Role of mpMRI: Implication and Implementation

In your decision to use an MRI, it’s probably one of the more important things to consider is that’s it’s extremely difficult to get consistency in the observers interpreting the MRI both correctly and consistently. There’s no question if you go an institution where they’re doing thousands of these, in their experience they’re going to be more likely to tell you what’s actually something that should be biopsied.

Sending somebody just for an MRI who hasn’t been doing a lot of these is probably not the best idea, just because you want to get the study. That’s the take-home message. Another commonly asked question is can I use a 1.5T versus a 3T, knowing that many of the centers have upgraded their magnets and their software, and the answer is yes.

The only difference between the higher energy magnet is that it’s better at discriminating patients who have prostatitis, and trying to distinguish the prostatitis from prostate cancer, especially if it’s more interiorly. So, the 3T magnet’s better at that, but it doesn’t mean you can’t do it, especially if you’re using a surface coil and you have updated software.

So, what is the multi-parameter MRI? We’re all familiar with the T1 weighted and the T2 images, so these are enhancements. Using the T1 weighted image, which doesn’t give you a very good anatomic picture, we use a contrast, and that’s called DCE, or Dynamic Contrast Enhancement.

The T2 weighted image, which we’re used to looking at because it gives a good anatomy of the prostate, there’s two enhancements, which are the apparent diffusion coefficient, with comes with the diffusion weighted imaging. So, DWI and ADC on the T2, and DCE on the T1. Spectroscopy is also an enhancement that I find that most centers are not using; spectroscopy.

Part of the problem is really no standard way to identify what are suspicious lesions. What it turns out to be is is if you see them, the radiologist sees them on the different sequences, they’re more likely to call the lesion highly suspicious and therefore that’s a target, but if they only see them on one or two of the lesions, one or two of the sequences, they’re less likely to label that lesion highly suspicious.

As we go forward and using regression analysis and discrimination studies, we’re probably going to be able to come up with more statistical mechanisms to evaluate the MRI result, but right now it’s really in the hands of the radiologists, and that’s based on his or her experience.

This is a fairly simple image. You can see the hypointense cancer in the posterior of the prostate there. Nobody would have trouble calling this a prostate cancer. Here is the diffusion weighted imagine. You see the bright white area. Here is the ADC map of that, which looks hypointense, and there is the T2 image for those other sequences.

So, what a radiologist would do, if you’re performing a targeted biopsy, for example, using the Phillips machine, now we’re using the Artemis Hoggin machine. They would have multiple screens up on the radiology suite, and they’d be looking at the T2 weighted image. They would see the DWI, they’d see it on the ADC, and they would circle it so they’d call it segmentation, and that would be the region of interest.

Then it has to appear on the T2, because at the end of the day, they have to get that dichroine electronic information outputted to the ultrasound machine so you can have a target. So, the requirement is to have software. The radiologists need software so they can visualize multiple screens, looking at the different sequences simultaneously, and then co-register everything back to one image, which would be the anatomical image, which is the T2 you see down there in the corner.

This is an example of the dynamic contrast enhancement, and you can see the lesion there. So, this requires an injection, so we have to give the patient a contrast image, and then the image of the lesion on the T1 weighted image. This would be another sequence the radiologist has to look at, and hopefully he or she sees it on this, and on the other images you’re going to have a region of high suspicion.

Lastly here is the spectroscopy, that’s of course choline citrate ratios, and you can see down there. You can see in the lower corner there an area of suspicion and the whole amount showing you that was Gleason 6 lesion. So, if the radiologist also has the spectroscopy, then that will add to the specificity of detecting prostate cancer.

Futterer put together a study using all these different sequences and they found that the area under the curve was 68, 91, and 80%. If you look at a reading from the radiologist and they’re looking at the different sequences, on the body we see the red line and everything was positive, they’re going to tell you that’s high probability, and sure enough, if you target that lesion you will probably find prostate cancer, and it will probably be high-grade.

Here’s a couple examples of the equipment used for the co-registrated target biopsies; on my left there is the Ika machines, and on the right is the Phillips machine.

Now, the problem comes–because things are not so simple–first we got to figure out whether they’re a lesion, and then we’ve got to take the information from the MRI and we’ve got to marry that information to the ultrasound image during the targeted procedure.

That means because a patient was prone, most likely, when the MRI was done, and now he’s on the side, or his legs are up if you’re doing it transperineally, that you’ve got to pull the margins together. One of them needs to be deformed to the other, and when you start doing that, lesions and sides start moving around. It’s always been a problem that if you have smaller lesions or hard, distinguished lesions, whether you’re going to actually a proper overlay and successfully be able to target it. So, that’s the weak point of this system and systems like it.

Here’s an example. You see some pictures of the DCE and T2 image and you see the contour of the prostate, which is now overlaid over the ultrasound image and the targets are overlaid, so the targets are made on the MRI, that information is then co-registered to the ultrasound if you’re doing this in the office, and then you use a targeting system to get to the biopsy. You see the results, and there’s another example of the same.

Now, of course, when you put pictures in the literature you always show the big, giant lesions, because they’re easy to see. You wish life was that way, because most of the time it doesn’t look like this. Here’s what this is telling us, this study, where the MRI showed no target, and PHI, meaning all the criteria are positive. So, when you look at, for example, the PHI group, the number of cases was 15 positive out of 16, so it’s got a very high accuracy rate.

The problem is that only represents 9% of the cases. The overwhelming majority’s in the middle, which is in the gray zone, no surprise.

This is a seminal study that came from Peter Pinto’s group that looked at the comparison of MRI-targeted biopsies with the addition of trans-rectal semi-blind biopsies that we’ve been doing for years. What they found is when you added the extra biopsies, random biopsies, you found more of the high-risk cancers; in fact, you found one-third more high-risk cancers when you added the random systematic biopsies in.

Now, this has really changed the approach, where before if people were at this meeting last year, Mark Emberton was up here talking about their MRI experience, and Mark Emberton said, “If I see that lesion, I can hit it. I don’t need to do more than one or two biopsies.”

That’s dramatically changed now. The average number of biopsies being done for one of these cases is probably 15-20. You’re getting 12 systematic biopsies, and you’re getting at least six targeted biopsies, and each lesion probably gets two biopsies, the targeted lesions, so if you see an average of three lesions, which is typical, you get 6 of those, and 8, 12 of the others, so you’re up to 18 biopsies.

