Episode 20

Pressure-Directed Therapy in TACE

with Dr. Justin Lee and Dr. Terence Gade

Dr. Justin Lee of Florida Interventional Specialists, and Dr. Terence Gade of UPenn discuss the utility of pressure-directed therapy in TACE treatments. Special thanks to our sponsor Surefire Medical.

Cite this podcast: BackTable, LLC (Producer). (2018, January 20). Ep 20 – Pressure-Directed Therapy in TACE [Audio podcast]. Retrieved from https://www.backtable.com/podcasts

Full Transcript Below

In this Episode

Podcast Participants

Dr. Justin Lee is a practicing interventional radiologist at Radiology Associates of Florida in Tampa, FL.

Dr. Terence Gade is a practicing interventional radiologist with at the University of Pennsylvania. 

Dr. Michael Barraza Jr is a practicing interventional radiologist at Radiology Alliance in Nashville.

Disclosure

Podcast sponsored by Surefire Medical.

Disclaimer: The Materials available on the BackTable Podcast are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.

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Full Transcript

Pressure-Directed Therapy in TACE

[Michael Barraza]
Hello and welcome to The BackTable podcast. BackTable is your resource to connect with your IR colleagues and learn tips, techniques and the ins and outs of the devices in your cabinets. You can find all previous episodes of the podcast and more on our free iTunes app. This is Mike Barraza returning as your host. Today's podcast is brought to you by Surefire Medical. Surefire has the only expandable tip catheter to help physicians maintain blood flow while reducing reflux during chemoembolization and radioembolization. The Surefire infusion system helps interventional radiologists deliver therapy deeper into tumors while protecting healthy tissues. Learn more at surefiremedical.com.

 

Today's episode is the second in a two-part series exploring the optimization of tumor uptake and therapeutic embolic materials delivered in transarterial interventions for HCC. In part one of this series, Dr. Charlie Nutting and Dr. Nainesh Parikh debated the merits of pressure-directed infusion to improve selected delivery of radioembolics and minimize nontarget embolization during Y90 radioembolization. Today, we're furthering that discussion to focus on maximization of tumor uptake and chemoembolization. I'm honored to be joined today by doctors Justin Lee and Terence Gade. Thank you both for being a part of this. If you don't mind, I'd like to begin by asking you each to tell us a little bit about yourselves and your practice as well as the role chemoembolization currently plays within it. Starting with you, Justin.

 

 

[Justin Lee]
My name is Justin Lee. I'm an interventional radiologist in Sarasota, Florida. I actually was a direct pathway resident, the first one, believe it or not, at Georgetown University. After I finished my training there, I stayed on as a faculty for four years and then kind of got burned out on academics and decided to move my family someplace a little bit more desirable to live. So we moved to Sarasota, Florida, which is a community on the west coast of Florida. It's a big hospital, 820-bed hospital that really had no interventional radiology going on when I accepted the job. Coming up in May, it'll be five years I've been here. 

We've really righted the ship, and we have a pretty robust IO program, doing a lot of radioembolization, a lot of TACE, a lot of ablation. Because of where we're located, which is we're about an hour and a half south of Tampa, we're about an hour and a half north of Fort Myers, we have a huge catchment area, so we have really been able to bring advanced IO procedures to the community and keep people here in the community, rather than having them travel to Miami or Moffitt in Tampa, and that's been really rewarding. In addition to that, we've just advanced a couple research trials, where I’m the PI, the local PI, and one of them is the Surefire registry for HCC. We're part of the Resin registry, and so we've incorporated things like the Surefire catheter into those trials because we believe that there is a utility in the catheter.

 

 

[Michael Barraza]
So next we have Dr. Terence Gade. I should probably mention that I know his story because I trained under him. Finished up about six months ago. For the sake of our listeners, Terence, tell us about chemoembolization at Penn and what you're doing.

