Dr. E. David Crawford presented “Prostate Cancer: Identifying the Toothless Lions” at the 25th annual Perspectives in Urology Point Counterpoint on Sunday, November 6, 2016.[su_spacer]


Keywords: prostate cancer, biomarkers, PSA, biopsy

How to cite: Crawford, E. David. “Prostate Cancer: Identifying the Toothless Lions ” Grand Rounds in Urology. November 6, 2016. Accessed Dec 2022. https://dev.grandroundsinurology.com/prostate-cancer-identifying-toothless-lions/.


Prostate Cancer: Identifying the Toothless Lions

The issues with prostate cancer are pretty straight. One, it’s the number one cancer in men, and it’s the number two cause of death, and that hasn’t gone away. we have tried to deal with that issue for decades, and not so long ago before we had PSA and widespread screening, most cases of prostate cancer were diagnosed in the metastatic stage. So through efforts of a number of organizations we started to go out and seek prostate cancer and find it early. Some people call that screening. I call it early detection, and we started national campaigns. One of the things we did in 1989 was start prostate cancer awareness week. The idea was to find prostate cancer early. At that time, several years before, there were efforts to find breast cancer early and breast cancer screening, and through a number of trials they supposedly showed it was beneficial. We didn’t have that with prostate cancer, so we started this.

We tried to get a national spokesperson for prostate cancer. At that time, there was a lot of press about Betty Ford, and Happy Rockefeller, and all of these women that had breast cancer. We couldn’t find anybody to talk about prostate cancer. Men that had it were relatively quiet and didn’t want to talk about it so we got a spokesperson, a guy named Rocky Bleier whose grandfather had prostate cancer. Most people don’t know who he is, but he was a running back for Pittsburg who was sort of a hero, a Vietnam war year and who started. That was 1989, and then PSA came along, and the revolution occurred. PSA—we were able to find prostate cancer, and so we saw the number of new cases of prostate cancer increase substantially in men who came in for screening, and we thought we were seeing a—we were sticking needles in prostate, and what became apparent is that maybe we were over diagnosing the number of patients that needed to be diagnosed, or over diagnosing prostate cancer and over treating, and that lasted for over a decade.

Organizations such as the U.S. Services Preventive Task Force looked at that, and they gave it an indeterminate for a while. Then they looked at it and said we don’t think you should screen men over the age of 73, and then the major blow came three years ago when they gave screening AD, which means don’t do it basically or if you do go out of your way with informed decision. So that was actually I think a good thing to happen. Most urologists don’t feel that way, but a correction was needed. We were over diagnosing and over treating people. A lot of us recognized this. Had we had some of the markers that we’re going to talk about here in the next couple of minutes, we wouldn’t have had that problem we have with over diagnosis and over treatment. So the focus today is to find the cancers that are threatening, and we pretty much know what they are.

They are not low-grade what we call Gleason 6 cancers, and as a matter of fact, these are being re-classified as group 1 rather than 6 because when a man hears a 6, I’ve got a 6 out of 10, most of us would say, well, that’s over halfway. That’s not good. But we know from studies of men that have had radical prostatectomies with Gleason 6’s that they don’t die of prostate cancer. That is something like 19,000 men. The issue is they had Gleason 6’s, they had it removed, and they didn’t have 7’s or pattern 4. So that tells you maybe we didn’t need to treat all of those guys, and maybe Gleason 6 is a toothless lion, which is sort of the title of this talk. We want to eliminate those.

We talk about active surveillance. I think we want to eliminate active surveillance. We don’t want to find those. We want to focus on men who have significant cancers, and that is what I’m going to talk about.

The other thing that we have to deal with is the damage that has been done by this over diagnosis and over treatment and the feeling of family practice doctors and internal medicine about the whole concept of screening, and that is what I want to talk about. So the current clinical needs I see in prostate cancer are we need—the primary care physicians need a simple message. The second thing is and I will tell you what I think that is. The second thing is we need to identify patients with clinically significant prostate cancers early, and the best I can tell is that these are men who harbor more aggressive Gleason scores, and we usually say that is a pattern 4, so a 4, 3, 7 and a 4, 5, 9, or a pair of 4’s, 8. We also—this was in the forefront of U.S. Services Preventive Task Force when they looked at all of this. We do 1.3 million biopsies in the United States every year. We diagnose a couple hundred thousand people. That means we do a lot of unnecessary biopsies. We need to hone in and have a higher positive biopsy rate of significant cancers, and the other thing is we still are going to find some Gleason 6’s or other low-grade cancers, or 3, 4, 7’s, and the issue is we need risk stratification because all of those people don’t need to be treated. That is the way forward. This is the challenge. We need to deal with all of this, as we talk to men.