Not that it’s bad, but that’s the way we’re doing it now. This is a review study that just came out in European Urology, and this is probably one of the best studies to read, so you can look it up in the book there, or on the slides. This is the question I was asking, which is what’s the most important statistics? A little hard to see there. That was a negative predictive value.

The way the world is moving now, we want to get an MRI not to do a biopsy, not to do a biopsy, but get an MRI not to actually have to perform the biopsy. So, if the MRI is negative and you don’t need to do a biopsy, you save finding possibly cancer that doesn’t need to be treated, because an MRI is really good at finding the larger high-grade lesions.

It’s a negative predictive value, which is the true negatives divided by the true negatives plus the false negatives. We don’t want to have any false negative scans. We want the scan to be correct 100% of the time, which means there’s no lesion there. The negative predictive value is wrong between about 80-95%; the average is low 80s.

But the problem is, what’s the bar? The bar is going to be for most of these studies, the definition of clinically-significant cancer. If you’re talking about any cancer, the negative predictive value is not going to be very good, but if you’re talking about clinically-significant cancers, and you can have a whole discussion about whether or not we should find them or not find them, then these are the criteria that these different 12 centers use.

For example, is it above the Epstein Criteria? Is it the UCLA Criteria? Is it 4 plus 3? Does 3 plus 7 get in there? These are substantial cancers, so there’s probably a gray zone for the cancers they’re not finding. But just keep in mind when you look at these statistics, it’s because these are the criteria that these centers use for clinically-significant disease. You may or may not agree with it.

So, in conclusion, the MRI has a high negative predictive value. It’s limited to the definition of clinically-significant disease. It finds harvest lesions of the interior of the gland missed by routine TRUS biopsies; no question, it’s very good at doing that.

Cost is an issue. I’ve been hearing in Europe now that the tests are down to $200-600, but in the U.S. it’s very expensive. It’s not covered by all insurance. We haven’t even mentioned the fact that the MRI-guided biopsy is not covered. There’s no reimbursement for the extra time for a urologist to spend doing these targeted biopsies.

I think the real question is if you’re using this test to exclude who’s going to have a biopsy, then will a negative biopsy mean no biopsy, or will it change your follow-up?

So, if you’re getting an MRI because the PSA was 4.2 in a 56 or 58-year-old man, and an MRI is negative, and then the patient comes back six months and the PSA has gone up a little bit, or he starts getting worried, or you start getting worried, are you going to just say, I’m not going to trust that MRI and bring that patient in? Because we know there’s a 20% miss rate. So, that really needs to be determined. I don’t think we know enough about that yet.

One more slide. This is a book that Dave Crawford and I just published on the prostate cancer dilemma. Many of the lecturers are authors in that book. It goes through MRI, it goes through surveillance, goes through markers, it’s got mapping; it’s a really nice book to read. It’s not that long. I even put movies in that book, which you can access online to see the procedures. So, hopefully you’ll take a look at it. Thank you.

When to Biopsy: The Role for PSA and Novel Biomarkers

As you know, the traditional approach to determining the need for prostate biopsy was just based on an absolute PSA threshold, that is, applying one-size-fits-all approach with one PSA value for everyone. So, that’s how it was approved by the FDA back in 1994, and that’s how it was used in the randomized studies of screening for prostate cancer, which were also designed in the early 1990s based on using just this one cut-off value for everyone to determine biopsy.

The problem with this that we’ve since learned so much more about PSA and the use of this, is that it’s not like a pregnancy test. I wish it was. My patients wish it was. Everyone loves things that are black and white, where it’s either you see the pink line or you don’t. But unfortunately, PSA really reflects the continuous risk of prostate cancer, and no better evidence on this than from the prostate cancer prevention trial where biopsies were done irrespective of PSA levels.

You can see that even at low PSA levels, they were below the traditional cut-off, the risk of prostate cancer increases continuously with PSA really across the whole spectrum. The same is true for high-grade prostate cancer.

The other issue, of course, is that PSA is affected by so many other factors, so it just is not the ideal test, and you know about these; age, race, having an impact of course, prostate volume and enlargement, androgen levels, obesity being linked to lower PSA levels. The type of assay you use–so we ran the same blood sample using different assay standardizations, and the results differed in the same sample by up to 20%. So, you can imagine over time you could get a pseudo-accelerating or deceleration just by using different labs for the PSA.

Some medications can have a small impact on it. Genetics; we found that some men have higher PSAs just based on their genotype, so maybe the screening of the future will involve genotyping patients. Benign prostate conditions, obviously urinary tract infections, manipulation, et cetera.

Clearly there’s limited specificity for prostate cancer and all kinds of other things that could have an impact on this. But, this is a problem because when we get an abnormal PSA, that triggers invasive follow-up testing, and we know the increasing risk of complications from prostate biopsy, not to mention other downstream effects like over-diagnosis leading to over-treatment.

So, what we need are biopsy triggers with greater specificity. We can do such a better job of this now. I agree with all the previous speakers. This is not the time to just–we’re coming upon the end zone; we’re not going to turn back around and run across the field the other direction.

We need to just keep moving forward with all the progress that we’ve made in our understanding. There’s better ways to use the PSA test, adjusting for some of these confounders. There’s new PSA-based markers. There’s new markers that are not related to PSA. We have better imaging and we have multi-variable tools. So, let’s keep moving forward.

First and foremost, just very simple stuff. Thinking about the impact of age on the PSA levels, and this nothing new, this was proposed by Dr. Osterling back in the early 1990s, this concept of using higher PSA thresholds for older men to take this age factor into consideration.

This is not dead; in fact, even the correct AUA guidelines suggest considering a higher threshold of 10 for men over 70, which I find particularly helpful, I must say. Of the entire AUA recommendations document, that might be one of my favorite ones, because it really helps to dissuade elderly men who are less likely from benefitting from wanting to have a biopsy that made do more harm than good.

Another way of adjusting PSA to make it more specific is PSA density. So, reducing the confounding for prostate volume, and if it’s above 0.15 this does indicate a greater risk of prostate cancer and aggressive diseases. Now, this has been somewhat limited, at least for initial biopsy, because traditionally we always did these calculations with the TRUS volume, and who is going to do a TRUS before the time of biopsy?

