Safety and efficacy of EUS-guided radiofrequency ablation for unresectable pancreatic insulinoma: a single-center experience

doi:10.21203/rs.3.rs-2221237/v1

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Safety and efficacy of EUS-guided radiofrequency ablation for unresectable pancreatic insulinoma: a single-center experience

https://doi.org/10.21203/rs.3.rs-2221237/v1

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Purpose

Insulinomas are rare, functioning pancreatic neuroendocrine neoplasms (pNEN), whose gold standard therapy is surgical resection. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a recent technique that has emerged as minimally invasive therapeutic option for patients with pancreatic lesions not eligible for surgery. In this study, we aimed to describe a series of patients with unresectable pancreatic insulinoma treated with EUS-RFA.

Methods

This is a single-center, retrospective study including all consecutive patients with functioning pancreatic insulinoma undergoing EUS-RFA for surgical unfitness or surgery refusal, between March 2017 and September 2021. Technical success, radiologic response, and adverse events rate were evaluated.

Results

A total of 10 patients (mean age: 67.1 ± 10.1 years; F:M 7:3) were enrolled. The mean size of insulinoma was 11.9 ± 3.3 mm. Technical success was achieved in 100% of patients, with an immediate normalization of serum glucose levels. Only one (10%) patient was successfully treated with two RFA sessions. The complete radiologic response within 3 months after EUS-RFA was observed in all patients (100%). Persistent euglycemia was assessed at 6 and 12 months for each treated patient. Three procedure-related early adverse events occurred, including two (20%) cases of mild abdominal pain, and one (10%) case of intraprocedural bleeding with spontaneous hemostasis. No major complications were observed within 48 hours after the procedure.

Conclusions

Data of this case series suggest that EUS-RFA is a feasible and safe therapeutic approach for unresectable pancreatic insulinomas with long-term efficacy.

endoscopic ultrasonography

radio-frequency ablation

insulinomas

neuroendocrine tumor

Insulinomas are the most frequent pancreatic neuroendocrine neoplasms (pNENs) and one of the most common causes of hypoglycemia, resulting from the inappropriate endogenous secretion of insulin. Hypoglycemia might cause a severe and invalidating syndrome characterized by neuroglycopenic and autonomic symptoms, such as diplopia, blurred vision, confusion, amnesia, weakness, and, most rarely, seizures and coma¹. Approximately in 5 to 10% of the cases, insulinomas are associated with multiple endocrine neoplasia type-1 syndrome (MEN-1)². Malignancy has been reported in less than 10% of patients¹.

Once the diagnosis of insulinoma is biochemically established by increased fasting serum insulin and C-peptide levels, endoscopic ultrasound (EUS) is the most accurate diagnostic tool for the detection of insulinomas, facilitating the recognition of lesions smaller than 2 cm and allowing tissue sampling by fine-needle biopsies (FNB) or aspiration (FNA). A recent meta-analysis reported that EUS has a sensitivity and specificity for the localization of insulinomas of 81% and 90%, respectively³. Computed tomography (CT)-scan, magnetic resonance imaging (MRI), and positron emission tomography (PET) are also commonly used to identify the primary tumor or metastatic lesions⁴.

According to the European Neuroendocrine Tumor Society (ENETS) Consensus Guidelines, surgery is the current therapy of choice for resectable pancreatic NENs⁵, being a curative treatment in 90% of patients with insulinoma^4,6. Surgical options range from enucleation to distal or partial pancreatectomy⁴, with sporadic but troublesome adverse events as pancreatic fistulae, deep vein thrombosis, and pancreatic insufficiency. In case of patients unfit or unwilling to undergo surgery, embolization or ablation have been reported to be effective alternative treatments in order to restore euglycemia⁷.

Radiofrequency ablation (RFA) is a technique that produces a selective thermal-induced coagulative necrosis of neoplastic tissue, and it has been used for a long time to treat abdominal tumors, as hepatocellular carcinoma⁸. The demonstrated efficacy and safety of EUS-guided radiofrequency ablation (EUS-RFA) applied to the pancreas of animal models has prompted to the use of this technique in humans with pancreatic lesions^9–11. However, to our knowledge a few case reports and small case series on EUS-RFA of pancreatic insulinomas are available, and whether this procedure is safe and clinically efficient has not been fully elucidated. In this observational study, we report a single-center cohort of patients that underwent EUS-RFA for pancreatic insulinoma to retrospectively assess the procedural safety together with its short- and long-term efficacy.

