EUS-guided therapies for pancreatic neuroendocrine tumors
Author: Stefano Francesco Crinò
Endoscopic ultrasound (EUS) with fine-needle biopsy has become a pivotal tool for the identification, diagnosis, and preoperative grading of pancreatic neuroendocrine tumors (pNETs). The outstanding spatial resolution of EUS and the availability of new technologies raised the possibility of therapeutic applications aimed at local ablation for pNETs1. The two most common are the radiofrequency ablation (EUS-RFA) and ethanol injection (EUS-EI). The clinical indications and treatment outcomes are different in the case of pancreatic insulinoma or other functioning or non-functioning pNETs (NF-pNETs). For functioning tumors, the treatment aim is symptom control. Differently, for NF-pNETs, the treatment outcome is the complete ablation of the tumor. Being local treatments, EUS-RFA and EUS-EI should not be considered when there is a risk of malignant behavior/distant progression. Therefore, as a general principle, these treatments are not recommended for NF-pNETs larger than 2cm, suspected malignant insulinomas, or other than insulinoma functioning tumors.
Overall, EUS-RFA and EUS-EI are effective for treating tumors of small dimensions. Indeed, a meta-analysis2 and a large retrospective study3 demonstrated higher clinical efficacy of EUS-RFA for small (<18mm and <20mm, respectively) lesions. Safety seems associated with distance from the main pancreatic duct. Higher adverse event rates (most commonly acute pancreatitis) have been reported if the distance is <1mm3 or <2 mm4 from the main pancreatic duct. There are no significant differences between the two techniques regarding safety and efficacy1. However, EUS-RFA is currently more widespread in Western countries. Tissue sampling before treatment, although not mandatory, is advocated for nature and grading assessment.
Technique principles
EUS-RFA is currently performed using a 19G internally cooled needle electrode (EUSRA™, Taewoong Medical, South Korea) connected to an RFA current generator (VIVA Combo generator, Starmed), creating thermal energy to cause coagulation necrosis. This device works similarly to conventional EUS needles. The operator can choose the needle active tip length and the current wattage according to the tumor size. Multiple applications of RFA can be performed during the same session, each one usually lasting until the increase of tissue impedance. EUS-RFA can be repeated in case of clinical failure or symptom recurrence.
EUS-EI is performed using a conventional EUS needle prefilled with ethanol or ethanol and lipiodol. The solution is injected until the hyperechoic blush extends to the tumor margin. Usually, a maximum volume of 2 mL of ethanol is injected5.
FIGURE
Published by author permission
EUS-RFA technique. A) The tumor is identified and measured. B) A safe distance between the lesion and the main pancreatic duct is ascertained. The length of the needle active tip is chosen according to the tumor size (usually 1-2mm shorter). C). The needle tip is introduced into the tumor, and the length of the active tip is measured to ensure it is entirely within the lesion. D) The generator is activated, and the ablation is performed with one or multiple applications.
Safety, outcomes, and indications for pancreatic insulinomas
Pancreatic insulinomas are generally small (<2cm), sporadic, and carry a very low malignant potential, making these tumors likely the best candidates for EUS-guided ablation. A meta-analysis including 101 patients found a 17.8% (95% CI 9.1–26.4%) adverse event rate, with less than 1% being severe. Clinical efficacy, defined as disappearance of symptoms, was 95.1% (95% CI 91.2–98.9%)6. A propensity-score matched study comparing EUS-RFA with surgical resection demonstrated a higher safety profile with shorter hospital stay in patients who underwent EUS-RFA, with similar clinical efficacy to surgery. However, 16.9% of symptom recurrence was observed after EUS-RFA4. Based on this study, guidelines included EUS-RFA as treatment only for patients with insulinoma who are unfit for surgery7. However, considering that EUS-RFA does not preclude subsequent surgical resection in case of symptom recurrence, considering also the good safety profile and its high clinical efficacy, EUS-RFA could also be considered for patients fit for surgery, especially for tumors requiring high-risk resections (e.g., pancreato-duodenectomy or central pancreatectomy). A more limited experience with EUS-EI has been reported, with preliminary results similar to those of EUS-RFA8.
