Salvage Cryotherapy

Salvage Cryotherapy

I’m going to show you a short video. One of the advantages of cryo that is emerging in the salvage setting is that we can do focal. I’m going to show you a short video on a focal patient that we repeated, that we have performed recently. But, as James mentioned, we are seeing a number of patients that have failed radiation therapy these days and 25 % of these patients will have a rise in PSA in 10 years. They’re not all due to cancer. Some of them may have progression of metastatic disease and you may not find cancer in the gland.

That’s one of the most frustrating things for me is a patient that has a rise in PSA and you do a biopsy and you really don’t have cancer. Metastatic survey is negative. What do you do for those patients? Do you start them on hormonal therapy? Do you do an observation? Do you watch and wait?

I typically, as I mentioned yesterday, will start some of the dietary regimens and see if that can’t halt or reduce the PSA progression. We see benign prostatic tissue in these patients. That can cause a PSA imbalance in the patients that had seen implant and, of course, there can be residual cancer.

My experience is if you biopsy these men, 70 % with a rise in PSA and I do agree with James that we have to get these patients in earlier. 70 % of them, though, will harbor disease in the prostate. I like to do seminal vesicle biopsies at the same time. These patients fail radiation for a number of reasons. They may have initially been under staged. When I look back, one of the first things I look at when I see a patient who’s had rising PSA after radiation, what was their initial clinical features? I said, Why didn’t you have surgery when you were initially diagnosed? Well, my PSA was 55. I had a Gleason 8 in all my cores. The metastatic survey at that time may have been negative.

But, clearly, these patients are probably being under staged and were probably much higher rate of failing after radiation therapy. Maybe they were under radiated. You’d like to look at the dose of radiation and now we’re going up higher and higher dose. Again, I congratulate James for taking on these cases because when you’re doing irradiated patients in a field with 81, 82 grade and those fat planes are just gone.

There’s just no plane between the prostate and the rectum. Even doing a no dissection as you mentioned to try to spare the opterator nerve is reasonable because there’s just no nodal package. It’s stuck down on to the veins and unless you have doing this, I think you’re running the danger of not only nerve damage, but also some major vascular injury there. There may be some biological resistance genes that have been started and I think Neal pointed that out quite well yesterday. Maybe we eradicated the disease and new cancers have developed.

The thing that you have to sit down with the patient out is Are there patients really optimal for salvage therapy before we start biopsying them and considering them? Before I start biopsying a patient if I didn’t feel that they were a candidate for salvage therapy, as James pointed out, reasonable health, life expectancy, go back to the original cancer. Are these patients surgical candidates? Were they surgically cured at the initial onset? A well motivated patient? You’d like the PSAs to be low. Let’s get them in earlier and you’d like a long PSA doubling time. These are the options.

What’s amazing is that I put this slide up 10 years ago at the AUA when I debated the other Chief of Memorial Sloan Kettering, Dr. Peter Scardino. AUA 2004. You look back–I look back. But, this is the same slide that I had then. So, it really hasn’t changed all that much in terms of options.

We have options like watchful waiting and androgen ablation, which is non curative and, still, I think is the knee jerk response by most urologists. Your PSA is going up, sir, and maybe you’re 75 years old at this point. You had radiation 10 years ago. Maybe you want to start on a short course of hormonal therapy and then watchful waiting and then the potentially curative options there on the right. Prostatectomy, cryo, brachy, HIFU which is in clinical trials here and photodynamic therapy.

Salvage cryo is approved as both a primary and a salvage by Medicare in 2001. It is considered a standard of care by the AUA in the salvage setting and also in the primary setting for T3 disease. The technology has improved over the time that I’ve been doing it. I’ve been doing it now about 20 years and the technology has no doubt improved.

There’s been over 75 publications on salvage cryotherapy. Most of these publications are single institution experiences, but there are several that contain data from the COLD registry. That’s the Cryo Online Database that I’ll show you where groups of urologists, both academic and community urologists have come together and put their data together online. The AUA policy on salvage cryotherapy which came out in 2008 and I was part of the guidelines are used for patients with a rising PSA level following radiation therapy that can either be IMRT, IGRT, stereotactic body radiotherapy or seed implant with no documented evidence of metastasis and you need to have a biopsy proven cancer. So, it’s not just the PSA rise.