So one of the things that we have in oncology and medicine are biomarkers. When I talk about biomarkers in prostate, I call them PCMs, prostate cancer markers, and they can come from three sources. The easiest source is urine and blood. A more difficult source to deal with is tissue, and what are biomarkers, what are PCMs? Those are molecules that can be found in these three areas, blood, tissue, and urine. That is a sign of an abnormal or normal process, so when we think of biomarkers in prostate cancer, the first comes to my mind is a blood test called PSA. Okay, that is a great—PSA actually is one of the most important markers and biomarkers in oncology. What other marker can give you a reading on recurrence of disease and you can follow someone. You don’t have that for breast cancer. You don’t have it for melanoma. You don’t have it for colon cancer. You have CEA and all of these other things. For testes cancer, maybe close. We have AFP and HCG, but PSA if you had a radical prostatectomy or radiation, basically you should have an undetectable PSA. The people that really do well with radiation, and we can argue that are people that get really low, undetectable, stable PSAs. So PSA is good. The issue, as has been alluded to already, PSA stands for prostate specific antigen, not prostate cancer specific antigen all of the time, and there are other things that give you an issue.

So we’ve got to move forward with family practice doctors and helping them with the simple message that defines who is at risk of having significant prostate cancers. We’ve got to stop these unnecessary second biopsies and so forth.

There are all of these terms being floated around right now about integrated precision medicine, personalized diagnosis and therapy. Well, we sort of do that with prostate cancer in a way. There are three risk factors, age, family history, and African American race. That is sort of personalized medicine that we are going after specific targets, but we can get better. We can get better on focusing so like one thing, one dictum doesn’t apply to the whole population.

When I ask a group of urologists what percent of PSAs are ordered by urologists? And they go, oh, 50, 60%. We know, as Dr. Rosenberg has pointed out, that urologists only order 6.1% of the PSAs in the United States. So if you’re going to focus on where the issues are, you go to the source. The source is that over 90% of these tests at least in the past that were ordered by family practice internal medicine doctors, so that is where you have to start, and here is the problem. The problem is that they’re confused, and it’s the urologist’s fault. We have PSA cut-offs at 1.5, 2.5 and 4. We have PSA velocity. We have PSA density. We have age-specific PSA. We have percent free PSA. We have complex PSA, and by the way we have five PCA3, select 4K score, and they go help. Urologists don’t even understand this. How are we going to understand all of this controversy? They need a simple message.

So what I did, and I knew this from the infamous PLCO trial. We were one of the ten sites in the United States. We also have data from our prostate cancer screening that started in 1989—that there is a cut-off of a PSA below which you have relatively little risk of having anything bad happen in the next 5 to 10 years. So, I did report this at the plenary session of ASCO a number of years from the PLCO trial that if your PSA was less than one within the next 5 to 10 years, and it’s actually closer to 10 years, your relatively risk of having an elevated PSA that was significant for cancer, and at that point we said above 2.5, was less than 1%. So that is personalized medicine. If your PSA was less than one, you had a—you probably didn’t need to be screened for a while, so what we did is we had to have a contemporary thing to give us the relative risk of cancer and so forth.

So I went to the Henry Ford database, which I’ve worked with before, and it’s a very robust database with follow up with 30% African Americans in that database, and what I said is based on what I know let’s look at the relative risk of prostate cancer in men who have a PSA of 1 to 4, because I knew less than 1 was not going to be anything from the hundreds of thousands we had from our screenings, and I also knew above four the risk is pretty steady of having prostate cancer from like 20 to 30% of the ten, and after it gets to 10 it goes up even higher. So what about this danger zone of 1.5 to 4?

So we started out with 350,000 in that cohort to look at and distilled it down to 21,000 where we had a first PSA, we had follow-up of five years, and they weren’t on anything that was going to alter the PSA like a 5-alphareductase inhibitor. So what we found out was the mean age was 55, 29% African Americans, and what we showed very nicely was if your PSA was less than 1.5, your relatively risk of being diagnosed with prostate cancer in the next five years is 0.51%. Most of those by the way were low-grade cancers. However, if your PSA was 1.5 to 4, we call that a danger zone, your risk of being diagnosed with prostate cancer was 15 5o 19-fold higher if you were Caucasian or African American, so the relative risk was about 8% if you were Caucasian and over 10% if you were African American, so here is personalized medicine. This is identifying high-risk patients. Now, the issue is most of the time that PSA elevation in that area is not just prostate cancer, but it’s BPH. And we showed and published and Clause Roehrbom started this, and we followed this up with the MTOPS trial that if you—and our average age in our study here at Henry Ford was 55, so if you were 55 and had a PSA of 1.5, you had a 30-gram prostate, what happens over a period of 15 years, that prostate size doubles because you’re on the slippery slope when that happens, that PSA of 1.5.

