Endoscopic submucosal dissection: Italian national survey on current practices, training and outcomes

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Contents lists available at ScienceDirect

Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld

Digestive Endoscopy

Endoscopic submucosal dissection: Italian national survey on current practices, training and outcomes Roberta Maselli a,∗ , Federico Iacopini b , Francesco Azzolini c , Lucio Petruzziello d , Mauro Manno e , Luca De Luca f , Paolo Cecinato g , Giancarla Fiori h , Teresa Staiano i , Erik Rosa Rizzotto j , Stefano Angeletti k , Angelo Caruso l , Franco Coppola m , Gianluca Andrisani n , Edi Viale c , Guido Missale o , Alba Panarese p , Alessandro Mazzocchi q , Paola Cesaro r , Mariachiara Campanale d , Pietro Occhipinti s , Ottaviano Tarantino t , Cristiano Crosta h , Piero Brosolo u , Sandro Sferrazza v , Emanuele Rondonotti w , Arnaldo Amato w , Lorenzo Fuccio x , Guido Costamagna y,z,A , Alessandro Repici a,B a

Digestive Endoscopy Unit, Division of Gastroenterology, Humanitas Research Hospital, Humanitas University, Milan, Italy Gastroenterology Endoscopy Unit, S. Giuseppe Hospital, Rome, Italy c Division of Gastroenterology & G.I. Endoscopy, Vita Salute San Raffaele University, Milan, Italy d Digestive Endoscopy Unit, Division of Gastroenterology Fondazione A. Gemelli–Università Cattolica del Sacro Cuore Hospital, IRCCS, Rome, Italy e Digestive Endoscopy Unit, USL Modena, Carpi Hospital, Italy f Division of Gastroenterology & G.I. Endoscopy, Ospedali Riuniti Marche Nord Hospital, Pesaro, Italy g Unit of Gastroenterology and Digestive Endoscopy, USL-IRCCS Reggio Emilia Hospital, Reggio Emilia,Italy h IEO, Digestive Endoscopy Unit, Istituto Europeo di Oncologia IRCCS Hospital, Milano, Italy i Digestive Endoscopy Unit, FPO-IRCCS Candiolo Cancer Institute, Candiolo, TO, Italy j Division of Gastroenterology & G.I. Endoscopy, S. Antonio Hospital, Padova, Italy k Digestive Endoscopy Unit, Sant’Andrea Hospital, a Sapienza university, Roma, Italy l Division of Gastroenterology & G.I. Endoscopy, Baggiovara Hospital, AOU di Modena, Italy m Digestive Endoscopy Unit, Division of Gastroenterology, ASLTO4, Turin, Italy n Digestive Endoscopy Unit, Campus Biomedico Hospital, Rome, Italy o Digestive Endoscopy Unit, ASST Spedali Civili, Brescia University, Italy p Department of Gastroenterology and Digestive Endoscopy, National Research Institute specialized in Gastroenterology " S. De Bellis" , Castellana Grotte, BA, Italy q Gastroenterology Endoscopy Unit, San Giovanni Battista Hospital, San Giovanni battista, Italy r Endoscopy Unit, Fondazione Poliambulanza, Brescia, Italy s Division of Gastroenterology, " Maggiore della Carità " Hospital and University, Novara, Italy t Division of Gastroenterology & G.I. Endoscopy, San Giuseppe Hospital, ASL Toscana centro, Empoli, Italy u Division of Gastroenterology, Hospital of Pordenone, Pordenone, Italy v Gastroenterology and Endoscopy Unit, Santa Chiara Hospital, APSS, Trento, Italy w Gastroenterology and Digestive Endoscopy Unit, Valduce Hospital, Como, Italy x Department of Medical and Surgical Sciences, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy y Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy z Cattolica del Sacro CuoreUniversity, Centre for Endoscopic Research Therapeutics and Training CERTT, Roma, Italy A Université de Strasbourg Institut d’Etudes Avancées USIAS, Strasbourg, France B Humanitas University, Department of Biomedical Science, Milan, Italy b

a r t i c l e

i n f o

Article history: Received 29 December 2018 Accepted 11 September 2019 Available online xxx Keywords: Early GI tumor

a b s t r a c t Background and Aims: Most of the evidence supporting endoscopic submucosal dissection (ESD) comes from Asia. European data are primarily reported by specialized referral centers and thus may not be representative of common European ESD practice. The aim of this study is to understand the current state of ESD practice across Italian endoscopy centers. Methods: All Italian endoscopists who were known to perform ESD were invited to complete a structured questionnaire including: operator features and competencies, ESD training details and clinical outcomes over a 2-year period.

