- Email: [email protected]
Therapeutic outcomes of endoscopic submucosal dissection of differentiated early gastric cancer in a Western endoscopy setting (with video)
ORIGINAL ARTICLE
Therapeutic outcomes of endoscopic submucosal dissection of differentiated early gastric cancer in a Western endoscopy setting (with video) Fabian Emura, MD, PhD, FASGE,1,2,3,5 Juan Mejía, MD,1 Alberto Donneys, EcE,2 Orlando Ricaurte, MD,4 Luis Sabbagh, MD,5 Luis Giraldo-Cadavid, MD, FCCP,6 Ichiro Oda, MD,7 Yutaka Saito, MD, PhD,7 Camilo Osorio, MD2,3 Bogotá, Colombia; Tokyo, Japan
Background: Large multicenter gastric cancer endoscopic submucosal dissection (ESD) studies conducted at major Japanese institutions have reported en bloc resection, en bloc tumor-free margin resection, and curative resection rates of 92.7% to 96.1%, 82.6% to 94.5%, and 73.6% to 85.4%, respectively, with delayed bleeding and perforation rates of 0.6% to 6.0% and 3.6% to 4.7%, respectively. Although ESD is currently an alternative treatment in some countries, particularly in Asia, it remains uncertain whether ESD therapeutic outcomes in Western endoscopy settings can be comparable to those achieved in Japan. Objective: To evaluate the ESD therapeutic outcomes for differentiated early gastric cancer (EGC) in a Western endoscopy setting. Design/Setting: Consecutive case series performed by an expertly trained Western endoscopist. Patients: Fifty-three patients with 54 lesions. Interventions: ESD for early gastric cancers (T1) satisfying expanded inclusion criteria. Main Outcome Measurements: En bloc resection, en bloc tumor-free margin resection, and curative resection rates were 98%, 93%, and 83%, respectively. The delayed bleeding rate was 7%, and the perforation rate was 4%. Results: The mean patient age was 67 years, and the mean tumor size was 19.8 mm, with 54% of the lesions located in the lesser curvature. The median procedure time was 61 minutes, with ESD procedures 60 minutes or longer associated with submucosal fibrosis (P! .001) and tumor size 25 mm or larger (P Z .03). In every ESD procedure, both circumferential incision and submucosal dissection were performed by using a single knife. Two of the 4 delayed bleeding cases required surgery, and all perforations were successfully managed by using endoscopic clips. Limitation: Long-term outcome data are currently unavailable. Conclusion: ESD for differentiated EGC resulted in favorable therapeutic outcomes in a Western endoscopy setting comparable to those achieved at major Japanese institutions. (Gastrointest Endosc 2015;-:1-8.)
Abbreviations: EGC, early gastric cancer; ESD, endoscopic submucosal dissection; HGD, high-grade dysplasia; SACE, systematic alphanumeric coded endoscopy; SM, submucosal. DISCLOSURE: This work was supported in part by a grant-in-aid for the Comprehensive Strategy to Control Cancer in the Americas from the Emura Foundation for the Promotion of Cancer Research. All authors disclosed no financial relationships relevant to this article. Copyright ª 2015 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2015.03.1960 Received October 4, 2014. Accepted March 13, 2015.
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Current affiliations: Advanced Gastrointestinal Endoscopy, EmuraCenter LatinoAmerica (1), Emura Foundation for the Promotion of Cancer Research (2), Division of Gastroenterology and Endoscopy, Universidad de La Sabana (3), Department of Pathology, Universidad Nacional de Colombia, (4), Centro de Exploraciones Digestivas, Clínica Universitaria Colombia (5), Department of Internal Medicine, Universidad de La Sabana, Bogotá DC, Colombia (6), Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan (7). Reprint requests: Fabian Emura, MD, PhD, FASGE, Advanced Gastrointestinal Endoscopy, EmuraCenter LatinoAmerica, Calle 134 No. 7-83, Oficina 341, Edificio Altos del Bosque, Bogotá DC, Colombia. If you would like to chat with an author of this article, you may contact Dr Emura at [email protected].
