Transarterial Microperfusion for Pancreatic Adenocarcinoma: A New Way of Addressing an Old Problem

Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, remains one of the most challenging solid organ malignancies to treat. It often is an aggressive cancer, presenting with metastatic disease approximately 50% of the time.

Of the patients with localized disease, many are ineligible for surgery due to major vascular involvement and are treated with neoadjuvant cytotoxic chemotherapy. In this setting, there are several potential benefits, including the following¹:

1. Treatment of unidentifiable micrometastatic disease
2. Evaluation of treatment response to identify patients who may benefit from invasive surgeries or testing biology
3. Reduction of local burden to facilitate complete resection. Unfortunately, tumors are infrequently radiographically downstaged. Study results show partial or complete RECIST response rates are typically less than 25%.

Many patients then undergo radiotherapy (often combined with oral chemotherapeutic agents to enhance sensitivity) in the hope of improving local response. Despite maximal therapy and no clear metastatic disease, patients are often not candidates for resection, either due to unreconstructable major vascular involvement or poor surgical candidacy due to comorbidities. Until recently, there were few options for these patients other than to continue systemic therapy indefinitely. This is often impractical, as these regimens have significant adverse effect (AE) profiles that limit their long-term use. Furthermore, immunotherapies and targeted therapies have failed to make a meaningful impact on survival, despite initial enthusiasm. Patients are typically placed on maintenance therapy with oral agents, which generally have limited efficacy and eventually do not respond to the treatment due to the development of tumor resistance.

PDAC resistance to treatment has been the subject of intense study. These tumors are characteristically hypovascular and embedded in dense desmoplastic stroma, which severely limits penetration of systemically administered chemotherapy. Standard intravenous treatments do not achieve therapeutic concentrations in the tumor.

Although there are multiple contributing factors to this efficacy valley, the lack of the drug reaching its intended target is certainly a substantial one. The desire to overcome this barrier has led investigators to pursue other delivery approaches.

Can intra-arterial or regional therapies improve outcomes in PDAC?

There has been a resurgence of interest in regional therapies for difficult-to-manage cancers in recent years. An analogous example would be the rapid increase in the utilization of hepatic artery infusion pump therapy for primary and metastatic tumors of the liver. This renewed interest has prompted similar evaluations for other tumors and other disease sites. Previous attempts at therapeutic delivery directly to the pancreas and tumor have focused on intra-arterial access to the pancreas via major mesenteric blood vessels and the instillation of drugs directly into the tumor microvasculature. The concept revolves around the idea that drug concentrations can be increased in the tumor, resulting in reduced systemic leakage and, consequently, fewer and/or less severe toxicities. Studies evaluating efficacy and local control, although small, suggested a potential benefit compared with systemic therapy alone, with predictably fewer systemic AEs. Despite these possible benefits, adoption has been essentially nonexistent for a whole host of reasons.

There are technical challenges associated with repeated catheter insertions into these vessels that require design innovations. There exists the risk of ischemia and a lack of ability for repeated administrations for embolic-based therapies. Additionally, despite the delivery of the drugs near the tumors and into the microcirculation, standard therapeutics experienced the same issue as systemic delivery: Hypovascular, dense stromal tissue resists intravascularly delivered drugs.

What is transarterial microperfusion?

Transarterial microperfusion (TAMP^TM) aims to overcome these limitations by temporarily isolating the arterial segment that feeds the tumor and delivering chemotherapy under pressure directly into the tumor’s microcirculation and interstitial tumor microenvironment. The technique uses a dual-balloon catheter (RenovoCath; RenovRx®) placed in an artery adjacent to the cancer, commonly the superior mesenteric, splenic, or hepatic artery. Once positioned, the proximal and distal balloons are inflated to occlude flow through that isolated segment. A drug is then infused slowly into the confined space between the balloons over a defined interval. The resulting rise in intra-arterial pressure, typically several tens of mmHg above baseline, drives the drug across the arterial wall into perivascular capillaries and the interstitial tumor compartment, effectively bathing the tumor region in high local drug concentrations.

An additional benefit of this controlled release is that, by stopping bulk flow during infusion, TAMP reduces early washout and promotes more homogeneous tissue penetration. After the infusion period, the balloons are deflated, and normal perfusion resumes. This approach achieves regional drug delivery without the need for permanent embolization or sustained ischemia, unlike embolic therapies. In addition, the RenovoCath system allows for the adjustment of balloon placement and spacing, enabling the length of the perfused arterial segment to be customized to match the tumor size and vascular anatomy, potentially accommodating lesions with diverse arterial supplies.

Practically speaking, patients undergo a procedure similar to cardiac catheterization, with access through the femoral artery. It is an outpatient procedure that does not require prolonged infusions and is typically repeated every 2 weeks for 4 to 5 months (8 to 10 cycles). Patients are often off any other therapies at that time. After 8 to 10 cycles, patients can continue with TAMP therapy longer, but may need to transition to monthly treatments due to theoretical concerns for vascular endothelial injury. Biologic and radiologic evaluations are performed throughout treatment to assess disease regression, conversion of eligibility for surgery, disease stability, or progression.

