## 4 Discussion
Regarding therapy monitoring using tumor biomarkers, it is important to note that up to 10% of the general population may have genetically undetectable CA 19-9 levels, potentially limiting its role as a reliable parameter [43]. Even among PDAC patients classified as non-secretors, a subset may still demonstrate abnormal CA 19-9 levels, adding further complexity [44]. It has been shown that CA 19-9 decrease during chemotherapy with gemcitabine predicts favorable survival outcomes in advanced pancreatic cancer [45]. However, this correlation of serum CA 19-9 dynamics before and after EUS-RFA with post-procedure survival was not demonstrated in the studies selected for this review. Thus, the serum decrease in CA 19-9 after EUS-RFA--while potentially encouraging--should be interpreted with caution and ideally, should be incorporated with imaging findings or other biomarkers in a broader analysis. Other modalities focusing on locoregional therapy for PDAC, such as irreversible electroporation, did not show any benefits for OS compared to those of multimodal therapy, at the cost of significant post-interventional morbidity [46]. As with EUS-RFA, these local therapies remain non-curative and are intended for non-surgical candidates. Tumor size before and after EUS-RFA was another efficacy outcome proposed by some authors. However, the lack of clear thresholds for defining morphological efficacy across the included studies made it unfeasible to elaborate any statistical comparisons. Only a subset of studies provided paired imaging data [26], but sample sizes were very small (n = 6 with evaluable imaging), and the results were described qualitatively as tumor volume reduction rather than with detailed numeric values. [PERSON] et al. [33] similarly noted that 7 of 10 patients exhibited measurable tumor regression, with 3 of them having a >50% tumor volume reduction, yet individual pre- and post-RFA paired dimensions were not reported. [PERSON] et al. [36] also found >50% tumor volume reduction in 5 out of 11 patients with advanced PDAC, again without individual lesion dimensions collected in a paired manner to serve as input data for statistical analyses. Overall, the limited data suggest a trend toward tumor size reduction in many patients, but the heterogeneity in outcome definitions limits a standard statistical approach at this time. Therefore, while there is evidence that EUS-RFA may induce local tumor shrinkage, a definitive pooled analysis or calculation of statistical significance (\(p\)-values) cannot be performed. Besides the local control of the tumor through cytoreduction, the benefit of RFA comes from the immune modulation and the abscopal effect achieved by exposing tumor antigens [21; 47; 48; 49; 24]. Moreover, in the study by [PERSON] et al. [20], the authors revealed an increased blood flow around the RFA ablated area using contrast enhancement during EUS, which might create premises for better response to systemic chemotherapy. The potential benefits of EUS-RFA in PDAC treatment are summarized in Figure 4.  
These findings generate intriguing questions regarding the possible role of combining EUS-RFA with immunotherapies, which could further contribute to better outcomes for patients with advanced PDAC [25; 47]. Future research should concentrate on elucidating the mechanisms driving this immunodulation and unraveling the synergistic potential of RFA added to novel systemic therapies [21; 47; 48]. Our review has several limitations. First, the studies included in this review were defined by small sample sizes and heterogeneous methodologies, which may affect the generalizability of the findings [32; 33]. In addition, long-term data on survival outcomes after EUS-RFA remain limited [20; 29]. A formal meta-analysis of overall survival (OS) and progression-free survival (PFS) was not feasible due to incomplete or heterogeneous survival data across the selected studies. Most studies lacked the necessary quantitative parameters, such as confidence intervals or event numbers.