MRI Guided Biopsy and Ablation

First I wanted to thank Dr. Crawford for inviting me and including me. I appreciate it. My task is to talk about MRI of the prostate, and as Dr. Klotz mentioned earlier, there has been an absolute explosion of data, and it’s somewhat challenging to take all of the data and condense it into a talk. But I’ve done my best. There is a fair amount of data in here that we are going to move through quickly, but hopefully you will find it useful and practical.

So I have one relevant disclosure late in the talk about an upcoming trial that we are involved in. so of the six things that I wanted to talk to you about, sort of the MRI at different stages; MRI for screening, prior to initial biopsy, prior to a repeat biopsy, what is the data on using it in surveillance, what about staging patients and operative planning, and MR guided ablation which we have seen more of lately.

When I think of prostate cancer and take a step back, sort of the 10,000 foot view, I think of it as the good, the bad, and the ugly. The good news is that fewer men are dying of prostate cancer. The good news is that we have all of these novel tools, tests, and drugs that we have heard about. The bad news is there is a pandemic of overdiagnosis and overtreatment, which we are doing better at. And at the other end of the spectrum, we have often insufficient treatment for men with really advanced disease.

And then the ugly, which I think we need to shine on ourselves is screening the treatment patterns, the Preventive Services Task Force, and then the explosion of cost with all of these novel tools and tests. The bottom line in the United States is that smart prostate cancer screening can save lives. There are 50% fewer men dying of prostate cancer. I think this is underappreciated within the medical community. We should be shouting this from the rooftops and be incredibly proud of it.

But we can’t talk about that without talking about the elephant in the room which is overdiagnosis and overtreatment. And the reason I mention this as a lead-in, when I think of how to minimize over-detection and overtreatment, I think of the seven things on the slide there as real practical ways of minimizing over-detection and overtreatment. And of the bolded five, MRI can help play a role in. So I do think MRI is incredibly useful in helping to progress the care of men with prostate cancer.

So some basics on MRI and this can be a whole topic in itself, but just to download some information. Wait at least six to eight weeks after a biopsy to limit inflammation and hemorrhage that might obscure your pictures. There is a whole literature on what type of magnet, what type of coil do you use. In general, a 3 Tesla is better than a 1.5 Tesla. Some groups get away from an endorectal coil for patient comfort and logistics, but most of the data suggests that the quality of the pictures are better with an endorectal coil.

Everyone uses a phase array body coil, and then the sequences matter. The reason it’s called multiparametric is in general there are three different types of sequences. The most valuable is probably DWI, diffusion weighted imaging, which gets you an ADC map. The second best if T2, and that is more anatomic. It can also show some cancers. By far the last useful is DCE, which is dynamic contrast enhanced. The size matters. It makes sense that the larger something is, the more likely you are to see it. or equally important is that the location matters, so all of these anatomic zones, the way the radiologist can interpret a potential cancer is different depending on what part of the prostate they are looking at.

And then a key point which I would encourage you to do at your home center is not only does the experience of the radiologist matter, but the expertise does as well. Just because someone has read a lot of them doesn’t necessarily make them good. It’s kind of like surgery. Just because you do a lot of surgery doesn’t necessarily mean you are a good surgeon. And the feedback loop of data is incredibly valuable if you find a radiologist that can continue to look at MRI’s, get better, and you can learn how useful MRI is at your institution.

This is incredibly important, this last line. There is a bunch of data within this past year, mostly from UCLA and NYU that MRI underestimates the tumor volume most commonly rather than the opposite. This is incredibly important for a biopsy or potential ablation. I do think MRI is valuable, but I tell the patients all of the time that we can’t hang our hat on it. Depending on your institution, it is good or great, but it is far from perfect. It should be integrated into the decision-making.

The PI-RADS system which you probably heard of is an ordinal system of grading the likelihood of there being cancer. It’s sort of been strong armed through as the de facto way of measuring it. There are many other systems out there that are often useful, and just another point to look at your own data at your institution or your medical center if you can’t.

So now let’s go through every little stage on what the data shows. So MRI for screening, it’s being done at some places. I think it’s the cart before the horse. There is no compelling data that it should be used for screening. Hopefully we will get there. In essence with an MRI for screening, you want to know how reliable is a negative MRI. A clean MRI, what is the likelihood of a meaningful cancer? Four institutions here, mixed cohorts, the bottom line is Gleason 7 or higher on a biopsy is less than 10% and as low as 1%. So it’s not zero, and a negative MRI, if a guy doesn’t want to have a biopsy, I would tell him, here is our data at our institution, a 6% chance you are missing a Gleason 7 or higher, and some guys say I still want the biopsy and some say no.