 

 

[Terence Gade] 
Like you just mentioned, my name is Terence Gade. I'm an assistant professor and attending interventional radiologist at the Hospital of the University of Pennsylvania. I'm assistant professor of cancer biology and radiology, and I'm a cofounder and codirector of the Penn Image-Guided Interventions Lab. My practice is a little bit different from most in the sense that I'm predominantly in the lab. I'm about 30 percent clinical and 70 percent research. My perspectives are a little bit colored by what my practice looks like.

 

You mentioned specifically chemoembolization at Penn. We're fortunate to have one of the real pioneers in interventional oncology at Penn, Michael Soulen. You and I both trained under him, and I think our approach is definitely influenced by his thoughts and considerations, and so we focus on conventional TACE using Lipiodol as a drug delivery agent, followed by an embosphere as the embolic. In addition to conventional TACE, which is predominantly what's done at HUP, we also perform DEB TACE, which we do predominantly at the VA. So I do get the opportunity to contrast and compare those different approaches.

 

 

[Michael Barraza] 
Terence, you've really run with a lot of this stuff that Michael Soulen was starting in. You were the first ever radiologist to receive the NIH Director's Early Independence Award. That grant was specifically to investigate imaging and metabolic changes in cells after chemoembolization. Is that correct?

 

 

[Terence Gade] 
Yes, that's right. We were fortunate enough to get some support from the NIH to start to think about some of the biology that underlies the cellular response to TACE, and how we can leverage that response to improve therapy. That emphasized the stress responses that these cells mobilize in the ischemic environment and how that generates vulnerabilities that are not necessarily sensitive to mutations. As we know, cancer is a genetic disease, and there are a number of mutations that underlie cancer. Cancer cells can further mutate those pathways, but there are a set of pathways that are not often mutated because they are so essential for these cells to survive. We've been looking at how the ischemia induced by different embolic methodologies can generate these dependencies and how we can go about targeting them. To target them, obviously, we first have to know that these cell populations exist, these populations that are dependent on these stress-response pathways, and we focused on developing a hyperpolarized metabolic imaging approach to be able to start to see cell populations that we can't visualize using conventional imaging approaches.

 

 

[Michael Barraza] 
Is the PIGI Lab following with this as well, or is that something separate?

 

 

[Terence Gade] 
This is all part of the PIGI Lab. The PIGI Lab was founded by Greg Nadolski and Stephen Hunt and I, as residents actually. Then as we developed into fellowship and stayed on as attendings, the PIGI Lab is sort of a team science lab, where we have multiple investigators with shared interests. So, it encompasses a broad range of different projects. All of them focus on the tumor microenvironment and how that can be modulated through image-guided interventions.

 

 

[Michael Barraza]
Before we get into this a bit more, I do want to bring up one point. There's been a lot of buzz about some of the more recent data comparing chemoembolization to radioembolization for HCC. Do either of you anticipate any changes to your approach in the coming years?

 

 

[Justin Lee]
I'm not really compelled by single institution data that suggests that Y90 is superior to TACE, particularly for a disease that falls in the spectrum for TACE. In my practice ... We're not a transplant center, so if I have a small lesion, for me, if it falls into my realm and that patient is not going to be a transplant candidate, and that happens often because we've got an octogenarian population here, and they might not be a great surgical candidate. They're out of the line for transplant. 

 

If I have a small lesion, I'm going to probably do TACE ablation if that person is not going to undergo resection. So we pretty much follow the BCLC, and we don't really amend it. So if they're BCLC-A, and they've got a small lesion or one lesion or maybe a few lesions, but they're all less than five centimeters or even less than three centimeters, then I'm going to TACE ablate that before I would apply Y90. For me, radioembolization is a tool for metastatic disease, and really in my practice at Georgetown that was the gateway for us to get into metastatic disease. By that I mean colorectal, pancreas … We apply it just about anything, anything that we think is radiosensitive or the patient would do better with a wider scope of embolization using a different model rather than vessel occlusion and a drug then we would apply radioembolization. 
 

So for me, if somebody has HCC with portal vein invasion or their disease is behaving more as if they were a patient that had metastatic disease … And by that I mean bilobar disease, large infiltrative lesions, vascular invasion. That is, for me, a radioembolization patient.