∗ Corresponding author at: Digestive Endoscopy Unit, Humanitas Research Hospital, Via Manzoni 56, Rozzano Milano, 20089, Italy. E-mail address: [email protected] (R. Maselli). https://doi.org/10.1016/j.dld.2019.09.009 1590-8658/© 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Maselli R, et al. Endoscopic submucosal dissection: Italian national survey on current practices, training and outcomes. Dig Liver Dis (2019), https://doi.org/10.1016/j.dld.2019.09.009

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2 Endoscopy ESD Survey

Results: Twenty-nine operators from 23 centers (69% response rate) completed the questionnaire: 18 (62%) were <50 years old; 7 (24%) were female; 16 (70%) were located in Northern Italy. Overall ESD volume was <40 cases in 9 (31%) operators, 40–80 in 8 (27.5%), 80–150 in 4 (13.8%) and >150 in 8 (27.5%). Colorectal ESD was predominant for operators with an experience >80 cases. En-bloc resection rates ranged from 77.2 to 97.2% depending on the anatomic location with an R0 resection rate range of 75.3–93.6%. ESD perforation rates in the colon and rectum were significantly lower when experience was >150 compared to 80–150 cases (p < 0.0001 and p = 0.006 for colon and rectum, respectively). Conclusion: ESD in Italy is performed by a significant number of operators. Overall, Italian endoscopists performing ESD have achieved a good competence level. However, there is much variability in training protocols, initial supervision of procedures, practice settings, case mix and procedural volume/year that are likely responsible for some of the suboptimal resectional outcomes and increased perforation risk, mainly in the colon. Standardized training programs, practice parameters and auditing of outcomes are required. © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

1. Background Endoscopic submucosal dissection(ESD) was developed to bypass the limits of endoscopic mucosal resection (EMR), facilitating en-bloc resection of GI (gastrointestinal) lesions >20 mm. En-bloc resection potentially leads to an oncologically adequate resection with a low risk of local recurrence. ESD was first described by Japanese endoscopists in 2008; only now is it progressively gaining more attention in Western countries. Depite its widespread adoption across Asian countries, in Europe ESD is still considered a difficult and risky procedure. Until now, only a few European centers have been able to achieve outcomes at the level reported by Japanese experts. The main difficulty in performing ESD is its long learning curve: this complex and delicate procedure involves many aspects, namely (1) lesion recognition and characterization; (2) accurate decision making to apply to correct treatment to the lesion at hand (mucosal resection vs. ESD vs. surgical resection); (3) understanding of patient positioning and use of gravity to provide traction; (4) many technical aspects including a deep understanding of the proper use of the electrosurgical unit, various instruments and devices; and (5) a high level of endoscopic skill and refined tip control so as to be able to safely complete the procedure and manage complications [1]. To our knowledge, a structured learning setting is still not available in Italy, as in many European countries, thus most of the current Italian ESD performers have been trained abroad, mainly in Japan, across different settings and periods of time. Due to these varying degrees of training and also to the different practice settings across the country (academic/community/tertiary), it is desirable to survey the Italian ESD experience in order to audit ESD performance as a prerequisite to the optimization of future training, practice parameters and patient outcomes. The aim of this study, therefore, was to gain a greater understanding of ESD adoption, training of physicians, volume of procedures and practice parameters (including intra-procedural, post-procedural, and follow-up outcomes) across Italian centers who routinely perform advanced tissue resection.

2. Materials and methods Between March and April 2018, Italian endoscopists who were known to perform GI (gastrointestinal) advanced tissue resection (identified through peer networks, conference participation and published works) were invited by email to complete a structured questionnaire comprising operator features and endoscopic competencies, details of ESD training and retrospective extraction of

ESD outcomes for esophageal, gastric and colorectal neoplasms over a 2-year period from January 2016 to December 2017. For the purpose of collecting detailed clinical information about ESD practice, participants were asked to retrospectively self-report outcomes for all consecutive GI tract lesions resected by ESD technique (inclusion criterion) excluding those resections intentionally performed from the beginning via hybrid techniques (exclusion criteria): specifically endoscopic mucosal resection (EMR) after small mucosal incisions, EMR after a circumferential mucosal incision, or EMR after partial submucosal dissection. Resectional outcomes were defined as follows:

- Complete resection = absence of any endoscopically visualized residual neoplasia at the end of the procedure. - ESD = complete resection performed with an electrosurgical knife without the use of a snare or other such accessory instrument (“pure” ESD). - Hybrid-ESD = complete resection initially planned to be performed entirely by ESD but converted to EMR for any reason. - R0 = histopathological complete resection with negative vertical and lateral margins (applied only to en-bloc resections). - Curative resections = depending on the organ, according to the ESGE criteria [2].