But things may change; now a lot more men are having MRI, so if you do have a prostate volume measurement available it’s possible to do this even before the initial biopsy. Actually, you can even make a very gross estimate of the volume from DRE. It’s not very good, but you can tell if the prostate is small or big, and make a very limited judgement on this.

PSA velocity; so this has gotten a lot of controversy, but these trends matter. We can’t just ignore the medical data that’s in front of us, so if the patient hands you a list of their last five PSA values, no doctor is going to tell them to throw that in the garbage. So, we do want to have a way to interpret these trends. Actually, the truth is that most men with BPH, it is not just skyrocketing over night.

So, if you look at some of the randomized studies of BPH, for example, and the placebo arm, and the control groups of men with moderate to severe BPH symptoms, typically the PSA velocity is around 0.15 per year. So, it’s not 0.4 or 0.75 per year; it’s much lower. Those types of rates of change would be much more consistent with prostate cancer.

Of course, if it spikes so much more than three in a year, then that suggests that it’s more likely to be prostatitis. But this is still not perfect. Not all men do come in with a list of their last six PSA values. As Vickers has shown, if you try to use only two tests that are separated by four years or more, in all of his studies it did not work. If you don’t have enough PSA data, then you’re not going to be able to use PSA velocity effectively.

Free PSA; so, I’m sure everyone here is very familiar with how PSA is circulating in two different forms, free and complex. This is dating back to the early 1990s, but this is still around. In fact, as you saw in the earlier slides, the 2015 NCCN guidelines still mention free PSA as a potential reflex test prior to an initial or a repeat biopsy.

This leads on to the next subject, which are some of these PSA-based marker tests. So, this is a schematic explaining what all these different forms of PSA are. So, actually what we now know is that there’s lots of different isoforms of PSA, and pro-PSA is more specific for prostate cancer. This forms the basis of the prostate health index.

This isn’t really a new marker; really what it is is just a mathematical formula that’s weighing the different concentrations of these types of PSA components. It looks super complicated with the square root and everything else, but what it’s saying is that if there’s more pro and there’s more PSA and the free is lower, that’s bad. So, if you think about the equation, that’s basically all that’s happening.

So, at any given PSA concentration, what’s happening with the amount that’s free and the amount that’s pro? That is what goes into this formula. This has been demonstrated to be more specific than PSA and large multi-institutional prospective U.S. studies, European studies; it’s been validated in Asia.

It predicts more aggressive disease at biopsy, at prostatectomy, and serial measurement of PHI, predict progression on active surveillance. We showed that in the Johns Hopkins Surveillance Program. This is out there; it’s FDA-approved since 2012, and it’s included in the NCCN guidelines for a reflex option for initial and repeat prostate biopsy.

This is the basic idea of PHI; you’re still getting all your separate values. For people who are not familiar with what the interpretation is of the test, you still see the PSA, in this case 4.4, with 21% free PSA, but it’s that pro component here that’s really high. So, the PHI is 97 on this example, which is a super-high value indicating a very high risk of detection, and especially of high-grade disease on a biopsy. So, this is a situation where knowing that pro value gives you more information than just from the free and the total.

Let’s go to our first audience response question. What actually are the three components of the Prostate Health Index? Can you identify which one on this list is not part of the formula?

Okay, good. Wow, everyone’s really listening, that’s great. Yes, intact PSA is not. It’s total, free, and pro; intact is part of the 4K score, which is our next topic.

So, the next PSA base marker test is the 4K score. This is a similar concept to the Prostate Health Index where we’re using these different isoforms of PSA, these different Kallikrein markers, but now we’ve got four of them instead of three. So, hence the name 4K; 4 Kallikrein’s.

Actually, the other difference between PHI and 4K that not everyone appreciates, I think, is that 4K is already taking into consideration age, rectal exam, and previous biopsy history in the algorithm. So, the formula is not just the PSA base markers, but also these other factors that are influencing prostate cancer risk. The company does the proprietary formula and what you get back is the risk of finding high-grade prostate cancer on biopsy.

Again, this also has improved specificity for overall and clinically-significant prostate cancer. It’s been shown many times in European populations. More recently it was validated in a large prospective U.S. study showing that it outperformed the PCPT risk calculator for high-grade disease. Also it predicts aggressive disease at prostatectomy.

You saw earlier some of the data about prediction of future metastatic disease. This did not use the FDA pathway, but it’s CLIA test, it’s commercially available, and also is included in the 2015 NCCN guidelines.

PCA3; this is the next category of markers. This is a urine marker now instead of blood tests, which is all of what we’ve discussed so far. This was actually first discovered to be over-expressed in prostate cancer tissue, and then it was later found that this could actually be measure in the urine. Many different studies of it showing that it predicts the risk of prostate cancer on repeat biopsy better than total PSA levels.

It was approved in 2012 by the FDA, same year as the Prostate Health Index, but this one only for men who already had a previous negative biopsy. Both the Prostate Health Index and the 4K score can be used prior to any biopsy. This one was specifically improved for prior to repeat biopsy because it didn’t perform as well in the initial biopsy setting.

My main concerns about it, though, are actually not so much that, but the fact that it’s not really clearly linked to more aggressive cancer. So, many conflicting data on whether it actually predicts aggressive disease. As I see it, the problem is finding significant cancer, not just finding any cancer, which we already do a pretty good job of. Head-to-head studies have actually shown that the Prostate Health Index outperforms PCA3 for detecting aggressive cancer, so I think that’s where we need to concentrate our focus.

But, it’s not over yet for the urine tests. We heard a nice lecture earlier this morning with all the work at University of Michigan of potentially combining some of these urinary tests together. So, combined with other markers like temp reserve, or perhaps this SChLAP1 in the future may be a multi-plex urinary panel. It could perform better than PCA3 does on its own.

Audience question 2; all of the following are considered options for both initial and repeat biopsy in the 2015 NCCN guidelines except…?

Okay, great. So, PCA3 is only listed in the NCCN guidelines as an option before repeat biopsy, whereas 4K, Prostate Health Index, and free PSA are listed in both settings.

