Pseudoscreening - High Risk and No Biopsy

Pseudo-Screening in Prostate Cancer Detection

We're now gonna move on to something that you may not have heard about. It's not screening, it's pseudo screening. And we're gonna start out with Dr. Ani and she's gonna be followed by Dr. Hader. So we're gonna talk a little bit about what's called pseudo screening. Not my choice of word, but a good one perhaps.

We've been talking a little bit already, a lot actually about the role of MRI in the detection of prostate cancer and at what point that imaging should be performed. And we've spoken yesterday about the possibility of adding the imaging in before the biopsy. And this obviously will be a very helpful step potentially. As we've discussed again at the panel just before lunch, in reducing the overall cost to society of the burden of prostate cancer. You think by adding imaging, what you're going to potentially be able to do is to reduce the number of men that need to go on to prostate biopsy. And hence the word screening is coming into play a little bit here. We have to be very sensitive about the use of that word as screening means many different things to different people.

What really is important I think, is to get the whole concept of prostate cancer risk assessment understood. And there's a lot of debate about what that really means. There's the AUA which talks about shared decision making between the urologist and the patient to determine should we get the PSA measured at all. The NCCN guidelines were initially early and often we should be screening men. We should biopsy lots of people. And they fairly quickly changed over in 2014 to refine that back down to sort of closer to the AUA where it's a negotiation. Should we do a PSA should we try to detect prostate cancer?

Many of these nomograms really take into play once the diagnosis has been made. As you've heard about things like the Partin nomograms, the Kattan nomograms, there's the Scardino ones. Those are really looking at the PSA and the biopsy data together. Looking at sort of risk stratifications, not quite what we mean in this context of this talk where we're trying to drill into the issue of screening a man without a diagnosis of prostate cancer.

So the two big variables sort of on the horizon today are looking at the genomic classifiers and molecular profiling classifiers and the potential role of MRI in screening patients.

Case Illustration: 80-Year-Old Patient

So just to illustrate a case before we get into too much more of the theory about this, this is a recent case that came to my hospital and patient called me up and said, actually the son called me up a cardiologist on staff at our hospital and said, my dad is 80. And he had his PSA measured and his PSA was 4.6, 3.8 after antibiotics. And he's on Avodart now. And his PSA is 6.3 and all kinds of questions come to mind. He's 80 years of age. Why are we measuring the PSA at all? He has BPH symptoms. This is Avodart. This is the dutasteride the medication that's used to reduce the volume of the prostate.

Now, one thing that's very important to know is this has an artificial lowering effect of the PSA. If that PSA really is 12, and this is something that's important to know, these have these medications will lower the measured PSA and that's an important marker. So when you think about that, his PSA becomes significant and he's a very healthy, very intelligent guy who's really interested in knowing what's going on. And they both wanted to get an MRI before they subjected him to a biopsy at all. And this is the kind of scenario that we're beginning to see and where we were chatting a little bit about over dinner and lunch, wrestling with how to manage these patients.

The patient himself was biopsy adverse. He didn't want to have multiple needles in his prostate. He was very concerned about infection. Infection is becoming an increasingly significant issue. Jeff showed a nice abscess case. There really are much more increased problems with the infection going on, particularly because of the incredible abuse and abuse perhaps of antibiotics. There's a lot of resistant bugs out there now. And so the infection rate is going up after standard biopsy of any form, transrectal biopsy it. But trans rectal biopsies, and if you speak with the Europeans, this is one of the reasons they're trending towards transperineal biopsies is because that's this much safer profile. There's no transgression of the rectal wall. So this issue is out there and people are talking about it.

Many of the urologists will say, oh, it's only about 5%, 2% of my population. But in the literature it's upwards of 20% of patients is a significant abscess or infection.

So let's go back to this patient. These are his images. These are the three T endorectal coil T two weighted images, which you can all take a look at and determine what you see coronal views. We'll go back and through all of these in a minute and I'll put all my little red circles up where the lesions are of the lesion on. And this is his arterial phase dynamic contrast. I'm not showing a baseline pre contrast, there's no subtraction here. But remember, he's never had a biopsy. So hemorrhage shouldn't be an issue. Alright?

So hopefully everybody was able to identify this lesion at seven o'clock. Significant low signal intensity lesion associated with extracapsular extension. There's extension of this lesion through the capsule. It's definitely abnormal. It'll look more abnormal when I go to the coronal view, where you see it again, where you can see a little bit of capsule of thickening. Now, we haven't spoken much about thickening thickening is a really good sign. We spoke a little bit about a percent or length of tumor abutting the capsule today at the panel. I think when you see that thickening as well as the abutment, you should be more concerned about invasion, not just the abutment.