To evaluate the safety of the ESD procedures, we also assessed the self-reported rate of serious adverse events during and after the procedure, namely intra-procedural bleeding (defined as bleeding sufficient to require ESD interruption), postprocedural bleeding (defined as any post-ESD hematochezia or a decrease in hemoglobin concentration of more than 2 g/dl requiring transfusion, endoscopic hemostasis, hospital re-admission or surgical/radiological interventons), intra- and post-procedural perforations and the details of subsequent management.

3. Statistics Data were collected, analysed and extracted with graphs and analysis performed using SPSS (IBM SPSS Inc, Chicago, Illinois). Percentages were calculated based on the total number of survey participants and the number of responses to each individual question. Data were collected and analysed by means of descriptive statistics (mean and standard deviation). The Student’s t test was used to compare the distribution of continuous variables by outcome. All differences were considered significant at two-sided P-value <0.05.

Please cite this article in press as: Maselli R, et al. Endoscopic submucosal dissection: Italian national survey on current practices, training and outcomes. Dig Liver Dis (2019), https://doi.org/10.1016/j.dld.2019.09.009

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4. Results Forty-two operators from 34 Italian centers were invited by e-mail to participate in the survey and 29 individuals (69%) from 23 centers completed the questionnaire. Data were analyzed according to four categories: (1) operator demographics and competencies; (2) ESD training and initial experience; (3) ESD practice settings; (4) ESD outcomes. Information was provided from 15 (65.3%) centers in Nothern Italy, 7 (30.5%) from the Center and 1 (4.2%) from the South. No centers were represented from the islands of Sicily or Sardinia (Fig. 1). Four centers (17.3%) had two ESD operators, only 1 (4.4%) had three; all the other centers had a single operator (78.3%) performing ESD. Of the participating centers, 7 (30.5%) were an academic hospital and 16 (69.5%) were community hospitals; in 3 (13%) the endoscopic unit was part of a Surgical Department and in 20 (87%) part of a Gastroenterological Department. Most of the centers (19/23, 82.6%) had an Emergency Department. 5. Demographics and competencies Data on the 29 phsyicians were analyzed; most (75.9%) were male (M/F = 22/7). Eleven (37.9%) were >50 years old, 10 (34.5%) 41–50 years old and 8 (27.6%) 30–40 years old; none were younger than 30 years old. The date of medical degree completion ranged from 1975 to 2010. Most of the operators (75.9% 22/29) were specialized in gastroenterology, 4 (13.8%) in surgery and 3 (10.3%) in both gastroenterology and surgery. Regarding endoscopic competencies, all declared to routinely perform EMR, 25/29 (86.2%) were also competent in ERCP, 11/29 (37.9%) in EUS, 14/29 (48.3%) in endoscopic suturing and 6 (20.7%) in per-oral endoscopic myotomy (POEM). Finally, almost all operators (28/29, 96.6%) routinely performed endoscopy for GI emergencies. 6. ESD training and initial experience Ranging from 2002 to 2017, 25/29 (86.2%) of the endoscopists interviewed had specific traning for ESD: 9 of them (31%) for a single period of time and 16 (55.2%) for more than 1 period. The total training period was <3 weeks for 12 participants (41.4%), 1 to 3 months for 8 (27.6%) and more than 3 months for 5 (17.2%). Thirteen endoscopists (44.8%) were trained in Japan, 6 (20.7%) in Europe outside of Italy, and 6 (20.7%) in Italy. All but 2 (6.9%) respondents started their initial ESD experience on ex-vivo models: 8 (27.5%) performed ESD on ≤5 models, 11 (11/29, 37.9%) on 6–10 models, 4 (4/29, 13.8%) on 11–25 models, 4 (4/29, 13.8%) on >26 models. The mean number of ex-vivo models used in this training phase was 11.57 ± 11.6. After the initial ex-vivo experience, all but 7 (24.1%) performed in-vivo animal ESD procedures: 14 of them (48.3%) in ≤5 models, 5 (17.2%) in 6–10 models and 3 (10.3%) in >10 models. The mean number of in-vivo models used in this training phase was 5.04 ± 5.8. Analyzing the first 40 cases performed in humans, ESD was mainly performed in the stomach and in the rectum, whereas few operators treated esophageal/GEJ (gastro-esophageal junction) and colonic lesions (Fig. 2). For most of the participants (19/29, 65.5%), the first few patients were treated without any expert supervision; a tutor was present in 1–5 procedures in 7/29 (24.1%) and in more than 5 procedures in 3/29 (10.3%). All participants were asked to estimate their overall GI ESD experience according to different anatomic locations and to seven different range frequencies (0, <10, 11–20, 21–40, 41–80, 81–150,

