Gut and Liver 2016; 10(5): 739-748 https://doi.org/10.5009/gnl15466 Short-Term Outcomes of Endoscopic Submucosal Dissection in Patients with Early Gastric Cancer: A Prospective Multicenter Cohort Study
Author Information
Il Ju Choi1, Na Rae Lee2, Sang Gyun Kim3, Wan Sik Lee4, Seun Ja Park5, Jae J. Kim6, Jun Haeng Lee6, Jin-Won Kwon2,7, Seung-Hee Park2, Ji Hye You2, Ji Hyun Kim8, Chul-Hyun Lim9, Joo Young Cho10,11, Gwang Ha Kim12, Yong Chan Lee13, Hwoon-Yong Jung14, Ji Young Kim2, Hoon Jai Chun15, and Sang-Yong Seol2,8
1Center for Gastric Cancer, National Cancer Center, Goyang, Korea, 2National Evidence-Based Healthcare Collaborating Agency, Seoul, Korea, 3Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea, 4Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea, 5Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea, 6Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, 7College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea, 8Department of Internal Medicine, Inje University Busan Paik Hospital, Busan, Korea, 9Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea, 10Digestive Disease Center, Soonchunhyang University Hospital, Seoul, Korea, 11Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, Korea, 12Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea, 13Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea, 14Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, 15Department of Internal Medicine, Institute of Digestive Diseases and Nutrition, Korea University College of Medicine, Seoul, Korea

Sang-Yong Seola and Hoon Jai Chunb. aDepartment of Internal Medicine, Inje University Busan Paik Hospital, 75 Bokji-ro, Busanjin-gu, Busan 47392, Korea, Tel: +82-51-890-6158, Fax: +82-51-891-6438, E-mail: seolsymd@hanmail.net. bDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Institute of Digestive Disease and Nutrition, Korea University Medical Center, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea, Tel: +82-2-920-5699, Fax: +82-2-953-1943, E-mail: drchunhj@chol.com
© The Korean Society of Gastroenterology, the Korean Society of Gastrointestinal Endoscopy, the Korean Society of Neurogastroenterology and Motility, Korean College of Helicobacter and Upper Gastrointestinal Research, Korean Association the Study of Intestinal Diseases, the Korean Association for the Study of the Liver, Korean Pancreatobiliary Association, and Korean Society of Gastrointestinal Cancer. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Background/Aims

Endoscopic submucosal dissection (ESD) is an effective treatment for early gastric cancer (EGC) that has demonstrated a minimal risk of lymph node metastasis in retrospective studies. We sought to prospectively evaluate the short-term outcomes of ESD treatment in EGCs.

Methods

A prospective multicenter cohort study of neoplasms 3 cm or less in diameter at endoscopic size evaluation was performed in 12 Korean ESD study group-related university hospitals and the National Cancer Center. Resected specimens were evaluated by the central pathologic review board.

Results

A patient cohort (n=712) with a total of 737 EGCs was analyzed. The margin-freeen bloc resection rate was 97.3%, and curative resection of 640 lesions (86.8%) was achieved. Lower curative resection rates were associated with lesions 2 to 3 cm in size prior to ESD compared with lesions 2 cm or less in size (78.6% vs 88.1%, respectively, p=0.009). Significant factors associated with noncurative resection were moderately or poorly differentiated histological type, posterior wall tumor location, tumor size larger than 3 cm, ulceration, and submucosal invasion. Delayed bleeding occurred in 49 patients (6.9%), and 12 patients (1.7%) exhibited perforations.

Conclusions

ESD is an effective treatment with a high curative resection rate for EGCs that meets relatively conservative pre-ESD indications. Long-term survival outcomes should be evaluated in follow-up studies.

Keywords: Stomach neoplasms, Endoscopy, gastrointestinal, Outcome assess, Prospective studies
Abstract

Background/Aims

Endoscopic submucosal dissection (ESD) is an effective treatment for early gastric cancer (EGC) that has demonstrated a minimal risk of lymph node metastasis in retrospective studies. We sought to prospectively evaluate the short-term outcomes of ESD treatment in EGCs.

Methods

A prospective multicenter cohort study of neoplasms 3 cm or less in diameter at endoscopic size evaluation was performed in 12 Korean ESD study group-related university hospitals and the National Cancer Center. Resected specimens were evaluated by the central pathologic review board.

Results

A patient cohort (n=712) with a total of 737 EGCs was analyzed. The margin-freeen bloc resection rate was 97.3%, and curative resection of 640 lesions (86.8%) was achieved. Lower curative resection rates were associated with lesions 2 to 3 cm in size prior to ESD compared with lesions 2 cm or less in size (78.6% vs 88.1%, respectively, p=0.009). Significant factors associated with noncurative resection were moderately or poorly differentiated histological type, posterior wall tumor location, tumor size larger than 3 cm, ulceration, and submucosal invasion. Delayed bleeding occurred in 49 patients (6.9%), and 12 patients (1.7%) exhibited perforations.

Conclusions

ESD is an effective treatment with a high curative resection rate for EGCs that meets relatively conservative pre-ESD indications. Long-term survival outcomes should be evaluated in follow-up studies.