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Therapeutic outcomes of gastric ESD in a western setting
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BACKGROUND
Endoscopist’s training background
Gastric cancer ranks as the most common malignant tumor in East Asia, Eastern Europe, and parts of Latin America.1 Although the incidence and mortality have decreased in the United States over the past 35 years, it is estimated that the disease will be diagnosed in approximately 21,600 Americans and that 10,990 will die of the disease in 2014.2 As in many other Latin American countries, gastric cancer is the main cause of cancer-related deaths in Colombia, with an estimated 7700 new cases every year, with the majority of those cases diagnosed at an advanced stage.3,4 Key factors in reducing mortality and morbidity, respectively, are early diagnosis and curative endoscopic treatment. Endoscopic submucosal dissection (ESD) was pioneered by Japanese endoscopists and revolutionized the management of early gastric cancer (ECG). ESD has a low risk of lymphnode metastasis and is widely accepted as a minimally invasive, safe, and curative procedure.5,6 En bloc resection is the major advantage of ESD over conventional EMR because it facilitates precise histological assessment, reduces tumor recurrence, and provides higher curability rates.7 Large multicenter gastric cancer ESD studies at major Japanese institutions have reported en bloc resection rates of 92.7% to 96.1%,8,9 en bloc tumor-free margin resection rates of 82.6% to 94.5%,8,9 and curative resection rates of 73.6% to 85.4%.9,10 Those studies have also reported delayed bleeding rates of 0.6% to 6%5,10 and perforation rates of 3.6% to 4.7%.5,10 Although ESD is currently an alternative treatment for EGC in some countries, particularly in Asia, it is still uncertain whether therapeutic outcomes of ESD when performed by suitably trained Western endoscopists are comparable to those achieved at major Japanese institutions. The aim of this study, therefore, was to assess the therapeutic outcomes of ESD for differentiated EGC in a Western endoscopy setting located in Bogotá, Colombia.
MATERIAL AND METHODS Patients and institutions A total of 54 differentiated EGCs in 53 consecutive patients were treated in Bogotá by ESD at either the EmuraCenter LatinoAmerica or Clínica Universitaria Colombia from October 2007 to September 2014. The EmuraCenter has served as a reference facility since 2007, where highly qualified local and Japanese endoscopists have provided training in specific endoscopic techniques such as narrowband imaging,11 magnifying colonoscopy,12 ESD,13,14 and systematic alphanumeric coded endoscopy (SACE).15 Informed consent was obtained from all patients, and the study was approved by the respective institutional review boards. An anesthesiologist administered either intravenous sedation with midazolam and/or propofol or general anesthesia. 2 GASTROINTESTINAL ENDOSCOPY Volume
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The Western endoscopist participating in this series (F.E.) was formally trained at the National Cancer Center Hospital in Tokyo, Japan, for 2 years (2003-2005) in a gastroenterology and endoscopy practice focused on therapeutic procedures. His ESD training consisted of a stepby-step approach encompassing upper GI endoscopy with an emphasis on EGC diagnosis and ESD indications, diagnostic and therapeutic colonoscopy, observing and assisting in more than 300 ESD procedures, performing at least 25 successful ESDs on ex vivo porcine models, and then performing ESDs on gastric lesions under the close supervision of highly experienced endoscopists.
