Can New Imaging Technologies Influence Therapy? by Eric vonSonnenberg, MD

SLIDES & TRANSCRIPTS
Wednesday, February 16, 2000

Can New Imaging Technologies Influence Therapy?
Eric vanSonnenberg, MD

Slide 1:

DR. HOFFMAN: Our next speaker is Dr. Eric vonSonnenberg who is a professor of radiology at Harvard Medical School, and he will be speaking on percutaneous tumor ablation that Dr. Ros alluded to.

DR. VANSONNENBERG: Thank you.

Let me go ahead and get started. I am going to give you kind of an overview. I know there has been a fair amount of discussion about ablation. So I will give you kind of an overview, and then Dr. Mayer who is soon to be, I think, a new colleague of mine, and actually we talked a little bit about this, and I will give you some questions I think that we wrestle with concerning tumor ablation.

Let me first thank Dr. Ros. You may not recognize him. This was probably 20 years ago, something like that, when he was a child, but I want to thank Pablo. I think he invited me, actually. Dr. Hoffman has hosted me, but Pablo invited me, and I want to thank him,

Pablo, if you are in a radiology meeting, everybody knows Pablo Ros. He is one of the most famous radiologists that there is, and you may not know it in this conference,

Slide 2:

but I do want to let you know what the definition of fame is, boring people at cocktail parties and having them think it is their fault. Pablo, don't take it too personally.

Slide 3:

It is hard to come to Washington and not have a little folklore. I came from Texas before.

Slide 4:

The difference between liberals and conservatives, according to John Sharpe, controller of Texas, is if you give either one a budget, they will use it all. The only difference is that the conservative feels badly about it. Last one --

Slide 5:

you see this about Hillary Clinton's proposed, not proposed anymore but real New York Senatorial attempt. Bumper stickers in New York read "Run, Hillary, Run." The difference is that Democrats put the sticker on the rear bumper. The Republicans put it on their front bumper.

(Laughter.)

Slide 6:

DR. VANSONNENBERG: Okay, I am going to give you a little bit of experience, not just from the Brigham because I am still fairly recent there but before that.

Slide 7:

I came from Texas, a Texan's view, if you will. I know there are a few other Texans in the audience. I know there are very few radiologists here, but

Slide 8:

I think if you focus your eyes clearly, you will understand radiology in Texas. If you haven't seen it, it is legal, by the way,

Slide 9:

and before that most of my actually adult life I have spent in California, and I assure you that California radiology is really different as you can see.

Slide 10:

Okay, this is interventional radiology, and I guess most of you are clinicians. I am not sure. I don't know the roster exactly. If you aren't, I would say that if you say, what does an interventional radiologist do,

Slide 11:

it is something like that I guess some people would think, and I often have surgeons say, oh, you are just a frustrated surgeon, and that kind of thing.

Slide 12:

But I would say that what we do and kind of what Pablo talked about as well is the precision of imaging that allows us interventionalists to do what we do. That is really key as Pablo talked about.

Slide 13:

So I am going to present a new way to look at it, if you will. If you come to the fork in the road take it,

Slide 14:

as I guess they were doing here, and sometimes, I think we get caught in the middle, as I will show you.

Slide 15:

Percutaneous tumor ablation,

Slide 16:

and again, this will be a quick overview. I know we are focused on liver. As a kind of general interventional radiologist I and my colleagues do tumor ablation, kind of everywhere. So you will see sprinkled in other areas other than the liver, and other than from colon mets,

Slide 17:

but the same idea, same techniques as you will see.

Tumor ablation includes, if you will, kind of a menu, cryo, laser, radiofrequency, high frequency ultrasound which is coming and pioneered at the Brigham, alcohol.

Slide 18:

Another way to look at that might be by injecting, freezing or frying, and injecting is alcohol used most commonly worldwide, hot saline, acetic acid, gene therapy that undoubtedly is going on at some of your institutions as well, freezing with cryo, frying with laser RF and now microwave, particularly from Japan has gained some favor.

Slide 19:

Alcohol is most commonly used and probably most effective for hepatocellular carcinoma and hypervascular metastases.