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>150). Considering a total volume <40 procedures performed as a low ESD experience indicator [3], data demostrated that almost 1/3 of the participants were in their initial experience phase (9/29, 31%). These data are shown in Fig. 3. 7. ESD settings Most of the participants (23/29, 79.3%) reported inpatient hospitalization of all patients after the ESD procedure; only 6 (20.7%) also used a day-surgery setting at times. Almost half of the participants used deep unconscious sedation administered by a dedicated anesthesiologist for both upper and lower GI ESD (44.8% for upper GI and 48.2% for lower GI). Only 4/29 respondents (13.8%) routinely performed an ECG, blood tests and/or a chest X-ray before all ESDs; 22/29 (75.9%) only performed them due to institutional anesthesiology policy requirements; 3/29 (10.3%) did not perform any routine pre-operative tests. Regarding endoscopic technique for ESD, all reported using an HD-endoscope with virtual/digital chromoendoscopy, the exact modality being dependent on the endoscope brand available in their center. As to the further characterization of GI lesions, different staining solutions were reported; dye solutions for conventional chromoendoscopy were routinely sprayed before resections by 13/29 (44.8%) participants, while only occasional use of conventional chromoendoscopy was reported by 16/29 (55.2%). Before resection, a radiological (CT or MRI depending by the organ) and/or EUS staging modality was routinely performed by 13/29 (44.8%) for upper-GI lesions and by 10/29 (34.5%) for lower GI lesions; 2/29 (6.9%) were using these modalities only in selected cases. The usage of ESD operating devices/accessories was variable: a CO2 insufflator was used and available for most of the operators (26/29, 89.7%); almost all (28/29, 96.6%) used a an endoscope with forward water-jet capability. Most of the participants (58.6%) preferred a straight distal attachment cap and 27/29 (93%) used either a Dualknife (Olympus, Japan) or a HybridKnife (ERBE, Germany) for the mucosal incision and subsequent submucosal dissection. In particular, 9/27 (33.3%) preferred a Dualknife, 6/27 (22.3%) preferred the HybridJnife and 11/27 (40.7%) used both knifes at times. A water-jet knife (ERBE Hybridknife, Olympus J-knives or Fujifilm flush-knife) was available in the endoscopic unit for 23/29 (79.3%) participants, and it was preferentially used by 17/29 (58.6%). The use of different knives during a single ESD procedure was reported to be very common (in >30% of the procedures) by 5 participants (17.2%), common (in 10–30% of the procedures) by 3 (10.3%) and uncommon (in <10% of the procedures) by 21 (72.4%). Most of the endoscopists interviewed (19/29, 65.5%) preferred saline +/- an additional solution (glycerol, hyaluronic acid, hydroxypropylmethylcellulose, plasma expander) to be injected in the submucosa; 6/29 (20.7%) and 4/29 (13.8%) preferred pure glycerol solution and plasma expanders, respectively. Finally, 26/29 (89.7%) added dilute epinephrine to the injectate. 8. ESD outcomes Outcomes data were collected for a two year period (Jan. 201–Dec. 2017) and included en-bloc resection rate, R0 resection rate, curative resection rate and complications. Esophageal/GEJ, gastric, colonic and rectal ESDs were separately analyzed. Overall, the data showed a high en-bloc rate, with a peak rate for esophageal ESD (95%), and a lower rate for colonic ESD (77%). A similar trend was observed for the R0 resection rate (88% for esophageal, 75% for colonic ESD). The curative resection rate was

Please cite this article in press as: Maselli R, et al. Endoscopic submucosal dissection: Italian national survey on current practices, training and outcomes. Dig Liver Dis (2019), https://doi.org/10.1016/j.dld.2019.09.009

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Fig. 1. Geographical distribution of the 23 centers that completed the ESD survey.