Diagnosis of EGC Endoscopic examination was indicated for both symptomatic patients and screening purposes. SACE was routinely used for diagnosis.15 A mixture of Nacetylcysteine to dissolve the overlying superficial mucus and polydimethylsiloxane to remove saliva bubbles was administered 20 minutes before the endoscopy examination.16,17 Chromoendoscopy was performed to clearly distinguish the margins of the lesions by using a 0.25% solution of indigo carmine dye injected directly into the working channel of the endoscope with a 20-mL disposable syringe.18 For all referral cases, an additional preoperative evaluation was conducted for endoscopic confirmation of the margins and to determine the appropriate ESD strategy to be used on each patient. All lesions were considered to be early cancers also referred to as T1 cancers because they were confined to the mucosa or submucosa based on both endoscopic findings and subsequent pathological analysis. Each lesion demonstrated either differentiated adenocarcinoma or high-grade dysplasia (HGD). EUS was used to estimate the depth of invasion in selected cases.19 The location was divided into the pyloric channel, antrum, angulus, lower third, middle third, and upper third according to a classification proposed by Emura et al.15 The cross-sectional position on the circumference was divided into the anterior wall, lesser curvature, posterior wall, and greater curvature.20 If a lesion extended beyond a particular wall or curvature, its cross-sectional position was based on the location of the larger portion of the lesion. Macroscopic types were determined based on the Paris classification.21
Indications for ESD All lesions satisfied the expanded indications criteria proposed by the National Cancer Center Hospital guidelines for ESD.22
ESD technique Procedures were performed by using an Olympus GIF H180 video endoscope (Olympus Optical Co, Ltd, Tokyo, www.giejournal.org
Emura et al
Japan), a standard video endoscope system (EVIS EXERA II; Olympus), and an ERBE ICC-200 (ERBE Elektromedizin GmBH, Tübingen, Germany) frequency generator. Marking around the lesions was performed by using a conventional needle-knife. A mixture of normal saline solution, indigo carmine dye, and epinephrine was then injected into the submucosal (SM) layer with Glycerol (Chugai Pharmaceutical Co, Tokyo, Japan)23 used in selected cases. After making a mucosal cut, a circumferential mucosal incision separated the lesion from the underlying healthy tissue followed by SM dissection by using an IT-Knife2 (KD-611L; Olympus) (Video 1, available online at www.giejournal.org).24 A soft, straight, and transparent attachment (D-201-11304; Olympus) to facilitate observation of the SM layer was used during ESDs, primarily for treating lesions located in the gastric body. A grasper forceps (Coagrasper; Olympus) was used for bleeding control and hemostasis, whereas endoscopic clips (EZ Clip HX-610-135L; Olympus) were used for bleeding control and closure of perforations. After retrieval, specimens were pinned on Styrofoam for pathological analysis (Fig. 1). All patients were maintained with intravenous isotonic solution and omeprazole infusion with no nourishment orally during the first 12 to 24 hours after ESD. If there were no adverse events, liquids were initiated at 12 to 24 hours and soft foods at 36 to 48 hours.
Adverse events and postprocedure course Delayed bleeding was defined as clinical evidence of bleeding by hematemesis or melena occurring any time from ESD completion to 30 days after the procedure that required subsequent endoscopic treatment.5 A perforation determination was made by direct endoscopic observation of any gastric wall disruption during the ESD. Intra-abdominal transmural air leakage was defined as a small amount of focal free air close to the stomach identified by a plain abdominal CT scan without any evidence of a perforation occurring during the ESD.25 Procedure-related mortality was defined as any death occurring within 30 days of an ESD or during the same hospital stay.5,27
Pathological analysis Specimens were immediately fixed in 10% formalin and embedded in paraffin. Serial slices of 2 mm were then stained with hematoxylin and eosin. Tumor size, specimen size, ulceration, grade of differentiation, depth of invasion, lymphovascular invasion, and tumor margins were assessed by expert GI pathologists according to the Japanese gastric cancer guidelines (version 3).26
Therapeutic outcomes definitions An en bloc resection was defined as a single-piece resection in contrast to a piecemeal resection, which was defined as a resection in multiple pieces. All piecemeal resections were considered to be noncurative resections. An en bloc tumor-free margin resection was defined as a www.giejournal.org
Therapeutic outcomes of gastric ESD in a western setting
single-piece resection in which both the vertical and horizontal margins of the resected specimen were free of tumor cells for a distance greater than 1 mm from the lesion’s edge. A curative resection was achieved when all of the following conditions were fulfilled: an en bloc resection with negative horizontal and vertical margins and no lymphovascular invasion and one of the following: (1) a mucosal cancer without ulceration regardless of tumor size; (2) a mucosal cancer 3 cm or smaller with ulceration; or (3) a minute SM (SM1, !500 mm from the muscularis mucosa) cancer 3 cm or smaller in size.22 A noncurative resection was defined as a resection that did not satisfy all of these criteria. Procedure time was measured from the first circumferential marking until complete removal of the lesion.28 SM fibrosis was defined as the presence of hard yellowish tissue assessed under white-light chromoendoscopy and classified as mild fibrosis (F1) or severe fibrosis (F2).29 A 1-knife ESD was defined as the use of a single knife for both circumferential incision and SM dissection. Multiple-knife ESD was defined as using more than 1 knife for both the circumferential incision and SM dissection procedural steps. A hybrid ESD was defined as the technique in which the circumferential incision was made by using a knife followed by a snare resection.