Keywords: Stomach neoplasms, Endoscopy, gastrointestinal, Outcome assess, Prospective studies
INTRODUCTION

As the National Cancer Screening Program provides esophagogastroduodenoscopy for gastric cancer screening every 2 years, early gastric cancer (EGC) is increasingly detected in Korea.1,2 The criteria without risk of lymph node metastasis in EGC were adopted as an absolute or expanded indication of endoscopic resection, and EGC meeting these criteria is treated with endoscopic submucosal dissection (ESD).3 In recent years, ESD has become the primary endoscopic treatment for EGC because of higher en bloc and curative resection rates compared to endoscopic mucosal resection (EMR), although ESD has higher rates of adverse events.46 Moreover, ESD provides a better quality of life to patients compares with surgical treatment.7

In retrospective studies, long-term survival outcomes of ESD were excellent in patients with EGC meeting absolute or expanded indications.812 Recent meta-analysis also showed that long-term mortality in the expanded indication group did not differ from those with conventional absolute indication group.13 However, local recurrences or distant metastasis in EGC cases meeting the indications may occur.14 Moreover, ESD outcomes from retrospective studies are based on pathological findings after resection and pre-ESD inclusion criteria are not usually defined, which might cause selection bias.4 Also, patients who might have poor outcome could be selectively lost to follow up in retrospective studies. To overcome these limitations, prospective studies with clearly defined pre-ESD criteria and with minimal follow-up loss rates are necessary, but have not been reported yet.

Pathological diagnoses for gastric cancer may have significant inter-observer variations15 and are subject to histological misclassifications.16 Moreover, the pathological criteria of diagnosing gastric cancer in Western countries including Korea, which adopted the World Health Organization classification of tumors, slightly differ from the Japanese criteria.17,18 Thus, it is uncertain whether the outcomes of ESD in other part of the world are compatible with Japanese outcomes.

In this study, we defined a prospective cohort to investigate long-term outcomes of ESD in the treatment of patients with EGC confirmed by a central pathological review. Herein, we preliminarily report short-term effectiveness and safety outcomes in the cohort.

MATERIALS AND METHODS

1. Study design

This is a multicenter, prospective cohort study to evaluate long- and short-term outcomes of ESD on EGC. From May 2010 to December 2011, patients who had planned ESD were prospectively enrolled from 12 university hospitals nationwide in Korea and the National Cancer Center. The minimum requirement for a center participating in the study was at least 20 ESD cases per year. This study was performed in collaboration with National Evidence-based Healthcare Collaborating Agency (NECA), which is the national research agency of Korea that was established to provide authentic and quality information about medical devices, medicines, and health technology through objective and reliable analyses.

2. Patients

Pre-ESD inclusion criteria for patients and lesions were (1) adults aged at least 20 years old; (2) endoscopically-estimated lesion sizes ≤3 cm; (3) histologically well-differentiated or moderately differentiated adenocarcinoma or adenoma based on pathological evaluation of the biopsy specimen; (4) no endoscopic active or healing stage ulceration on the lesion; and (5) no evidence of lymph node metastasis on abdominal computed tomography (CT). Patients were ineligible if they (1) had history of cancer in other organs; (2) had a history of stomach surgery; (3) had a severe comorbid condition; (4) had a bleeding tendency; (5) were pregnant or possibly pregnant; or (6) were unable to provide informed consent.

3. Participant selection and follow-up

Informed consent was obtained from patients who were subjected to ESD for EGC or adenoma/dysplasia. Patients were enrolled if they fulfilled the requirements for eligibility according to the inclusion and exclusion criteria. Pathological evaluation after ESD was performed initially by a gastrointestinal pathologist at each participating center. Decisions about further treatment were made based on the pathologic results at each center. Follow-up periods were defined as 3 months, 6 months, 1 year, and yearly for 5 years after ESD, at which times endoscopy, abdominal CT, chest radiography, and laboratory tests were planned.

4. ESD procedure

ESD was performed under sedation with monitoring of cardiorespiratory function according to the standard procedure in each hospital, including marking, mucosal incision, and submucosal dissection with hemostasis. Detailed procedures and used devices were described in a previous study.5

Briefly, marking was made 2 mm outside of the lesion using the tip of an electrosurgical device or argon plasma coagulation. Then, various submucosal solutions were injected into the submucosal layer, and a circumferential mucosal incision was made using an electrosurgical knife according to the endoscopist’s preference. Complete dissection of the submucosal layer is recommended, but snaring for resection was allowed after 50% of submucosal dissection was completed. Endoscopic hemostasis was performed for any oozing or exposed vessel both during and after the procedure. High-frequency generators (VIO 300D; ERBE, Tübingen, Germany) were used for the entire procedure.

5. Pathologic evaluation

Resected specimens were fixed in 10% neutral-buffered formalin and embedded into paraffin for histological evaluation. Sections (2-mm interval) were stained with hematoxylin and eosin. Diagnoses were made according to the World Health Organization classification of gastric cancer.17 After the initial evaluation, slides of specimens were sent to an independent central pathology review board, which consisted of 16 specialists in gastrointestinal pathology who are members of the Korean Society of Pathologists. To make the final pathologic diagnoses, an agreement rate of 70% or more was required. Pathologic diagnoses composed the standard for primary outcome evaluation and subgroup analyses.

6. Efficacy and safety assessments

Patients who had adenoma at central pathological review were excluded from the analysis. The primary outcome variables in this study are short-term outcomes of ESD and safety analyses. Short-term outcomes included histological complete resection rate, procedure time, treatments after ESD, and adverse event rates. Safety analyses included any adverse events and either death or life-threatening events associated with the procedure within 30 days of ESD. Long-term outcomes will be reported after the 5-year follow-up of the last enrolled patient, which is expected to be in December 2016.

