Is the time of ethanol injection over?—has endoscopic ultrasonography-guided radiofrequency ablation become the preferred approach for small pancreatic neuroendocrine tumors?

To the editor, we read with great interest the prospective multicenter study by Matsumoto et al. (1). The paper reports a retrospective multicenter study including 25 patients treated in 6 Japanese centers over 3 years. The aim of the study was to evaluate endoscopic ultrasonography (EUS)-guided ethanol lavage for pancreatic nonfunctional neuroendocrine tumors (pNFNETs) grade 1 (histology required) measuring less than 15 mm. Ethanol injection was performed using a 25-gauge fine needle aspiration (FNA) needle. A maximum of 2 mL of pure ethanol was injected per session, with no more than 1 mL per puncture (maximum of 3 punctures). The needle was left in the lesion for at least 1 minute after injection to prevent ethanol backflow.

The cohort of 25 patients who underwent EUS-guided ethanol injection was compared with a group of 23 patients who underwent surgery in one of the 6 participating centers. The primary endpoint was a composite criterion combining efficacy and safety. Secondary endpoints evaluated efficacy and safety separately. Safety was assessed within one month after the procedure, with diabetes evaluation at 6 months. Efficacy was defined as the absence of enhancement during the arterial phase of computed tomography (CT) imaging, assessed by two independent expert gastroenterologists.

Because safety outcomes favored EUS-guided ethanol injection, the primary endpoint was met. For the secondary endpoints, the reported complete radiological response rate of 88% at 6 months and the low incidence of severe adverse events (AEs) (4%) are encouraging. The authors concluded that this treatment could be a good therapeutic option. They should be commended for conducting a rigorous prospective study in a rare disease setting with carefully standardized inclusion criteria and procedural methodology.

We fully agree that minimally invasive ablative therapy represents an attractive alternative to surveillance in selected patients (2) as it was highlighted in a recent meta-analysis (3). Although current international guidelines support or consider watchful waiting for tumors <2 cm because growing over the time is not clear. However longitudinal data show that a substantial proportion of small pNFNETs exhibit growth during follow-up. In our own experience, tumor enlargement occurred in up to 35% of cases over a median follow-up of 47 months, with no reliable predictive biomarkers of progression (4).

However, while acknowledging the quality of this study, we believe the central question has evolved. The issue may no longer be whether to ablate small pNFNETs, but rather which ablative technique should be preferred.

The historical evolution of liver tumor treatment is instructive. Percutaneous ethanol injection was progressively replaced by radiofrequency ablation (RFA) due to superior local control, reproducibility, and procedural standardization (5,6). A similar shift now appears to be occurring in pancreatic endotherapy.

Ethanol injection induces chemical necrosis through diffusion, a mechanism inherently difficult to control in solid pancreatic tissue (7). Some teams have described ethanol lavage for pancreatic cysts with few AEs (8,9), likely because injection into a cystic cavity limits diffusion and reduces the risk of severe complications. However, we cannot deny the existence of severe complications—some unpublished—associated with EUS-guided ethanol lavage for endocrine tumors. The major problem with intratumoral alcohol injection is that it is impossible to control the intra- or extratumoral diffusion of the alcohol, due to the more or less fibrous nature of the tumor. Extratumoral diffusion of alcohol into normal pancreatic parenchyma can cause extremely serious acute necrotizing pancreatitis. The favorable safety profile reported by Matsumoto et al. likely reflects strict patient selection (≤15 mm lesions, >2 mm from the main pancreatic duct) and strict limitations on injected volume. Moreover, 32% of patients required additional sessions to achieve complete ablation, underscoring the challenges of achieving homogeneous necrosis with a diffusion based technique.

Since the first reports of EUS-guided RFA for pancreatic NETs in 2016 (10,11), accumulating evidence has demonstrated technical success rates exceeding 99%, complete radiological response rates around 85–90%, and severe AE rates below 1% in large systematic reviews including nearly 300 patients. However, when applying Appraisal of Guidelines for REsearch & Evaluation (AGREE) criteria ≥3, AEs approach 10% (12). However, limitations exist when the lesion is too close of the pancreatic duct (probably less than 1mm). Nevertheless, ethanol injection, RFA delivers controlled thermal energy with predictable ablation zones and adjustable power settings, allowing improved standardization and reproducibility across centers.

In our own practice, we initially performed EUS-guided ethanol injection (13) but progressively transitioned to endoscopic ultrasound-guided radiofrequency ablation (EUSRFA) due to greater procedural control, more predictable outcomes, and increased operator confidence (14,15). This evolution mirrors the broader international trend. Matsumoto et al. also appear to be moving toward RFA in a recent publication (16).