I travel around the country and we obviously are doing a lot of radioembolization for HCC, and I see IRs treating five centimeter unilobar lesions with Y90, and I just think you're applying something that costs more. It's got a lot more nuances to it, and without a real demonstrable survival benefit except potentially for cases of portal vein invasion. And I think that you're walking down a road of healthcare cost and risking, particularly if you're in the community, you're risking marginalizing your medical oncologist too. What's sneaking around the corner are the PD-1 inhibitors, which are being widely applied, for better or for worse, and I think that if you stray from guidelines just because your institution has a lot of experience with radioembolization, you're going to get all of us in trouble. Again, that's my opinion.

 

 

[Michael Barraza]
I'm a huge fan of the TACE ablation approach. I think you bring up a very important point when you mention the community aspects, specifically with marginalization. It bears reminding that we have so much more history with TACE as a procedure, and it's much more accessible in smaller communities, much smaller than Sarasota, even. You're not going to find Y90 200 miles from where you are outside of a larger city.

 

 

[Justin Lee]
I think you'd be shocked, actually. I just helped to open an account in Inverness, Florida, which is kind of in the middle of nowhere. It took me two and a half hours to drive there. The thing is is that for me, I feel like Y90 is a very ... I will agree with Northwestern, Y90 is a very well-tolerated procedure. Clearly, they've shown that TACE and Y90, TACE has more side effects. Some of the initial articles that were all CAM TACE, which I'm really interested to hear from Terence in terms of they're still using Lipiodol. I would say that most people are not using Lipiodol. For me, DEB TACE ... I don't know. I send people home oftentimes on the same day as a DEB TACE. 

 

The point you bring up about accessibility, I'd like to see Y90 more accessible in the community, but it is true. We did a little analysis: 25 to 30 percent of our population does not have Medicare, and they are on Medicaid. I already know before I see that patient that they're not a Y90 candidate. Whether I want them to be or not, I've got to be a little bit creative with how I'm going to treat those patients. I can get somebody scheduled for a TACE the next day, pretty much, versus a Y90. You can wait sometimes a long time still in that predetermination area, and if you're not fast in the community, your oncologist is going to move along. I think that's another point that people don't really think about. 

 

When I was in academics, I was in that role where we were getting people from the community. A lot of them were failures or people didn't want to treat them in the community because HCC doesn't really have a whole lot of infusional therapies. Okay, then, you can start applying Y90. When you start to get out into — I don't want to call it the real world and be a jerk or anything — but in the community, you're not going to have that luxury. You're not going to be able to apply a therapy that the dose alone is $16,000, and you've got to map them once and then treat them again. 

 

I'm getting long-winded here, but even when you look at Northwestern, they were doing mapping and treating on the same day, and their own institution told them to stop that because from a standpoint of your own hospital, that's just not financially feasible for them. They want you to treat them on separate days. When you look at the nitty gritty of the program, I think TACE is just easy, it works, it's effective, patients do well from it, and it's been tried and true since the '90s.

 

 

[Michael Barraza]
Right. Terence, anything to add there?

 

 

[Terence Gade]
I would echo a lot of the things he just mentioned. I would say that we're clearly, especially with the work that's coming out of Northwestern and the PREMIERE trial making significant strides with respect to characterizing the variety of different endovascular local regional therapies we can apply - we obviously, as Justin mentioned, have a lot of important progress to make. Specifically, I think we really need to use all the information at our disposal. This is how I think about it and I think a lot of my colleagues think about it too: [do] not assume that every tumor is alike or every HCC is alike and really consider the biology of the tumor and what data we have from our imaging to influence that. Our ultimate goal, with the Cancer Moonshot and a lot of these initiatives going on, is to apply a precision medicine approach. While that can mean a lot of different things to different people, I think we do have tools to generate a precision medicine approach in this regard [when] looking at the vascularity of the tumor and things of that nature. 

 

We tend to choose therapies on a patient by patient basis, factoring in all the things that Justin mentioned, clinical considerations, in particular liver function. Like I mentioned, the biology of the tumor in terms of vascularity. Where available, and this is becoming increasingly common, is data regarding tissue biopsy, what we know on a molecular level about the tumor itself and what that can mean for its susceptibility to radiation versus a more ischemic driven technology.