Demographic data, clinical variables, lesion characteristics, and treatment-related variables were collected. Helicobacter pylori infection was evaluated by histological staining, rapid urease test, or noninvasive urea breath test.

7. Definitions

After evaluation of resected specimens, lesions were classified as complete or incomplete resection. In our protocol, complete resection was defined when an EGC was resected with tumor-free horizontal and vertical margins and was confirmed to be a differentiated-type carcinoma confined to the mucosal layer without lymphovascular invasion.

Curative resection was defined based on the Japanese Gastric Cancer Association (JGCA) recommendation for curability criteria. Lesions meeting the absolute or expanded indication and removed by en bloc resection with tumor-free horizontal margin and vertical margin were considered curative resection, if there was no lymphatic or venous invasion.3 Absolute indications for ESD included mucosal differentiated-type histology carcinoma with the size ≤2 cm without ulcerative findings.3 Condition for expanded indications were (a) differentiated–type histology mucosal cancer of tumor size >2 cm if ulcerative finding was negative; (b) differentiated–type histology mucosal cancer with tumor size ≤3 cm if ulcerative finding was present; (c) undifferentiated-type mucosal cancer with tumor size ≤2 cm without ulcerative finding; or (d) differentiated–type histology cancer with tumor size ≤3 cm without ulcerative finding if the lesion invaded superficial submucosal layer (<500 μm from the muscularis mucosae).3

Adverse bleeding events were defined as clinical symptoms including melena or hematemesis, or a 2 g/dL decrease in hemoglobin levels after the procedure. Perforation was categorized as frank or microperforation. Frank perforation was defined as a perforation noticed during the procedure by visualization of an intraperitoneal organ or visceral fat through a full-thickness laceration of the stomach wall. Microperforation was defined when recognized after the procedure by intraperitoneal free air on plain chest radiography or abdominal CT without frank perforation noticed during the procedure.

8. Statistical analyses

Demographic information is presented as descriptive statistics. Efficacy measurements including complete or curative resection, and safety measurements are presented as percentages and 95% confidence intervals (CI). Multiple logistic regression analyses were performed to evaluate the associated factors for complete or curative resection. For all analyses, p<0.05 was considered statistically significant. Statistical analyses were conducted using SAS version 9.3 (SAS Institute Inc., Cary, NC, USA).

9. Data integrity and confidentiality

All data were collected, recorded, and managed based on clinical research coordination platform (Velos Inc., Fremont, CA, USA) using electronic case report forms. For data consistency and accuracy, the institutions were regularly visited and source documents were checked. Confidential patient information was not collected. Access to the Velos system was restricted to authorized persons.

10. Ethics statement

This study was reviewed and approved by the NECA Institutional Review Board (IRB) (NECAIRB09-013-1) and each local hospital’s IRB. The protocol was registered at ClinicalTrials.gov (identifier number: NCT01132469). This study was conducted according to International Conference Harmonization/Good Clinical Practices, clinical regulatory guidelines, and the ethical statements of the Declaration of Helsinki.

RESULTS

1. Patient and lesion characteristics

Among the 1,160 patients registered for screening between May 2010 and December 2011, a total of 737 EGC lesions identified from 712 patients were included in this short-term outcome study (Fig. 1). Patient characteristics are presented in Table 1. Male patients composed 77% of the study population, and the mean age (standard deviation [SD]) was 62.8 (9.2) years.

The lesion characteristics are presented in Table 2. Although enrollment criteria were adenoma or differentiated-type intramucosal cancer of size 3 cm or smaller, several factors deviated from the initial assessments in terms of depth, size, and histologic type. Submucosal layer invasion was the most common deviation from pre-ESD assessment (16%). Horizontal or vertical resection margin involvement of the cancer was uncommon and noted only in two (0.3%) and 13 cases (1.8%), respectively. Lymphovascular invasion was noted in 32 lesions (4.3%) for lymphatic vessel invasion and in two lesions (0.3%) for venous invasion.

2. Efficacy evaluation

The en bloc resection rate was 99.2% (731/737) and the margin-free en bloc resection rate was 97.3% (717/737). Complete resection was obtained in 602 lesions (81.7%; 95% CI, 78.7% to 84.4%), which was defined in our protocol as a differentiated adenocarcinoma limited to the mucosal layer with tumor-free margins in the resected specimen (Fig. 2). Among the incomplete resection cases (n=135), 50 (37.0%) were treated with further surgery, one case (0.7%) was treated with argon plasma coagulation, and 84 cases (62.2%) were not treated further (Fig. 2).

The mean (SD) duration of the procedure was 58.8 (40.2) minutes and ranged from 10 to 265 minutes. As lesion number increased, procedure duration also increased: 56.7 (38.6) minutes for one lesion and 91.2 (51.9) minutes for two lesions treated in a single ESD session.

3. Curative resection rates and further treatment

Curative resection criteria, including absolute and expanded indications suggested by the Japanese guidelines, were achieved in 640 lesions (86.8%; 95% CI, 84.2% to 89.2%) (Table 3). Among 97 noncurative lesions, additional curative surgery was performed for 41 lesions (42.3%). Curative resection rates were significantly lower in lesions that were 2 to 3 cm at the pre-ESD estimation compared to lesions 2 cm or less (78.6% vs 88.1%, respectively, p=0.009).