So there it is there. And then you can see it over here coming through the capsule. There it is breaking into that vein that Massou nicely showed us on that very first talk. Can you all remember back to that talk? I can hardly remember, but I do remember the nice illustration of the veins. And you see the vein is invaded right there. It's obliterated. And there as well.

So we now know, of course, the mantra that the PC lesions should be. We should look at our diffusion images. And so we went, you saw the diffusion images here on this patient. So his DWI abnormality was there. Here it is here. So here you can see it on the DWI, we have a PI-RADS five lesion here, which is really large. It's greater than 1.5 centimeters, a significant lesion. And then on DCE of course, it's positive 'cause we have that early arterial enhancement or type three curve.

So with discussion with this patient, this lesion was identified and we proposed to him a transperineal biopsy of a single targeted lesion into that core, which he agreed to. And of course, as we've demonstrated so many times now, once you have these high PI-RADS lesions, they will all contain an element of Gleason four almost uniformly. And whether it's a four plus or a three four, the four pattern is what we're detecting with those PI-Rads four and five. And he also had perineural invasion.

So when we combined all of that with his staging, MRI, which was done at the same time as the quote screening examination, you're getting everything at the same time. He is a T three cancer with a significant disease. And now the debate is going on between him and his doctors as to how to be treated. Again, remember, he's aged 80. So really he's, I think he's debating radiation and radiation and hormones. And the big discussion is how much hormones and all the rest of it. So he's not gonna have surgery.

Definitions of Screening and Biomarkers

So let's just talk a little bit about, and we're gonna go into some definitions on what screening is. We've already spoken about the PSA and it's downgrading to grade D. So I won't belabor that too much. And then talk a little bit, and I'm not a world expert on many of these things, but we're gonna discuss some of the biomarkers that are out there. And as you know, the word biomarker and screening are both equally sensitive terms that shouldn't be used without clear understanding of what you mean.

But a biomarker should be able to tell the difference between benign and malignant disease be high specificity and sensitivity, non-invasive and cheap. And so you want this sort of thing, the ideal world, you want everything in one test. Well, that course doesn't exist for prostate cancer today. So we're really looking at combinations and what combination will play out in the next 10 years will be very exciting.

So let's just look at the urine PCA three. We've heard a little bit about that this morning. Andy did a nice review of that and showed us some illustrative great cases. And then genetics work. And of course we all know about MPM.

So looking just at the definition of a good screening test, this is not new. They've been around for a long time. But things to be that really need to be considered, if we're going to talk about MRI in the terms of screening, ubiquity, the thing, the tests and the diagnosis and the procedure should be available everywhere, should be something that's available to all sites. And this, again, was discussed well at the panel was the new and increasing penetration of prostate MRI across the country. And there should be agreed upon policies as whom to treat. I'm not sure that that's really there yet. And there's lots of issues. And then an economically balanced proposal as we discussed as well, I think we're gonna have to do that American dollar equation and determine the results on the cost benefit ratio of early screening versus not doing it with MRI.

Urine PCA3 and Other Biomarkers

So you heard about the PCA three. This is a urine analysis test done after the prostate is massaged and the area under the curve is quite good, not great. You could say that it's not as good as MRI, but when it works, it works. And when it doesn't, it doesn't. So it's not particularly great. It hasn't got wide acceptance in our area, but is definitely used. And we recently did have a case where it was wildly positive just like Andy showed. And the MRI was negative and the patient did go on to have biopsy positive. So it can be very helpful. And particularly if the initial biopsies are negative and it is positive, it encourages folks to go ahead and get another biopsy.

There are multiple other forms of genetic forms of testing, and this one is the prostate health index, the PHI, which is another is ovarian form of PSA, basically, which improves the predictive value for cancer, for detecting it. And better than just looking at regular PSA and free PSA. And the cut points here, and you can see that at your PHI is above the 27 mark. 55 per 15% of your biopsies can actually, below that 15% of the biopsies can be avoided. And some of the studies, there's been a very big European study that's just being published. It's an e publication status right now. Looking at a large number of patients applying this technique really unfortunately did not demonstrate a significant benefit from this population in this sort of attempt to screen. So this may or may not go forward as being a useful tool in our selection of men for biopsy.