Now, another option is available, and I’m not sure why this wasn’t initially listed in the NCCN guidelines for repeat biopsy, but this is a tissue test. Interestingly, most of the tissue tests that we discussed at these meetings are focused on tumor tissue, but this one is the only one looking at benign tissue.

So, what we’re using ConfirmMDx to do is determine does the benign tissue have changes of hypermethylation that suggest an occult cancer? This tissue test is checking benign tissue to look for these methylation changes, suggesting a field effect around a cancer that the need just didn’t hit the first time around.

You saw this report earlier in Dr. Crawford’s update. What’s nice about ConfirmMDx, as you’ll see, is that you actually get a picture. So, just like doing an MRI gives you not only the idea of who has greater risk, but also gives you a map of where to look for the tumor.

This one gives you a map because you see, here are the methylation changes, we’re at the left base and the left lateral base. So, if you were going to do a repeat biopsy, clearly those were the locations that you would want to focus on. It’s nice that it gives risk information and localization information.

Which segues nicely into MRI. This isn’t really the subject of my lecture, but it wouldn’t be really complete without at least mentioning the huge expansion and improvements in imaging technology, standardization of scoring with the PI-RAD system. If you do have a PI-RAD 3, 4, and especially 5 lesion, you’re at a much higher risk of prostate cancer detection. We do a lot of MRI-targeted biopsies at NYU, and I think this is the future. It has been shown to be cost effective in both Europe and in a U.S. setting, at least before repeat biopsy.

Just to summarize with all these things, all of these new markers are definitely big steps forward, but we have not found the golden bullet. We need to consider multiple factors together to make the best decisions for our patients.

Everyone has a different amount of risk based on their history and their risk factors, and there are some risk calculators available that can help conglomerate these variables, whether it’s the PCPT risk calculator online, giving it more information on the risks of finding prostate cancer on biopsy, or this app from the Rotterdam Group, where you can enter some of the values. It’s under Rotterdam Risk app in the app store.

You can use some of these if you want, manual assistance, in trying to put together some of these risk factors to give the patient a more individualized estimate of the risks that you’ll find cancer or aggressive disease.

In conclusion, we do now have multiple variations on PSA with greater specificity, including PSA density, PSA velocity, free PSA. There are several new PSA-based markers, both the Prostate Health Index and the 4K score predicting higher risk of high-grade disease on biopsy, both part of the 2015 NCCN guidelines. PCA3 is another FDA-approved test. Some concern about whether it predicts aggressive diseases, but it is an option. Maybe combined with other urine tests in the future.

ConfirmMDx tissue tests, looking at negative biopsy to predict a cancer that was missed, and an increasing body of evidence supporting MRI as having a role in biopsy decision-making and in targeting of the biopsy.

Finally, a one-size-fits-all approach like we saw at the beginning with total PSA is totally out, and multi-variable approach is in. So, we’re in the era of personalized medicine; we know how to do a much better job of this now. Let’s keep moving this forward.

Why 1.5 is the New 4.0 for the PCP?

I was asked to talk about family practice and prostate cancer screening. We’ve done this for a couple of years, and I’ve evolved. When I first came up here a couple of years ago I was asked to take a critical look at the United States Preventative Service Task Force, which I did. Whether we agree or disagree with the Task Force recommendations, they can’t be implemented; that’s the reality.

The other reality is there’s a lot of cancer out there that unfortunately we’re going to miss unless we do something about it. I want to start by giving my conclusion. You see in the title, why is 1.5 the new 4.0? What I hope today is at the end of this lecture that you think about this and you realize that you should be telling your colleagues in primary care 1.5. When they have a question to you about prostate disease, say 1.5. When they ask what to do, say 1.5, because we need to make it simple, and 1.5 is simple. I’m going to explain why now.

We just heard a nice lecture on the recommendations and the guidelines; I don’t need to go over this. Some guidelines say to talk about it, some say don’t. Some say don’t do it; they all talk about shared decision-making. So, what is shared decision-making’s three tenets? Provision of information, elicitation of patients’ perspective, and guiding final decision making. If you do a good job it takes 23 minutes. 23 minutes per patient, per adequate conversation.

Now, the bad news, and Dave harassed me about this yesterday at the meeting – you probably thought I was going to forget about this – he said I said PSA was a horrible test. I actually used worse words than that, and I was corrected. Gerald said, Matt, it’s not that, it’s we use it improperly, which makes it bad, and that’s true. So, I’m going to change that. I’m going to yield that point to them. It is not a great test; it’s used poorly.

The reason for that is PSA’s prostate-specific, I don’t need to tell you that. It goes up, it goes down, with various disease states. Depending on your lab it can change within lab or other labs. What happens when we have a limited test is we end up with a dilemma.

We end up with a lot of false positive numbers. We end up biopsying people who don’t need it; it’s not going to have any end–it’s not going to give them a benefit in their life, in fact, if anything, it’s going to make their life worse. It’s going to be inconvenient. It’s going to be painful. It’s going to give them an infection.

The problem is if we give up on it like the Task Force recommendations are telling us, then we miss the opportunity to get people who we could otherwise help. Dave already mentioned this–I’ve shown this at every meeting for the last three years–this is a problem for primary care. You are the leaders in the field. You need to help us. But primary care are doing the overwhelming majority of PSAs.

Now, the reality of it is I do a lot during the day, and you guys need to know that. When I see a patient–this is my annual check-up, this is every day–we go through their medical history, their physical, we have a myriad of problems. They’re coming in not only for their prostate, which I’m loving it if that’s what they come in for, and that’s all they come in for.

They’re here for their hypertension, their diabetes, their hypolipidemia, their ingrown toenail, their dog died and they’re grieving, their mother needs to go to a nursing home and they have a hemorrhoid. And oh, by the way, they have ED. That’s my day. That is my day, and I have to deal with a lot of issues.

I look at PSA and me, as a specialty, as primary care, we look at the PSA and say, what are you guys talking about? It’s word soup out there. What do you mean by velocity or prostate density, or what is 4.0? Why was that okay once upon a time a few years ago, but now it’s not okay? What happens with age-related changes? I get confused. As a result of that, as a result of the confusion, I don’t relay this information to my patients very well.