In multivariate analyses, significant factors associated with noncurative resection were moderately- or poorly-differentiated histologic type, posterior wall location of tumor, tumor size larger than 3 cm, presence of ulceration, and submucosal invasion (Table 4). H. pylori infection negative status shows trend to the risk of noncurative resection (odds ratio, 2.46; 95% CI, 0.90 to 6.73).

4. Adverse events and safety assessment

Delayed bleeding occurred in 49 patients (6.9%) and was the most common adverse event (Table 5). Among delayed bleeding cases, 67% occurred within 24 hours. Management of ESD bleeding was successful in 35 cases by endoscopic hemostasis using electrocautery, argon plasma coagulation, or clipping. Other cases were treated conservatively, and any interventions such as surgery or transarterial embolization were not needed.

Twelve patients (1.7%) had perforation. Six cases of gross perforations were closed successfully with clipping, but three cases required additional surgery due to incomplete resection. Six cases of microperforation were treated conservatively and recovered uneventfully.

One case of stenosis was found after ESD, which occurred 4 weeks after ESD for a cardiac lesion. The stenosis improved after balloon dilation. One case of cerebral infarct occurred 8 days after ESD, but no other serious adverse event including infection or procedure-related mortality was found within 30 days of ESD.

DISCUSSION

In this prospective cohort study, we evaluated the effectiveness and safety of ESD for the treatment of EGC, which was estimated at the pre-ESD evaluation to be within the absolute indications except for the estimated lesion size of 3 cm or smaller. In this predefined group with EGC, we confirmed that complete resection and curative resection rates were as high as those of previous retrospective studies. Our data also confirmed that ESD is a safe technique in terms of adverse events, which could be managed endoscopically or conservatively.

In this study, the margin-free en bloc resection rate was 97.3% and horizontal margin-positive cases were 0.3%, which are better than previous Korean retrospective data of 90.1% and 2.6%, respectively.5 These findings might reflect increasing ESD experience among endoscopists. A previous study recruited patients when ESD had just been introduced and was not yet popular in Korea.5 ESD is a technically challenging procedure and requires a learning curve of approximately 30 cases to obtain a good performance.19,20 Our current study enrolled participants in 2010 to 2011 when most participating endoscopists had extensive experience with ESD technique.

Our study found that the complete resection rate was 81.7%. Previous studies considered en bloc margin-free resection only or without lymphovascular invasion as the criterion for complete resection.21,22 Our definition of complete resection, however, is rather strict and we considered submucosal tumors or undifferentiated-type histology as incomplete resection because these conditions may not be completely free of lymph node metastasis.23,24 Our previous retrospective study that applied the same criteria showed a complete resection rate of 87.7%, which seems higher than our study.5 The main difference results from the submucosal invasion rate, which was 16% in our study compared to 7.4% in the retrospective study. Because our definition of complete resection is conservative, we performed analyses according to Japanese expanded criteria (JGCA 2010 guideline).3 Our curative resection rate of 86.8% was comparable to those reported in the literature, which were as high as 82.7% to 93.4%.21,22,25

In this study, we included gastric lesions smaller than 3 cm because (1) ESD can provide technically successful tumor removal; (2) there is a high chance of curative resection in terms of an expanded indication, even if minute submucosal invasion or ulceration was found in the resected specimen;3 and (3) although the current Korean national health insurance system reimburses ESD only for absolute indication, a 2 to 3 cm lesion may indicate ESD if the patient pays by themselves. In our post hoc analyses, a clinically-estimated lesion size of 2 to 3 cm before ESD was significantly associated with lower curative resection rates (78.6%). Because approximately 20% of such ESD cases required additional surgery, it is necessary to provide patients with careful explanation before ESD, that additional surgery might be required due to significant discrepancies between pre- and post-ESD pathological diagnoses.26 A large number of these patients, approximately 58% in our study, did not undergo additional surgery and might compromise their long-term survival.27

Although ESD is the recommended treatment for differentiated intramucosal tumors larger than 2 cm,3 tumor size larger than 3 cm is associated with compromised complete resection rates.28,29 In our multivariate analyses similar to previous reports, tumor size larger than 3 cm is a significant risk factor for noncurative resection.30 In addition, significant factors associated with noncurative resection include poorly-differentiated histologic type, presence of ulceration, and submucosal invasion as previously reported, and those factors were already reflected in the expanded criteria for ESD.3,31,32 Tumor location at upper part of stomach was associated with noncurative resection in the univariate analysis as previously reported.30,32 However, it lost significance when considered with posterior wall location, which maintained its significance even after adjustment. This result was similar to recent report, which showed posterior wall location of tumor was the more significant factor than upper location probably due to technical difficult and poor visual field.33 Unfavorable outcomes in H. pylori-negative cases might be partly explained by the previous finding that H. pylori eradication changes tumor morphology by flattening the superficial-elevated type lesion and covering the tumor with normal epithelium. This makes the tumors indistinct at the time of endoscopic detection.34 Poorer prognoses in gastric cancer patients having H. pylori-negative status were also reported even after surgical treatment.35 Future studies should examine the mechanism of different outcomes according to H. pylori status. Currently, the association of noncurative resection and moderately-differentiated histology is not well-understood and future study is needed to confirm our finding.