 

 

[Michael Barraza]
Now Terence, because you have experience with both conventional TACE and DEB TACE, could you tell us a bit more about your experience with both? The benefits, advantages, disadvantages and if you have a preference?

 

 

[Terence Gade] 
Sure. Again, I agree with Justin. I think the side effect profile for DEBs is far better and patients tend to do better afterwards. How much, it's a hard thing to say, I think. From a biological standpoint, I do believe that, and I think Karen Brown's work underscores this, that the ultimate therapeutic effect comes from the ischemia we're inducing. So I think that I'm a big believer in the embolization component, and I'm less of a believer in the chemotherapeutic. My concern with DEBs tends to be that that's more focused on drug delivery. It's about getting more doxorubicin or what have you to the tumor. 

 

I think that in terms of what data we do have, those chemotherapeutics are probably not the best choice. The ones we're using are probably not the correct drugs. If we're talking about inducing vulnerabilities, if we embolize a tumor and we block off the vasculature and we induce ischemia, those cells are now fundamentally different from the cells that were growing without the embolization. The cells without the embolization tend to be proliferating, as we see on scans. We see tumors grow. But after embolization, they can hang out there without growing, and that tells us a lot about the cell status. In that circumstance, you have cells that aren't cycling anymore or using an agent that's meant to potentiate the ischemia. Using an agent that targets proliferating cells is probably not going to potentiate that ischemia much. Again, I think that JCO article from Karen Brown underscores that concept. 

While I do prefer the side effect profile for DEB TACE over conventional TACE, I think that ultimately, the biology we're targeting is better served through conventional TACE approach than it is through DEB TACE. I would caveat that by saying that I think we really need to start thinking, and there's a lot of research being done in this area, but start thinking about which drugs we're combining to potentiate the ischemia. There's a lot of progress being made in that area, and I think that we as interventionalists really need to start thinking about that biology and integrating some of those therapeutics into our practice rather than taking what's always been administered and really, when the decision was made to start using those drugs — cisplatin, mitomycin and doxorubicin — there wasn't any real reason. It wasn't that HCCs are susceptible to those drugs because they can be ... HCCs are among the most chemoresistant cells that we know of in cancer. I think we need to do a little better job of thinking rationally about the therapeutics we're using and integrating our science.

 

 

[Michael Barraza]
Justin, a question I have for you because most of my experience is limited to conventional TACE. Comparing DEB TACE to Y90, we're obviously dealing with a difference in the relative embolic effect of the treatment material. For Y90, you're generally committed to delivering a precalculated dose, which is generally attainable due to the comparatively low embolic load, but for chemoembolization, at least for Lipiodol, for conventional TACE, the goal is just to deliver as much as you can safely before reaching stasis. With conventional TACE, I think we've all been surprised by how much or little it takes to get to stasis in certain patients. What is your goal mainly for DEB TACE? How do you know when you've gotten there, and is it really about how much of vial you give?

 

 

[Justin Lee]
First, I'd actually like to ... For me, the way I was trained was exactly the way you guys were trained. CAM TACE was what it was. DEB TACE didn't come around until I was actually practicing. The interesting thing about it was that we saw the drugs one by one go away - lack of availability. I have to plug one of my attendings at the time. His name is Karun Sharma. He was part-time at Georgetown, part-time at the NIH. He was probably the first guy to use drug-eluting beads, and at the time, what we had was 300 to 500 micron-sized beads. When I first became an attending, I was like I don't see the real reason to use this. This was before PRECISION V, and I persisted trying to do essentially CAM TACE with doxorubicin, but at that time too, doxorubicin was no longer in a powdered form. It was liquid. Instead of having this concentrated, red, toxic-looking mix, you would get this diluted-looking mix, and I actually had treatment failures. That's what pushed me over the edge into DEB TACE. 