So the PSA of 1.5 is a marker for BPH also and progression so that’s important. When you have larger prostates in general you are going to have more urinary symptoms. All right, so this was just published in Renal and Urology News not quite a year ago and showed that as the size of your prostate increases in 10-mL increments or 10 grams, your risk of urinary symptoms go up 12%. We knew this a long time ago. This is not new, and Clause Roehrbom and we published that in the MTOPS trial.

So the question is what percent of people have a PSA above 1.5? Because the question is if you are going to use that PSA of 1.5, what it’s going to do is are you going to open the floodgates to a lot of people that would need to be evaluated and biopsied? We knew this actually, these numbers from our screening from prostate cancer awareness week basically that about 30% of men will fall into that bucket of having a PSA of 1.5 whereas 70% won’t, and Matt Rosenberg very nicely looked at the data from bio reference labs, and 217,000 and I recently updated to 450,000 men that in fact when you look at it, 73% of men, and this is from Matt’s data, have a PSA of less than 1.5 that don’t require a discussion.

Why are we saying that? It’s because family practice people operate like this. When you come in to see them, they don’t get informed decision. They check your blood pressure. They check your weight. They take blood from you and anything else. They don’t tell you if I draw a cholesterol on you, I might have to put you on statins and you might have rhabdomyolysis or liver problems and die. They don’t tell you that. They talk to you after the diagnosis is made. They don’t tell you if you have hypertension that if I treat you, you might go out, pass out, wreck your car, get up in the middle of the night, faint, break your hip and die. They don’t tell you all of that stuff when they check your blood pressure. They talk to you about it afterwards. The other thing is there are levels of tests that you do. You might start out with a screening test like fasting blood sugar and then go to the next level.

So my point is, and Dr. Rosenberg’s and others is that you treat PSA like every routine thing that they do. The informed decision comes after the abnormality so you are not wasting your time talking to 73% of men that don’t need it, and so the way forward is that this is treated like vital signs and many other testes, informed decision occurs when they are abnormal. Why not PSA and that sort of grey zone, danger zone is 1.5?

Now, here is the issue, a PSA of 1.5 to 4 is not associated with prostate cancer as much as it is with BPH. So everybody that has an elevated PSA of 1.5 to 4 does not need a prostate biopsy. They need to be evaluated like AUA symptoms scores. I think family practice doctors should use AUA symptom scores. They’re very simple. It saves you time. It’s reproducible to see what’s going on with it, and I know that there are a lot of forms that patients have to fill out, but it saves you questions, it’s documentable, it’s reproducible, and it gives you an idea. So a guy comes in, and his PSA is 1.9, and he has got an AUA symptom score of 19. You might think about, okay, he has probably got an enlarged prostate. He could have prostate cancer. You can’t say he doesn’t, but maybe what you should do is evaluate him and treat him for BPH. Or we’ll talk about in that group that is suspicious going on to another test. It’s your A1C hemoglobin. It’s your new biomarkers and things like that.

So we published a paper on this and the PSA of 1.5 cut off for primary care, it just came out this month in urology. We’ve got leaders from around the country here, and it wasn’t easy to get these people to have a consensus, so the way forward is that the most common surrogate for this elevated PSA is BPH. Prostate cancer is there. Long-term risk of prostate cancer is there also.

This is Hans Lilly’s work looking at initial PSA. We’ve got to get into the mud of when do you stop screening, when do you start screening and things like—you are never going to get a consensus on that. People say you should have your first PSA at 45. I agree. If your PSA at 45 is 1.2, you probably have a problem whereas if it’s 0.3 you probably don’t. I don’t think there should be a cut-off by age of 73 or 70 ’cause we see a lot of 80-year-old men right now that are going to live into their mid-90s, and if they have a high-grade prostate cancer it can kill them. So again you have to be focused. Urologists need to be good citizens now if this is turned around, so everybody that comes with a PSA of 1.5 does not need a biopsy. They need an evaluation or the family practice doctor can evaluate them. Can these markers help?


Anyway so the point is that PSA is out there and it’s important and people are getting it. So here is my view of life here. Family practice doctor, a patient comes in to see the family practice doctor. PSA is a routine lab test in somebody that has a 10-year life expectancy, that is your decision when you stop. If it is less than 1.5, you get a green light and you come back in five years. Maybe we will have some data very shortly that that can be extended to ten years. If it’s greater than 1.5 you get a yellow caution light. You don’t get a red light. You get a caution light, something is wrong. That is where maybe the family practice doctor can take it from here, and do the next level of test, evaluate it or refer to a urologist, and that is where the evaluation for BPH and other things occur, and the thing you do is do some of these new tests. The new biomarkers—what do they do? They help us determine who has a higher-grade pattern for cancer present. So Gleason 7’s and above. That is what it’s all about, to find those, and not find the 6’s.