Statistical analysis Data were analyzed by using the IBM SPSS version 20 (IBM Corporation, Armonk, NY). Qualitative variables were evaluated by the Fisher exact test and quantitative variables by Student t test or the Mann-Whitney U test. For all statistical tests, a 2-tailed P value !.05 was considered significant.
RESULTS Clinicopathological characteristics The mean patient age was 67 years (range 45-89 years), and the male:female ratio was 1.1:1. Lesions were located in the pyloric channel, antrum, angulus, lower third, middle third, and upper third in 7%, 41%, 15%, 11%, 11%, and 15% of the cases, respectively. Regarding crosssectional position on the circumference, most of the 50 lesions, exclusive of the 4 lesions involving the pyloric channel, were located in the lesser curvature (58%, 29/ 50) followed by the anterior (16%, 8/50) and posterior (16%, 8/50) walls and then the greater curvature (10%, 5/ 50). Macroscopically, there were 30 (55%) IIa þ IIc, 10 (18%) IIa, 7 (13%) IIc, 4 (7%) IIc-Is, and 3 (5%) Is lesions. The total presence of a IIc component was 76% (41/54). Thirty-three cases (61%) were diagnosed at our institutions with 21 (39%) referral cases.
Histological analysis The mean specimen size was 45.9 mm, and the mean tumor size was 19.8 mm. All lesions were T1 cancers. Volume
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Figure 1. ESD technique. A, IIa þ IIc lesion 25 mm in diameter located on the antrum posterior wall. B, Indigo carmine dye spraying clearly shows the lesion’s margin and superficial erosion. C, Marking around the lesion. D, Submucosal injection and mucosal cut. E, Circumferential incision with an ITKnife2 separating the tumor from the underlying healthy tissue. F, Submucosal dissection. G, Total exposure of the muscle layer was accomplished in 25 minutes (Video 1, available online at www.giejournal.org) H, The lesion is fixed before immersion in formaldehyde. Histopathological analysis revealed a well-differentiated adenocarcinoma invading the SM1 layer (300 mm). Ulcer, lymphovascular invasion, and margins were negative.
Well-differentiated adenocarcinoma and HGD were identified in 37 (68%) and 15 (28%) of the lesions, respectively. Two lesions (4%) diagnosed preoperatively as HGD by biopsy were subsequently diagnosed as low-grade dysplasia after ESD. Based on depth of invasion, 46 lesions (85%) were intramucosal, 2 (4%) were SM1, and 6 (11%) invaded deeply into the SM layer (SM2, R500 mm from the muscularis mucosa), with 2 of the latter lesions also demonstrating lymphovascular invasion. Ulceration was detected in 11% (6/54) of the lesions. Overall assessments of curability and clinicopathological characteristics are shown in Table 1.