 

Things have obviously changed too. We had a Lipiodol shortage, which also pushed us to DEB TACE. So I wonder a little bit outside of Penn, if a lot of people just did DEB TACE because they had to. It was out of necessity. It wasn't necessarily that we thought it was superior. One of the things that I look at when I trained, one of our endpoints for TACE when using Lipiodol was that we would see portal venous staining. You don't get that when you're using beads. Everybody assumes also from a Y90 standpoint because the Y90 beads are so much smaller — 20 to 60 microns in size — that smaller is better. Dave Lu has a great talk on that. The smaller beads, the M1 beads and the ones that are under 100 microns, they drop their drug really quickly. 

 

One of the funniest things that happened is a little anecdote. When I introduced DEB TACE down here, DEB dox TACE, I said use doxorubicin, and they hadn't really been doing it. They're like, why would you use doxorubicin? We know that that doesn't work on really anything except breast cancer, really. So it was kind of funny. I don't have a response for that. It is. It's an old, crappy cytotoxic drug that has a lot of side effects. Here we say we're going to ... This is cutting edge. I'm going to introduce this to Sarasota. We're going to put doxorubicin on a bead, and I'm going to administer it via the artery. I think that's sometimes a little hard for a community oncologist to swallow.

 

Getting back to your question, again, I think for me, I agree, and I'm not a bench guy, but I agree that for me, embolization is more important. If you really look at PRECISION V, which I know is old at this point, after they put in DEB dox, they went to stasis. That's probably my endpoint. If I don't achieve stasis, I feel like I haven't done my job. So I'll bland endo after that. Again, I'm really big on ablating the lesions after if I can. 

 

The rationale for that for me is I have to live in the world of competitive medicine. We do have tumor boards and whatnot, but I need to offer as close to a surgical resection as possible. And then to take it one step further, which again, this is more in Terence's world, but I believe a little bit in trying to potentiate the immune system with ablation. I don't know which one would work better, but there's a lot of science out there. Damian Dupuy has a review article in Nature about ablation and how that can alert the immune system to the presence of the cancer or the presence of not self. I think that's an exciting area, particularly when you're talking about the encroachment of Opdivo and Keytruda into the HCC world, it's something that you want to keep on your radar screen. 

 

It's also for the IRs that would listen to this and they're not in an academic setting, it's something to start talking about with your medical oncologist because GI ASCO and ASCO are really hot on immunotherapies, and you want to try to position yourself in a way to let them know that you're thinking about it too. Lastly, I would also plug ... I was trained that we never biopsy HCC. We've had a couple hirings here, and we get people out of fellowship, and they say the same thing. The AASLD would support that. If you have an MRI that shows a hypervascular lesion with washout and the patient's got an AFP, and they've got a cirrhotic liver, a history of Hep C, why would you biopsy that? I actually went to Dave Lu's meeting, the SIO meeting in Worcester, which I'll plug, because I think it's a great meeting. I have absolutely no affiliation with it. I just like to go skiing and do my thing there. There was a medical oncologist from Canada, which obviously is a different system than we have in America, and she discussed this concept of each tumor is an individual in a sense. We've got these mixed type HCCs. They may be a mixed type cholangio/HCC. A cholangio is treated totally differently, at least in my practice, than is an HCC. 

 

A cholangio is going to get Gemcitabine - Cisplatin. We're probably going to do Y90 for it. I'm actually pretty big on biopsying. That's a real change from what I was doing at Georgetown. We would never touch an HCC. We never ablate an HCC for risk that we would track seed. Now, I'm completely the opposite. I biopsy every Y90 at the mapping. I biopsy almost every liver lesion, even if I'm confident it's an HCC because I think, as Terence was alluding to, it's going to be important. We need to embrace that and be on that front. So for an endpoint, for me, it's stasis. For DEB TACE, it's stasis. I like to see a tumor stain. I like to get a cone beam at the end of a TACE because I know that in all likelihood, I'm going to try to ablate the lesion. This is a long answer to a short question.

