Various treatment options exist for intermediate-stage HCC including lipiodol-based conventional transarterial chemoembolization (cTACE) and drug-eluting bead transarterial chemoembolization (DEB-TACE). Dr. Terence Gade discusses chemotherapeutic options, how tumor biology influences embolic delivery, and how these treatment modalities can be used to treat HCC.
The BackTable Brief
DEB-TACE allows for the local delivery of chemotherapeutics (such as Doxorubicin), yet the therapeutic effect likely comes from ischemia induction.
Dr. Terence Gade suggests pressure-directed therapy may improve embolic delivery in DEB-TACE, however, its role may be limited for cTACE due to issues with early stasis and sub-total delivery of the chemotherapeutic agent.
Current chemotherapeutic options target cell proliferation and may not significantly potentiate tumor ischemia; the tumor biology of HCC may be better served through cTACE, says Dr. Terence Gade.
There is a better side effect profile with DEB-TACE compared to cTACE.
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What are the advantages and disadvantages of working with cTACE vs. DEB-TACE?
Dr. Terence Gade suggests ischemia induction within the tumor is the most important principle when treating HCC. Despite DEB-TACE having an improved side effect profile, cTACE effectively induces ischemia due to improved embolization of the tumor vasculature.
[Michael Barraza] Now Terence, because you have experience with both cTACE 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, 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.
[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, 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.
How does tumor vasculature affect embolic delivery in HCC?
Capillaries of the liver are up to 30 microns in diameter while embolic options for conventional and DEB-TACE are 100+ microns in size. Smaller embolic particles travel deeper into the arterial system and subsequently cut off more collaterals within the tumor circulation. Dr. Terence Gade suggests improved distal delivery of embolic agents may result in a greater embolic effect.
[Terence Gade] … 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.
Understanding Tumor Biology to Maximize Therapy
Current chemotherapeutic drugs for DEB-TACE include doxorubicin, cisplatin and mitomycin, all of which treat proliferating cell populations. According to Dr. Terence Gade and the recent work of Dr. Karen Brown, such agents that target proliferating cell populations likely will not significantly potentiate tumor ischemia. Therefore, therapy that primarily induces ischemia (conventional TACE) may be the best treatment option for improved therapeutic results.
[Terence Gade] I think that in terms of what data we do have, those chemotherapeutics are probably not the best choices. 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.
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. Cite this podcast: BackTable, LLC (Producer). (2018, January). Ep 20 – Pressure-Directed Therapy in TACE [Audio podcast]. Retrieved from https://www.backtable.com/podcasts Medical Disclaimer: The Materials available on the BackTable Blog 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. Disclosures: The podcast referenced in this article was sponsored by Surefire Medical.