Table 1 ESD outcomes related to 2016 and 2017, separately reported for esophageal/GEJ, gastric, colonic and rectal ESDs. Esophagus/GEJ

N Age, mean (±SD) Female sex, n (%) Total en-bloc, n (%) ESD en-bloc Hybrid ESD en-bloc Piecemeal complete resection Incomplete resection Total R0, n (%) ESD R0 Hybrid ESD R0 Total Curative resection, n (%) ESD curative resection, n (%)a Piecemeal curative resection, n (%)a

Stomach

Colon

Rectum

2016

2017

2016

2017

2016

2017

2016

2017

60 63.8 ± 11.6 25 (41.6) 57 (95) 53 4 3 – 53 (88.3) 49 4 48 (80) 48 (84.2) –

49 62.7 ± 8.8 9 (18.4) 47 (95.9) 44 3 1 1 43 (87.7) 40 3 38 (77.5) 37 (78.7) 1 (100)

251 79.8 ± 30.9 59 (23.5) 240 (95.6) 219 22 8 2 235 (93.6) 216 19 211 (84) 209 (86.7) 2 (25)

251 55.8 ± 29.3 88 (35) 244 (97.2) 205 40 5 1 228 (90.8) 197 31 206 (82) 201 (82.0) 5 (100)

316 80 ± 33.4 97 (30.7) 244 (77.2) 181 63 67 5 239 (75.6) 174 65 236 (74.6) 179 (73.3) 57 (85.0)

293 42.3 ± 34 91 (31) 241 (82.2) 188 53 46 6 226 (77.1) 175 51 214 (73) 182 (75.5) 32 (69.6)

383 68.9 ± 5 123 (32.1) 331 (86.4) 262 69 47 5 314 (81.9) 252 62 276 (72) 236 (71.3) 40 (85.1)

353 68.7 ± 4.2 103 (29.2) 292 (82.7) 232 60 59 2 266 (75.3) 211 55 241 (68.2) 201 (68.8) 40 (67.8)

a The percentage refers to the relative curative resection rates for ESD and for piecemeal resection (number of curative resections obtained by ESD and piecemeal resection, compared to the total number of ESD and piecemeal resections, respectively).

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Fig. 2. Reported anatomic location and number of lesions treated at the beginning of human ESD experience (first 40 patients).

highest for gastric and esophageal lesions (84% and 80%, respectively) and lowest for rectal lesions (68%). At all anatomic locations, the curative resection rate was similar for en-bloc resections compared to piecemeal complete resections, although a smaller number of piecemeal resections have been performed compared to ESD. These data are summarized in Table 1. Analyzing the safety outcomes (Table 2), colonic ESD was associated with a higher risk of complications (intra-procedural perforation rate of 8.5% in 2016 and 7.1% in 2017). Overall, postprocedural perforations were rare, with the frequency ranging from 0.3-0.8% across the anatomic locations. In total, eight out of 130 (6.1%) perforations (intra- or post-procedural) required surgery. Intra-procedural bleeding caused the interruption of the ESD procedure in 0.3–1.0% of cases. On the contrary, significant postprocedural bleeding occurred more commonly, especially in the stomach (10.7% in 2016 and 7.9% in 2017). Regardless of the site of ESD, in most of the cases (55.6–100%), endoscopic intervention led to successful control of the bleeding episode; few cases required surgery and/or radiological interventions (5.0–8.7%). Death within 30-days of the ESD procedure was reported after 1 gastric ESD (0.4%) and 1 rectal ESD (0.3%). The patient who underwent the gastric ESD was a 78 year-old man with a history of remote myocardial infarctions. His chronic anti-platelet agent had been held for 5 days prior to the procedure. Forty-eight hours after an uneventful ESD procedure he suffered a cardiac arrest (the day he was to resume his antiplatelet agent) and died 3 days later. The second fatal event was in a 76 year-old woman who underwent a rectal ESD complicated by a small intraprocedural perforation that was successfully clipped. She died 4 days after the procedure most likely due to a pulmonary embolism. Considering the expertise of the operators, en-bloc ESD rates in the esophagus were higher when experience was ≥40 cases com-

pared to <40 cases (p = 0.002). ESD perforation rates in the colon and rectum were significantly lower when experience was >150 cases as opposed to 80–150 cases (p = 0.0001 and 0.006, for colon and rectum, respectively) although no different when compared to operators with experience range of 40–80 cases (p = 0.7 and 1.0, for colon and rectum, respectively). In particular in colon and rectum ESDs, perforation rate was higher in much experienced operator (80–150 ESDs) compared to those with less experience (40–80 ESDs) (30 vs 6% p = 0.0001 for colon and 18 vs 4% p = 0.002 for rectum). The outcomes according to operator experience are summarized in Table 3.