The complication rates, and I’ll show you overall, the incontinence rates they are nowhere near the salvage radical prostatectomy and I quote my patients that it’s typically under 5 %.
The use of pads in my patients with modern day cryotechnology is really quite rare, is quite rare. I don’t really have a discussion about a sphincter because I can’t remember the last patient that we put a sphincter in and I do four to five of these every week. The rectal fistula rate, the dreaded F work in cryotherapy is really close to zero at this time modern day ultrasound and thermal mapping.

Most of the systems–there are two systems that are available–they use this Joule Thompson effect that can drive high pressured argon or helium gas through a tubing and the cryo needle at the tip. You just get ice at the tip of the needle. This is the system that I’ve employed and have done about 500 cases now.

Ultrathin 17 gauge needles that can get into a radiated capsule. Very sharp tip at the needle. I don’t know if any of you have experience doing this. In the old days, the needles weren’t as sharp and it would deflect off of that radiated capsule. It’s very much like brachy therapy. If you’ve done brachy therapy and you’re a radiation oncology, you can clearly take your skills to doing cryotherapy and it’s all done monitored using thermocouple devices and temperature monitoring devices that go in and around the prostate and especially in the external sphincter.

This is what the ice rod looks like. This is a computer guided mapping system which I typically do not use. But, for the early cryo adopter, I think it’s reasonable. It gives you a template and you’re able to outline the prostate at multiple sections from the apex to the base at 5mm sections and it gives you kind of an isotherm. These dark blue areas, the negative 40–that’s the area that you’d like to drive the temperature down.

If you want to do focal ablation, you don’t have to map the whole prostate. I typically will do a hemi ablation. We’ll do just one side of the prostate that I’ll show you and you can map that out. It will tell you the number of needles or ice rods that you need in that particular zone and where they should be placed in the grid. It’s a guide. It can be helpful–again, I think for the early cryo adopter. Then, there are a number of different needles based upon the size of your glands. The majority of patients that I’ve seen that have radiation therapy, their gland for the most part are small and I think that’s where the incontinence can come in especially with the salvage radical prostatectomy series when you’re dealing with a 15, 20gm radiated prostate. It’s very difficult to take that prostate out and spare the sphincter.

So, there are different needles and will generate different size ice balls based up the size of the gland and will give you different isotherms.

Then, the multiple thermal sensors. If you are monitoring the temperature and you want to do, let’s say, the right side of the gland, you can drive the temperature down or one cycle down. You can see we’re getting below negative 40 on this cycle, warm it up and, then, we do a double freeze thaw.

Typically, for cryotherapy and most cryotherapy biologists will tell you you need a double freeze thaw cycle and that’s shown there. These temperature monitors will tell you the temperature at 10mm sections. This is really towards the bladder base. So, this is 10mm, 25, 35 and 45mm measuring the temperature throughout the entire length of the prostate. I think it gives you a great reassurance that not only are you ablating what you want to ablate, but you’re sparing areas such as the nerve bundle, if you want to spare a nerve bundle, or a rectal wall or a sphincter.

This is taken from John Baust, who’s a cryobiologist. It’s telling us that you really need to drive the temperature down below negative 40 degrees. There are a couple of cellular processes that go on both directly by interfering and disrupting the cell membrane, interfering with metabolic processes and also causing the angiogenic process to occur by creating thromboembolic emboli there.

There are multiple ways that cryo can kill. In my own experience and, again, I’m doing it about 20 years. I’m impressed that cryo can kill Gleason 8, Gleason 9 cancers that come back after radiotherapy. It really can destroy high grade tumors and this is what you’d like to see–a biopsy. If you do this a year after cryotherapy, you see no epithelial elements left in the tissue. It’s a little bit unlike radiation therapy where you’ll still have some of these epithelial elements. After cryo, it’s a complete obliteration and just stroma. This particular biopsy associated with an undetectable or very low PSA in the long term has been associated, with my experience, excellent cancer specific survival rates in these patients.