Others that are out there that many of your patients will be talking about doing. These are all commercially available genetic tests, most of which are done on bloods, blood analysis. You can use the Polaris Myriad test, which is a 31 cell cycle progression of genes. And looking at the over the average expression of 15 genes, Oncotype, and then Decipher. Many of these are out there. They're being used already, I suspect not being an expert in this area. But there's not enough validated data to say any one of these tests is any better than the other. And really how they'll fit into our imaging really remains to be seen. And this is something that I think is a very exciting area of future research, will be the marriage of these genetic tests and the testing of them formally in a prospective way against multiparametric MRI and targeted biopsies.

Additional Case Examples

We can find small lesions, as we've shown you in many cases already to already these last two days. And it's a small lesion. This man had no rectum and we haven't talked about them very much. They're not that many out there. But the transperineal approach may be the only approach for biopsying this patient who clearly has no rectal access. And it's quite relatively easy, as we've talked about, to sample small lesion like that. And this is an older case where we didn't even have diffusion. So this goes back several years. We weren't doing it back then, but you can see how nicely the gadolinium shows this. And without the rectum of course, and any pressure in that area, the peripheral zone is much easier to see. And so maybe it's a rectal scis excision, Jeff, that you need to be doing at Yale rather than just a ectomy, dare I even use that word.

So here's a patient that came from the outside. He is 66 PSA was five. He had a biopsy proven and he was coming in for to surveillance. So this isn't really a screening case. But again, just to show you small lesions that can be detected. One out of 10 physicians actually palpated a focal abnormality in this patient, which again, I think goes to the problem of the DRE very insensitive test.

So you can see his images here, the T twos, the diffusion, a little bit like the one Ms. Assume just showed, where you see this tiny little lesion here at three o'clock, but clearly seen on the T twos, the T twos and the ADC there, and then biopsy into that lesion. You can see the needle tip in the biopsy in the target there, which I think is so important to demonstrate that you're sampling the right place. And again, he had positive cores up to four to four, Gleason four, and went on to have radical prostatectomy. So the PSA and the MRI did actually change the course of management here. He unfortunately then had a biochemical failure subsequent to his robotic radical prostatectomy and had salvage radiation treatment and androgen deprivation therapy.

The probable reason for that, I'm not terribly sure, I think it was confined to the prostate within, but maybe there was a positive margin. I honestly don't know.

So another patient here, rising PSAs, again, the same story as we've seen so many times now, but again, trending upwards, it had bumped up and these PSAs will bounce around and then come back down again. Met a lot of people will go on antibiotics because it's thought to be a transient prostatitis and then they'll come down again. But this patient came to look at the MRI for potential planning for a biopsy.

And so this case here really showed just minor changes, sort of in the pires two category throughout the peripheral zone. This is sort of classic prostatitis here, where you see these linear wedge-shaped band like areas in the peripheral zone, no significant enhancement. We really looked at this long and hard in here and found no specific abnormalities on T two, really nothing very sensitive. This was very, this was a well circumscribed lesion here. And this again, I agree with msum entirely. Well, this is an area that we spend a lot of time and it is our Achilles heel, but we felt comfortable enough saying that had a sharply defined margin on it, and it was well encapsulated. And this patient has gone back to the routine PSA assessment surveillance. And further this baseline MRI is now available for further comparison.

The question is, what do we do next? Should we be following him with repeat MRIs on a yearly or every other year? And how often should the PSA be done? I think the PSA should be done as often as it would normally be in clinical practice. And so probably at a six month to yearly at a minimum. And the MRI, we're finding an anxious group of patients who probably will be seeing more frequently than two years. I suspect we'll end up somewhere between a year or a year and a half with repeat MRIs in this patient to determine whether or not we should intervene and do a biopsy.

One of the things that's interesting about this is we would like to also caution folks when you're doing pelvic MRI for any reason at all in men who are older or what at risk for prostate cancer, such as this man who came for staging for bladder cancer, look at the prostate. And this is our protocol for staging bladder cancer. It's a body coil technique. No endorectal coil is used. And I'm showing you of course, T two weighted images, which are showing a significant lesion on the T twos here.

The diffusion images I find with these body coil sequences are external coil sequences are clearly not as nice and you get a fair amount of artifact, but there's no doubt there's a very significant lesion on the right side of this prostate. And so we staged his bladder cancer, which is what he came for, and then sent him off, unfortunately with a report that's saying he needed to have a prostate biopsy here. And as of when I left to come for this meeting, that report was not back yet. So I have no pathological correlation on this guy yet, but I'm pretty sure that's going to be a significant gleason lesion for his prostate. And then of course, the bladder may eventually be removed and a radical cysto prostatectomy will be the probable result of his plan for surgery. And as you know, if anybody's worked in bladder cancer, radical cysto prostatectomy that performed routinely, and there's a lot of prostate cancer that's found in those. But look at the prostate in all of your pelvic MRIs and you're going to see an awful lot more than you used to see when we were doing exams like this.