9. Discussion ESD is a precise and complex oncological procedure that requires a dedicated training program to acquire an adequate skillset even for physicians with proven expertise in other areas of therapeutic endoscopy. Moreover, the procedure is time consuming and both cognitively and technically demanding. In 2008, a panel of Asian and non-Asian experts proposed a “step-up approach” to establish an ESD program; their recommendations comprised a minimum case load per year (10–20 ESDs per year) and the creation of a prospective registry [1]. Due to the lack of data regarding ESD practices and outcomes in our country, we felt it was appropriate to construct an updated picture of real-world ESD practice in Italy. The idea of the survey and its structure was generated during an ESD meeting in Milan, when after a fruitful discussion it was realized that ESD was more commonly performed than expected. This raised the need to ascertain more details on the type of training completed, practice settings and quality metrics for ESD procedures being perfomed in Italy.

Please cite this article in press as: Maselli R, et al. Endoscopic submucosal dissection: Italian national survey on current practices, training and outcomes. Dig Liver Dis (2019), https://doi.org/10.1016/j.dld.2019.09.009

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Fig. 3. Estimated overall ESD volume/operator according to different anatomic locations.

Table 2 Safety outcomes related to the years 2016 and 2017, reported separately for esophageal/GEJ, gastric, colonic and rectal ESDs.

N Total Intrap. Perf., n. (%) Intrapr. perf, conservative treatment Intrapr. perf, surgery Total Postp. Perf., n. (%) Postpr. perf, conservative treatment Postpr. perf, surgery Intrapr. bleeding, ESD interruption, n. (%) Total postpr. Bleeding, n. (%) Postpr. bleeding, endoscopic emostasis, Postpr. bleeding, surgery/rad Postpr. bleeding, transfusion 30-day mortality, n. (%)

Esophagus/GEJ

Stomach

2016

2017

2016

2017

2016

2017

2016

2017

60 1 (1.6) 1 (100) – – – – – 1 (1.7) 1 (100) – – –

49 1 (2) 1 (100) – – – – – – – – – –

251 14 (5.6) 12 (85.7) 2 (14.3) – – – – 27 (10.7) 15 (55.6) 2 (7.4) 10 (37) 1 (0.4)

251 17 (6.8) 16 (94.1) 1 (5.9) 1 (0.4) – 1 1 (0.4) 20 (7.9) 12 (60) 1 (5) 7 (35)

316 27 (8.5) 26 (96.3) 1 (3.7) 2 (0.6) 1 1 1 (0.3) 9 (2.8) 5 (55.6) – 4 (44.4) –

293 21 (7.1) 21 (100) – 1 (0.3) – 1 1 (0.3) 12 (4) 7 (58.3) 1 (8.4) 4 (33.3) –

383 28 (7.3) 27 (96.4) 1 (3.6) 3 (0.8) 3 – 4 (1) 23 (6) 13 (56.5) 2 (8.7) 8 (34.8) 1 (0.3)

353 12 (3.4) 12 (100) – 2 (0.5) 2 – 1 (0.3) 24 (6.8) 17 (70.8) – 7 (29.2) –

As the experts have declared, “Quality control for ESD should provide some guarantee that the right endoscopists are doing the appropriate procedures for their level of expertise” [1]. Due to the high level of skill required (in doing the procedure itself and managing its complications), ESD should only be attempted by expert endoscopists. In line with this statement, all operators who participated in this survey declared to routinely perform EMR; almost all (96.6%) routinely performed endoscopic emergencies; 86.2% were also competent in ERCP. During the initial ESD experience, as Japanese experts have suggested, one should be aware that lesions located in the distal stomach and rectum may be easier and safer to treat; once expertise is gained in these locations, one could move to more difficult locations (namely the proximal stomach and then finally the

Colon

Rectum

colon and esophagus) [4]. Several studies report the achievement of en-bloc resection in >80% and a complication rate of <10% as the competence level to be achieved in the early learning phase [3–5]. Moreover, the suggested cut-off for this competence level assessment is after 30 tutored gastric procedures [6,7] and 40 tutored colorectal procedures [8,9]. From this point of view, we must recognize a lack of mastermentors and structured training programs in Western countries. For most of the participants in our survey (65.5%), the first patients were treated without any supervision. Only for 3/29 (10.3%) endoscopists was a tutor was present in ≥5 procedures during the initial human experience. Despite this deficiency, for most of the respondents in our survey, the first 40 lesions treated in humans were appropriately