Slide 20:

Cryotherapy has been used most extensively probably for prostate although it has had its ups and downs as anybody who deals in that are knows. Certainly it is now in liver somewhat and largely, as has been mentioned in surgical, we are doing percutaneous now as one of the initial sites, percutaneous cryotherapy guided by MRI, and I will show you that in a few moments.

Soft tissue cryotherapy B we have done a variety of tumors all over the body, if you will, bone tumors. We did our first percutaneous femur metastatic lesion the other day as well.

Slide 21:

Laser for liver mets and breast lesions, in the United States it has fallen out of favor somewhat. It is still used in Europe. There is really no great trial as has been discussed here previously comparing one or the other, but I would tell you by and large RF is in. Laser is out. I know somebody will raise his hand and say we love it, and that is okay.

Slide 22:

High-frequency ultrasound for benign breast lesions, if we look down the road, high-frequency ultrasound, which is really the least invasive and virtually non-invasive, and in a sense may be the real answer down the road but certainly not quite ready for prime time

Slide 23:

Now, does it work? How can we monitor if it works? This is a hepatocellular carcinoma, and how can you tell the phase? This is the arterial phase. The way you tell that, of course, is here is the aorta filled with contrast very early and the tumor itself filling as well very early indicating a hypervascular arterialized lesion characteristic of hepatocellular carcinoma.

Slide 24:

Post-radiofrequency therapy, notice again still the aorta is relatively bright, and there is virtually no contrast in it, no viability, no blood getting to that lesion at all, and that is a necrotic lesion. So that is a good result.

How else do we tell? Serum markers when relevant.

Slide 25:

This is a patient with colon carcinoma whose CEA plummeted soon after this radiofrequency therapy,

Slide 26:

and of course, biopsy. There are some who don't biopsy. The pathologists here will know way more about it, but this is a post-RF biopsy case, and many of the institutions and many workers don't do biopsy because of the problems with false negativity, and some do, and we do if there is a question about it as in this particular case.

Slide 27:

Some of the original lab work -- this is a VX2 tumor model that we had done a while back. This is the tumor right there, and there is actually a needle in it. This is the RF probe once upon a time.

Slide 28:

Here you can see the lesion. This is the RF frying of the lesion itself,

Slide 29:

and there is the appearance for those of you who have seen this before, and you will see this actually a few times as we go through the talk of this very echogenic material that develops. Whether it is by injection or whether it is by heating it pretty much looks the same,

Slide 30:

and there is a section afterwards where you can see the burn that occurs with the heating therapy.

Laser looks the same. RF looks the same. Microwave looks the same, basically burning and frying the tissue.

Slide 31:

Now, how do patients do and what happens? I have been fortunate enough to know well and actually have some training from -- this is Tito Livragi, and if you have read the literature on alcohol and now RF you will know Tito Livragi is really the radiology pioneer.

I spent a couple of days with him, and it is a mill. I mean he does like five, ten patients a day, in and out, and this is the patient that he was doing alcohol therapy on

Slide 32:

and this is like 15 minutes later. The patient is up, ready to go, in and out.

So patients get in and out pretty quickly with this. Generally speaking with RF and cryo we have the patient stay overnight. I think many of them would not have to, but we are still doing that for now.

Slide 33:

How about complications? I will show you more complications in a moment, at least some trials, some personal ones. This is a patient, recent patient actually with myoglobinemia, myoglobinuria. This was a colon metastatic lesion,

Slide 34:

no sequellae, no renal failure but nevertheless the patient had it.

This is a patient with a lesion high in the dome as you can see, diaphragmatic pain afterwards likely from irritation, probably from some bleeding around it, but again reasonably self-limited, by and large relatively well-tolerated procedures.

Slide 35:

What we are talking about in radiologically is really focal tumor therapy as opposed to systemic, obviously. Surgery is the gold standard. Percutaneous therapy would be considered an alternative or probably should be right now.

Slide 36:

When are we getting involved? Obviously it will probably get more and more primary therapy, but frequently if the surgeon says too many lesions, too many different sites

Slide 37:

or the lesion is stuck at the confluence of the bile duct running up into the hepatic veins or IVC, obviously not good surgical candidates.