Anecdotal cases of EUS-guided treatments have been published for other functioning tumors. In this setting, EUS-guided ablation should be limited to symptom palliation in patients unfit for surgery.
Safety, outcomes, and indications for NF-Pan-NETs
A meta-analysis including 95 patients found a 24.6% (95% CI 7.4–41.8%) adverse event rate, with less than 1% being severe. Clinical efficacy, defined as disappearance of vascularized tissue on imaging, was 93.4% (95% CI 88.4–98.4%)6. For small (<2cm) NF-pNETs, EUS-RFA should find a place between active surveillance and surgical resection. Although active surveillance can be considered a safe option in the absence of suspicious signs (e.g., upstream dilation of the main pancreatic duct), in the real-life up to 20% of small NF-pNETs undergo surgical resection9. The most common reasons for resection are patient or physician’s preference, or, more rarely, tumor growth during follow-up9. In this scenario (treatment indication without risk signs), a local treatment could be justified, and EUS-RFA/EI could be considered as an alternative to surgical resection. Possible indications for considering EUS-guided treatments are summarized in the Table.
| Possible indications for considering EUS-guided treatments |
| Functioning pNETs in unfit for surgery patients |
| Small (<2cm) benign insulinomas distant more than 1mm from the main pancreatic duct |
| Small (<2cm) NF-pNETs if treatment is indicated for the following reasons: 1) Patient’s preference 2) Physician’s preference 3) Tumor growth during follow-up but still <2cm* |
| NF-pNETs of ≈ 20mm in fit patients but at high surgical risk (e.g., fatty pancreas, obesity, etc.) |
* Consider repeating EUS-guided sampling for Ki-67 assessment before treatment.
References
- Garg R, Mohammed A, Singh A, et al. EUS-guided radiofrequency and ethanol ablation for pancreatic neuroendocrine tumors: A systematic review and meta-analysis. Endosc Ultrasound. 2022; 11: 170-85.
- Imperatore N, de Nucci G, Mandelli ED, et al. Endoscopic ultrasound-guided radiofrequency ablation of pancreatic neuroendocrine tumors: a systematic review of the literature. Endosc Int Open. 2020; 8: E1759-E64.
- Napoléon B, Lisotti A, Caillol F, et al. Risk factors for EUS-guided radiofrequency ablation adverse events in patients with pancreatic neoplasms: a large national French study (RAFPAN study). Gastrointest Endosc. 2023; 98: 392-9.e1.
- Crino SF, Napoleon B, Facciorusso A, et al. Endoscopic Ultrasound-guided Radiofrequency Ablation Versus Surgical Resection for Treatment of Pancreatic Insulinoma. Clin Gastroenterol Hepatol. 2023; 21: 2834-43 e2.
- Choi JH, Park DH, Kim MH, et al. Outcomes after endoscopic ultrasound-guided ethanol-lipiodol ablation of small pancreatic neuroendocrine tumors. Dig Endosc. 2018; 30: 652-8.
- Armellini E, Facciorusso A, Crino SF. Efficacy and Safety of Endoscopic Ultrasound-Guided Radiofrequency Ablation for Pancreatic Neuroendocrine Tumors: A Systematic Review and Metanalysis. Medicina (Kaunas). 2023; 59.
- Hofland J, Falconi M, Christ E, et al. European Neuroendocrine Tumor Society 2023 guidance paper for functioning pancreatic neuroendocrine tumour syndromes. J Neuroendocrinol. 2023; 35: e13318.
- El Sayed G, Frim L, Franklin J, et al. Endoscopic ultrasound-guided ethanol and radiofrequency ablation of pancreatic insulinomas: a systematic literature review. Therap Adv Gastroenterol. 2021; 14: 17562848211042171.
- Partelli S, Massironi S, Zerbi A, et al. Management of asymptomatic sporadic non-functioning pancreatic neuroendocrine neoplasms no larger than 2 cm: interim analysis of prospective ASPEN trial. Br J Surg. 2022; 109: 1186-90.
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