What are the preclinical rationale and supporting data?

Early laboratory work has demonstrated TAMP’s pharmacologic and biologic advantages. In porcine experiments, researchers found that dual-balloon catheter chemotherapy under pressure substantially increased local drug delivery compared with standard administration routes. Tissue concentrations within the targeted zone after isolated TAMP infusion were reported to be up to 100 times higher than those achieved with systemic intravenous dosing.²

Preclinical comparisons also show that TAMP produces more uniform perfusion of the target region than intra-arterial injection without flow occlusion, which tends to distribute drugs unevenly across vascular territories.

What do current clinical experience and emerging data show?

Early clinical experience indicates that TAMP is deliverable and generally well tolerated in patients with locally advanced pancreatic cancer. A phase I dose-escalation trial established intra-arterial gemcitabine at doses up to standard systemic doses without dose-limiting toxicity. What was also notable was the lack of serious AEs. Common AEs included transient gastrointestinal symptoms and mild liver enzyme elevations. Some catheter-related infections in patients with stents prompted the addition of antibiotics to the protocols. Otherwise, treatments were well tolerated. Small cohorts reported encouraging survival signals, including a nearly 60% 1-year overall survival rate in the phase I group and several long-term survivors, which prompted a larger multicenter registry and pooled analyses.

A follow-up single-arm multicenter registry study (data pooled from NCT02237157 and NCT02591082) of locally advanced pancreatic cancer showed that patients who received chemoradiotherapy before TAMP fared substantially better, with a median survival of approximately 27 months, compared with approximately 14.6 months for those who had prior chemotherapy only.³

Local control and prolonged stable disease were commonly observed; many patients tolerated multiple infusion cycles, and higher cumulative treatments correlated with better outcomes. This improvement, achieved by adding radiotherapy before TAMP, is believed to result from reduced systemic leak caused by obliteration of the tumor microvasculature and greater drug retention within the tumor. Given the positive results, the randomized phase 3 TIGeR-PaC trial (NCT03257033) was launched, and early data show a favorable trend for TAMP in median survival and a marked reduction in serious AEs. However, definitive conclusions await full accrual and final analysis.⁴

Where are we now?

Any innovations that can be added to the armamentarium of treatments are welcome. TAMP represents another opportunity to improve the disease control and long-term survival of patients with a cancer that, up until relatively recently, had a 5-year survival of nearly 0%. Currently, it is approximately 14% and continues to improve year after year. Despite these improvements, PDAC remains a frustrating disease. As such, continued improvements in outcomes require a multimodality approach, and, as with any cancer treatment, patient selection remains critical. TAMP is generally not utilized for metastatic or very early/resectable disease.

As more data emerge and experience grows, TAMP may be integrated into all aspects of the treatment discussion. For example, consider patients with borderline resectable disease that is technically removable, but who are at very high risk for residual disease. Might those patients be candidates for TAMP to sterilize the margins? Could it be used to target metastatic sites in patients whose disease recurs after surgery but aren’t candidates for other treatments? Pancreatic cancer’s defense mechanisms limit the impact of even the best systemic drugs. Overcoming these barriers requires not only improved agents but also novel delivery methods that ensure drugs actually reach and penetrate the tumor microenvironment. TAMP takes this challenge head-on. Clinicians look forward to mature trial results and practical, evidence-based ways to integrate TAMP into treatment algorithms.

References

1. Zhan JF, Xu JW, Wu D, et al. Neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of prospective studies. Cancer Med. 2017;6(6):1201-1219. doi:10.1002/cam4.1071
2. Farsad K, Novelli PM, Laing C, et al. Double-balloon catheter-mediated transarterial chemotherapy delivery in a swine model: a mechanism recruiting the vasa vasorum for localized therapies. J Vasc Interv Radiol. 2024;35(7):1043-1048.e3. doi:10.1016/j.jvir.2024.03.016
3. Hatoum H, Rosemurgy A 2nd, Bastidas JA, et al. Treatment of locally advanced pancreatic cancer using localized trans-arterial micro perfusion of gemcitabine: combined analysis of RR1 and RR2. Oncologist. 2024;29(8):690-698. doi:10.1093/oncolo/oyae178
4. Pishvaian MJ, Zureikat AH, Lopez CD, et al. Targeted intra-arterial gemcitabine vs. continuation of IV gemcitabine plus nab-paclitaxel following induction with sequential IV gemcitabine plus nab-paclitaxel and radiotherapy for unresectable locally advanced pancreatic cancer (TIGeR-PaC): a randomized phase 3 multicenter study. J Clin Oncol. 2023;41(suppl 4):TPS773. doi:10.1200/JCO.2023.41.4_suppl.TPS773