 

 

[Terence Gade] 
I'm really glad that Justin mentioned that. I'm really excited to hear that other people out there are biopsying the HCCs or these tumors in general because we've been running a biopsy clinical trial looking to characterize a variety of different features of HCCs before and after TACE with respect to immune response and metabolic response. We’re also looking at some of the genomics of these tumors. Like Justin mentioned, we're finding some really surprising things in terms of what these tumors really are, whether they be mixed tumors or truly cholangios. I think there are real limitations to the imaging approaches we're applying toward diagnosing these tumors. I think we find a lot of surprising things just at baseline about what these tumors truly are. 

 

But, like Justin mentioned and as with a lot of the work that's coming out of Sloan Kettering, we're learning a lot about how we can use genetics and even CRISPR based technology to start to think about generating these precision medicine approaches, which are going to change outcomes without a doubt. I think for us, outcomes are a real moving target just because there is so much heterogeneity in the way that people apply their methodologies in terms of what they embolize to or are they applying bland embolics after their DEBs. That makes it hard for us to draw conclusions from our clinical trials, but I do think that we may begin to be able to stratify some of these responses more effectively using the characterization of these genetic features within the tumors.

 

 

[Michael Barraza]
I know I personally have contributed some beautiful biopsies to that trial. We should all be thanking.

 

 

[Terence Gade] 
They're the best. I want you to know they're the best ones we have.

 

 

[Michael Barraza]
Exactly, our future patients will be thanking me.

 

 

[Justin Lee]
How do I get in on this trial?

 

 

[Michael Barraza]
So Terence, you and I actually talked a little bit before this about tumor uptake for HCC and some of those barriers. Could you expound on that a little bit?

 

 

[Terence Gade] 
Sure. I think there's been a lot of work already in the literature that talks about the different barriers to therapeutic delivery in cancer. I think it sometimes surprises me that we don't have more discussions about this. I think they're coming up more and more within IR and I know that the SIO has been sponsoring fellows and other people to go to a barriers to drug delivery meeting that's run by Rakesh Jain in Boston, who's one of the real pioneers in this field. I think we have to think about it compartmentally. There are a variety of different barriers in terms of drug delivery. As IRs, we overcome probably the most important one: getting the more local regional delivery of our therapeutic to the tumor. It doesn't really stop there. I think we really have to think about the other factors that contribute to chemoresistance on the part of the cancer itself in terms of not just how it reacts to the drug but how the drug gets to the tumor. So we deliver our embolics into the vasculature, and the drug that we administer has to traverse the endothelium and get into the tumor itself. 

 

Once it's into the tumor itself, we have to try to create an effect so that it translates through the tumor homogeneously, right? We want every cancer cell to see the same amount of drug. We don't want heterogeneous delivery of that therapeutic. I think the primary thing that will help us get that drug across the endothelium are the differences in hydrostatic pressure. We know that tumors are made to mitigate this. But ultimately, we need the hydrostatic pressure within the vessel to be higher than it is within the interstitium of the tumor. That will get the drug out of the vessel and into the tumor. 

 

But that's really, in my mind, only 25 percent of the job. We need next to generate or change the interstitial fluid pressure within the tumor so that we favor convection of that drug through the tumor. If there's no difference ... if there's high interstatic fluid pressure within the tumor, then that drug is going to get out of the vessel and basically sit just outside the vessel and not move anywhere within the tumor. I think we have to think about Starling's equation and how we can modulate that in order to favor drug delivery throughout the tumor.

 

 

[Michael Barraza]
Pressure-directed therapies seem to be a way to improve that. What kind of benefits can we get from that in the tumor microenvironment?

 

 

[Terence Gade] 
I think that one of the things that certainly pressure-directed therapy will do, and the data for this is starting to come out more and more, it should allow us to increase that hydrostatic pressure within the vessel. That will enable a number of things. Number one, it's going to allow us to drive more drug into those vessels. So we're delivering more of our payload to the vasculature itself. We've also seen how it can induce a reversal of blood flow so that we're sort of sumping blood away from nontarget structures or areas of the liver and toward the tumor. Finally, it should mitigate that hydrostatic pressure gradient I was talking about, where now we are driving those hydrostatic pressures in the tumor vasculature up above the hydrostatic pressures within the interstitium of the tumor, and that should favor translocation of the drug from the vessel into the tumor.