Patients

This is an observational, retrospective study which planned to include all patients who underwent EUS-RFA for pancreatic insulinoma between March 2017 and September 2021 at the Digestive Endoscopy Unit of our Institution (Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy). After multidisciplinary team assessment, EUS-RFA was indicated in patients unfit for surgery or unwilling to undergo it. Informed consent was obtained from each patient. All relevant demographic features, medical history, and procedure-related data were retrospectively collected, anonymized, and recorded into a predefined spreadsheet. This retrospective study was performed according to the Declaration of Helsinki for research in human subjects and was approved by our Ethical Committee (number 0012777/22).

EUS-RFA procedure

Endoscopic procedures were performed with a linear EUS endoscope (GF-UCT180, Olympus, Tokyo, Japan) by an endoscopist with a solid experience in EUS. All patients were previously hospitalized, and prophylactic intravenous antibiotic was administered prior to the procedures. EUS-RFA was performed under deep sedation with propofol by using a 19 Gauge monopolar RFA needle (EUSRA™ EUS-Guided RFA, TaeWoong Medical, Gyeonggi-do, South Korea) with a 5- or 10-mm active tip, and a dedicated RFA current generator system (VIVA Combo, STARmed), as presented in Fig. 1. An inner cooling system of the probe with circulating cold saline solution prevented tissue charring and increased ablation accuracy. RFA needle was inserted into the target lesions under EUS guidance, avoiding crossing pancreatic and bile ducts and major vessels (Fig. 2a). Needle tip was initially positioned at the far end of the lesion; additional passes were performed by the use of a fanning technique. RFA energy was applied at a variable power setting ranging from 10 to 50 W, in 1 to 14 cycles, each pass with a maximum duration of 20 seconds. Upon radiofrequency activation, the generator was switched off once hyperechoic bubbles started appearing around the needle tip, confirming tissue ablation.

- Contrast-enhanced harmonic EUS guidance

Contrast-enhanced harmonic EUS (CH-EUS) with intravenous injection of SonoVue (Bracco Imaging, Milan, Italy) was performed at the beginning of the procedure to better define lesions’ location, margins, and vascularity. CH-EUS was then repeated during the RFA procedure to delineate real-time vascular perfusion and detect residual neoplastic tissue to ablate.

Outcomes and follow-up

All patients were kept hospitalized for 48 hours and carefully monitored for any occurrence of early post-procedural adverse events (AEs), such as abdominal pain, acute pancreatitis, bleeding, and perforation. Clinical evaluation was planned within a month after the endoscopic procedure, in order to assess persistent hypoglycemia-related symptoms and low serum glucose levels. Radiologic response, assessed at 1 to 3 months by means of abdominal contrast-enhanced (CE)CT scan, was defined as the presence of a hypodense area at the site of the ablated lesion, suggestive for central necrosis (Fig. 2b).

After successful RFA treatment, recurrence was evaluated at 6 and 12 months by clinical monitoring.

Statistics

A descriptive statistical analysis was performed for all available variables, and data were expressed as number of total and/or percentage, mean and standard deviation (SD), or median and range when appropriate. Statistic software SPSS (IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp) was used for all computations.

We retrospectively collected data from 10 patients (7 females and 3 males, mean age 67.1 ± 10.1 years) who underwent EUS-RFA for pancreatic insulinoma in our Institution. Patients’ characteristics are summarized in Table 1. In this cohort, 2 (20.0%) patients had a multiple endocrine neoplasia type 1 (MEN-1) syndrome, while the remaining 8 (80.0%) subjects had sporadic insulinoma. All patients presented with hypoglycemia-related symptoms, and 9 (90.0%) had positive fasting test. 5 (50.0%) insulinomas were detected by CECT scan, and 3 (30.0%) by abdominal MRI. Moreover, an increased uptake on 68Ga-DOTATATE PET/CT was assessed in 8 (80.0%) out of 10 lesions. Finally, all insulinomas were identified through EUS evaluation and EUS-guided fine needle biopsy (FNB) sampling was performed. 3 (30.0%) lesions were localized in the uncinate process, 3 (30.0%) in the pancreatic body, and 4 (40.0%) in the pancreatic tail, with a mean size of 11.9 ± 3.3 mm, ranging from 8 to 19 mm. Upon histopathologic examination, 9 (90.0%) out of 10 insulinomas were well-differentiated G1 tumors (Ki67 < 3%); only one (10.0%) patient had well-differentiated G2 insulinoma (Ki67 range 3–20%). After multidisciplinary assessment, EUS-RFA as treatment of choice for pancreatic insulinoma was indicated for surgical unfitness in 7 (70.0%) cases, while the remaining 3 (30.0%) patients refused surgery.