The flip side of it is how reliable is a positive MRI. These are two institutions using two different types of MRI. The reference standard was different whether it was transperineal or radical prostatectomy, but the PI-RADS scoring system is useful as it gets higher, the higher the likelihood of getting cancer. And Larry Klotz’s data that he just presented is incredibly valuable because his PI-RADS numbers were very different than what was presented in the literature. And what is relevant for his patients are Canadian patients at those institutions, you can’t rely on this published data from two centers of excellence.

We will eventually have data relatively soon on the role of a screening MRI, so there is a big trial that we are involved with and it is the PRECISION trial. And I will just walk you through it. It’s biopsy-naïve men with an elevated PSA. They get an MRI done. If it’s negative, then no biopsy; but if it’s positive, they are targeted. And then the randomization to the other arm is just a standard 12-core TRUS biopsy. And the primary outcome is a Gleason 7 or higher. It is accruing ahead of schedule and there will be 460 men. This is the algorithm. Don’t biopsy PI-RADS one or two. You biopsy three’s, four’s, and five’s. And we will have very meaningful data on whether it’s worthwhile or worthless in this study.

What about routine MRI prior to an initial biopsy? It is done routinely at select centers. We have a big center in Chicago where, right before every biopsy, everyone gets an MRI. I do not routinely do it. The NCCN does not recommend it, though if you look at the guidelines they do say or sort of hint at it, that MRI could potentially be useful to find more aggressive cancers and keep your hands off of the Gleason 6’s. So I would not be surprised if at some point this gets integrated in, but on a population-based level in the U.S. where MRI is very expensive, it’s just hard to imagine that before every single biopsy everyone gets an MRI, but perhaps we’ll get there at some point.

In Europe and in other places, MRI is a lot more cost effective because it’s cheaper. Now there are a load of papers out there on the role of MRI before biopsy. This is probably the single best known for good reason at a center of excellent, and this is out of the NCI and it was published in JAMA. There were 1,000 men undergoing an MRI before a biopsy, and only about 20% of them was it their initial biopsy, and 80% was a repeat. And the take home message is it helps you find more higher Gleason grade lesions and helps you not to find the Gleason 6’s as frequently which I think is favorable.

The great news is we even have some randomized studies now on the use of MRI, and I am presenting a couple of them to you throughout this talk. This is a randomized study that is in press out of Italy, and this is 212 men with an elevated PSA and a normal DRE, and they are randomized to getting a biopsy 1.5 Tesla with an endorectal coil. If there are lesions there, they target the lesions. If there are no lesions, they get a standard 12 core. The other half of the study just gets your regular 12 core biopsy, no MRI. What does it show?

In this study, the MRI kicked butt. It basically found a lot more cancer, which I don’t think is necessarily an advantage, but most importantly, it found a lot more clinically significant cancer. And if you look at the third row there, 43% of clinically significant cancers in the MRI arm, there were only 18% in the control arm. That is meaningful information. And at this center or in this trial, a negative MRI was pretty powerful. So only basically 4% of the guys with the negative MRI had a Gleason 7 or higher. So that is good feedback data for that institution where maybe men with that technology at that institution with the people reading it don’t necessarily need a biopsy if they have a normal MRI.

This is a well-known study that was published at ASCO last year and it was just recently released in the past couple of weeks in Lancet Oncology spearheaded by the group out of the University College in London, but it was more of a population-based study. It took place at 11 centers in the UK and tried to make it as transferable as possible. So they did a 1.5 Tesla MRI without an endorectal coil. Guys with an elevated PSA and a normal DRE, and God bless these 576 men. They all had an MRI, then they all had a 12-core TRUS biopsy, and they all underwent transperineal mapping. So this is for the love of science, and I am selfishly glad they did it because it provided useful data.

The UCL group has really woven the flag on a primary endpoint of a meaningful cancer, primary pattern four or tumor length of more than 6 mm. That is a separate discussion on whether that is appropriate or not, but in this trial that is what they used. Here is their data. The red is a clinically significant cancer based on the PI-RADS score, so yet more evidence that some type of ordinal system, scoring system, helps you determine the likelihood of there being a meaningful cancer there.

Now the ideal test if you think about it, if you want high sensitivity and a high negative predictive value, do you want to identify all of the guys with meaningful cancer, that is a sensitivity that is high, and you want a high negative predictive value so that if you have a normal scan you don’t have to subject them to a biopsy. And the MRI basically destroyed transrectal ultrasound in sensitivity and in negative predictive value. And you can see the numbers there on the table.