 

 

[Michael Barraza]
Justin, do you have anything to add about that? I know you've got a lot of experience with pressure-directed therapy for HCC.

 

 

[Justin Lee]
From a scientific standpoint, I would be a neophyte in that, but for me, an antireflux catheter was initially, it was really just ... I got introduced to it very early because Bill Banoveck, who was the chief of the section at Georgetown, happened to be fraternity brothers with Jim Chomas, who's the CEO of Surefire. We were doing a lot of Y90 at Georgetown, and he basically said would you mind trying to use this thing? In the beginning, it was all about the convenience of delivery and antireflux and not coiling in the GDA and that type of thing. The catheter was pretty clunky. It had a lot of issues with it. Right from the beginning, I have some cases that I shared with Jim, where I would be doing a right-load treatment, and we would sometimes do it with MAA just to look at it, and you would see left-load uptake. It was odd. It wasn't something I was really thinking about at the time because we were really thinking about okay, we have this embolic that will fry your guts out if it goes to the wrong place, so we want to make sure it goes to the right spot.

 

I left Georgetown and left Surefire a little bit, but in that interim, until we re-engaged with it back in Sarasota, there were some small little studies that looked at particulate uptake. Specifically, there was a JVIR paper that looked at MAA end-hole versus with an antireflux catheter, and they showed that there was more tumor uptake in that environment, where the arterial flow is altered by opening the cone. I had an opportunity to meet with Jim again, and he espoused this concept of the Surefire being a spring that pushes your embolic into the tumor. We circled back with that. And then Aravind Arepally, who's the developer of the Surefire, he had a paper that looked actually at HCC specifically, and it looked at tumor necrosis and then, I think, particulate. I believe they blinded the pathologist, or something like that. It was an explant thing, where they were taking the HCCs out for transplant. I think they had a degree of necrosis that was increased in the antireflux catheter segment of patients. Again, a small single-institution study, but that turned my attention onto it. And so that's kind of where I am. 

 

Oftentimes, let's say the way that I do DEB dox, you have smaller beads and then you have a group of larger beads. At what point do you transition away from your smaller beads? When do you go for the larger stuff? Should you just put in the smaller beads so you get to the end and then not put in the larger beads? Again, this is a very macroscopic thought process, but if you can somehow prescribe a dose of a drug, be it 100 milligrams of doxorubicin, 150 milligrams of doxorubicin, whatever you're using, you kind of feel like you want to get that in, right? 

 

That's kind of where I am on that. When it comes to radioembolization, which is where I really use Surefire, is that one of the problems that I have is that people are looking at radioembolization as ... again, this is a little bit of my Resin versus class bias, but it's like more dose is better. As long as we can get more dose in, it's going to be better. We're going to nuke the tumor, etc., etc. As you're seeing in the literature right now, this concept of a subclinical RALD, not necessarily putting people into liver failure, but getting that veno-occlusive effect, just like you would if you had a Budd-Chiari, but on a microscale. That's there. There is radiation injury that happens. 

 

For me, I'm a big dosimetry guy right now. I've really taken a hard turn toward, not prescribing more, but prescribing the right dose. Again, I don't know where that is right now. I'm not sure what the right dose is, but I kind of in my own practice, I use the partition method, plus I use BSA. Granted, I'm a Resin guy, but I think about it a lot. If I prescribe a dose, I want to deliver that dose. Be it I'm doing a segmentectomy or a lobectomy, I want to be able to deliver that dose. It's not just because I want to get lots of beads in there and I want to get lots of radiation in there. It's because I want it to be efficient, and I want it to go to the tumor. 

 

I look at some of those small centered papers, and I feel like there's a signal there that it's going to be difficult to show in a big study because there's a lot of heterogeneity, as Terence was talking about, in these different tumors. I want to be able to deliver that dose, so I apply Surefire to my practice because I think it helps me to deliver what I want, be it drug, be it volume of beads, be it activity of Y90. That's my goal. While that's a very biased, I guess we want to call it single-center opinion, which is really what it is, the one thing that's become true in my practice is I can balance the cost of the Surefire with the fact that I don't coil people anymore on mappings. It's very, very rare.

