Cryotherapy: Update on the International COLD Registry

Cryotherapy: Update on the International COLD Registry

Thanks, James, and thanks, David, for inviting me to one of the best meetings in urology. I’ve been excited to be here for a long time and I’m pleased today to be able to share with you some work we’ve done on cryoablation. I went into practice in 1992, and at that point there was a flurry of interest in cryoablation. And that faded pretty quickly because the results frankly were not very good and there were significant complications and the science was worse than not very good.

And, unfortunately, what it did was it colored the word cryoablation or cryotherapy probably moving forward forever. And so what we have now is the opportunity to look at what has happened since that time. Now why is the COLD registry important? It’s because actually you know there is no significant funding in cryoablation. A number of people have completely shut off that it could be a possible modality, so there aren’t going to be large studies like some of those that you have seen in other modalities moving forward.

So the COLD registry is an opportunity for us to be able to share real world experience at a number of centers, both private and in academic settings. The disclosure on the COLD registry is actually an important part of this. It’s an online retrospective database sponsored by Endocare or Healthtronix [phonetic], and importantly what that means is that we have the ability to look at real world experience again. We do have funding from outside, which we go over the top to make sure and disclose. But I want to talk to you about how we separated that in a way that we believe brings the science better.

And the first is by having it run by an independent board of directors. I have had the ability to be the chair of that now for over a decade. Some of the people in this room have been a part of that, and it’s allowed us to actually be able to go into the data and do some quality work on it to bring the publications that you’ve seen. It’s currently housed by Watermark which is an independent data and center. That was done soon after I took over the COLD registry.

And the ability to take that completely away from the company having direct access to the data in a way that was able to protect it, and it is the largest dataset in existence. When they approached me now over a decade ago, there were several things that I asked for in agreement to run the registry. The first is that I chose to take no compensation for my work on the registry. And as I would always disclose, I do other work with the company over the years that I have been paid for. I want to, not by any means, pretend that that has been the case.

But all funds that have been related to work on the registry have been diverted to charity or other purposes, so I have not taken any money in that regard. And that was important to me. Second is that I would be the senior author on all of the manuscripts, and that was to assure that as the data came out that I had the ability to assure that what really came out was something that I felt we could stand behind. The independent board we talked about, and then we had a 100% decision on whether things got published or not. And the company immediately gave me permission and an endorsement to do that and they followed through on that.

So there have been publications that show a significant efficacy. I will share some of that with you. There have been publications that have shown actually places where cryoablation doesn’t work, and by the same token they have never exerted an influence to try to say anything other than we need the data to be out there. So there are a number of limitations to the registry that I think others can learn from moving forward.

It is a situation where the sites enter their own data, so it becomes a heterogeneous data set. It’s rare that I go to a meeting that someone doesn’t come up and say they want to be a part of the COLD registry and enroll their data. In the first couple of years I fell for that, and then after that we learned that what became clear was that people would often enter their data even for the first few months and it would fall off for a number of reasons, so we did get away from that.

And we are trying to now work specifically with centers that have an interest in continuing to assure that the data continued. In addition, it’s hard to get long term data. That is due to a number of things, including the fact that the investigators retire, they move to other places, they die. We had one investigator who lost their license, and once they’re there, the IRB approval says that we have to have licensed physicians. So we at that point have to take the data out of the registry and that will explain some changes in the registry that I will show you.

In addition we’ve got some fields that we feel very confident in. The PSA’s are obviously easy to do. We are very confident that if there is a fistula, it will show up in the registry. No one is going to miss that diagnosis. But in other fields like IEF’s and biopsy details, we just did not succeed in getting to the degree that we would be able to publish anything meaningful from that. But we have had 16 peer-reviewed publications coming from the registry.

The current data are a little bit different than I may have shown at any other point in time, again, because if someone retires or leaves, we can’t keep their data in the registry. We just can’t continue to analyze those data. so it is the largest dataset. We have other 4,000 patients who have primary whole gland ablation, salvage patients almost 1,000 similar to primary focal. We’ve got a small number of salvage focal patients that is a little bit lower than what we published recently because, again, some patients had to be pulled out.

And then we have a smattering of repeat biopsies. So now almost ten years ago we published the first group out of this, 1,200 patients that had undergone primary whole gland ablation. It’s a pretty typical population, but importantly only 136 of those had at least a five year follow-up. So we found a number of things. One is that only about a fourth of the patients actually underwent biopsy. Of those who underwent biopsy for cause, in other words, had a rising of PSA as we would have taken in any other setting, the positive biopsy rate was almost 40%, so and then if they had no cause, if it was done for protocol, it was a positive biopsy rate of about 15%.