Now what about the clinically significant cancers that were missed in this trial? Basically no matter what your definition of the significant cancer─ and the Gleason 6 there is more than 6 mm of Gleason 6. And the others are Gleason 7, but basically MRI was far less likely to miss a meaningful cancer compared to what most people do is a TRUS-guided biopsy. So the conclusion of this PROMIS trial, which I think is a landmark trial, is that a negative MRI as a triage test would avoid biopsies in about a quarter of men. And you basically diagnose the same amount of clinically significant cancers.

I think that is an advance. The only additional thing is the added cost and the logistics of the MRI. A positive MRI is the flip side of it with only targeting those lesions detects more cancers than if you just across the board did a TRUS biopsy. So, it’s a really well done study showing MRI is useful.

Now what about men with a previously negative biopsy? The NCCN guidelines show this is a very complex and muddy space. There are a whole bunch of biomarkers, urine, tissue, blood, and imaging that can contribute to this space. I essentially think of MRI as a biomarker. I think it’s an anatomic marker and a biologic marker. And it can be useful in this space just like many other things can be useful in this space.

Recently the AUA as well as the Society of Abdominal Radiology put some content experts together, and we put together some guidelines or recommendations for using MRI and then who had had a previously negative biopsy. And most of this is self-evident, but this is the take home point of the paper. Basically, higher PI-RADS lesions probably warrant a biopsy. There are many different ways of targeting these lesions; in-bore, cognitive, fusion technology, and at least two cores should be taken from each target.

And then a targeted biopsy alone, and I keep bringing up this point, should only be considered once you’ve looked at data at your big institution at your group to know whether that is a smart move for that individual patient going forward.

Another randomized trial, now this is a randomized trial using MRI for men with a previously negative biopsy. The PSA remains greater than four, they all undergo an MRI, and if there is a lesion on the MRI, they are randomized. And one arm is basically just targeting the MRI lesion, and the other arm is targeting the lesion plus your standard 12 core. And at the interim analysis this was halted because they were basically equivalent. Whether you wanted to define all of the cancers, just the Gleason 7’s or higher, the targeted MR biopsies basically got you all of the information that you needed and you didn’t have to do the 12 core.

Now remember these are guys with a previously negative biopsy. So it suggests that perhaps in this clinical state, maybe just targeting the MRI lesions is all we need to do. What about MRI for active surveillance? So it makes a lot of sense. There is a load of data out there on the MRI. I love this one out of the University of Toronto because it’s so simple and it makes sense and the data is so dramatic. Sixty guys with low risk cancer all getting restaged with an MRI and a repeat biopsy to look for higher grade cancers. They made their radiologists commit on the MRI to say it’s either normal, something less than 1 cm, or something greater than 1 cm, pretty clear cut. And look at the dramatic difference in upgrading, looking at that simple three-tiered system which speaks to the power of the MRI with restaging biopsies in guys with low volume cancers.

How do I do surveillance? Well, I get an MRI fusion restaging biopsy similar to what the women and men at Toronto did. I typically do it within six months. Some guys want to do it sooner and some guys want to wait a little bit longer. Not a huge deal. A PSA and DRE every six months; the NCCN guidelines and most experts say you don’t need to be checking it every three months. A surveillance biopsy every one to three years and it’s easy to risk stratify based on age, health, total millimeters of cancer at their initial diagnosis, and PSA density.

Those are your big ticket items. How much Gleason 6 cancer was there and what is their PSA density? I don’t think there is any convincing data yet for routine surveillance MRI. However, I am going to show you data to suggest that maybe we will be getting there at some point.

So what is the data on the use of MRI while a guy is on surveillance? Here is the data from Sloan Kettering. It’s a bit of a mixed bag in different types of MRI’s. About a third of their patients were found to have Gleason upgrading, but if you look to the right there on the figure, basically the higher the Likard [phonetic] score or PI-RADS score, the more likely you are to find a higher grade Gleason score. And the black there are the targeted biopsies.

So, most of the higher grade cancers were found from a targeting of the MRI lesions. It’s convincing data. the NCI also has a similar study where they took those low or intermediate risk men and they are looking for the worst cancers in using MRI. So 30% were upgraded. Their definition of MRI progression is not commonly used, but they basically gave points for each of the three things listed there. And you got either a zero, one, two, or three points. And, lo and behold, look, the more points you got on your MRI, the more likely you are to find those higher Gleason scores. It is encouraging data that MRI is useful.

The UCLA data is a similar study. The guys on active surveillance, they have a 3 Tesla MRI without an endorectal coil. Of the men who were upgraded, 32 of the 33 men that area that had upgraded, the upgrading was found within the lesion on MRI. So three centers of excellence, three well done studies suggesting that maybe MRI’s should be useful for guys that are on surveillance now. Should they get it how often, can you obviate the biopsy, and these are all questions worth asking that require a prospective analysis.

