DOI: 10.17632/x53gcmjwsm.1
title: Efficacy of Endoscopic Ultrasound-Guided Ablation with the HybridTherm Probe in Locally Advanced or Borderline Resectable Pancreatic Cancer: A Phase II Randomized Controlled Trial.

description: doi: 10.3390/cancers13184512.
The National Comprehensive Cancer Network (NCCN) subclassified the “locallyadvanced” pancreatic ductal adenocarcinoma (PDAC) into borderline-resectable and locally-advanced categories and established the 4- or 6-months induction chemotherapy as standard of care to control and eventually downsize the locally advanced PDAC and select the borderline resectable PDAC at higher risk of non-radical resection. However, chemotherapy and radiotherapy regimens in locally advanced PDAC have only led to a marginal survival improvement, with a 5-year survival rate less than 8% only. Recently, tumour local thermal ablation has been investigated in PDAC, hypothesizing that it may add local efficacy to the chemotherapy systemic activity, inducing changes of the tumour microenvironment and increased intra-tumour drug uptake and efficacy. We recently demonstrated that endoscopic ultrasound-guided local thermal ablation with HybridTherm-Probe significantly reduced the tumour volume in locally advanced PDAC. In this phase II/III randomized controlled trial, originally designed as multicentric, we investigated the efficacy of local thermal ablation with the HybridTherm probe under endoscopic ultrasound-guidance (EUS) as first-line complement to chemotherapy (HTP-CT arm) versus standard first-line chemotherapy alone (CT arm), in locally advanced and borderline resectable PDAC. Evaluation of the 6-months progression-free survival (PFS) rate was the primary endpoint. A sample size of 33 patients per arm in the phase II trial was calculated to verify a 20% improved 6-months PFS rate adding the HybridTherm ablation. Up to three EUS-guided ablation could be performed. Restaging was planned at 2-months, 4-months and 6-months after chemotherapy onset, assessing the response to therapy using the Choi criteria and tumor volume at contrast-enhanced multidetector CT scan and magnetic resonance imaging, and the serum levels of CA19-9. Between November 2014 and June 2019, we randomized 17 patients and 20 patients to HTP-CT arm and CT arm, respectively. Because of  unforeseen problems in patients’ enrolment in other centres and withdrawal of the HybridTherm probe by the manufacturer in 2020 as consequence, it was established to stop enrolment and perform the phase II trial analysis as monocentric despite the smaller sample size than required. Baseline and chemotherapy-related features were evenly balanced. Although not significantly, we found an improved 6-month PFS rate in the HTP-CT arm over CT arm (41.2% vs. 30%), as well as with regard to the decrease ≥50% of serum CA19.9 levels (75% vs. 64.3%) and reduction of tumor volume (64.3% vs. 47.1%). However, no impact on the resection rate has been observed and the overall survival was similar between the two arms. As the study, originally designed to be multi-centric, is underpowered these results suggest further investigation on EUS-guided thermal ablation in selected patients with localized disease.