Slide 38:

If the lesion is straddling the lateral segment, medial segment of the left lobe could be done surgically

Slide 39:

but not infrequently what we see the patient has cardiopulmonary disease, something of that sort that may, also limit the patient's applicability for surgery.

Slide 40:

So frequently or virtually always actually our patients are evaluated by surgeons and then referred to us. So as we say, percutaneous tumor ablation mimics surgical removal and really margins are the issue, and that is what we wrestle with, with attempting to Acure@ these patients if we can.

Slide 41:

One of the issues is which modality, and I had a little PET but I cut it out because the next speaker is going to speak on PET. So I am going to talk about CT ultrasound and MRI.

Slide 42:

This is our open magnet interventional MRI unit, the so-called Adonut@ where the operators stand. There are monitors where we monitor the patient that sit across that way, and major operations are done. Actually the majority of procedures that are done on our open bore MRI are done by neurosurgeons, but this is where we do our percutaneous, particularly cryotherapy.

Slide 43:

Ultrasound is, of course, the simplest and I know what goes on around. Most commonly radiologists use ultrasound for these kinds of therapy, and here is the lesion. This is radiofrequency, and I will show you the unit that is used in just a moment. The needle has multiple prongs, as you can see right there to increase the surface area of the burn and increase the size of the lesion.

Slide 44:

Again, that echogenic material after one either injects or heats, a pretty specific finding as you see with that form of therapy.

Slide 45:

Problems, too, with ultrasound because often you cannot see very well behind the lesion. This is an RF effect where the whole machine actually gets wiped out.

Slide 46:

If you notice with ultrasound, once this echogenic material comes in there, you cannot really see distal to where the probe is coming in. So there are clearly limitations with ultrasound for evaluating and monitoring as you are going,

Slide 47:

i.e., intraprocedural monitoring.

Slide 48:

The advantages of ultrasound are of course precise placement. You see it in real time, visible intravasation if the fluid that is being injected, for example, alcohol, is not going where you want it, you can actually see it in real time and make adjustments as you need to.

Doppler can be used to monitor as well, and I will show you that in a few moments.

Slide 49:

CT, as opposed to ultrasound, and some people use that. When we are doing our RF we usually do that with ultrasound, but predominantly CT and we use real-time CT now as well. Better visualization of the tumor effect post alcohol or post RF, whatever it turns out to be. PEIT is percutaneous ethanol infusion therapy. Note real-time ultrasound artifacts so that echogenic material is really an impediment. We don't have that problem with CT.

Seeing complications, that can probably be done better with CT and then CT contrast enhancement for recurrence is a method that is used by many as being able to tell whether there is viable tumor or not, i.e., is there vascular uptake in the lesion itself?

Slide 50:

As we said, here is CT and the monitoring of CT.

Slide 51:

There is the needle in a very high lesion, angled up into the lesion, and this is a lesion where we use ultrasound to help us with real time and then you actually get the lesion in under CT and see it better. There is no doubt that we can see that better by CT than by ultrasound.

Slide 52:

Now, MR, this is a large colonic metastasis, about a 5-centimeter lesion.

Slide 53:

One of the beauties of MR, as you know is the multiplanar imaging as you can see there, and this is the coronal section.

Slide 54:

Targeting, here is the patient and we are actually in the open bore, so-called "MRT" or "MR guided therapy unit" right now with targeting and the cross hairs on the lesion,

Slide 55:

and there you see the cryo probes. In this particular case there is the lesion, the diaphragm, lung and multiple cryo probes percutaneously placed in the lesion.

Slide 56:

Here is the axial view of that same lesion that we saw again with multiple cryo needles or cryo probes. These are 2.4 millimeter needles/probes. They are getting so small now that they are virtually needles.

Slide 57:

To continue that story, now, this is what we call the sticking phase, i.e., you turn the cryo needles or cryo probes on, and the idea is just to stick them in the lesion so they don't come out, and then we can see where we are. So the lesion is actually in this area, and here are the three cryo needles or cryo probes, and there is this beautiful black imaging of the ice ball. That is actually the ice ball, and this is really so far the most elegant kind of imaging that we have to monitor during ablative therapy.

