

Dr. Ablin: I will give you an example of why I call this a public health disaster, as you wrote in your book, The Creative Destruction of Medicine (Basic Books, 2013). Our healthcare system is broken. The latest statistics show that the annual budget for the National Cancer Institute is about $5.1 billion; of that, approximately $300 million goes for urologic research. But every year, we spend $3 billion on PSA screening in asymptomatic men, using a test that can't do what it's purported to do.

Every year, we spend $3 billion on PSA screening … using a test that can't do what it's purported to do.

Dr. Topol: Even though the recommendations have changed by the US Preventive Services Task Force and AUA, there doesn't seem to be any decline in the use of PSA screening. Has it changed?

Dr. Ablin: Some reports have suggested a slight decrease. The other reason for calling this a public health disaster may hit closer to you because of your interest in genomics. The Human Genome Project, which took 13 years, also cost $3 billion, but look at all the information that we got out of the Human Genome Project. Just think: We spent $3 billion through Medicare and the Veterans Administration in 1 year, not over 13 years, on PSA screening, using a test that can't do what it's purported to do.

Dr. Topol: And the cost is much larger than that, because of all the procedures that are done. You also discuss in the book that it is not just the fact that all of these biopsies, surgeries, and radiation treatments are being done, but use of the surgery has also led to such technologies as robotic surgery of the prostate, proton beams, and Dendreon immunotherapies. It developed this medicine-industrial complex. Do you want to elaborate on that?

Dr. Ablin: Robotic surgery is a train that is ready to come off the tracks. When the FDA approved robotic surgery for the prostate, the basis of that approval was cystectomy of pig bladders. There was never any study on the use of robotic prostatectomy.

Dr. Topol: There were no human data?
Dr. Ablin: No. We are seeing the results now, which have been disastrous in many cases. The machine for robotic prostatectomy costs $2 million, with a $100,000 contract. Now we have proton-beam centers that cost $200 million. With the PSA test, we have tried to make a silk purse out of a sow's ear. It can't be done.

In the book, I talk about 4 cruxes that explain why the PSA test is not being used appropriately. First, the PSA test is not cancer-specific. Second, there is no cut-off, no dichotomy in the response for a certain PSA level. For many years, we used 4 ng/mL, but we now know that a man can have a PSA of 0.5 ng/mL and have cancer, or a PSA of 11 ng/mL and not have cancer.

Dr. Topol: Genomics can play into that. Some men are walking around with high PSA levels from a very young age.

Dr. Ablin: Third, we can't tell the difference between latent cancer or nonclinical cancer and aggressive cancer. I make the analogy in the book of a rabbit and a turtle and an open box. The turtle crawls around the box and goes nowhere. That's the nonaggressive, indolent cancer. The rabbit, representing the aggressive cancer, can jump out of the box and metastasize anytime. The problem is, we can't tell the difference between a rabbit and a turtle.

The most important crux is that prostate cancer is an age-related disease. If you get, for example, 100 men -- black or white -- between the ages of 60 and 69 years and do biopsies, you will find that 65% of these men have prostate cancer because it's age-related.

Dr. Topol: But rarely is it aggressive. In the future, is it possible that we will identify a marker that will help sort out whether someone has an aggressive type of prostate cancer that warrants the big-gun treatments?

Dr. Ablin: Going back to when I started working on this in 1967, up to the present time, no one has found a cancer-specific antigen for the prostate. As we talk today, there are 11 -- and probably more -- tests out there that have been proposed as a replacement for the PSA. These tests are awaiting validation and clinical trials. I have reviewed these tests. So far, it's questionable as to whether any of them right now will fulfill what we are looking for.

Dr. Topol: They are not likely, at least imminently, to get us out of this bind of not being able to partition the serious types of prostate cancer from the innocent types. Is that right?

Dr. Ablin: One problem is that people are still using the PSA test. They go from PSA, to ultrasonography, to biopsy. It's a cash cow.

Dr. Topol: Have you suffered any repercussions from the book? Have there been any lawsuits or any retaliatory-type tactics?

Dr. Ablin: No. In fact, there has been silence. Several articles have come out. I've had several interviews with the local papers.

Dr. Topol: You had a nice review in The Economist.That's pretty widely read.

Dr. Ablin: That was the poorest review that we received, because it was anonymous, and whoever wrote it said that I made hyperbolic claims. Every single statement in this book is supported by a reference.