This is an article that just came out this year. There was another article that just came out last night that a friend of mine, Jed Folk, shared with me. It’s showing that shared decision-making is failing. I told you that three years ago when we were here. I told you that shared decision-making doesn’t work, because I don’t have that kind of time.

But, when we look at that, only 10% of patients received all the tenets of shared decision-making. 55% got a PSA, which meant 45% didn’t. 22% understood that some doctors recommend and some don’t–this is patients, by the way–and 14% were informed that we’re not sure about PSA. So, we can put a big F on this. This is a failure of shared decision-making.

Now, I tried to understand this a little better, and I did a survey this year at the American Academy of Family Practice, which is just down the way in Denver, and actually I just had this accepted, so I’m presenting this at the AUA in San Diego. What I did was, I looked at 153 doctors that came by and I gave them a survey. You can see the split there, a few more males than females, and they were split between employed and not-employed. I asked them a bunch of questions.

What describes your practice in terms of prostate cancer screening? 23% said they don’t do it at all. 39% start at 45, 31% start at 55. But, then I asked them what guideline do you follow, and if you look at the numbers and add them up, 72% follow the United States Preventive Service Task Force; either that or the AFP guidelines, which go along with that, or a combination of them, which they don’t screen.

When you look at this slide, the prior slide and this one right here, what it shows is confusion. They don’t know what’s going on. I asked them, for those of you who don’t recommend PSA testing, what guideline do you follow? 77% knew the right answer. When I asked them, for those of you who said you started screening at 55-69 years of age, what was the guideline? Only 10% knew that those were the AUA guidelines.

So, what are we seeing? Massive confusion. I asked them what age they start screening; 48. I said, what’s a suspicious PSA? And this really got me nervous. Under the age of 59 or younger, the range was 1.5 to 10, and it was a pretty even bell curve with an average of 4.99. I had one guy who said to me, well, at 8 or 9, I repeated a couple of times, and then when it’s above 10 I refer.

You guys cringe at this. I know you cringe at this. You look at the data for the guy who’s over 60, 1.5 to 12. I’m like, ugh, that’s not right. But, where are they getting the education? The bottom line is, they’re not. We’ve made this too complex.

With regard to velocity, forget it. 52 people answered that question; 10 said 0.5, which obviously not correct, and then five said maybe one a year, and the rest of them were all over the place. No consistency at all with those answers.

Now, they did note that some cancers are more aggressive than others, and they also said if we had a way of defining or differentiating an aggressive cancer from a non-aggressive cancer, I’d take it. I’d use it. They understand that aggressive cancers are bad. They understand that we want to take care of those patients; what they don’t want to do is make unnecessary patients.

So, when you look at the problem with shared decision-making and you look at the problem with these doctors, how is this panning out? Well, this is from Jemal’s article in JAMA just came out a few months ago. It shows the data here, that we peaked in 2008 in regards to the incidence of prostate cancer. Then a precipitous drop in 2012. We see a peak in the incidence of 540 in 2008; in 2012 it was 416 per 100,000 patients. If we do the math, what we see here is a drop in the absolute number of prostate cancers that are diagnosed.

In 2011, 213,000, and in 2012, 180,000. So, you get the people, the proponents of not screening, saying, yes, we did the right thing. We get you in the audience who deal with prostate cancer saying, wait a minute, there’s 33,000 guys out there with prostate cancer and we’re not taking care of them. Yes, the reality is, a couple of those patients will have indolent, low-grade tumors; it won’t matter, but not all of them, not all of them.

He mentioned in the summary, authors noted the incidence change in the drop, noted the rate drop, and they said further follow-up, longer follow-up is needed, but what if we’re wrong? We can’t afford to be wrong, so we have these people saying–making all these recommendations, but the reality is we cannot afford to be wrong. I’m going to take a line from Lenny Gomella’s article years ago. He saw this happening, and he said, dare we go back to the pre-PSA era where all we do is diagnose men with their metastatic.

Now, you’ve seen this slide three times; this is the thrid. What it shows here is that by using PSA we drop the incidence of metastatic disease. We drop the incidence–we drop mortality. You see there, mortality dropped 20%, and they looked at that, and they said in the article, well, it’s not such a big deal; 20%, a tumor that’s not going to kill you; is it worth all the effort? That was his argument. He put a value on life. Now, I disagree with that, but I disagree with the metastatic issue, too, because we reduced metastatic disease 50%.

Now, part of the problem is what you guys do. Over the next couple days, you’re going to hear some tremendous lectures on what we can do to keep the patient with metastatic prostate cancer alive. You guys have a done a phenomenal job, so much that when I’m in my office and a patient says I have metastatic prostate cancer, I put my arm on their shoulder, I say, you know what? The likelihood of this killing you is not very high. We’ve got great stuff to you keep you alive. You guys have done fabulous with that.

But, I’m going to ask you a question, and I’d love to ask Welch this thing; I would rather be alive and healthy than alive with metastatic disease and having to deal with all the side effects. So, we have to point that out. The drugs, and the meds, and the chemos, and the radiation we have are phenomenal, but they all come with side effects.

So, we end up with this issue. What do we do? We’re not doing shared decision-making well. We’re confused about this. The incidence is going down, which means that we’re going to be seeing metastatic disease up the road, so how do we do this? Can we simplify this? If we simplify this in primary care for your primary care colleagues, this is what you need to do. You need to decrease the needless evaluations, because that’s what they want to hear.

They don’t want to make unnecessary patients. They don’t want to do 23 minutes of shared decision-making in a disease that they’re not comfortable with. It’s like asking you guys to read an EKG; you don’t do that. I don’t deal with prostate cancer in a primary care setting, other than the fact that I screen. So, the question is, is it possible to just have one value, and why is 1.5 the only value I need to know? What is my case there?

Well, it’s easy, let’s go back to the data. You’ve already seen a little bit of this. Prostate cancer doesn’t happen at low levels of PSA, it happens at higher levels, at 1.5. First there’s a paper on the curve, there’s a paper from Aus, the second is from Vickers, which pointed out a single PSA measurement of greater than 1.6 in men aged 45-49 is associated with a greater risk of dying of prostate cancer. So, there’s something about 1.5.