This is the algorithm that I followed. Patients with a rising PSA, typically 18 months, so that you don’t have that bounce phenomenon or a change in digital rectal examination.
Initially, I go to a CT scan and bone scan and if there’s metastatic disease, the patient goes on to hormonal therapy. If there’s no disease outside of the gland, they go on a prostate seminal vesicle biopsy. High grade disease in the past, I was doing pelvic lymph nodes and I pretty much stopped doing that. Then, the patients go on for an ablation.
I’m just going to show you a quick video on a patient that we presented that we did last year. This is a 65–you can start the video–year old gentleman who had IMRT and had a recurring cancer in the gland.

These patients are all done in an outpatient center. In fact, we don’t do them in a hospital. They’re all done in an outpatient center. They all get spinal anesthesia. The first thing we do is we insert an 18Fr Foley catheter and distend the bladder, so that you can really see the bladder and the prostate very well and, then, tack up the scrotum to the interior abdominal wall with some scrotal clips. Then, you take a transrectal ultrasound. I’ve been using a B and K [phonetic]. I have no allegiance to B and K. I just think that they’re a great ultrasound for doing this. You can see the urethra quite well. You can see the anterior part of the prostate. This is nice when I see this. A nice distance between the posterior capsule and the rectal wall. Then, you’ll start placing these ice rods through the brachy style grid into the posterior capsule. You’ll monitor this under ultrasound guidance and you can see there’s no doubt where these needles are. You can see them from the sagittal view on the apex of the base. You can see I have two needles in there now.

The difficult cases are the post seed implants. In those cases, you have to do the entire case in this view right here–the sagittal view–because you can’t see what’s a needle and what’s an ice rod. You can see these rods going in. We have right now three rods. Typically, for a hemi ablation, this size prostate, we’ll put in about four needles. You want to make sure that the needles are poked up all the way to the base of the gland and, then, you insert your thermal couple devices.

If you’re doing a hemi ablation on one side, I’ll typically put two or three thermometers on that side of the prostate as well as in to the sphincter. You can see I’m placing on in the posterior aspect of the gland and, then, also on the right lateral aspect of, making sure that the ice goes beyond the capsule and extending laterally.

You can see this is the Foley catheter here and this is where I think the sphincter is right beyond the apex of the gland. I’m going to now take out the Foley catheter and, then, I’m going to perform a flexible cystoscopy. This is done with your typical Olympus flexible cystoscope and you’ll need direct monitoring.

What you want to see is that you haven’t placed any needles into the urethra. That would be bad. Then, if that happens, it’s pretty rare. You just reinsert it. Then, you want to show that this is the sphincter and you want to be able to show that if you just push and you just wiggle that thermal couple on the sphincter, you can see it right here quite well. Then, you insert a guide wire through the hub of the scope. Then, you take out the scope. Over the scope, you then insert a urethral warming catheter. This has been, in my experience, a dramatic change in the overall incontinence rates of patients with a urethral warming device and also preventing the other dreaded complication which we saw, which we rarely ever see now which is urethral sloughing.

Then, we just do a double freeze thaw cycle and you’re monitoring the temperature in the gland. You can see we’re just ablating his right side of the prostate and, then, we’re going to drive the temperatures down pretty rapidly in the prostate.

We’re measuring the temperature. You can see the anterior thermal couple device dropping down below negative 20. Then, we’ll continue that until it reaches typically around negative 40 and, then, we’ll turn on our second row and, then, our third row.

But, the key is that you want to monitor as well the external sphincter temperature which is right here. That sphincter temperature, once it reaches negative 40, the ball will turn red indicating that that area is typically frozen and it’s done.