Dr. Topol: As you look back on the past 5 decades of PSA and what you have learned, do you think that it was a conspiracy, that it was intentional, or that it was unwittingly done trying to help men to try to prevent the sequelae of a horrible cancer? What do you really think?

Dr. Ablin: My opinion is that the driver of this, beyond the use of the PSA test as a harbinger of the recurrence of the disease, is money. There are some highly intelligent people in the industry. No one has ever refuted my 4 cruxes, so I believe that the use of the PSA test for screening asymptomatic men was strictly for money -- a lot of money. A company wanted to develop a blockbuster drug, some form of immunotherapy, which they talked about in the early days back in San Diego. Many people could see that this test couldn't do what it was purported to do.

I remember talking to a couple of CEOs at biotech companies a couple of years ago, and explaining to them why this test doesn't work. Their answer was, "Dick, this is very interesting, but nobody is going to be interested in your story." I asked why. They said, "Too many people are making too much money to stop this." This is why I wrote the book, and why it's so important that the average man and his family read it and have a better understanding of what's going on.

Dr. Topol: Thank you not only for writing the book, but for sharing your views. There is, obviously, another side to all this. I know we will hear from our Medscape audience -- not just urologists, but primary care physicians -- about their views, and there will be a lot of disparity and even polarization of views about the PSA and screening for prostate cancer. Nevertheless, we are very appreciative to you for what you have done over these years, and for taking the time to join me on Medscape One-on-On. So this was the interview but I find everything about this game as confusing and probably something has to be sorted out with this man because for me my interest is not on the money people are making from the PSA test but if the test is beneficial for some group of men such as black men what is the problem?

In one article I also came across, The Problem with Prostate Screening - NYTimes.com www.nytimes.com/2014/11/26/.../the-problem-with-prostate-screening.htmlNov 25, 2014

According to the article the medical community has roundly embraced the results of a recent study finding that PSA screening reduced prostate cancer deaths by 20 percent. The study, the European Randomized Study of Screening for Prostate Cancer, joined another survey, the so-called Swedish Goteborg study (the results of which provided a basis for the European Randomized Study), which found an astounding 44 percent reduction.

But there's a big problem with both of these studies: In March the Goteborg study's authors announced in the British Medical Journal that their data “are not available to outside investigators.”

That the researchers would block access to government- and charity-supported research is bad enough. Even worse, it calls into question why, if the data was strong, the researchers wouldn't open it up to independent scrutiny.

As it turns out, there are some major concerns about the methodology and results of the studies, first raised last fall in the Journal of the National Cancer Institute by two Australian researchers.

The European Randomized Study reported results from seven countries, while Goteborg was a single-site study in Sweden. In both, men were divided into two groups: One underwent regular PSA tests, while the other was not screened. The results were published in The New England Journal of Medicine and the journal Lancet Oncology, respectively.

As the Australian researchers, Ian E. Haines and George L. Gabor Miklos, noticed, there was something strange about the data sets: A large amount of the data in the European Randomized Study came from a separately reported Finnish study, which showed no significant lifesaving benefits of PSA screening.

They found further red flags in terms of biased patient treatment. Many of the men who developed prostate cancer received excessive amounts of a treatment called hormonal monotherapy, which some research now indicates can actually accelerate cancer. Depending on which groups — screened and not screened — those men were in, the results of the study could be significantly compromised. And yet that information was missing from the published reports. When Drs. Haines and Miklos requested the European data to undertake independent analyses, researchers in both studies were unwilling to release it.

Even more troubling was that the European Randomized Study investigators transferred an astounding 60 percent of the data from the Swedish Goteborg study into their own data pool. Since the Goteborg study was alone among country-specific studies in showing an almost 50 percent reduction in prostate cancer deaths for screening recipients, such an overweighting of the data obviously tipped the balance in favor of lives saved. This is a bright-line ethical breach: Without this biased transfer, the lifesaving claims of PSA screening vanish.

Get some of the debate terms.
Sensitivity: Is the capability of a test to identify the presence of disease expressed as the ratio of true positives to the sum of true positives and false negatives.

Specificity: Is the capability of a test to identify the absence of disease expressed as the ratio of true negatives to the sum of true negatives and false positives.