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Table 3 ESD outcomes, in terms of en-bloc resection and perforation rate, reported according to experience level. P1 statistical difference between <40 ESDs and 40–80 ESDs; P2 statistical difference between 40–80 ESDs and 80–150 ESDs; P3 statistical difference between 80–150 ESDs and >150 ESDs. Operator experience levels <40 ESDs

40–80 ESDs

80–150 ESDs 1

>150 ESDs

N (%)

N (%)

P

N (%)

P

N (%)

P3

En bloc Esophagus Stomach Colon Rectum

4 (80) 79 (96) 22 (91) 83 (84)

40 (95) 156 (98) 76 (79) 131 (85)

0.002 0.68 0.02 1.0

10 (100) 77(97) 36 (90) 49 (87)

0.05 1.0 0.04 0.83

49 (94) 172 (94) 349 (78) 360 (87)

0.02 0.49 0.03 1.0

Perforation Esophagus Stomach Colon Rectum

0 2 (2.4) 5 (21) 7 (7)

0 11(7) 6 (6) 6 (4)

1.0 0.001 0.003 0.5

1 (10) 8 (10) 12 (30) 10 (18)

0.001 0.6 0.0001 0.002

1 (2) 11 (6) 29 (6) 22 (5)

0.03 0.4 0.0001 0.006

performed only in the stomach (62%) and/or the rectum (58%), in line with the training steps proposed by our Japanese colleagues. In constrast, the overall Italian ESD series comprises more colonic and rectal cases than upper-GI cases; even the Italian “super-experts” (>150 cases) had a limited experience in the stomach, compared to their experience in removing colorectal lesions. This is almost certainly due to the lower Italian incidence of dysplasia/superficial gastric cancer. Japan has 10-fold higher incidence of gastric cancer than in most Western countries [10], leading to programmatic gastric cancer screening and an increased opportunity to find neoplasia at an early stage. Another key aspect is the lower capacity of Western endoscopists, compared to Eastern endoscopists, in early upper-GI cancer detection and characterization, thus in accurate endoscopic tumor staging and finally in making the correct therapeutic decision. Essentially we are chasing our own tail: the low number of superficial upper-GI cancers found lessens our ability to detect and potentially treat them. Along these lines, the cognitive aspect of lesion assessment and decision-making as to whether ESD is the best approach for a particular lesion (as opposed to EMR or surgery) cannot be underscored enough. Errors in judgment can lead to both over-treatment of lesions (for example, choosing ESD for a lesion with likely only LGD that could be more easily and more safely treated by EMR techniques) or under-treatment (for example, choosing to attempt ESD for a lesion with clear signs of deeply invasive cancer, exposing the patient to potential complications and an incomplete resection). Although one may be able to acquire the technical skills to safely perform ESD in a relatively short period of time, this cognitive aspect takes much longer to fully develop and a proper ESD training program should be designed to be comprehensive in this key area [2–11]. In our survey, it is difficult to judge this aspect as we were unable to collect specific data as to the size/morphology and final histology of all lesions. Further studies are needed to investigate this aspect and ideally a centralized national registry would make these details readily available. The second ESD competence level cut-off, as previously reported, is the achievement of an en-bloc resection rate >80% and a complication rate <10%. In our group, this goal was achieved at all levels of endoscopist expertise, regardless of ESD location. Considering the expertise level of the operators, particularly regarding the perforation rate, there is a paradox in that the operators who have performed 80–150 ESDs had a higher perforation rate compared to those an experience of <80 ESDs; on the other hand, super-experts (>150 ESDs) reported a lower perforation rate than experts (80–150 ESDs). This could be explained by the fact that more experienced operators attempt more difficult ESDs with a higher inherent risk of perforation, yet only the super experts can maintain a low complication rate.