We acknowledge that longterm data remain limited for both techniques based on indirect comparison and that randomized controlled trials are unlikely in such rare tumors. Nevertheless, when considering standardization, reproducibility, and predictability of ablation, EUSRFA appears to offer both theoretical and practical advantages over ethanol injection.

Matsumoto et al. have provided important prospective data supporting the feasibility of EUS-guided ethanol injection in highly selected patients [neuroendocrine tumor (NET) grade 1: lesions <15 mm, distance >2 mm of the pancreatic duct] and suggest ethanol injection as an alternative for these cases. However, based on current evidence and technological evolution, ethanol injection probably may represent a transitional technique rather than the future standard.

In the era of controlled thermal ablation, it may be time to reconsider whether ethanol injection should remain a firstline endoscopic strategy for small pNFNETs.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0220/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0220/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Matsumoto K, Kato H, Itoi T, et al. Efficacy and safety of endoscopic ultrasonography-guided ethanol injections of small pancreatic neuroendocrine neoplasms: a prospective multicenter study. Endoscopy 2025;57:321-9. [Crossref] [PubMed]
2. Caillol F, Godat S, Giovannini M. Reply to the letter to the editor. Dig Endosc 2022;34:1258. [Crossref] [PubMed]
3. Armellini E, Facciorusso A, Crinò SF. Efficacy and Safety of Endoscopic Ultrasound-Guided Radiofrequency Ablation for Pancreatic Neuroendocrine Tumors: A Systematic Review and Metanalysis. Medicina (Kaunas) 2023;59:359. [Crossref] [PubMed]
4. Marx M, Caillol F, Godat S, et al. Outcome of nonfunctioning pancreatic neuroendocrine tumors after initial surveillance or surgical resection: a single-center observational study. Ann Gastroenterol 2023;36:686-93. [Crossref] [PubMed]
5. Giovannini M, Seitz JF. Ultrasound-guided percutaneous alcohol injection of small liver metastases. Results in 40 patients. Cancer 1994;73:294-7.
6. Bertrand J, Caillol F, Borentain P, et al. Percutaneous hepatic radiofrequency for hepatocellular carcinoma: results and outcome of 46 patients. Hepat Med 2015;7:21-7. [Crossref] [PubMed]
7. Giovannini M. Concentration-dependent ablation of pancreatic tissue by EUS-guided ethanol injection. Gastrointest Endosc 2007;65:278-80. [Crossref] [PubMed]
8. Gan SI, Thompson CC, Lauwers GY, et al. Ethanol lavage of pancreatic cystic lesions: initial pilot study. Gastrointest Endosc 2005;61:746-52. [Crossref] [PubMed]
9. DeWitt J, McGreevy K, Schmidt CM, et al. EUS-guided ethanol versus saline solution lavage for pancreatic cysts: a randomized, double-blind study. Gastrointest Endosc 2009;70:710-23. [Crossref] [PubMed]
10. Lakhtakia S, Ramchandani M, Galasso D, et al. EUS-guided radiofrequency ablation for management of pancreatic insulinoma by using a novel needle electrode (with videos). Gastrointest Endosc 2016;83:234-9. [Crossref] [PubMed]
11. Waung JA, Todd JF, Keane MG, et al. Successful management of a sporadic pancreatic insulinoma by endoscopic ultrasound-guided radiofrequency ablation. Endoscopy. 2016;48:E144-5. [Crossref] [PubMed]
12. Khoury T, Sbeit W, Fusaroli P, et al. Safety and efficacy of endoscopic ultrasound-guided radiofrequency ablation for pancreatic neuroendocrine neoplasms: Systematic review and meta-analysis. Dig Endosc 2024;36:395-405. [Crossref] [PubMed]
13. Caillol F, Poincloux L, Bories E, et al. Ethanol lavage of 14 mucinous cysts of the pancreas: A retrospective study in two tertiary centers. Endosc Ultrasound 2012;1:48-52. [Crossref] [PubMed]
14. Marx M, Trosic-Ivanisevic T, Caillol F, et al. EUS-guided radiofrequency ablation for pancreatic insulinoma: experience in 2 tertiary centers. Gastrointest Endosc 2022;95:1256-63. [Crossref] [PubMed]
15. Marx M, Godat S, Caillol F, et al. Management of non-functional pancreatic neuroendocrine tumors by endoscopic ultrasound-guided radiofrequency ablation: Retrospective study in two tertiary centers. Dig Endosc 2022;34:1207-13. [Crossref] [PubMed]
16. Matsumoto K, Uchida D, Takeuchi Y, et al. Efficacy and safety of endoscopic ultrasonography-guided radiofrequency ablation of small pancreatic neuroendocrine neoplasms: A prospective, pilot study. DEN Open 2025;5:e70073. [Crossref] [PubMed]