If you do one of these tests, and I’ll talk about them in a minute, and they are low-risk, you come back into the normal screening mechanism. If they are high risk, you do a biopsy, and if the test is negative, the biopsy is negative, there are biomarkers, we’re going to talk about this later on, to help us determine who to rebiopsy, and one of them is Called ConfirmMDx. If that test does not show a risk for prostate cancer, you are back into the screening population. If it does show—so this is a person who has had a biopsy. The test shows that there is still a risk of prostate cancer, then I think this is where MRIs come in multi-parametric MRIs for targeted biopsies. If the biopsy, the initial TRUS biopsy has pattern 437 and above, the patient is healthy, they should get a local treatment, radiation, surgery. We could spend an hour talking about the pros and cons of each.

In general, the survival rates for both are similar. The side effects are not similar all of the time, and long-term outcomes may be beyond 15 years. So consider treatment. Gleason 3, 4’s, or 6’s. People argue about the 3, 4’s. That is where we need to make sure we’re not missing anything when genomic markers come in such as OncoType Dx and Prolaris that look at the genetic profile that give us a new level there, and if those markers are high risk, consider treatment. If they are low-risk, this is where active surveillance goes.

So we all—we know that there are some guidelines. I’m just going to talk a minute or two about treatment because we’re talking about toothless lions, and who gets radical prostatectomy and radiation, and that is what we really want sort of away from where we should have been by over-diagnosis and over treating them. But we have guidelines. The AUA says a patient with clinically—and American urological association, clinically localized prostate cancer should be informed about the commonly accepted initial interventions including at a minimum active surveillance, radio therapy and radical prostatectomy. A discussion of the estimates for the benefits and harms should be offered to each patient, and this is not something that you just gloss over. It takes time to talk to the patients, and this is where multi-disciplinary treatment occurs.

Then we see that when they talk—sort of, you know, it’s—some people are balanced. We’ve had people go to the radiation oncologist, and they walk away with this picture is that people leak all the time, they all have erectile dysfunction, and they recur. We have patients that go to see the urologist, and we portray the patient as you’re going to have side effects from radiation. You’re going to have rectal irritation, burning, things like that, erectile dysfunction. We know that a lot of these things have to do with the institution, the treatment, the expertise, and various other things like that, but all of these treatments have side effects, and I tell every man that when they cross this barrier about being diagnosed with prostate cancer that no treatment is going to make you a better man than you are right now. They all have side effects, and if somebody tells you they are not going to have side effects walk away because even in the best of hands you have side effects.

So, you know, things are often not what they appear to be, and there is a lot of stuff about robotic surgery that it is—you are going to be a better man than you are right now, and we see that, and that sort of got knocked with some of the stuff in lawsuits filed on the internet about that very thing.

Okay, so what we have is PSA doesn’t tell you what disease to treat. It sort of helps you to make that and then look at all of the different navigations from observation treat, patients that fail adjuvant therapy, a whole bunch of things like that, but PSA is good at defining failure early.

So we can sort of say this that radical prostatectomy is the optimal treatment for clinically localized prostate cancer, particularly even at high risk. Urologists are making up these guidelines, but there are actually some data that reflect about the response to higher-grade cancers, and long-term outcomes and risks and benefits, so but I think that they need a balanced discussion from radiation oncologists particularly when we’re talking about higher-grade cancers, and there are a lot of data about androgen deprivation and radiation therapy together.

We hear a lot of stuff about robotic prostatectomy outcomes appear to be better, but they’re not better. They’re similar to open prostatectomies in people that do a lot of them. It’s just a learning curve that is a little different. That train has left the station, we’re tired of arguing about it and its benefits. It’s been shown study after study. Again, it is the person doing it. It’s not a robot. Just because you have a racecar doesn’t make you a racecar driver and things like that.

Extended node dissections in high-risk patients are probably recommended. We have all sorts of new methods right now. We have clinical trials ongoing. I think that in the future we are not going to be seeing as much radiation and radical prostatectomy because we are going to find other ways to ablate the prostate, targeted therapy, and – – the prostate, focused therapy. You don’t need your prostate, so if you have an immunological way to attack acid phosphatase, PSMA or some other antigens in your prostate, you can get rid of it, and that is happening right now. There are companies that are doing it. It’s on the forefront, so it’s sort of we have to consider that, and we have to consider molecular risk stratification to help us with that so you know, there’s—in the future I think we’re going to see this whole thing turned sort of upside down.