This is a paper from Europe, an old paper, that basically shows your pre-test probability of prostate cancer and what happens after you have a PSA. What do you see here? At a PSA of 0.5 and 0.1, your chance of cancer is low. It doesn’t go up until we get past 1.0. So, there’s something resonating here. There’s a number that’s making sense. Dave already pointed out in his paper at the Henry Ford System, a PSA of 1.5 or less than 1.5, you’re pretty safe. It goes up after 1.5, and even higher in African-American males.

So, what you’re thinking right now is wait a minute–and this is what my primary care colleagues say–wait a minute; 1.5 is really common. It’s really common, Matt; that means we’re going to be screening everybody. That’s not the case. I asked my friends about a reference lab to look at data, to look at the all the PSAs that were done in the last 12 months in men aged 40-75, and we found 217,000 patients who had a PSA of 1.0.

I kept it to 1.0 PSA because if it was 2.0 or 3.0 we were probably looking for something. 1.0 was screening. Then I had them take out the extreme levels, which only dropped 1,400 patients off, so we had over 215,000 patients, and this is the curve. What do we see? 27%–only 27%–of men aged 40-75 had a PSA above 1.5, which meant 73% didn’t.

73% of men were safe, in terms of we didn’t need to do anymore. So, really we can look at an algorithm that Dave and I have published this year which looks at–the male comes to the office, gets screened, if the PSA is less than 1.5 we’re done; if the PSA is greater than 1.5, maybe we consider doing something. It’s not even maybe, we do consider doing something.

We get a further investigation by the PCP or by the urologist. We use biomarkers, we make a decision. We use this intelligently, which means, just as Dave said, we use the PSA as a vital sign. I don’t need to go have a discussion on your cholesterol level until I get your cholesterol level. I don’t talk to you about your blood pressure until I get this.

I shouldn’t have to talk to you about your prostate level until I have an abnormal level, and the reality is, I’m only going to have to talk to 26, 27-30% of the men. Then we can evaluate them with a bio marker. This allows us to make these intelligent and personalized decisions that have been so recommended with shared decision-making. I can focus on things that are smart; age, health, quality measures. I use the PSA wisely.

I take a test that’s not so good, but I make it good by using it wisely, which means I have satisfied what is happening. Instead of criticizing the PSA, I’m just saying, let’s have thoughtful evaluation before we do intervention, and primary care love this. We have analogies in primary care for this. My guess is you all have gone to a doctor at some point. Guess what, we check a blood sugar, and if your blood sugar is high I get an A1C. I don’t put you on insulin. I evaluate it.

If you come in and get an EKG, I don’t set up cardiac surgery for you. I evaluate the normal EKG. So, why should prostate, and prostate cancer, and prostate surgery be any different? So, rounding the horn here, I want to help you make your colleagues in primary care happy. We’re dealing with so much. We need basic information. We want to do what’s best for the patient. Is the information about prostate screening based on evidence and beyond dispute? Because that’s what I need.

Can the patient be presented with a clear framework? Because that’s what I need; is the process appropriate for primary care, because that’s what I need. Don’t assume I have a lot of time to do this, and don’t assume I have the education that allows me to do this in a good fashion. Unfortunately, the reality is, we don’t have that information. We don’t have that clear framework, but we have 1.5, and 1.5 is simple and appropriate.

This is my call to arms. You guys are the specialists in the field; I’m looking to you for leadership. You have to take the lead in this. You can sit and argue the guidelines, and argue everything else, but I’m in this abyss of not knowing what to do. 1.5 may not be how you do it, because you’re going to look at different factors. You may look at age, you may look at risk factors, you may do a lot of things. But, from a primary care standpoint, I need something simple.

Because as we talk about patients taking care of their disease, we’re going to end up taking care of these patients with metastatic disease because we’re not going to be able to get the patients early on. That’s the key thing. I heard a very wise statement last night at dinner, which is the death of PSA is actually the death of active surveillance, because we’re not going to have active surveillance anymore. We’re going to find these patients with metastatic disease. It really hit home for me; it was a brilliant, brilliant comment.

You have to help us with this. You have to make it simple for us. We obviously know screening is important, it has to be done correctly. The PSA is a first-line test. Bio markers, we’re going to hear a lot about that at the meeting, are very, very good. I think given the information we have, given the successes and failures we’ve had up to this point, the reality is we can start that conversation at 1.5.

Prostate Cancer Screening: What We’ve Learned and Where We Should Go

As David alluded to, we’ve gotten into a lot of trouble with the way we’ve been doing PSA testing over the last 15-20 years. So, here’s the first question I’d like to pose to you; what is the most common age stratum of men in the United States who are getting a PSA test? Is it men between 45-50, 50-55, 55-60? 65-70, or 70-75? If you could just vote for the group by 5-year age stratum that you think is most likely to be tested with PSA.

Well, I’m going to show you that it’s actually men between the ages of 70 and 75, and that’s been a huge part of the problem, and it’s not urologists doing it, mind you. As we heard, it’s probably more likely our family doctor internist colleagues. How about the next question? The 2015 NCCN recommendation for biopsy–to consider biopsy–is it a PSA level of 2 or 2.5, 3, 4, or it should be age adjusted? The latest NCCN guidelines.

In some sense it is true, but you’ll see later on that it’s actually at 3. Since this is a CME, here are my disclosures. You can see the various companies and the two institutes from the national institutes of health.

I’d like to give an overview of screening. I’d like to talk at a high level about the results of the big randomized trials, and then review some of the specialty guidelines. I actually won’t be touching this because many of the later speakers will be going into a lot of this in a lot more detail than I can.

So, here’s the top level summary of where we stand. Based on what we’ve been doing, mass screening on the basis of age alone has a small effect on prostate cancer mortality. It’s either somewhere between 0.0-0.9 absolute risk reduction, in other words, the average U.S. man has about a 3%; if you put in some of the best results, you can lower that chance of dying to prostate cancer down to 2.1%.

As we’ll show, PLCO didn’t show a benefit; ERSPC did show a 20-30% relative risk reduction in a subgroup. There’s certainly some limitations to that trial, as well as PLCO, and we’ll talk about those. But, the real problem, as we’ve talked about for the last couple of years has been a significant risk of over-diagnosis, and a significant risk of over-treatment, and those are the things that have really hampered us.