Perforation and bleeding rates were comparable to those of previous retrospective studies. Oda et al.36 reviewed 28 papers that included 300 or more ESD cases, and reported that perforation rates ranged from 1.2% to 5.2%, and delayed bleeding rates were between 0% and 15.6%. Our rates of adverse events were in agreement with those reported in the literature, and endoscopic or conservative management was successful without the need for emergency intervention. One patient with a cardiac lesion developed stenosis within 4 weeks of ESD. Endoscopic balloon dilation was successful in this patient, but the procedure does have a risk of perforation.37,38 Steroid use or pre-emptive ballooning should be considered in cases with risk factors for post-ESD stenosis.39

Our study has several advantages. First, this was a multicenter prospective study. Most data about the effectiveness and safety of ESD are from retrospective studies, which have the limitations of selection bias, recall bias, and high follow-up loss.16 Thus, the retrospective outcome results must be confirmed by prospective studies. To the best of our knowledge, patient enrollment in a Japanese prospective observational study for ESD began in 2010 to evaluate long- and short-term outcomes.40 The study results have yet to be reported after a 5-year follow-up.

Another important strength of our study is that an independent central pathology review board composed of pathologists who specialize in gastrointestinal tumors performed pathological evaluation for ESD specimens. It is well known that interobserver variations in diagnoses of gastric tumors are high, even among specialists.15 The importance of a central pathology review for ESD cases was also presented in a case of EGC within the expanded indication of distant metastasis, which turned out to be a case beyond the expanded indication.16 Furthermore, there was a large discrepancy between Western and Japanese pathologists in diagnoses of gastric lesions, with a κ-value of only 0.16. This discrepancy could be largely resolved by the introduction of the Vienna classification of gastrointestinal epithelial neoplasia.15 Because Korean pathologists have Western viewpoints in the diagnosis of gastric lesions and follow the Vienna classification,41 our study suggested that ESD outcome data were excellent even when used Western pathological criteria

Our study has the following limitations. First, these data are from high-volume centers and the endoscopists are experts in ESD. This might overestimate the efficacy and safety of ESD, and our results might not be applicable to novice endoscopists from low-volume centers. Various in vivo or ex vivo training programs and live case observations will help Western endoscopists become competent in ESD procedures.42 Second, various ESD devices were used according to the endoscopist’s preference. We think this might result in more acceptable outcomes, as there are no significant performance differences for ESD knives.

In conclusion, our prospective study confirmed previous retrospective data that ESD is an effective treatment for EGC with excellent short-term outcomes in terms of effectiveness and procedure-related adverse events, particularly for EGCs estimated within the absolute indications. However, long-term outcome evaluation regarding survival and cancer recurrence in this selected EGC cohort is necessary.

ACKNOWLEDGEMENTS

This study was conducted as part of project number NA2010-001 funded by the National Evidence-based Healthcare Collaborating Agency (NECA) in Korea.

Contributors: S.Y.S., H.J.C., J.J.K., and J.H.L. were responsible for the concept and design of the study, which all authors subsequently accepted and contributed. N.R.L., S.H.P., J.H.Y., J.W.K., and J.Y.K. were responsible for data management and for the implementation of the statistical analysis. I.J.C., S.G.K., W.S.L., S.J.P., J.J.K., J.H.L., J.H.K., C.H.L., J.Y.C., G.H.K., Y.C.L., H.Y.J., H.J.C., and S.Y.S. contributed to the enrolment of patients and to the data collection. The initial draft was written by I.J.C., N.R.L., and J.W.K. and was revised based on comments from all of the other authors. All authors reviewed the final version of submitted manuscript and agreed to its contents. The authors take full responsibility for the report.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

Figures
Fig. 1. Flow chart of participant selection.

EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection.

Fig. 2. Pathological and clinical outcomes after endoscopic submucosal dissection (ESD). Complete resection was defined when an differentiated type mucosal early gastric cancer (EGC) without lymphovascular invasion was resected with tumor free margins.

LVI, lymphovascular invasion; PD, poorly differentiated adenocarcinoma; Sm, submucosa; M, mucosa; APC, argon plasma coagulation.

Tables

Patient Characteristics (n=712)

Characteristic  No. of patients (%) 
Gender
 Male548 (77.0)
 Female164 (23.0)
Age, yr62.8±9.2
 <405 (0.7)
 40–4954 (7.6)
 50–59214 (30.1)
 60–69275 (38.6)
 ≥70164 (23.0)
BMI, kg/m224.2±2.8
 <25441 (61.9)
 ≥25271 (38.1)
Smoking
 Never smoker337 (47.3)
 Ex-smoker184 (25.9)
 Current smoker      191 (26.8)
Drinking
 Never drinker226 (31.7)
 Ex-drinker86 (12.1)
 Current drinker400 (56.2)
Cancer family history
 No558 (78.4)
 Yes154 (21.6)
Stomach cancer family history
 No613 (86.1)
 Yes99 (13.9)
Helicobacter pylori infection
 Negative255 (35.8)
 Positive214 (30.1)
 Unknown243 (34.1)
Comorbidity
 Hypertension238 (33.4)
 Diabetes69 (9.7)
 COPD2 (0.3)
 Angina8 (1.1)

Data are presented as number (%) or mean±SD.

BMI, body mass index; COPD, chronic obstructive pulmonary disease.