Details regarding EUS-RFA procedure are summarized in Table 2. Technical success was achieved in all patients. 9 (90.0%) out of 10 subjects underwent a single EUS-RFA session, and symptomatic and biochemical signs of hypoglycemia disappeared within 24 hours. In 8 (80.0%) treated patients, real-time CH-EUS findings showed the disappearance of intratumoral enhancement pattern. Given the larger tumor size (19 mm), the residual hyperenhanced pattern on CH-EUS, and persistent hypoglycemia-related symptoms after the first RFA treatment, one (10.0%) patient was treated with an additional session of RFA, observing a subsequent normalization of serum glucose levels.

In 2 (20.0%) cases, mild post-procedural abdominal pain occurred within 24 hours and was treated with a single administration of non-opioid analgesics. In one single case early bleeding was reported, followed by spontaneous hemostasis. No late AEs related to the procedure were reported.

Radiologic complete response, assessed by abdominal CECT as above-mentioned within 90 days after the EUS-RFA, was achieved in all treated patients (100.0%). However, the 2 (20.0%) patients with MEN-1 met the need of systemic therapy with octreotide. Clinical remission, meant as the presence of normal serum glucose levels and the absence of hypoglycemia-related symptoms, was assessed for all patients (100.0%) at 6 and 12 months after the procedure. Moreover, abdominal CECT performed at 12 months was available in 3 (30.0%) out of 10 patients, and showed in all cases a central nonenhancing hypodense area on the site of the ablated lesion.

In the present study we retrospectively described 10 cases of selected patients with pancreatic insulinoma treated with EUS-RFA. To our knowledge, we herein reported the largest European series of patients with insulinoma undergoing this procedure.

EUS-RFA was technically successful in 100% of the cases, with excellent immediate benefits on the regulation of blood glucose levels and complete relief of hypoglycemia-related symptoms. After the endoscopic treatment, a radiologic evaluation documented hypovascularization with central necrosis of all ablated insulinomas. Moreover, EUS-RFA has proved to be safe, and no severe adverse events were observed after the procedure. Mild abdominal pain occurred only in 2 patients and was treated conservatively. Finally, we documented the long-term efficacy of EUS-RFA on pancreatic insulinomas by reporting a persistent maintenance of patients’ clinical remission.

RFA is widely used as a minimally invasive therapeutic alternative in several gastrointestinal diseases^12,13. The introduction of this technique in pancreatic disease occurred in 1999, when Goldberg et al. first documented the use of EUS-RFA in porcine pancreas⁹. Since then, the application of this procedure in human subjects with pancreatic lesions, such as pNENs, pancreatic carcinomas, and intraductal pancreatic mucinous neoplasms (IPMNs), has gradually increased¹⁴. However, the role of EUS-RFA in the management of functioning pancreatic insulinomas has not been fully established.

To date, a quite good number of observational studies with a very limited volume of patients have described the application of EUS-RFA in pancreatic insulinomas^15–28. These are summarized in Table 3. In total, 44 cases with 100% technical success have been reported, and post-procedural euglycemia was reached in all patients. More than one RFA treatment was required in only 4 subjects complaining of persistent hypoglycemic symptoms with partial radiologic response^15,23,28.

Mild to severe procedure-related adverse events were described in 10 patients, including fever, edematous and necrotic acute pancreatitis, and bleeding^{18,20,23,25,27,28}.

Our data show that EUS-RFA is a safe and feasible option in the treatment of pancreatic insulinomas for all individuals with high surgical risk, and for those that prefer a less invasive treatment than surgical resection. In fact, EUS-RFA allows for selective ablation of small neoplastic lesions with minimal damage to the surrounding normal tissue, preventing the development of pancreatic insufficiency in the case of pNENs.

Lacking standardized protocols for power settings and number of passes, we reported different technical approaches for each treated patient. Specifically, in our first case a higher power (50 W) was used within a single session. Despite the favorable outcome, we thereafter reduced the medium applied wattage, and concurrently increased the number of passes per session together with the time of RF application. This is in line with previous studies, in which higher power setting was noted to be associated with smaller ablation zones, and with a major risk of procedure-related adverse events¹¹.

Nevertheless, a multidisciplinary evaluation of all subjects with pancreatic insulinoma is recommended to provide the most appropriate therapeutic option. Lesions difficult to approach, as the ones close to the mesenteric vessels and pancreatic duct, and increased size of insulinomas may affect safety and effectiveness of EUS-RFA. Hence, endoscopic treatment of pancreatic insulinomas could be indeed very challenging even for expert operators, and complications occurrence is not always foreseeable. Aiming at preventing post-procedural acute pancreatitis, Kandla et al. documented the positioning of a prophylactic pancreatic stent 20 days prior to the EUS-RFA of an insulinoma close to main pancreatic duct²⁰. Though, after the procedure the patient experienced a mild acute pancreatitis, that was treated conservatively²⁰. To our warning, this technique does not have enough evidence to decide for its application, and further data are necessary to fully explore the role of pancreatic stenting prior to EUS-RFA.