Slide 58:

Here again is now the growing ice ball, and part of the lesion that we still have to grow up over. So we know intraprocedurally what needs to be done as opposed to ultrasound where that clearly would be shadowed out, and CT, you just don't see as much on CT,

Slide 59:

and notice the lesion is now engulfed, and you can tell that by the ice ball engulfing the lesion. So this is clearly most elegant currently.

Slide 60:

This is the thaw phase, and what we are seeing here, this is still remaining ice ball. This is a hyperemic zone that occurs within the ice ball, and as it melts you can actually characteristically see that hyperemic zone.

Slide 61:

What types of tumors can we treat? Dynamically changing as we speak. As I mentioned last Friday we had our first metastatic femur case, liver, kidney, GYN, soft tissue, lung, pancreas. I mean you name it, it is coming.

Slide 62:

This is a recent article in the radiology literature, the first report that I am aware of on RF for lung tumors and I think we will all be doing that pretty soon as well.

Slide 63:

Hepatocellular carcinoma, we have talked about probably the most frequently percutaneously ablated tumor in the world,

Slide 64:

and there we see alcohol in it. This is what one sees on CT. It is probably what is thought to be nitrogenous gas released from necrosis of the lesion. That is virtually immediate when you see that, and I mean immediate. You see that right away as it happens.

Slide 65:

Prostate, for anybody who delves into that, this is cryotherapy of prostate cancer. You can see these are, again, probes being placed into the prostate,

Slide 66:

three in this particular case.

Slide 67:

You put sheathes in. This is the ice ball, again, similar, but again, the difference between this and MRI, is, if you will, night and day in what you can see by ultrasound monitoring.

Slide 68:

This is a young lady with cervical carcinoma who had a very painful metastatic lesion right there after removal, exenteration, reconstruction of her genitals, et ceera,

Slide 69:

and we did radiofrequency. This is a multi-prong needle, and that is radiofrequency therapy of that particular lesion. So virtually anything, I suppose, will come under this kind of therapy.

Slide 70:

Former Chicago Cubs manager, Don Zimmer after a road trip during which the Cubs won four and lost four: It just as easily could have gone the other way. I think that is what we think sometimes.

As Dr. Mayer mentioned, a radiologist without two slides projectors is naked.

Slide 71:

Which agent? I don't know, and virtually every question that I will show you that I am posing to you, we don't know the answer, and So very fertile, if you will, freezing, heating, et cetera.

Synergy? Dr. Mamon, who is a radiation therapist at the Brigham, and I discussed the other day synergy. Should we be doing radiation therapy and there was a Ten Commandment discussion previously. We are on very uncharted waters here but certainly interesting with this new tool of percutaneous ablation.

Slide 72:

So cryo, these are the cryo needles that I was mentioning to you. Here is actually ice that is created. That is that ice ball, that black ice ball that we see on MRI.

Slide 73:

This is one of several. There are about three RF units that are commercially available. They all work. I have used all three of them. They have different mechanisms beyond what we need to know now.

Slide 74:

Heating effects on tissue, 42 to 45 irreversible changes, 60 to 100, we approach 100 degrees with our RF. Conversely with cryo we go down to minus about 150 centigrade. We actually with heating don't want to go above 100. The tissue chars, and that limits conduction past the charring area.

Slide 75:

This is that multi-prong needle that is one of the types of RF instruments that one can use. Again, the idea here is to increase the surface area and the volume that can be treated by these RF probes.

Slide 76:

Alcohol cell death occurs by dehydration, coagulation of protein, vascular thrombosis.

Slide 77:

This is a lesion that was treated with alcohol. We are monitoring here by Doppler, and again, it is like what kind of activity is there vascularwise, and you can see there is a little bit in the rim. This is the tumor. There is a little bit in the rim, and that in that particular case can help guide where we are going to go and do subsequent therapy.

Slide 78:

Another alcohol case, with a lesion there, as you see,

Slide 79:

and again, that very characteristic echogenic material. You know you are in the lesion, but what part is treated, what part isn't treated, you cannot tell very well. With small lesions it may not matter as much. As lesions get more than 2 centimeters it becomes an issue and harder to tell.