There are a lot of factors that promote the over-diagnosis of prostate cancer, and this was a nice review article by Gill Welch a few years ago. I put it to you that prostate cancer really could be the poster child, because it does fulfill each one of those factors that promote the over-diagnosis of a cancer.

I want to say it’s not just prostate cancer that when you screen for it you over-diagnose. It’s true for thyroid cancer, it’s true for breast cancer, and it may be true for some of the other cancers, as well. Recently NCI, in conjunction with Oxford, had a 3-day conference on how to minimize the over-diagnosis of prostate cancer.

So, everybody knows there’s a huge reservoir of prostate cancer just waiting to be discovered by the process of putting a needle into the prostate. You can see the relatively high rates of cancer in both black and white ment, and a little bit underappreciated, it’s even true in Asian men. There’s a very fine study from Alex Zlotta that came out a year or two ago, that not withstanding a very low death rate from prostate cancer, there’s a pretty high autopsy rate of prostate cancer in Asian men; in this case it was Japanese men.

When you crunch the numbers as Vickers is known to do, he took data from the PCPT trial where there was annual repeat screening, and based only on sextant biopsy. If you bootstrap that analysis and consider only men who started out with a PSA of less than 1.0, after 25 years you would have found three times as many cases of prostate cancer as you would have expected to be clinically diagnosed.

You would have found 21.6 times as many cases as men would have ever developed metastatic disease, and you would have found 65 as many cases for every man who actually died of prostate cancer. So, there’s a real great opportunity with serial PSA testing, and even just a crummy sextant biopsy to over-diagnose prostate cancer.

But, as I said, it’s not just prostate cancer. Here’s a summary of what’s been going on with mammogram-based screening for breast cancer. You can see a high rate of false positives, unnecessary biopsies, and 57 out of the 302 were cases were considered to be over-diagnosed. That’s despite the fact that the mortality benefits of mammography are really not well-established.

There’s a recent summary showing that when you look at different counties throughout the United States, the more mammograms that are done in the counties increases the incidence of the disease, but it really doesn’t change very much the breast cancer mortality. David already showed this slide, that mammography as presently practiced is unable to reduce the incidence of metastatic disease, whereas we certainly know that PSA testing can.

I mentioned to you about thyroid cancer. The Koreans are doing an experiment right now, they started screening with ultra-sonography for thyroid cancer, and you can see how they’ve increased the incidence of that disease. This is what is happening in the United States where there’s no organized screening, but here is the mortality from thyroid cancer, well below 1.1% in both of those countries.

If you start looking for cancers, you’re going to find them. The problem with over-diagnosis, as we all know, is that it ruins peoples’ lives, and in the case of prostate cancer, this study from a number of years ago showed that even men without a history of cardiac events, within a week or a month after being told they had prostate cancer had between a 3- and a 4-fold increased chance of sustaining a major cardiovascular event.

The message we give over the phone that this is a toothless lion, don’t worry about it, isn’t being translated to the patients. Even an increased risk of suicide in the next 30 days after a prostate cancer diagnosis.

These are some studies from the ERSPC that Fritz Schroeder published a year ago showing that there’s nothing we do in screening for prostate cancer that improves a man’s quality of life. In comparison to the control group of ERSPC, the screened guys were a lot worse. The only time they got better was if you prevented the institution of endocrine therapy. Every step along the way prior to that only ruins a man’s life.

This is why the World Health Organization, a number of European societies, and there’s probably some American societies, have started the “choosing wisely” campaign. Think twice before you embark upon cancer screening.

What about activities that have been happening in the United States? This is an advertisement from Kaiser a few years ago showing that 76% of Medicare-aged men were getting screened. Here are data across the United States between the years 2000-2005, and this is where you see the group most likely to be screened were men in their early 70s. You would say, well, we didn’t know what we were doing then; we’re a lot smarter now.

The answer is, we’re not, because here was an analysis that appeared late 2014 showing that among men over the age of 75 years, the frequency of screening actually increased between 2005-2010. Furthermore, the stunning thing was, if you looked at men who had a high risk, more than a 50% chance of dying within the next five years, half of those men had a screening PSA within the last two years. These are behaviors not probably by urologists, but by our colleagues.

Just remember, the one study that shows the survival benefit for treating prostate cancer is a radical prostatectomy in the SPG-4 Scandinavian study. That benefit accrued to very young men under the age of 65 who had clinically-detected cancers. Remember, screen-detected cancers are usually discovered 4-6 years before they’re clinically discovered. So, we’re clearly screening way too late.

This has gotten the attention of people who pay the bills, measuring low-value care in medicine. $447 million annually spent screening men over the age of 75. That’s why there’s a number of proposals out there to measure the quality of a physician. This is from HEDIS® saying non-recommended PSA-based screening percentage of men 70 years or older who are screened unnecessarily using PSA for this measure, both measures, a lower rate indicates a better doctor. That came out in March of 2015.

Towards the fall, I’m sure we’re all aware that CMS also made a recommendation or a survey not recommending PSA-based screening for men who are Medicare-eligible.

Finally, prostate cancer does have a long natural history. When you look at the big trials for screening or treating prostate cancer, not many of the many actually go on to die of prostate cancer irrespective of which arm they’re in. Even when you look at the best small study out there, the Göteborg Trial, if you screen 1,000 men for 14 years, you help five of them. There’s a number of them who still go on to die of prostate cancer, but along the way you discovered 127 of them to have prostate cancer.

This is sort of the summary statement from the National Cancer Institute that was used by the U.S. Preventive Services Task Force, sort of trading off the bad news against the potential good news of saving somewhere between 0-1 life per 1,000 men between the ages of 55-69 who are screened for a decade. That’s the cusp of the matter here.

I’d just like to roll through a few of the salient points about PLCO. I should say the much-criticized PLCO trial. It’s true; there was a lot of prescreening before the men enrolled. There was contamination in the control arm, so 85% of the men who should have been screened were; 42% of the men who shouldn’t get screened were. The group that volunteered for PLCO was a very, very healthy group.

But, I want you to remember this slide; it’s very busy but it shows you that the men diagnosed with cancer in PLCO were treated evenly, whether you were in the control arm or the screened arm. That’s going to be an issue when we review quickly the ERSPC. You can see that after 13 years of follow up, there were only half as many deaths from prostate cancer as we had anticipated when we designed the study.