Limited data regarding the use of CH-EUS during EUS-RFA of insulinomas are currently available. To our knowledge, only Choi et al. reported 19 cases of solid abdominal tumors treated with CH-EUS-assisted RFA, of which only one was an insulinoma²⁹. In this case series, the one male patient with insulinoma experienced immediate remission of hypoglycemic symptoms after the ablation, although he had a recurrence at 19 month-follow-up²⁹. However, the Authors highlighted all benefits of CH-EUS as part of EUS-RFA, such as the identification of the residual neoplastic tissue, and the assessment of early response to the ablation. In line with Choi et al., real-time CH-EUS guidance allowed us to detect with high sensitivity remnant neoplastic areas within a single RFA session, and to decide for an additional RFA treatment of a larger insulinoma without an earlier CT assessment.

Our study has some limitations. First, this is a non-comparative, retrospective study with a very limited sample size. Secondly, the median follow-up of all treated patients was relatively short: as most part of insulinomas are slow-growing neoplasms and the risk of recurrence after RFA is currently unknown, a constant monitoring should last appropriately at least a few years. Third, presumptive ablation response has been immediately assessed in 8 out of 10 cases with CH-EUS, and later in each patient by a CT-based imaging. Though in line with the previous published studies, no histopathological confirmation of the complete necrosis was obtained.

In conclusion, EUS-RFA is a less invasive alternative to resection of pancreatic insulinomas in patients not eligible for surgery or refusing surgical treatment. In our retrospective study, we reported the successful treatment with EUS-RFA of a series of symptomatic insulinomas, providing the feasibility, safety, and long-term efficacy of this endoscopic procedure. Multicenter studies with larger sample size, comparing surgery with RFA are required to standardize the procedural settings, define a longer follow-up, and assess potential response predictors of EUS-RFA. This could consecutively open a new path for an alternative therapeutic option for pancreatic insulinoma.

Funding: The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Competing Interests: Ivo Boskoski is a consultant for Apollo Endosurgery, Cook Medical, BostonScientific, and Nitinotes. Guido Costamagna is a consultant for Cook Medical, Boston Scientific, and Olympus. All the other authors have nothing to declare.

Author Contributions: Federica Borrelli de Andreis, Ivo Boskoski, and Fabia Attili planned the study. Fabia Attili performed the endoscopic procedures and collected the data. Federica Borrelli de Andreis interpreted the data and drafted the manuscript. All the Authors revised and approved the final version of the manuscript.

Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome (number 0012777/22).

Consent to participate: Informed consent was obtained from all individual participants included in the study.

Consent to publish: The authors affirm that human research participants provided informed consent for publication of the images in Figures 1a, 1b, 2a, and 2b.