Characteristics of Adenocarcinoma Lesions according to Post-ESD Central Pathology (n=737)

Characteristic No. of lesions (%) 
Location of the lesion
 Lower 1/3465 (63.1)
 Middle 1/3187 (25.4)
 Upper 1/385 (11.5)
Circumferential location
 Anterior wall148 (20.1)
 Lesser curvature282 (38.2)
 Posterior wall140 (19.0)
 Greater curvature167 (22.7)
Histologic type
 Papillary5 (0.7)
 Tubular adenocarcinoma, well differentiated488 (66.2)
 Tubular adenocarcinoma, moderately differentiated 226 (30.7)
 Tubular adenocarcinoma, poorly differentiated18 (2.4)
Histologic type by Lauren classification
 Intestinal712 (96.6)
 Diffuse8 (1.1)
 Mixed17 (2.3)
Tumor size, cm
 ≤2.0545 (73.9)
 2.1–3.0128 (17.4)
 >3.064 (8.7)
Depth of invasion
 Invades lamina propria of mucosa (pT1a)367 (49.8)
 Invades muscularis mucosa (pT1a)252 (34.2)
 Submucosal invasion118 (16.0)
Type
 Depressed395 (53.6)
 Elevated182 (24.7)
 Flat109 (14.8)
 Unclassified51 (6.9)
Horizontal resection margin involvement
 Present2 (0.3)
Vertical resection margin involvement
 Present13 (1.8)
Piecemeal resection
 Present6 (0.8)
Microscopic ulceration
 Present35 (4.7)
Lymphatic invasion
 Present32 (4.3)
Venous invasion
 Present2 (0.3)

ESD, endoscopic submucosal dissection.

Curative Resection Rates according to Estimated Pre-ESD Lesion Size

Pathologic criteriaPre-ESD size

 Total (n=737)  ≤2.0 cm (n=639)  2.1–3.0 cm (n=98) 
Curative resection640 (86.8)563 (88.1)77 (78.6)
 Absolute indication  446 (60.5)418 (65.4)28 (28.6)
 Expanded indication*
  Total194 (26.3)145 (22.7)49 (50.0)
   A1359342
   B22202
   C660
   D31265
Noncurative resection97 (13.2)76 (11.9)21 (21.4)
p-value0.009

Data are presented as number (%). ESD, endoscopic submucosal dissection.

*Curability criteria for the expanded indication included in the Japanese Gastric Cancer Association guidelines.3 Curative A: size >2 cm, differentiated type, pT1a (muscularis mucosa or lamina propria), Ulcer (−). Curative B: size ≤3 cm, differentiated type, pT1a, Ulcer (+). Curative C: size ≤2 cm, undifferentiated type, pT1a, Ulcer (−). Curative D: size ≤3 cm, differentiated type, pT1b (submucosal invasion <500 μm);

Chi-square for noncurative resection.

Risk Factors Associated with Noncurative Resection (n=737)

FactorTotal no.Curative resectionUnivariate analysisMultivariate analysis



No.%OR95% CIp-valueOR95% CIp-value
Age, yr
 <6028324787.3Ref (1)---
 61–7028324887.60.9680.589–1.5920.899---
 ≥7117114584.81.230.714–2.1210.4556---
Gender
 Female17315388.4Ref (1)---
 Male56448786.31.210.716–2.0430.4771---
BMI, kg/m2
 0–2545639286Ref (1)---
 ≥2628124888.30.8150.52–1.2770.3721---
Smoking
 Non-smoker34830687.9Ref (1)---
 Current smoker20116883.60.9660.557–1.6720.9006---
 Ex-smoker18816688.31.4310.874–2.3440.1541--
Drinking-
 Non-drinker23721088.6Ref (1)---
 Current drinker41235185.20.8860.399–1.9680.7668---
 Ex-drinker887989.81.3520.833–2.1940.2226---
Gastric cancer family history
 No63454786.3Ref (1)---
 Yes1039390.30.6760.339–1.3480.2664---
Helicobacter pylori infection
 Positive26224091.6Ref (1)Ref (1)
 Negative25320882.22.361.372–4.0610.00192.4640.902–6.730.0786
 Unknown22219286.51.7050.953–3.0500.07252.7730.914–8.4160.0717
Histologic type
 Papillary or well-49346093.3Ref (1)Ref (1)
 Moderately differentiated  226174774.1662.604–6.664<0.00012.7931.165–6.6970.0213
 Poorly differentiated18633.327.8789.837–79.008<0.0001239.57231.417–>999.999<0.0001
Location
 Lower 1/346541088.2Ref (1)Ref (1)
 Middle 1/318716588.20.9940.587–1.6830.98190.4420.16–1.2220.1155
 Upper 1/3856576.52.2941.291–4.0750.00460.4110.131–1.2890.1274
Circumferential location
 Lesser curvature28225289.4Ref (1)Ref (1)
 Anterior wall14812685.11.4670.813–2.6470.20351.560.497–4.9020.4462
 Posterior wall14011380.72.0071.14–3.5320.01573.3271.068–10.3640.0381
 Greater curvature16714989.21.0150.547–1.8830.9631.5670.477–5.1520.4592
Size, mm
 ≤2054549390.5Ref (1)Ref (1)
 21–3012810682.81.9681.146–3.3790.01422.0630.73–5.830.172
 >30644164.15.3192.963–9.548<0.000128.6547.053–116.411<0.0001
Ulcer
 Not identified70261888Ref (1)Ref (1)
 Present352262.94.3472.111–8.954<0.000114.0762.236–88.6120.0048
Depth of invasion
 Mucosa (T1a)61960998.4Ref (1)Ref (1)
 Submucosa (T1b)1183126.3170.87180.933–360.754<0.0001462.34132.183–>999.999<0.0001
ESD
 Without snare66057487Ref (1)---
 With snare776685.71.1120.565–2.1900.757---
Gross type
 Depressed39534186.3Ref (1)---
 Elevated182151831.2960.801–2.0980.2905---
 Flat1099889.90.7090.357–1.4080.3256---
 Unclassified5150980.1270.017–0.9330.0426---

