Inside Access is a new column from IR Quarterly that provides interviews and behind-the-scenes on open access articles from the Journal of Vascular and Interventional Radiology. Read the full article and learn more about JVIR's open access options at JVIR.
Double-balloon, catheter-mediated transarterial chemotherapy delivery in a swine model: A mechanism recruiting the vasa vasorum for localized therapies
Farsad K, Novelli PM, Laing C, Gandhi RT, Cynamon J, López CS, Stempinski ES, Strasser R, Agah R.
Tell us about yourself, your research team and institution.
Khashayar Farsad, MD, PhD: I am currently interim chair of interventional radiology at Oregon Health and Science University, and director of the Dotter Interventional Institute. As the birthplace of interventional radiology, we take a lot of pride in our history of research and innovation and are looking to carry this forward with the ongoing evolution of IR as a specialty. Our research program has a focus on cancer therapies, portal hypertension and vascular disease. Complementing our clinical trials program, we have translational models that we hope will help inform future bench-to-bedside clinical trials. Historically, our department has focused on medical device development, and our more recent models are helping to drive newer therapeutic opportunities for cancer and venous disease.
What was the focus of your study?
KF: This study aimed to better understand the mechanism of drug delivery for the RenovoCath catheter by RenovoRx (Los Altos, CA). The catheter is currently being used in a phase III multicenter international randomized controlled clinical trial (NCT03257033). We assessed the benefit of intra-arterial gemcitabine delivery using the RenovoCath catheter compared to standard-of-care IV gemcitabine for locally advanced pancreatic adenocarcinoma. The intra-arterial treatments have shown promise for improved outcomes in earlier phases of the trial; RenovoRx was interested in better understanding the mechanism of drug delivery as it is somewhat unique relative to existing transarterial treatment paradigms. For example, the mode of treatment for RenovoCath does not use tumor-feeding arteries akin to typical embolotherapies. By contrast, the treatment paradigm is based on transmural passage of a drug across the arterial wall and directly into the tumor-infiltrating tissues. I think of it as conceptually more similar to a direct tumor injection of drug rather than delivery via the tumor blood supply. The study was designed to better understand the effect of drug delivery with this catheter by using gemcitabine, gold nanoparticles and dyes to assess tissue infiltration.
Why did you set out to research this topic?
KF: RenovoRx reached out to our lab to collaborate on this project. Since we were a site for the clinical trial, we were interested in helping better understand how this catheter functions for drug delivery. Certain aspects of how the catheter functioned were unknown, including what happens to the intra-arterial pressure during delivery, and by what means the drug is passing through the arterial wall to penetrate the surrounding perivascular tissues. For example, we observed that clinical outcomes with intra-arterial therapy for pancreatic cancer were better after tissue radiation. But it is unknown whether this was simply a result of “leakier” blood vessels related to alterations in cell–cell connections, defects in the basement membrane, influences of the peritumoral lymphatics and venules, or from some other mechanism.
What were the key takeaways?
KF: Through this study, we were able to identify the vasa vasorum as likely one of the primary means of transmural drug delivery based on the localization of gold nanoparticles by electron microscopy. We were also able to obtain preliminary data showing greater local tissue concentrations with RenovoCath delivery using dye and gemcitabine, supporting the favorable pharmacokinetic profile observed in a subset of patients enrolled in the clinical trial. The data also suggested this increased drug delivery was predicated on an increase in local mean pressure in the isolated arterial segment that was not seen when the segment was not able to be fully isolated. For example, when side branches were in the perfused segment.
What do you consider the impact of these findings?
KF: I think the primary impact of these findings will be more relevant for future iterations of clinical use and trials for this catheter. For example, true arterial isolation may be key to optimizing tissue penetration. Moreover, knowing that the vasa vasorum are likely critical for drug delivery, we can think of other agents that can potentially be used for targeted delivery beyond chemotherapy drugs that are best suited to the structure and morphology of delivery via the vasa vasorum.
How do you think this research could impact treatment, practice or clinical processes?
KF: Presently, we are awaiting the results of this phase III clinical trial to see what its impact will be on the management of locally advanced pancreatic cancer. If there is a good signal for improved outcomes, I feel this would open the door for exploring avenues to target pancreatic adenocarcinoma with other novel therapeutic agents leveraging improved local delivery.
What are the next steps? Any additional research planned?
KF: An upcoming clinical trial is currently in development for unresectable bile duct cancer in combination with immunotherapy using RenovoCath.
