Herein we describe a novel treatment protocol for resectable PDAC with the use of NAC + EUS-RFA. To the best of our knowledge, this is the first literature report of pancreaticoduodenectomy following NAC plus EUS-RFA for patients with resectable PDAC. The primary goal of this initial experience was to determine the safety and feasibility of this treatment protocol. Although EUS-RFA in the treatment of PDAC is not currently standard of care, this RFA therapeutic modality is FDA-approved for solid tumors. All patients were enrolled in a prospective cohort study and understood the experimental design. We also sought to determine if this therapy would impact the complex nature of pancreatic resection, specifically pancreaticoduodenectomy. According to current published reports, resection rate following NAC is 70–90% as some PDAC patients are found to be unresectable at the time of surgery [12]. In these three cases, there was no appreciable scarring or fibrosis from the RFA that prevented, negatively influenced or potential prevented the standard pancreaticoduodenectomy (Whipple operation).
Chemotherapy in combination with surgery for PDAC is tolerated; however, both modified FOLFIRNOX and Gem/nab-P have noted toxicities and adverse events [13]. In this report, patients tolerated 4 months of NAC plus EUS-RFA. Following the RFA treatment, there were no adverse events specific to the ablation observed. The protocol was designed to provide at least 1 month of NAC before the first EUS-RFA. This was done to ensure some component of systemic treatment in the event there was a complication following RFA. After the 1st, 2nd and 3rd months of NAC, patients underwent RFA treatments. This was followed by a final month of chemotherapy and then a 4-week break before surgery. All 3 patients underwent successful pancreaticoduodenectomy without evidence of anastomotic leak or delayed gastric emptying complications that are frequent with this procedure. Thus, in this limited initial experience, NAC + EUS-RFA is both feasible and well-tolerated. It is unclear if EUS-RFA is superior or equivalent to radiotherapy in the treatment of PDAC. The role of neoadjuvant radiation has not been well established as available data does not demonstrate improving resection rates or overall survival [14]. The recent PREOPANC trial compared neoadjuvant chemoradiation to upfront surgery for resectable and borderline resectable PDAC [15]. This trial showed benefit to neoadjuvant chemoradiation; however, the treatment effect was only 1.4 months improved overall survival. The current European PREOPANC2 trial comparing neoadjuvant chemoradiation (gem/nab-P) to total neoadjuvant chemotherapy (mFOLFIRINOX) is open and accruing patients [16].
In this experience, all patients appeared to have a meaningful pathologic response as residual tumor was less than 1 cm. This may be a significant benefit of this treatment as standard NAC response rates are quoted to be less than 35% seen in the PRODIGE and SWOG-1505 trials [12]. In two of the three patients the final preoperative CT scan demonstrated a more organized, homogenous mass consistent with necrosis. Standard hematoxylin and eosin staining demonstrated areas of fibrosis in the pathology specimens. In addition, there appeared to be a concentrated areas of endothelial proliferation at the periphery of the ablation zone. These areas of vascular proliferation may enhance chemotherapy penetration into the PDAC. In addition, thermal necrosis and tumor disruption may release PDAC immunogenic material. Thus, treatment of the primary tumor may impact other distant sites of metastasis, the so-called “abscopal effect.” This phenomenon may provide an additional systemic immunotherapy against the PDAC. Future studies are needed to confirm these hypotheses.
At this point, it is too early to determine if this novel protocol may be associated with any significant harm or benefit. The initial peri-operative recovery was normal in this small group. There was no evidence of vascular thrombosis or injury of the superior mesenteric/portal vein confluence, superior mesenteric artery or common hepatic artery from the RFA. A recent report of a phase-II randomized trial of EUS-RFA for PDAC demonstrated a similar safety profile [17]. This trial included both borderline resectable or locally-advanced PDAC and was eventually closed as the RFA probe was no longer produced. Unfortunately, subject accrual was slow and did not meet prespecified criteria. The patients that did receive chemotherapy + EUS-RFA demonstrated a higher response rate; however, there was no difference in the outcomes measure. In our institutional experience, outcome data is not mature and it is unknown if this treatment will improve upon long-term survival. The median survival following standard NAC in the recent SWOG 1505 demonstrated at only 24 months [12]. This quoted statistic for resectable PDAC as well as known survival rates for the past several decades highlight the need for better systemic treatments. The encouraging radiographic and pathologic responses suggest this protocol requires further study.
This initial experience of neoadjuvant chemotherapy plus EUS-RFA appears promising. These results have led to the design of the PANcreatic CAncer RaDiofrequency AbLation-1 trial (PANCARDINAL-1) clinicaltrials.gov (NCT04990609). This is a single-arm phase II trial designed to further test the safety and feasibility of this protocol and is currently recruiting and enrolling patients. This new EUS-RFA therapy may provide another modality of PDAC treatment. At this time, EUS-RFA is not standard of care and use should be limited to the context of a clinical trial. Currently there are many unknowns for pancreatic radiofrequency ablation. It will take several years to determine if this is truly an effective therapy. The optimal timing and number of ablation sessions needed to maximize treatment effect. This report provides initial details of this EUS-RFA protocol and future studies will determine this role.