And if you think in the acute setting, although it’s been quoted here earlier today that only 25% of the biopsies are positive, about 40% to 50% of all initial biopsies are positive in almost every study that has come forth in the past decade or more. And so what you see here is if you are suspicious of cancer and you do a biopsy, you have about a 40% chance of having cancer. And if you’re not suspicious of cancer, so if we went through everybody in the room here who had hair as gray as mine and did biopsies, we would find out that about 15% of those men have cancer.

So it’s really not any different than in that setting. Urinary retention rates were low, rectal fistula rate which is the area that originally ran cryoablation out 20-plus years ago, 0.4%. Incontinence was about 5% and 3% in PADS, and most patients who were sexually active did not return to intercourse, and frankly most patients who were sexually active don’t end up getting cryoablation in most of the practices. Now as far as determining whether there was a successful procedure, there is no standard yet as far as determining when cryoablation was successful other than if we did prostatectomies afterwards of course.

So you could look at Astro or Phoenix. You could look at undetectable PSA which one of the reviewers in the Journal of Urology required us to put in there, and it’s a meaningless study considering we know that we preserved tissue in cryoablation, and then a nadir PSA. So, as opposed to choosing one of those, we actually have pretty consistently reported both Astro and Phoenix with all of our outcomes. And basically you see the Kaplan Meier curves that are not anything different from other forms of accepted therapy.

We also, though, came back later with a group of patients, and over 1,000 patients had had a minimum of a five year follow-up, so some five year papers you see, the first patient had five years and everybody else had less than five. All of these patients had a minimum of a five year follow-up, and we saw again Kaplan Meier curves that are comparable to other forms of treatment based on low, intermediate, and high risk cancer.   What we found otherwise, though, is that the nadir, post-cryoablation, which was typically the six week read which we know now may not be the true nadir. We are working on some research on that.

But we see that the patients reach a nadir of less than 0.4, they have very good biochemical outcomes regardless of risk structure. And if the nadir doesn’t reach below less than 0.4 in that primary setting, in all likelihood we fail to cure the cancer. We subsequently have been able to look at a number of other scenarios including bulky disease, high risk patients in the elderly category many of which are now being diagnosed and the option is for surveillance. We have the salvage setting and the focal setting and I will go through those.

So with patients with high grade cancer one of the original hypotheses was you shouldn’t use cryoablation because maybe it wouldn’t be as good. What we see actually is high grade cancer will die like low grade cancer, but there are some caveats to that. So even in those patients with high grade cancer, if their PSA is higher, actually we do see separation in cure rates regarding the lower PSA. More importantly in my opinion is that if they have pure pattern 4, so if you have Gleason 8 cancers, we see that they actually do less well than patients who have any pattern 5 cancer. So there is probably some sensitivity issue there but in that setting we again get affirmation that post-treatment nadir is the determinant of whether they are likely to have a long term good outcome.

We have also published in patients who have had whole gland primary treatment in the elderly, and actually a number of patients have been treated as you see with the numbers there in that greater than 75-year old population who have mostly high risk disease. And I often have the question of should you treat a patient who is 76-years old, and if his father is there and he is in great health, as you know, and I recently saw a patient who had been treated with active surveillance with Gleason 9 disease because he was 85-years old, well, he had widespread metastatic disease at 91 and he was perfectly healthy other than having incurable metastatic disease at that point. So we have to rethink that.

In the salvage setting, our original studies again now almost a decade ago were 280 patients, so obviously fewer patients. And it was the same thing, a five year follow-up only in about 50 of those patients. In that setting we chose not to separate the high, low, and intermediate risk, and this has been an ongoing debate amongst some of the board is that I would regard anybody who has post-radiation recurrence as being high grade. Others would say we could segment them, and we started doing both.

But again what you see there is we would respect [phonetic] that depending on definition, a 50% to 60% chance at five years post-treatment that we would still have biochemical success in the post-radiation setting. In that setting we know that complications are a little bit higher with a fistula rate of 1.2% in that group, a retention rate of about twice as high, about 3% required TURP’s, and the incontinence rate which seems low to me considering our recent data, but at least in that setting the incontinence rate was actually only about 5% or 6%.

When we do stratify them, though, we see now in unpublished but subsequent data is that you do see some differences if you take the post-radiation setting and segment by high, low, and intermediate risk based on traditional definitions. You do see some separation of the curves and they are in the high risk patient. Less than 5% of those patients five year post-treatment will be biochemically free.