OR, odds ratio; CI, confidence interval; BMI, body mass index; ESD, endoscopic submucosal dissection.

Adverse Events Occurring within 30 Days after the Procedure

 No. (%) 
Bleeding49 (6.9)*
 Presenting symptom
  Hematemesis36 (73.5)
  Decrease in hemoglobin >2 g/dL 1 (2.0)
  Melena12 (24.5)
 Timing
  0–24 hr33 (67.3)
  25–48 hr10 (20.5)
  49 hr–1 wk6 (12.2)
  >1 wk0
 Management of bleeding
  Endoscopic treatment35
  Conservative treatment14
Perforation12 (1.7)*
 Type
  Frank6 (50)
  Micro6 (50)
 Management of perforation
  Clipping only3 (25)
  Surgery after clipping3 (25)
  Conservative6 (50)
Stenosis
 Cardia1 (0.1)*
Cerebrovascular accident
 Infarct1 (0.1)*
Infection (pneumonia or peritonitis)0

*Percentage of the 712 patients;

Surgery after clipping was performed in the context of incomplete resection and not for the perforation itself.

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Tables

Patient Characteristics (n=712)

Characteristic  No. of patients (%) 
Gender
 Male548 (77.0)
 Female164 (23.0)
Age, yr62.8±9.2
 <405 (0.7)
 40–4954 (7.6)
 50–59214 (30.1)
 60–69275 (38.6)
 ≥70164 (23.0)
BMI, kg/m224.2±2.8
 <25441 (61.9)
 ≥25271 (38.1)
Smoking
 Never smoker337 (47.3)
 Ex-smoker184 (25.9)
 Current smoker      191 (26.8)
Drinking
 Never drinker226 (31.7)
 Ex-drinker86 (12.1)
 Current drinker400 (56.2)
Cancer family history
 No558 (78.4)
 Yes154 (21.6)
Stomach cancer family history
 No613 (86.1)
 Yes99 (13.9)
Helicobacter pylori infection
 Negative255 (35.8)
 Positive214 (30.1)
 Unknown243 (34.1)
Comorbidity
 Hypertension238 (33.4)
 Diabetes69 (9.7)
 COPD2 (0.3)
 Angina8 (1.1)

Data are presented as number (%) or mean±SD.

BMI, body mass index; COPD, chronic obstructive pulmonary disease.

Characteristics of Adenocarcinoma Lesions according to Post-ESD Central Pathology (n=737)

Characteristic No. of lesions (%) 
Location of the lesion
 Lower 1/3465 (63.1)
 Middle 1/3187 (25.4)
 Upper 1/385 (11.5)
Circumferential location
 Anterior wall148 (20.1)
 Lesser curvature282 (38.2)
 Posterior wall140 (19.0)
 Greater curvature167 (22.7)
Histologic type
 Papillary5 (0.7)
 Tubular adenocarcinoma, well differentiated488 (66.2)
 Tubular adenocarcinoma, moderately differentiated 226 (30.7)
 Tubular adenocarcinoma, poorly differentiated18 (2.4)
Histologic type by Lauren classification
 Intestinal712 (96.6)
 Diffuse8 (1.1)
 Mixed17 (2.3)
Tumor size, cm
 ≤2.0545 (73.9)
 2.1–3.0128 (17.4)
 >3.064 (8.7)
Depth of invasion
 Invades lamina propria of mucosa (pT1a)367 (49.8)
 Invades muscularis mucosa (pT1a)252 (34.2)
 Submucosal invasion118 (16.0)
Type
 Depressed395 (53.6)
 Elevated182 (24.7)
 Flat109 (14.8)
 Unclassified51 (6.9)
Horizontal resection margin involvement
 Present2 (0.3)
Vertical resection margin involvement
 Present13 (1.8)
Piecemeal resection
 Present6 (0.8)
Microscopic ulceration
 Present35 (4.7)
Lymphatic invasion
 Present32 (4.3)
Venous invasion
 Present2 (0.3)

ESD, endoscopic submucosal dissection.

Curative Resection Rates according to Estimated Pre-ESD Lesion Size

Pathologic criteriaPre-ESD size

 Total (n=737)  ≤2.0 cm (n=639)  2.1–3.0 cm (n=98) 
Curative resection640 (86.8)563 (88.1)77 (78.6)
 Absolute indication  446 (60.5)418 (65.4)28 (28.6)
 Expanded indication*
  Total194 (26.3)145 (22.7)49 (50.0)
   A1359342
   B22202
   C660
   D31265
Noncurative resection97 (13.2)76 (11.9)21 (21.4)
p-value0.009

Data are presented as number (%). ESD, endoscopic submucosal dissection.