You can see the ice is going to extend down through the posterior capsule now you’re monitoring. This is all ice here. This is the edge of the ice ball.
This is viable tissue that has not yet been frozen. We need to drop this ice ball down to the anterior rectal wall, but not into the rectum. This is the area of the sphincter. This is still staying warm and we continue this and, then, do a double freeze thaw cycle. You can see those are the temperatures in the anterior part of the prostate.

Let’s maybe take the video off, because I don’t want to take up too much time. We can go back to the presentation.

That’s the procedure. Basically, the patients all get spinal. They have a Foley catheter. It’s all done outpatient, as I said. You perform your ultrasound. You insert your needles and thermal couples. You do a flexible cystoscopy. You place your external sphincter temp probe. Insert your urethral warming device. You do the double freeze thaw cycle. Patients then go to the recovery room and, then, they go home.

Everybody goes home. It’s all outpatient. The typical time that it takes is about an hour and 20 minutes. There is no bleeding. The patients do go home with a catheter. I’ve done about around 600 of these in a salvage setting as of right now. I have never transfused a single patient. Nor, has any patient stayed overnight.

The patients go home with a catheter. I do them on Thursday. They come back on Monday. They have the catheter removed on Monday. 98 % of the patients void well on Monday and they don’t see me back for three months. Very rare–maybe 2 or 3 % of the patients don’t void and need the catheter for another week. They all go home with some Ditropan and some Flomax or Rapaflo, your alpha blocker of choice.

I think that it’s an excellent choice for patients that have recurrent disease over salvage radical prostatectomy. There is no hospital stay. There are no transfusions. I have not seen any delayed or long term complications with this. I do not see the bladder neck contractures. I can’t think of a patient that I’ve had to dilate or had to bring back to the OR because of a TURP or needed a problem with obstruction.

It can be repeatable, although I think it’s a little dangerous to start repeating the procedure on patients who have already had radiation therapy. It can. There’s no doubt that it can delay the use of hormonal therapy. The incontinence rates are very low, even in the salvage setting. Minimal anesthesia.

A lot of these patients that we’re seeing that have recurrent cancer, they’re older. I don’t know if they’re going to be a good candidate for a salvage radical. I think James’ point is right, that if they are very young–maybe they were radiated when they were 40 years old or 45 years old and now they’re in their 50s, maybe they should consider salvage radical prostatectomy.
But, the majority of these patients can do very well with salvage cryotherapy and have a normal return to work if their catheter comes out on Monday. I tell them that they can start exercising and go back to work and their routine life in about a week.

For urologists, I think the technology has improved greatly. All of the things that I have showed you–the flexible cystoscopy, placing needles, knowing the ultrasound anatomy is all urologically friendly.

There have been improved outcomes and same day. One surgeon is required. It’s just me in the operating room and an anesthesiologist. That’s it. I don’t even need scrub nurses. I can do everything myself. Just take the needles and place them in and run the machine myself.

I think there’s a relatively short learning curve, even in the patients that have had recurrence after radiation. This is the data that I published recently showing the overall–when I was in Columbia.

This is the PSA plot defined as a PSA greater than 0.2 that’s still, even out at 10 years, about 50 % of the patients have not had a PSA above 0.2, which I think is excellent.
But, most importantly to me, and as James pointed out, what is the overall cancer specific survival rate? This is what these patients are concerned about. These patients come in. They have recurrence disease now after radiation therapy. They’re concerned. Many of them are very anxious frankly. Many of them have upgraded their cancer.
The question is can you really Gleason grade these cancers? That is still up for debate among pathologists. But, I do see patients who come back and they say, Oh, my Gleason is 6 and now that my urologist biopsied me and I have now Gleason 8 and 9 in my prostate. That, I see very, very commonly.

This is the overall cancer specific survival rate out to 10 years and still over 90 % of these patients have not died. The COLD registry data with 277 patients that I published back in 2009 with the average age of 70. You see the Gleason is 7. The follow up was not that great–overall, 21 months. But, still there were 47 patients in the registry that had at least a 5-year follow up.
The question is–and, it was pointed out is What is the proper PSA failure? Should we use ASTRO? Should we use Phoenix? It’s still unclear. But, overall, you see that either definition is used.