And in the salvage whole gland setting we also looked at patients who have had neoadjuvant treatment. And the important thing we find here is that although the hypothesis is in that setting that giving neoadjuvant treatment before cryoablation is done, some investigators clearly felt that that would be beneficial. That turns out to be absolutely the opposite. And the patients who had neoadjuvant treatment actually did worse, not better. My hypothesis on that would be that those patients may have had worse disease, but very clearly neoadjuvant treatment is not a panacea in the post-radiation cryoablation setting.

And then in that same setting we see continued the same separation on if the patients get a low nadir of less than 0.6, and actually subsequently our data would support less than 0.4, we know that that is the patient who is likely to have local disease or biochemical recurrence, and biopsy is probably not necessarily in follow-up barring some significant changes in PSA.

Here again we’ve done the same thing and shown that that will go across risk groups that in that salvage setting the nadir maintains across all risk groups. The final population is the focal treatment setting, and we have basically developed a series of nomenclature, or a definition of nomenclature. We have this in the registry such that when patients undergo focal ablation, the investigators can put which type of focal ablation they have.

And what I can tell you is that almost all of those are actually hemi-ablations in the series that we have reported. John Ward and I several years ago published that the growth on this was actually substantial and that focal therapy was taking off. Importantly in that group we found that focal therapy was not being done just on those patients who shouldn’t be treated, which are the low risk patients, but the majority of the patients were intermediate and high risk disease that were getting focal therapy at that point and subsequently as well.

And what we see in that focal setting is compared to whole gland at the bottom─ the bottom line is that we tend to see biochemical outcomes or Kaplan Meier curves with biochemical outcomes actually being similar in the focal group to the whole gland group meaning that most of the patients who are undergoing focal therapy appear to be doing that based on the right choices or the right patients are getting focal therapy.

The other issue with focal therapy, of course, though is why do we do it if we are doing organ-sparing. It is theoretically to protect some outcome. And so we do see in bold there compared to whole gland or salvage treatment, we see that the patients actually are going to be less likely to have incontinence, about half as likely. They are going to be less likely to have fistula. Only one patient in the entire 1,000, patients had a fistula, and urinary retention was less than 2%, so all of those are favorable.

What is not clearly favorable is protection of erectile dysfunction, so in those patients who underwent again mostly hemi-ablation, the bottom line is that is still about 40% of those patients that had direct erectile dysfunction afterwards. And so at least hemi-ablation clearly again is not a panacea for preserving erectile dysfunction.

Other issues we’ve looked at in the salvage setting I should say is that we developed a concept of a bifecta, so we’ve talked about the trifecta with thoratical prostatectomy, in the patient who has been radiated previously and undergoing cryoablation, whole gland cryoablation in this report here, we would not expect them to be sexually active. As we know many of them might not be sexually active because of their age or because of the prior radiation, but we felt that was not even something that was trying to be accomplished in the whole gland salvage setting.

But we did expect them to be continent and we did expect them to have a biochemical disease-free survival. And we found that about 75%─ 70% to 75% of those were able to accomplish those two goals. One of the other findings that we published is that salvage patients have poor outcomes if they have single vesicle involvement. And that actually is in my own experience, but I suspect that it’s why we also published it in the T3 setting, extra prostatic disease, that cryoablation does not tend to do as well as other modalities. So in a patient with extensive extra prostatic disease, our publication would suggest that that is not the patient to treat with cryoablation.

Then the last frontier would be the patient who could undergo focal salvage or partial gland treatment is again theoretically we could reduce the morbidity while still carrying the cancer in appropriately chosen patients. And for the biochemical disease free survival, we show that that turns out to be the case and that we actually have a high likelihood to have the disease controlled as we would with the whole gland setting or whole gland treatment. What we weren’t able to accomplish though was to have inadequate reduction in post-cryoablation complications, so again post-radiated patients who undergo focal ablation and that we actually had as high of a risk, if not higher, there were three patients out of slightly over 100 that had a fistula in that setting. Urinary retention certainly was not lower, and the 12 month incontinence was not lower as well.

So my initial enthusiasm for focal salvage cryoablation has waned some. I believe we could do this better, but at least in the first 100 cases it’s not uncommon for the first 100 cases of anything, did not turn out to provide the benefit that we had hoped for in the short term, and then again segmenting it by risk category. So the key take-away’s from that would be that the COLD registry is the largest source of cryoablation data and that it is the best data that we have got to be able to evaluate the role of cryoablation in any of these settings.

The primary and salvage therapy can be accomplished with either whole gland or focal therapy if the right treatment is given to the right patient, and I think that is the real key here to any form of ablation. And then finally, as we know, there are increasing numbers of men who have previously had radiation and that we believe that is highly likely to be a growth area in our practices for focal ablation. I appreciate it very much.