Curability criteria for the expanded indication included in the Japanese Gastric Cancer Association guidelines.3 Curative A: size >2 cm, differentiated type, pT1a (muscularis mucosa or lamina propria), Ulcer (−). Curative B: size ≤3 cm, differentiated type, pT1a, Ulcer (+). Curative C: size ≤2 cm, undifferentiated type, pT1a, Ulcer (−). Curative D: size ≤3 cm, differentiated type, pT1b (submucosal invasion <500 μm);

Chi-square for noncurative resection.

Risk Factors Associated with Noncurative Resection (n=737)

FactorTotal no.Curative resectionUnivariate analysisMultivariate analysis



No.%OR95% CIp-valueOR95% CIp-value
Age, yr
 <6028324787.3Ref (1)---
 61–7028324887.60.9680.589–1.5920.899---
 ≥7117114584.81.230.714–2.1210.4556---
Gender
 Female17315388.4Ref (1)---
 Male56448786.31.210.716–2.0430.4771---
BMI, kg/m2
 0–2545639286Ref (1)---
 ≥2628124888.30.8150.52–1.2770.3721---
Smoking
 Non-smoker34830687.9Ref (1)---
 Current smoker20116883.60.9660.557–1.6720.9006---
 Ex-smoker18816688.31.4310.874–2.3440.1541--
Drinking-
 Non-drinker23721088.6Ref (1)---
 Current drinker41235185.20.8860.399–1.9680.7668---
 Ex-drinker887989.81.3520.833–2.1940.2226---
Gastric cancer family history
 No63454786.3Ref (1)---
 Yes1039390.30.6760.339–1.3480.2664---
Helicobacter pylori infection
 Positive26224091.6Ref (1)Ref (1)
 Negative25320882.22.361.372–4.0610.00192.4640.902–6.730.0786
 Unknown22219286.51.7050.953–3.0500.07252.7730.914–8.4160.0717
Histologic type
 Papillary or well-49346093.3Ref (1)Ref (1)
 Moderately differentiated  226174774.1662.604–6.664<0.00012.7931.165–6.6970.0213
 Poorly differentiated18633.327.8789.837–79.008<0.0001239.57231.417–>999.999<0.0001
Location
 Lower 1/346541088.2Ref (1)Ref (1)
 Middle 1/318716588.20.9940.587–1.6830.98190.4420.16–1.2220.1155
 Upper 1/3856576.52.2941.291–4.0750.00460.4110.131–1.2890.1274
Circumferential location
 Lesser curvature28225289.4Ref (1)Ref (1)
 Anterior wall14812685.11.4670.813–2.6470.20351.560.497–4.9020.4462
 Posterior wall14011380.72.0071.14–3.5320.01573.3271.068–10.3640.0381
 Greater curvature16714989.21.0150.547–1.8830.9631.5670.477–5.1520.4592
Size, mm
 ≤2054549390.5Ref (1)Ref (1)
 21–3012810682.81.9681.146–3.3790.01422.0630.73–5.830.172
 >30644164.15.3192.963–9.548<0.000128.6547.053–116.411<0.0001
Ulcer
 Not identified70261888Ref (1)Ref (1)
 Present352262.94.3472.111–8.954<0.000114.0762.236–88.6120.0048
Depth of invasion
 Mucosa (T1a)61960998.4Ref (1)Ref (1)
 Submucosa (T1b)1183126.3170.87180.933–360.754<0.0001462.34132.183–>999.999<0.0001
ESD
 Without snare66057487Ref (1)---
 With snare776685.71.1120.565–2.1900.757---
Gross type
 Depressed39534186.3Ref (1)---
 Elevated182151831.2960.801–2.0980.2905---
 Flat1099889.90.7090.357–1.4080.3256---
 Unclassified5150980.1270.017–0.9330.0426---

OR, odds ratio; CI, confidence interval; BMI, body mass index; ESD, endoscopic submucosal dissection.

Adverse Events Occurring within 30 Days after the Procedure

 No. (%) 
Bleeding49 (6.9)*
 Presenting symptom
  Hematemesis36 (73.5)
  Decrease in hemoglobin >2 g/dL 1 (2.0)
  Melena12 (24.5)
 Timing
  0–24 hr33 (67.3)
  25–48 hr10 (20.5)
  49 hr–1 wk6 (12.2)
  >1 wk0
 Management of bleeding
  Endoscopic treatment35
  Conservative treatment14
Perforation12 (1.7)*
 Type
  Frank6 (50)
  Micro6 (50)
 Management of perforation
  Clipping only3 (25)
  Surgery after clipping3 (25)
  Conservative6 (50)
Stenosis
 Cardia1 (0.1)*
Cerebrovascular accident
 Infarct1 (0.1)*
Infection (pneumonia or peritonitis)0

Percentage of the 712 patients;

Surgery after clipping was performed in the context of incomplete resection and not for the perforation itself.

Figures
Fig. 1. Flow chart of participant selection.

EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection.

Fig. 2. Pathological and clinical outcomes after endoscopic submucosal dissection (ESD). Complete resection was defined when an differentiated type mucosal early gastric cancer (EGC) without lymphovascular invasion was resected with tumor free margins.

LVI, lymphovascular invasion; PD, poorly differentiated adenocarcinoma; Sm, submucosa; M, mucosa; APC, argon plasma coagulation.

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