Now, those are appropriate criticism of PLCO. There’s been a ton of inappropriate criticism of PLCO. Low biopsy rate, delayed biopsy, missed the chance for a cure. The thing that was good about PLCO was that it was it was a real-world study. We did the DREs and the PSA and reported them back to the patient and the primary doctors; they made the decision whether any further evaluation was necessary.

That’s very different from ERSPC where everything was basically done by urologists and done at urological centers of excellence. So, if there was such a low biopsy rate in PLCO, why is the rate of prostate cancer discovery higher in both PLCO arms than certainly the control arm of ERSPC? That’s because we did a lot of biopsies in PLCO.

Remember, the death rate from prostate cancer in PLCO was 30% lower than the death rate in the screened arm of ERSPC. So, if PLCO was such a lousy study where we didn’t biopsy patients and we ignored their PSAs, why were these very favorable mortality rates and death rates observed?

What are the criticisms of the ERSPC? There were different cut points for biopsy, there were different screening intervals, but the big difference was that if you were randomized to be screened you came to a center of excellence, whereas if you were not screened you probably didn’t even know you were in the study and you were treated in the community.

The NCCN briefing document put it nicely; the potential shortcomings of ERSPC included a lack of screening on all mortality, overreliance on secondary analysis, adjusting for noncompliance, because they had the same noncompliance rate in the screened arm. Finally, unbalanced treatment differences between the study arms.

There are other criticisms that you could point to. The big one in my mind that concerns me is that the finish arm of the ERSPC is the largest component of the ERSPC. It was actually slightly bigger than PLCO; they had 80,000 men versus 76,000. They had many more deaths from prostate cancer; 415 versus 174.

Now, one of the smallest components was the Swedish or Göteburg arm, which only had 20,000 patients in it. So, now you have two different sites within the same trial. One of these sites is four times the size of the other. Now, you have the smaller site showing a large benefit to screening. You have the larger site showing no benefit to screening. So, faced with those two things, which are you apt to believe? The smaller site result or the larger site result?

The other thing is that if you rank order, mortality from prostate cancer among the various countries shown here, Sweden, Finland, and the Netherlands have the highest mortality for prostate cancer. It would have been nice if the high risk, the high-mortality countries all showed a benefit to screening, which unfortunately, they did not.

But, the big problem here is how the patients were treated. When you adjust these patients by the D’Amico risk classification, statistically significant treatment differences at the 0.05 level were seen in each one of those arms.

But, the big one that I think is here, the men with high-risk localized disease, if you were in the screened arm you had a 34% chance of a radical prostatectomy, only a 20% chance if you were in the control arm. That’s the one treatment we know that works, whereas if you had high-risk localized disease and you were treated in the community, 30% of the time you only got hormonal therapy, whereas that occurred in only half as many patients who were in the screened arm.

As I mentioned before, treatment location differed. Screened patients were six times more likely to be treated at large academic medical centers, so therefore these screened men likely received more aggressive and better radiation therapy, and more aggressive treatment for hormone relapsing disease. We know that those can make a difference in prostate cancer mortality.

Why is everybody concerned about that? Well, remember, mortality rates in the United States started decreasing in the early 1990s. Screening didn’t even start until that time. So, the mortality reduction that we see had to be due to treatment. If you look back, the radical prostatectomy rates for Medicare beneficiaries increased more than 10-fold between 1980-1990. That’s because of Dr. Walsh’s anatomic radical prostatectomy.

One thing I’ll ask you to do is keep your eye out; there’s a nice paper coming out that Rubicinno is writing that’s going to be a combined analysis of all the patients in PLCO and ERSPC. I think it’ll make a lot more sense when you look at the data that way.

Everybody knows about the U.S. Preventative Services Task Force. I just want to touch on a few of the other guideline recommendations. Early detection reduces the risk of being diagnosed with metastatic prostate cancer. We already talked about that here; the real-time data from the ERSPC. Here’s what happened in the United States when PSA screening started in the early 1990s. You can see very large drops in prostate cancer mortality.

How about this idea of an early-in-life PSA? PLCO doesn’t get credit for this, but Dave alluded to it, that the first publication on the fact that if you had a very low PSA, and that conferred a very low risk of aggressive prostate cancer in the next decade, started in PLCO. Then it was observed also in the ERPSC, where if you start with very low PSAs, you have to screen an enormous number of patients, and treat and enormous number of patients to prevent one death.

Then, of course, there was the Malmo Preventive Trial, which showed the value of getting early-in-life PSAs, and the statement that if you have three PSAs less than 2.0 up to the age of 60, you should be exempt from screening. This is corroborated to some extent by the U.S. Physicians’ Health Study. Mark Preston and his team reported this recently in The Journal of Urology. There’s a study going on evaluating that.

The AUA recently changed the guidelines, as you know, and recommends screening for men between 55-69, but again, stipulating that there’s a fairly small benefit. The AUA is recommending, to reduce the harms of screening, an interval of every two years.

Here are the NCCN guidelines recommending starting around the age of 45. If your PSA is greater than 1.0, frequent testing if it’s less than one, less frequent testing at every 2-5 years. When you have a PSA of greater than 3.0 you should consider having a biopsy, or you should consider having some of these reflex tests, such as free PSA Opko 4K or PHI.

I just want to talk a little bit about Opko 4K. Looking at the ERSPC, looking at the Malmo data, if you had a PSA of greater than 2.0 at the age of 60, you were considered at relatively high risk, and you should be screened, but if you also know that meant Opko 4K score, about half of those men would be reclassified as having low-risk disease, and therefore would need less aggressive screening.

I apologize for this. We just did an analysis that we’ll present at the AUA in the PLCO trial showing that if we had known Opko 4K scores, we could have reduced biopsy in about 35% of the patients, and we would have misdiagnosed about 1 or 2% of the high-risk cancers. So, that really would have saved a lot.

So, in summary, I think PSA-based screening can in fact reduce prostate cancer mortality. It’s not right to just screen men on the basis of age. Risk-adapted screenings starting at an early age in life is good, but as we’ll hear later on, there’s no doubt that new markers in better biopsy is really going to turn the tide in our favor.