Positive predictive value: Is the capability of a test to identify patients with disease among all patients demonstrating positive results

The PSA Test-How they do it. The commercial PSA assays measure this glycoprotein in the serum using immunoassays. The difference of results between different commercial assays is well recognized and causes a lot of problems in diagnosing and properly staging Prostate cancer. The standardization of these assays will eliminate or at least minimize most of these problems. The commercial assays use different techniques to measure PSA. Some are immunoradiometric, some are enzyme immunoassays and one is a chemiluminescent immunoassays. The explanation of the HybritechInc Tandem-R assay which was approved by the FDA for detection of Prostate cancer is illustrative and as follows: The assay is a solid-phase, two sites, monoclonal antibody immunoradiometric assay. The PSA in serum binds to a unique monoclonal antibody fixed on a plastic bead. Concurrently, a separate distinct epitope of the PSA molecule is detected with a second radiolabelled monoclonal antibody. Six calibrators are used in this test at different concentrations covering the range of the test. Radioactivity is quantitated using a gamma ray counter and concentration is calculated from a standard reference curve using a plot of total counts per minute versus the log of the dose (ng/ml), connecting a straight line between each of the calibrator points.

PSA and Age PSA is also age dependent, as we get older the PSA tends to increase and therefore the normal range varies with age. The following is a guideline adjusted for age: Age 40-49 0.0-2.5 ng/ml

Age 50-59 0.0-3.5 ng/ml
Age 60-69 0.0-4.5 ng/ml
Age 70-79 0.0-6.5 ng/ml
Note: The normal 4.0 ng/ml is no longer recognized as the cutoff point.

It is therefore significant to identify that the real value of the PSA test in early detection is based on establishing a baseline PSA value and frequently, on a yearly basis, measuring the PSA to detect changes from the baseline value. Incremental changes of 0.75 ng/ml in a year should be examined. A trend is more important and one must always remember that PSA is not specific for cancer. A high PSA could be caused by infection, prostate enlargement, manipulation or even urine retention. Never react to ONE variance. Another important function of the PSA test is in maintenance aftertreatments. A PSA measurement after a radical prostatectomy is a sign of residual disease and normally requires further treatment. The same is true of all other therapies including hormonal suppression. In other words, PSA is a valuable tool to watch disease progression and help decide on treatment options as early as possible.

PSA and its Forms. In 1990, Christensson et al. discovered that PSA exists in more than one form circulating in serum. These forms are: Free PSA (PSA-f), bound PSA (PSA-ACT) and complexed PSA (PSA-MG). Since the complexed form, PSA-MG is not immunoreactive, it is not measured by any of the available commercial assays at the present time. Total PSA is the result you get when they draw your blood and they use a commercial assay. It is a combination of PSA-f and PSA-ACT.

Other PSA Tests. PSA II is an assay that measures both the total PSA (by commercial assay) and also the free PSA by using an investigational immunoradiometric assay. The concept behind the use of this test is based on the fact that the percentage of free PSA is lower in patients with untreated Prostate cancer than in patients with BPH. In other words, the higher the ratio of PSA-f to total PSA the less probability of cancer. This test can help discriminate between BPH and Prostate cancer. In the 4.0 to 10.0 ng/ml. PSA range, at a cutoff of 20% free/total PSA ratio the sensitivity is 80% and specificity of 49% with a 95% confidence interval. One exciting observation is that in developing this test, the researchers found no Prostate cancer patients with 25% or higher ratio of free/total PSA.

The PSA RT-PCR is a totally different type of test. RT-PCR technology is common in molecular testing. By using PSA derived primers the researchers at Columbia University used RT-PCR technology to try to detect micrometastatic cells circulating in serum and identify extraprostatic disease at the staging level. This test is also investigational and once fully developed and refined can potentially help in avoiding unnecessary treatments (RP and RT done on systemic Prostate cancer patients).The positive predictive value of PSA RT-PCR in the Columbia series was 77%. What men of West African descent should know is that most of the research is based on white men not black it is therefore ridiculous to call for total abolishment of the PSA test in the black communities and make your informed decision on screening and treatment. We must make our information decision before screening for prostate cancer and also know you risk for prostate cancer.

Yours in Prostate Health!
Dr. Raphael NyarkoteyObu: ND
Registration no: TAP00396
Integrative oncologist
MSc Prostate Cancer-Sheffield Hallam University, UK

Founder of men's Health Foundation Ghana
E. MAIL:[email protected]
Tel; 0541090045