Pancreatic ductal adenocarcinoma remains difficult to treat, and outcomes for borderline resectable (BRPC) or locally advanced pancreatic cancer (LAPC) treated with systemic therapy are suboptimal. The multiagent regimen FOLFIRINOX is a standard chemotherapy approach for BRPC and LAPC, but response rates and survival gains remain limited. Mechanical effect–dominant non‑thermal focused ultrasound (FUS) is hypothesized to enhance intratumoral drug delivery through mechanical effects without thermal tissue damage. This exploratory phase II study assessed the safety and efficacy of adding non‑thermal FUS to FOLFIRINOX during initial cycles in patients with BRPC or LAPC.
This was a prospective, exploratory phase II clinical trial (registered at clinicaltrials.gov as NCT05262452). Participants with BRPC or LAPC received combined therapy consisting of non‑thermal FUS plus FOLFIRINOX during the first four cycles of chemotherapy; FOLFIRINOX was continued thereafter per protocol. The trial used a propensity score–matched historical cohort of patients treated with FOLFIRINOX alone as a comparator. The predefined primary endpoint was objective response rate (ORR). Secondary endpoints included overall survival (OS), progression‑free survival (PFS), and treatment‑related toxicity.
A total of 60 patients were enrolled in the combined FUS plus FOLFIRINOX arm. Fifty‑six of these patients completed the four cycles of combined treatment and were matched to 56 historical controls who had received FOLFIRINOX alone. The matched design aimed to reduce bias when comparing the exploratory cohort with historical patients, though details of matching variables and the historical cohort characteristics were not reproduced here beyond the reported numbers. FUS in this protocol was specified as mechanical effect–dominant and non‑thermal; the abstract reports no FUS‑related or collateral organ injuries.
The primary endpoint, ORR, favored the combination: 64.3% in the FUS plus FOLFIRINOX group versus 35.7% in the FOLFIRINOX‑only group (P = 0.003). Secondary survival outcomes also favored the combined approach. Median OS was 24.0 months for the FUS plus FOLFIRINOX group compared with 17.0 months in the historical FOLFIRINOX group (hazard ratio [HR] 0.63; 95% confidence interval [CI], 0.41–0.97; P = 0.029). Median PFS was 16.0 months versus 11.0 months, respectively (HR 0.65; 95% CI, 0.43–0.99; P = 0.039). These results indicate higher response rates and longer survival intervals associated with the addition of mechanical non‑thermal focused ultrasound in this exploratory cohort.
Rates of high‑grade toxicity were similar between groups. Grade ≥3 toxicities occurred in 55.4% of patients who received FUS plus FOLFIRINOX and in 57.1% of patients in the FOLFIRINOX‑only control group (P = 0.849). Importantly, the study reports no FUS‑related injuries or collateral organ damage attributable to the focused ultrasound procedure. Specific types or distributions of grade ≥3 adverse events were not detailed in the abstract; those details were not reported in the provided source text.
In this phase II exploratory trial, the addition of mechanical effect–dominant non‑thermal FUS to FOLFIRINOX during initial chemotherapy cycles was associated with an increased ORR and improvements in median OS and PFS compared with a propensity score–matched historical cohort treated with FOLFIRINOX alone. Toxicity rates were comparable and no FUS‑related organ injuries were reported. The authors interpret these findings as supportive of further evaluation in randomized phase III trials.
Limitations inherent to the reported design include the exploratory phase II setting and use of a historical, propensity‑matched control rather than a randomized contemporaneous control; the abstract does not provide full details on matching variables, baseline comparability beyond matched numbers, or granular toxicity breakdowns. Those methodological details and full data should be consulted in the full manuscript for complete appraisal.
The trial is registered at clinicaltrials.gov under identifier NCT05262452. The authors disclosed competing interests: Jae Young Lee reported financial support from the Focused Ultrasound Foundation and from the Korea Ministry of Science and ICT. The remaining authors reported no known competing financial interests or personal relationships that could have influenced the work, according to the conflict of interest statement provided in the source.
Overall, the published abstract reports that mechanical non‑thermal focused ultrasound combined with FOLFIRINOX achieved higher response rates and improved survival versus historical FOLFIRINOX alone in patients with BRPC or LAPC, without increasing observed toxicity, and supports further randomized evaluation.