Maggio I, Mollica V, Brighi N, et al. The functioning side of the pancreas: a review on insulinomas. J Endocrinol Invest 2020; 43: 139–148.
de Herder WW, Niederle B, Scoazec J-Y, et al. Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology 2006; 84: 183–188.
Wang H, Ba Y, Xing Q, et al. Diagnostic value of endoscopic ultrasound for insulinoma localization: A systematic review and meta-analysis. PLoS One 2018; 13: e0206099.
Tsoli M, Chatzellis E, Koumarianou A, et al. Current best practice in the management of neuroendocrine tumors. Ther Adv Endocrinol Metab 2019; 10: 2042018818804698.
Falconi M, Eriksson B, Kaltsas G, et al. ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. NEN 2016; 103: 153–171.
Mehrabi A, Fischer L, Hafezi M, et al. A systematic review of localization, surgical treatment options, and outcome of insulinoma. Pancreas 2014; 43: 675–686.
Mele C, Brunani A, Damascelli B, et al. Non-surgical ablative therapies for inoperable benign insulinoma. J Endocrinol Invest 2018; 41: 153–162.
Nikfarjam M, Muralidharan V, Christophi C. Mechanisms of focal heat destruction of liver tumors. J Surg Res 2005; 127: 208–223.
Goldberg SN, Mallery S, Gazelle GS, et al. EUS-guided radiofrequency ablation in the pancreas: results in a porcine model. Gastrointest Endosc 1999; 50: 392–401.
Gaidhane M, Smith I, Ellen K, et al. Endoscopic Ultrasound-Guided Radiofrequency Ablation (EUS-RFA) of the Pancreas in a Porcine Model. Gastroenterol Res Pract 2012; 2012: 431451.
Gollapudi LA, Tyberg A. EUS-RFA of the pancreas: where are we and future directions. Translational Gastroenterology and Hepatology; 7. Epub ahead of print 25 April 2022. DOI: 10.21037/tgh-2020-11.
Rhim H, Lim HK. Radiofrequency Ablation of Hepatocellular Carcinoma: Pros and Cons. Gut Liver 2010; 4: S113–S118.
Becq A, Camus M, Rahmi G, et al. Emerging indications of endoscopic radiofrequency ablation. United European Gastroenterol J 2015; 3: 313–324.
Dhaliwal A, Kolli S, Dhindsa BS, et al. Efficacy of EUS-RFA in pancreatic tumors: Is it ready for prime time? A systematic review and meta-analysis. Endosc Int Open 2020; 8: E1243–E1251.
Waung JA, Todd JF, Keane MG, et al. Successful management of a sporadic pancreatic insulinoma by endoscopic ultrasound-guided radiofrequency ablation. Endoscopy 2016; 48 Suppl 1: E144-145.
Bas-Cutrina F, Bargalló D, Gornals JB. Small pancreatic insulinoma: Successful endoscopic ultrasound-guided radiofrequency ablation in a single session using a 22-G fine needle. Dig Endosc 2017; 29: 636–638.
Choi J-H, Seo D-W, Song TJ, et al. Endoscopic ultrasound-guided radiofrequency ablation for management of benign solid pancreatic tumors. Endoscopy 2018; 50: 1099–1104.
Gueneau de MP, Lamine F, Godat S, et al. A case of benign insulinoma successfully treated with endoscopic ultrasound guided radiofrequency ablation. In: Endocrine Abstracts. Bioscientifica. Epub ahead of print 8 May 2018. DOI: 10.1530/endoabs.56.P121.
Oleinikov K, Dancour A, Epshtein J, et al. Endoscopic Ultrasound-Guided Radiofrequency Ablation: A New Therapeutic Approach for Pancreatic Neuroendocrine Tumors. J Clin Endocrinol Metab 2019; 104: 2637–2647.
Kandula S, Aurangabadker G. Management of a difficult case of insulinoma with radiofrequency ablation. Indian J Endocrinol Metabol; 23: S46–1S7.
de Nucci G, Imperatore N, Mandelli ED, et al. Endoscopic ultrasound-guided radiofrequency ablation of pancreatic neuroendocrine tumors: a case series. Endosc Int Open 2020; 8: E1754–E1758.
Furnica RM, Deprez P, Maiter D, et al. Endoscopic ultrasound-guided radiofrequency ablation: An effective and safe alternative for the treatment of benign insulinoma. Ann Endocrinol (Paris) 2020; 81: 567–571.
Lakhtakia S, Memon SFF, Medarapalem JB, et al. 728 SUSTAINED CLINICAL RESPONSE WITH EUS GUIDED RFA OF PANCREATIC INSULINOMA. Gastrointestinal Endoscopy 2020; 91: AB64.
Jonica ER, Wagh MS. Endoscopic treatment of symptomatic insulinoma with a new EUS-guided radiofrequency ablation device. VideoGIE 2020; 5: 483–485.
Kluz M, Staroń R, Krupa Ł, et al. Successful endoscopic ultrasound-guided radiofrequency ablation of a pancreatic insulinoma. Pol Arch Intern Med 2020; 130: 145–146.
Brown NG, Patel AA, Gonda TA. Immediate and durable therapeutic response after EUS-guided radiofrequency ablation of a pancreatic insulinoma. VideoGIE 2020; 5: 676–678.
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: 1256–1263.
Rossi G, Petrone MC, Capurso G, et al. Endoscopic ultrasound radiofrequency ablation of pancreatic insulinoma in elderly patients: Three case reports. World J Clin Cases 2022; 10: 6514–6519.
Choi J-H, Seo D-W, Song TJ, et al. Utility of Contrast-Enhanced Harmonic Endoscopic Ultrasound for the Guidance and Monitoring of Endoscopic Radiofrequency Ablation. Gut Liver 2020; 14: 826–832.

Tables 1 to 3 are available in the Supplementary Files section.

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Safety and efficacy of EUS-guided radiofrequency ablation for unresectable pancreatic insulinoma: a single-center experience

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusions

Figures

Introduction

Materials And Methods

Patients

EUS-RFA procedure

- Contrast-enhanced harmonic EUS guidance

Outcomes and follow-up

Statistics

Results

Discussion

Declarations

References

tables

Supplementary Files

Status:

Version 1