What about MRI for staging and operative planning? I think the two big ticket items that MRI is not as good as we had all hoped, the patients need to understand this. I mentioned one earlier. It tends to underestimate the tumor volume, and then the operating characteristics for looking for ECE, seminal vesicle invasion, not great. So if you are going to get an MRI before radical prostatectomy, do not hang your hat on the MRI suggests or don’t suggest ECE and make your nerve-sparing decision solely on that.

I do think the pictures can be useful, but integrated into all of the other information you have about that guy before you go to the operating room. This is a study out of UCLA where they did MRI’s before the prostatectomy. They whole mounted all of the pathology, and as you can see here the blue is basically identifying it or detecting an MRI, and the orange is missing it. So it doesn’t project great, but as the tumor diameter gets bigger, the more likely you are to see it on the MRI.

As the Gleason score gets higher, the more likely you are to see it. The index lesions are far more likely to be seen than non-index lesions. And what about predicting ECE? This is sort of a caution. A well done study at a center of excellence that had been pioneers in MRI of the prostate, so nearly 200 men that underwent a radical prostatectomy, they all had an MRI beforehand, 50% had ECE. And look at that sensitivity in the negative predictive value. So I would argue that you should not be making your nerve sparing decision solely on your MRI.

MRI actually does a decent job of picking up gross ECE, sort of macroscopic ECE. It does a really poor job of picking up microscopic ECE. So a UCLA study that was done on MRI’s and how it impacts nerve-sparing, the short summary of this is it changed the plan for nerve-sparing in about a quarter of the patients. But I would echo what was mentioned in an earlier session. You have no idea if that change was a good thing or a bad thing. So the MRI might have told me I am not nerve-sparing on that side, I am going wide, but you might have just resected a guy who was organ confined on that side and took his nerve with it.

So unfortunately without erectile function data as an outcome which wasn’t reported, you don’t know if that change in plan was ultimately good for the patient. Here is a well done study, a randomized controlled trial of using MRI before prostatectomy. Over 400 men getting a robotic prostatectomy randomized to no MRI versus a 1.5 Tesla MRI, and the positive margin rate was no different on whether they had an MRI or not.

Now, a subset analysis which was not the primary analysis suggested that amongst low stage patients, perhaps it was useful in decreasing the rate of positive margin. Kudos to these investigators for studying it, but again unfortunately there is no erectile function data. And just because you’ve lowered the positive margin rate doesn’t necessarily mean that was a good long term strategy for that man.

I’m running out of time and I want to be respectful of the others, so I am really going to whip through the rest of it. MRI is useful for predicting continence and basically the urethral width and the urethral volume can be useful. There is a bunch of studies that suggest that urethral length could help predict long term continence. I am not aware of anyone that gets an MRI that measures the urethral length and then says, oh, your rate of continence is going to be so low you shouldn’t have a prostatectomy.

And then lastly, but importantly, there is an MRI-guided treatment with many different ways of doing this. We are in the very early stages of developing it. We have participated in a couple of trials. We have done a phase I and a phase II of in the MRI machine putting lasers into regions of the prostate that have important cancer and MRI lesion, and the rest of their prostate looks healthy. The laser basically heats up and ablates that area. We have shown it is safe, we have shown that the early data, the primary endpoint is 96% of the guys no longer had cancer in that region of the prostate at three months when we biopsied it. I have no idea what the long term outcomes are going to be, but I’ll be happy to shout it out whether it’s worthwhile or worthless down the road.

It’s basically safe. We have proven that there is a very low rate of side effects from it, but from an oncologic standpoint, it’s unknown. There are people doing MRI TRUS-fusion focal cryo. There is not great data published. There are great PSA responses. This is a study where they didn’t do any follow-up biopsies, so you sort of shrug your shoulders as to what is going on within the prostate.

Here is a trial, a phase I study, and this is transurethral ultrasound ablation in the MRI machine. This was a safety study that basically showed it is safe. The median treatment time was about a half of an hour. That is just the time ablating the prostate. The total treatment time is significantly longer on the order of three to six hours of spending time in the early learning curve of trying to do this technology.

Now remember how long the first lap nephrectomy took, the first lap prostatectomy, and maybe we will get the times down. For most men, there is no impact on the quality of life; however, a beacon call in this phase I, and remember phase I’s aren’t meant to look at oncologic outcomes, but after this treatment, 30% of the men continued to have clinically significant cancers within their prostate. And this is whole gland treatment.

So in conclusion, hopefully you will agree with me based on the data I’ve showed you. I skipped ahead. The bottom line is that MRI can be helpful. There are significant limitations to it. Use it wisely, and get feedback within your own institution. We have dreamed for years about imaging prostate cancer. In the last 10 to 20 years we are now able to do it much better.