Updated: Mar 9, 2019
Hepatocellular carcinoma is the third leading cause of cancer-related deaths. Treatment options for HCC depend on extent of disease, severity of underlying liver disease/cirrhosis and the patient's performance status. Arterial therapies such as bland embolization, transarterial chemoembolization and transarterial radioembolization are important treatment options for many patients with intermediate-stage HCC. Effective drug delivery systems attempt to maximize homogeneous distribution of the respective agent to the entire tumor to induce cytotoxicity and tumor necrosis. Dr. Justin Lee and Dr. Terence Gade discuss how pressure-directed therapy improves drug delivery to areas of tumor burden in cases of HCC.
The BackTable Brief
Achieving homogenous drug delivery is an obstacle when treating HCC; increasing vascular hydrostatic pressures favors drug delivery across the tumor endothelium and improved distribution throughout the tumor interstitium.
Pressure-directed therapy facilitates the drug delivery into the tumor by increasing hydrostatic pressures in the tumor vasculature.
The Surefire Infusion System helps translocate the correct dose into the tumor to maximize therapeutic benefits. Dr. Justin Lee uses it to administer the right dose, and to avoid overprescribing.
Disclaimer: The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
What are the barriers to drug delivery in HCC?
Local delivery of drug therapy to a tumor is one of the greatest obstacles when maximizing drug delivery. Interventional techniques allow for precise delivery of chemo- and radioembolics to a tumor. Distribution across the tumor endothelium is another important consideration. Increasing vascular hydrostatic pressures allows for successful movement of the drug into the tumor from the vessel. [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 expand 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. 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.
How does pressure-directed therapy work?
TACE or Y90 coupled with pressure-directed therapy increases the hydrostatic pressure within a given vessel. The increased pressure results in greater drug delivery into the tumor vasculature. Ultimately the high pressures favor drug translocation from vessel into the tumor.
[Terence Gade] 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 shunting 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.
Using Surefire Pressure Directed Therapy
Effectively delivering chemo- or radioembolics to the tumor is important. Dr. Justin Lee recommends using the Surefire Infusion System to deliver the entire drug dose or volume of beads to the tumor site. [Justin Lee] … 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. 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.
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.
---------- 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. 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.