2

World-leading centers in East Asia have reported high en-bloc resection rates ranging from 87% to 97% but lower rates of R0 resection (75% to 91%) [12,13]. Furthermore, a 2018 meta-analysis of all English language ESD studies (regardless of location) showed significantly higher curative (82% vs 71%), en-bloc (95% vs 85%) and R0 rates (89% vs 85%) for Eastern versus Western countries [14]. In comparison, our data show an overall high en-bloc rate, highest for esophageal ESD (95%) and lowest for colonic ESD (77%). This trend was confirmed by the R0 rate (88% for esophageal, 75% for colonic ESD). Curative resection rate was highest for gastric and esophageal lesions (84% and 80% respectively) and lowest for rectal lesions (68%). A recent meta-analyis by Fuccio et al. [15] on the outcomes of colorectal ESD, comprising Asian and non-Asian studies, reported an 82.9% R0 resection rate for the standard ESD technique, but a significantly lower rate in non-Asian countries (71.3% vs. 85.6%). Compared to these results, taking together colonic and rectal ESDs, our outcomes show an en-bloc resection rate of 82.4% and R0 rate of 77.7%. Regarding the second competency parameter, the complication rate, the overall intra-procedural perforation rate was 6.2% in our survery, in concordance with a previous national Japanese survey reporting an incidence of 5.9% [16], both <10% as aspired. Despite these good results, in our study 8/130 (6.1%) perforations required surgery. One aspect to consider is that different training protocols for the early phase of experience and lack of training in the colonic location may be responsible for this suboptimal outcome. In the cited meta-analysis above, surgery was required in 1.1% of ESDrelated adverse events, with a significant difference between nonAsian and Asian countries (3.1% vs 0.8%). Overall, the achievement of the proposed cut-offs for ESD practice outcomes (although the en-bloc rate of colonic ESDs was slightly lower than 80%) confirms, that from this survey, Italian endoscopists have achieved a good competence level. This is particularly important considering the lack of mentors or a structured training program as well as a lower opportunity to consolidate training in the gastric location. The European ESD experience has been mostly published from single centers [17–21]. To our knowledge, only other two national ESD surveys have been previously conducted: one from Asia on colorectal ESD [22] and one from France [23] on all GI ESDs from 2008–2013. Our results are similar to those achieved in the French survey in terms of en-bloc resection rate, R0 resection rate and complications. The strength of our study is the large number of endoscopists involved (69% of all invitees), thus the results of our survey should be considered reliable. This is an honest and accurate representation of current Italian ESD practice: all known ESD performers

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were invited, regardless of experience, ranging from those who were at the initial experience to those considered very expert. On the other hand, the main limitations of our study are the retrospective design and reliance on self-reported experience and outcomes. It is all possible that not all endoscopist performing ESD in Italy were invited to participate. We also do not have data on the size, morphology or final histology of the lesions removed to comment on the appropriateness of ESD as the chosen treatment; this highlights the lack of a structured ESD program at most centers and the absence of an ESD registry. This clearly needs to be changed for the future. In conclusion, we can affirm that ESD in Italy is performed by a high number of operators who are not homogenously distributed across the different regions of the country. Overall, based on this survey, it would seem that ESD is being performed safely and above the aspirational goals set by expert consensus opinion. However, this real-world snapshot of Italian ESD performance reveals much variability in training, endoscopy unit set-up and the initiation of individual ESD practices. In particular, we must highlight the wide variation in the quantity and quality of training and that for most operators the first patients were treated without adequate expert supervision. Ideally, a standardized and certifiable ESD training program for Western endoscopists should be established that includes an absolute requirement for expert supervision of initial human cases at the trainee’s home institution. In fact, this is one of the advertised goals of the ESGE education committee for the near future. As to the practice setting, CO2 insufflation was not universally available and the method of sedation was non-standardized. Although this may be due to practice constraints at individual worksites, and thus seemingly unavoidable, it is better to delay performing ESD until these important patient safety parameters are in place. Finally, the absence of data on lesion characteristics and histology speaks to the lack of institutional registries to monitor ESD appropriateness and outcomes. Ideally, a comprehensive national ESD registry would be launched. This study establishes the need for a structured training program, standardized service delivery and a national ESD registry, in order to optimize ESD practice in Italy. Conflicts of interest None declared. References [1] Deprez PH, Bergman JJ, Meisner S, Ponchon T, Repici A, Dinis-Ribeiro M, et al. Current practice with endoscopic submucosal dissection in Europe: position statement from a panel of experts. Endoscopy 2010;42:853–8. [2] Pimentel-Nunes P, Dinis-Ribeiro M, Ponchon T, Repici A, Vieth M, De Ceglie A, et al. Endoscopic submucosal dissection: european society of gastrointestinal endoscopy (ESGE) guideline. Endoscopy 2015;47:829–54.

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Please cite this article in press as: Maselli R, et al. Endoscopic submucosal dissection: Italian national survey on current practices, training and outcomes. Dig Liver Dis (2019), https://doi.org/10.1016/j.dld.2019.09.009