The numbers here are pretty good, that still you’re getting about over 50 % of these patients have not failed by PSA and you can significantly delay the use of hormonal therapy. The positive biopsy rates overall in this series was relatively low of 6 %. Incontinence rates whatsoever was 6.4 %. This was again all urologists that were doing this in the community and academic based. 3.4 % pad use and 1.2 % fistula rate.

Just to look at the Medline review that was salvaged recently looking at the salvage prostatectomy data. Again, I’m not here to put it down. I think it has a role. It’s just that many of these patients are older. Many of these patients are concerned about incontinence rates. I think this can be done, as Dr. Eastham–I do send him patients—and a handful of urologist that can take on these cases.

But, overall, the urinary incontinence rates are fairly high. Biochemical results are not different than cryo nor are the cancer specific survival rates. As well, this recent paper by Joe Smith down at Vanderbilt with salvage radical prostatectomies and the robotic. Again, 18 % of them failed. Not bad. Positive margin rates were 26 %.

But, there was a significant number of patients–61 %. 61 % in hands that are really skilled hands that are incontinent. I think that’s just way too high for many of these guys.
This is what I tell my patients regarding salvage cryo. There’s no hospital stay, no transfusions, minimal incontinence, repeatable if necessary. We didn’t really talk about sexual function and it’s difficult to assess. I that in my experience, anecdotally, the majority of these patients, if you do a full ablation on them, they’re impotent. I don’t find that the oral agents help these patients and they really need a penile implant.

But, you can maintain their erections to a reasonable degree of certainty if we do focal ablation on these patients. Obviously, it depends on their baseline and potency. But, I think that’s a way we can look at this. I’ve been doing this and had some very good results with potency as well as using the color Doppler on the ultrasound intraoperatively to measure the pulse in this area.

These are my final take home thoughts. As Dr. Eastham pointed out, act early if there are signs of disease recurrence and I think we need to let our radiation oncologists know that there are salvage options that can be performed in these patients and not just to hold off on referring them to a urologist. Rebiopsy only if you think the patient would be a candidate for salvage therapy assuming that there is no metastatic disease first.

There are many treatments now for disease recurrence and, as Dr. Eastham pointed out, there are no randomized trials that any one of these treatments is superior to the other. I believe that a personalized approach, a real thorough sit down conversation and it does take a long time, especially when you’re dealing with a patient with recurrent disease, to help them just to lay the landscape for them and just to find out the best that a treatment is. Maybe there is no treatment and maybe we should just continue to monitor it.
I do believe that targeted focal therapy, even in the salvage setting, is promising to the problem of overtreatment especially in this salvage setting.

I have two ARS questions. Can I have the first? The risk of urinary incontinence requiring pad usage following argon based salvage cryo, with the use of the urethral warming for the treatment of local recurrence following IMRT is 10 % or less, 20 %, 30 % or 40 % or higher?
Right. The answer is 10 % or less. That is correct.

The following question–and, these are questions–in the 10 year prostate cancer specific survival rate following salvage cryo, is it 40 %, 50 %, 60 %, 70 % or above or the same as those men who undergo salvage radical prostatectomy or DNE [phonetic]?

That’s the right answer. It is DNE. It is 70 % or higher and there really doesn’t appear, at this point, any overall cancer specific survival rate for these patients that had cryo versus those who are undergoing the salvage radical prostatectomy.

That’s all I have. Thank you for your attention.

1. The risk of urinary incontinence requiring pad usage following argon based salvage cryo, with the use of the urethral warming for the treatment of local recurrence following IMRT is 10 % or less, 20 %, 30 % or 40 % or higher?

The answer is 10% or less.

2. In the 10 year prostate cancer specific survival rate following salvage cryo, is it 40%, 50%, 60%, 70% or above or the same as those men who undergo salvage radical prostatectomy or DNE?

It is DNE. It is 70% or higher and there really doesn’t appear, at this point, any overall cancer specific survival rate for these patients that had cryo versus those who are undergoing the salvage radical prostatectomy.