Future Directions: MRI Before First Biopsy

Thank you very much for your attention. This issue of doing MR before the first biopsy, I think is really the one of the key future directions that all the data is pointing towards. If we're really gonna have a paradigm shift, we need to really start looking at this and get the trials done to show that this is what we need. So I think we're in an early stage. And what I wanted to do was to just tell you about where this fits in right now.

So in prostate cancer detection, we're really talking about bringing the MR in right up front, right with the PSA, in terms of the assessment. And we've already talked about a variety of these other insertions in the current care paradigm for mr. And I'll start by showing you some cases.

This first case, and this is what's happening in Canada in my practice, is all these people are either people I know, friends of people I know, or doctors or relatives of doctors or friends of doctors. So these are very anxiety provoking cases, to be honest, this is my father's MR. And where's the cancer? Yes. No, there it is. Now, this cancer, we just did targeted biopsies only. We did, it was done with the fusion system.

One of the first questions and interesting things that came up, we know that, and I'm just sort of telling you the questions that came up. 'cause again, I think the cases are instructive. The first thing that I ask myself and the we do our biopsies in radiology by radiologists, is if the needle goes through that and we fire the gun and it goes past the anterior fibromuscular stroma, are we seeding cancer cells outside the prostate? We decided we didn't really have a good solution to avoid that. But we ended up taking six cores through this. It was a Gleason three plus four tumor. The ADC was 672, which makes me worried. You can see the morphology here is clearly one where there's a bit of a smudge, but really the ADC helps direct your eye to that area. And it was relatively low volume and he's in his early seventies, but in extremely good health. And so it's very debatable about what you do next. Do you go ahead and do a systematic set of biopsies to make sure there's not disease elsewhere? Should he go for radiation now? Should he go for radical prostatectomy now or should he go on active surveillance? He's got three plus four disease. And to be honest, I don't think we have clear guidelines on what to do. And this is the conundrum that you're gonna get yourself into if you start doing a lot of these, is that you're gonna start to find a lot of questions coming when you start to apply Mr in these areas.

The discussion happened between him and two urologists. One who does robotic, one who does non robotic, both excellent surgeons in Toronto. And he decided that I can't live with the prospect even though we can do follow up Mrs. And he decided to have a prostatectomy. He's doing fine. Margins were negative, and god willing, everything will be fine for him. But I thought this case, and he's quite happy with me showing this is quite illustrative of what's gonna happen. The surgeon has told me, and I've, I have no evidence of this again, that the prostatectomy with the robot was one of the fastest he'd been able to do because the prostate just came out very, very easily. And I've heard this from a couple of surgeons, no evidence that when you really do a limited biopsies, they haven't had multiple repeat biopsies that the surgery might be easier. Again, don't know. But it was an interesting thing that the total time in the OR was very short. The blood loss was extreme. He said it was one of the easiest robotics he's done.

We've already heard about the movement away from PSA in Canada. You have to pay for a PSA, the incidences of radical prostatectomy or prevalence of radical prostatectomy are going down as are the prevalence of biopsy. I won't go over that again, but we started getting these questions. Should we be screening all men? And I think Pete Jo's slide about showing that setting a rational PSA threshold to do MR as opposed to doing Mrs on all men is a very important area of study. And we really need to understand what the PSA threshold should be for mr If we're gonna be doing cost containment. We also need a lot of clarity on what our threshold for clinically significant disease out. 'cause we picked the wrong one, costs are gonna balloon. And we need to have some clarity on that.

The impact on this, as I said, is gonna depend, the utilization depend on the thresholds. And again, we are focusing on Gleason four disease in Toronto. And the data here, this is a retrospective study with transperineal template saturation biopsy is the reference standard from the UCL group sensitivity for three plus four and higher. So any Gleason four components was 93% positive. Predictive value is only 24%, but negative predictive value remains high at 92%. And the reason I show this NPV thing is the mean. And the other thing to, by the way, when you're reading any of these studies in the literature, is to look at the mean PSA in the population, the behavior of the test in terms of its PPV and NPV will shift depending on the median PSA, these studies with transperineal biopsy will tend to underestimate the PPV because they're not doing direct targeted biopsies with co-registration, et cetera. So PPV numbers tend to be higher in studies that don't include targeted biopsy. So this is probably under this 24% is probably an underestimate, but the NPV is still high. 92%. You'd expect that the PSAs are low, but that's where I think that's where the RADS three threshold with a PI-RADS four threshold, our sensitivity drops to 70% in this study.