Slide 80:

How about synergy? We are just beginning to talk about this,

Slide 81:

and I can tell you we don't know. These are some of our current experiments that are going on. This is liver. Here is cryo followed by RF. Here is RF followed by cryo. You can see the lesion looks different, very preliminary. I don't have any answers yet, but I can tell you that is certainly in the area that we need to investigate.

Slide 82:

This is a concept. Again, Dr. Mamon and I talked about this the other day, cure versus tumor control. Small lesions can be cured by these techniques. Larger lesions, a lot of tumor can be killed. We don't tell patients we can cure them because we know we cannot, and should we be doing this synergistically? Does it make a difference? These are with respect to the discussions that went on this morning about prolonging life, prolonging survival, having an effect. We don't know the answers, but we know we have a tool that I think we all have to put in perspective, what can we do with it.

Slide 83:

Small lesions, such as these, these are positive small tumors; these were hepatocellular carcinomas, can be cured

Slide 84:

and relatively straightforward. There is the multiprong needle. We are doing RF in this particular case. That is reasonably straightforward now,

Slide 85:

but what about these big tumors for which all therapy previously has been done? There is no surgery for this patient. She has had chemo. Radiation therapy was not done in this case. What do we do about these large tumors?

Slide 86:

We are attempting to treat these. Where we are going, I am not quite sure.

Slide 87:

Again, into different parts of the lesion, as you can see this is radiofrequency into different parts of large tumors,

Slide 88:

knocking out 70, 95, 90 percent of tumor. Again, the margins is our issue, how much tumor is left

Slide 89:

and we have talked about the viability and the enhancement. Notice there is some enhancement. This is necrotic tumor, and you can see a ton of tumor was wiped out in this patient. We still have margins perhaps where PET will come in to help guide us in what is left with these tumors,

Slide 90:

and finally, clinical trials. There are no good clinical trials, really that have been done.

I don't if anybody is involved with the so-called "Akron." I know Dr. Staub is involved with that actually in the radiology world with an RF trial that is being discussed currently.

Slide 91:

This is an RF versus alcohol trial by Dr. Levodgi whom we talked about before, 86 patients, 112 tumors, small tumors. The follow-up was CT. Complete necrosis over a number of sessions. RF averaged 90 percent necrosis, 1.2 sessions; alcohol 80 percent necrosis, 4.8 sessions; necrosis though a difference was not statistically significant between the two.

Slide 92:

Complications that he had in his series, and again, we are talking about probably the most experience tumor ablater radiologically, RF one major was a bleed, four minors, none with alcohol; hospitalization RF 2 days, alcohol no days.

Some pluses for alcohol, some pluses for RF and some minuses conversely.

Slide 93:

Complications, hemothorax, intraperitoneal bleeding, hemobilia, pleural effusion, cholecystitis. Complications were divided. He called one major. All delayed hospital discharge though in that particular series.

Slide 94:

This is an article from Cancer on again small hepatocellular carcinomas, 105 patients, cirrhotics with A and B, Child's A and B. Survival you can run your eyes down and see, and kind of typical of many of these Italian series which have the largest series in the radiology literature.

Slide 95:

These small hepatocellular carcinomas, alcohol therapy, survival depended on the Child's classification as to whether or not there was ascites, the AFP level, the size and severity of cirrhosis, did not depend on tumor grade etiology, age of the patient or gender.

Slide 96:

Okay, I think we have had a quick run through and that is kind of what it looks like. I think we have a broad overview now,

Slide 97:

plenty of area for research obviously as we have talked about

Slide 98:

and probably more questions than answers. I realize that is above the diaphragm, but we work there as well.

Slide 99:

I hope it wasn't boring,

Slide 100:

and I will remind you the Gettysburg Address took 2 minutes. I know Dr. Hoffman talked to us about timing,

Slide 101:

and this is important for interventionalists, knowing when to stop before you start,

Slide 102:

and finally, George Bernard Shaw: AThe reasonable man adapts himself to the world about him. The unreasonable man persists in trying to adapt the world to himself. Therefore all progress depends on the unreasonable wherever we stand in that.@

I thank you all.

(Applause.)