I'm kind of evil about the dose. It drives me crazy when I go and I just hear, well we put two vials, 120 gray each. It's like, well no, you're not. You have absolutely no idea what that absorb dose is because you're assuming there that there's uniformity in your distribution of beads. In reality, we know that doesn't happen. That's a failure of all the dosimetry models. So if a radioembolization ... If I say, okay, I want an activity of 30 millicuries, and I want to give it in this specific location, well I want to get 30 millicuries in because that's what my formulas told me. That's what the combination of cone-beam volumetrics and all that other stuff told me. I think if you approach the different treatments, TACE or radioembolization in that manner, you need to have something that helps you overcome those hydrostatic forces. The fact that a lot of these patients are on VEGF or EGFR in addition, and that's going to change that microenvironment as well. If you're not preparing yourself to deal with that, then you're going to fall on your face.

 

 

[Michael Barraza]
Terence, do you think that pressure-directing infusion has the same potential benefits for conventional TACE that it does for DEB TACE? What's the difference there that you would get?

 

 

[Terence Gade] 
In my mind, as I was mentioning, I don't think there should be a huge difference because you're only talking about differences in the delivery vehicle. Some of the problems with Lipiodol direct infusion, even if you're using a water and oil emulsion, which is supposed to be focused on drug delivery and not on embolization, which it would be if you had it in oil and water emulsion, is that you will get some early stasis. 

Ultimately, when I'm administering conventional TACE, I'm focused on trying to generate that water and oil emulsion so that I can deliver the whole dose. Sometimes, I'll have to thin that out a little bit just so I can ensure that I'm not reaching stasis before I get to my actual embolics. So I think it's going to be hard to tease these two things apart, but potentially, you might get an added benefit from pressure-directed infusion in combination with DEB TACE only because you're going to be able to ensure you're going to deliver that whole dose more easily and not have the complication associated with potential stasis through the Lipiodol. 

 

Like I said, it's going to be a really hard thing to tease those apart, and I'm not sure it would be significant enough where I would favor one over the other in the setting of pressure-directed delivery.

 

 

[Michael Barraza]
That helps. I think we have covered as much of this as we could feasibly get through in a reasonable amount of time. We could never get through all of TACE and Y90 and pressure-directed infusion, but I think this gives a great start. Is there anything that either of you would like to add before we sign off?

 

 

[Terence Gade] 
One of the things I just wanted to think about for a few seconds is we talked about bead sizes and how to think about that. Just one of the more basic concepts is where are we trying to get our therapeutics. I think ultimately, on average, the size of capillary in the human body is somewhere under 10 microns, but the largest capillaries actually exist in the liver, and they can be up to 30 microns in diameter. This means that in a lot of cases, if you say that the average size of a SIR-sphere is 32 microns, you are functionally delivering these things distally as much as possible into the tumor, which is where you're going to get your greatest therapeutic effect from the radiation, obviously. Whereas with embolics and setting up DEB TACE or conventional TACE, these things are going to be on the order of 100 microns or greater. 
So you're really talking about, at best, administering embolics that get to the arterials. I think that in the way we think about targeting the vasculature, we have to think about how best to achieve the endpoints of embolization. I think that as Justin was mentioning, in terms of using smaller particles, we'll be able to get these things more distally and that means we're going to cut off more collaterals, and we're going to achieve a greater embolic effect in principle. I think it's just something we should consider when we start thinking about bead sizes and uniformity of bead size and how that may influence our practice going forward.

 

 

[Michael Barraza]
Well, Terence, Justin, thank you both for taking the time to share your experience and help all of us battle this challenging disease. Lastly, a big thanks to our sponsor, Surefire Medical. Please visit Surefire Medical dot com to learn now the Surefire infusion system can help you deliver therapy deeper into tumors while protecting healthy tissues. Thanks everyone, and join us again next time.

 

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