Now, again, it's a little disturbing that we're missing 30% in this study, but they used one and a half T MR in a significant number of patients without endorectal coil in this study. But again, NPV is high close to 90%.

The impact on this is what I wanted to maybe focus on in terms of the care paradigm. And what I would say is that I said yesterday that, and we've seen multiple examples in multiple clinical contexts, that our first and most important job is to find the killer tumor, the index tumor, the one with the Gleason four components. Make sure we don't miss that. But as we start to push Mr further and further back in the care paradigm to make this cost effective to make it work, our second biggest task is to make sure that we have a meaningful number of patients avoiding the care paradigm or having less frequent involvement or less frequent involvement with the healthcare system if we don't do that. In other words, if we're calling a bunch of PI-RADS threes all over the place and patients still need close follow up and still need a lot of PSA testing, need a lot of mr, need a lot of visits to urologists, we are not going to be able to accomplish a lot cost effectively with mr. And so I think it's very important that when we look at these paradigms and we establish how we're gonna bring MR in earlier as in a second risk assessment test after PSA, that we make sure that we are culling out patients from biopsy, the risk of biopsy, the impact of the healthcare system on radical doing unnecessary radical treatments.

Projected Care Paradigm and Patient Flow

So let's go through, and these are based on some of the numbers published in the patient flow in the Brisbane study, which was done in this population. So you take a hundred patients with a PI-RADS cutoff of three, what's gonna happen? Well, a number of those are going to, all of those are gonna then go to have a MR of those 65 will have a positive read on the MR three, four or 5 35 will not. So we've been able to, if we take RADS one or two and say we're not gonna biopsy them right away, we're gonna do follow up PSA and follow up MR on them at some frequency, they're gonna cycle back. So that's this purple arrow here. 35% of patients we've saved a biopsy 65 will go on to some sort of fusion biopsy. Of those 45 will have a clinically significant cancer. They had a quite a high yield in that study, which kind of makes sense because remember this is, I mean, 12 core systematic biopsy works pretty well in picking up a large number of patients up front. This is a very different scenario. So the fact that 45 patients had a cancer found with a limited number of cores, much fewer cores, that's probably a good thing. They go on to therapy. So that's this arrow down here. 15 of those patients though will have a negative biopsy and they're gonna go back and they're probably gonna need some sort of follow up Mr for sure, and they're gonna go back into this PSA mr, but maybe more frequently, right? So they're gonna cycle a little faster on the left side of this flow chart.

And then I'm throwing this out as the suggestion of where we might see MR Biopsy come in. 'cause this is gonna be more expensive. It's gonna pull things outta the hands of urologists, probably some resistance to that. So the suggestion is here that if the transrectal biopsy is negative that you might be considering in those patients then saying, well, we have an MR target. What if we took those patients and did an MR fusion biopsy with needle confirmation that were in the lesion? I made up these numbers, those three two split. But you can see that it's actually a very small number that fall through into needing the MR guided biopsy.

So this is a projected or my best guess at a paradigm with some numbers from a study about what will happen if we take RADS three. What if we take PI-RADS four, if we take RADS four, these numbers on the, as you'd expect on the negative side start to go up. And so 50 patients, half the patients are now getting biopsy avoidance. So certainly if we are not gonna be doing transrectal biopsy, if we're worried about urosepsis, if we're worried about the downstream costs of pathology and over-diagnosis, this is a good thing. Again, not a huge drop here. 43 patients instead of 45 end up going on a definitive therapy and a little more, I think we definitely are gonna want the confirmatory MR for the fours or fives. If we don't get a positive on the fusion, a little more would go to the MR biopsy. A little more expensive. So I think this is sort of my attempt at trying to project what's gonna happen and what our jobs are gonna be and why we need to consider three versus four as we look at applying a state-of-the-art PI-RADS v2.

Brisbane data on the workflow of patients through a PSA MR combined strategy. There has been simulations done of these kind of paradigm, essentially showing that there is a savings in quality life years by using this. So there are simulations. It's based on European cost profiles. The savings might actually be bigger in the United States, given the higher costs of some of the other aspects. Unfortunately, your MR costs may also be higher, so I don't know. But certainly the European Canadian context, there is some simulation data showing that this is potentially helpful.

So early days, but very exciting time to be in watch out for the relatives.