ESD outcomes En bloc and piecemeal resections resulted in 98% (53/ 54) and 2% (1/54) of the cases, respectively. The lone lesion with a piecemeal resection involved the pyloric channel. En bloc tumor-free margin resection and curative resection rates were 93% (50/54) and 83% (45/54), respectively. Of the 9 noncurative resection cases, 5 of the lesions involved SM2 invasion, 3 lesions had positive horizontal margins, and 1 lesion was both SM2 invasive and had a positive horizontal margin. Surgery was recommended for those patients with SM2 invasion and additional argon plasma coagulation treatment for patients with positive horizontal margins.30,31 SM fibrosis was observed in 24% (13/54) of the cases, with 3 mild F1 cases and 10 severe cases classified as F2. The median ESD procedure time was 61 minutes, and ESD times 60 minutes or longer were significantly associated with SM fibrosis (P ! .001) and tumor size of 25 mm or larger (P Z .03), whereas procedure times for lesions located in the antrum were signif4 GASTROINTESTINAL ENDOSCOPY Volume
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icantly shorter in duration (P ! .03). Overall assessments of ESD procedure times and clinicopathological characteristics are shown in Table 2. A single IT-Knife2 was used for both circumferential incision and SM dissection in each ESD case, so all procedures were considered to be a 1knife ESD. There were no multiple-knife or hybrid ESDs performed in this series.
Adverse events Delayed bleeding was observed in 7% (4/54) of the cases, with 3 of the 4 cases involving patients having associated comorbidities. Chronic renal failure was previously diagnosed in 1 such patient who experienced delayed bleeding 4 hours after ESD. Neither removal of a large blood clot at the ESD site for bleeding source location nor the use of epinephrine sclerotherapy was effective; therefore, surgical control was successfully performed on the patient. Another chronic renal failure patient underwent successful endoscopic treatment by epinephrine sclerotherapy for delayed bleeding on the fifth postprocedure day after hemodialysis. The third such patient had liver cirrhosis, and bleeding was initially controlled endoscopically but resumed after 12 hours, requiring surgical intervention. This particular patient was then admitted to intensive care and died on postprocedure day 33 because of multiple-organ dysfunction secondary to liver cirrhosis. The patient without any associated comorbidities experienced bleeding 20 hours after ESD that was successfully treated with endoscopic clips and epinephrine sclerotherapy. Perforation occurred in 4% (2/54) of the cases, with 1 affected lesion located in the antrum posterior wall and the other lesion located in the pyloric channel, which www.giejournal.org
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Therapeutic outcomes of gastric ESD in a western setting
TABLE 1. Curative resection in relations to clinicopathological factors
Factors Mean age, y
Lesions (N [ 54) Curative Noncurative P value 66.6
62.5
67.4
28 (52%)
23
5
26 (48)
22
4
4 (7)
2
2
.13
Antrum
22 (41)
21
1
.07
Angulus
8 (15)
6
2
.61
Lower third
6 (11)
6
0
.57
Middle third
6 (11)
5
1
1.00
Upper third
8 (15)
5
3
.12
Anterior wall
8 (16)
8
0
.33
Lesser curve
29 (58)
23
6
.48
Posterior wall
8 (16)
8
0
.33
Greater curve
5 (10)
4
1
1.00
IIc component
41 (76)
33
8
No IIc component
13 (24)
12
1
Sex
.20 1.00
Male Female Location Pyloric channel
Macroscopic type
.42
Mean tumor size, mm
1.00
R25
16 (30)
13
3
!25
38 (70)
32
6
Ulcer
.57
Present
6 (11)
4
2
Absent
48 (89)
41
7
required performing an extended ESD up to the duodenal bulb to facilitate achieving a negative horizontal margin. Successful closure by using endoscopic clips was performed in both perforation cases. One instance of transmural air leakage without any evidence of a perforation occurring during or after endoscopic treatment was observed in a patient who underwent 2 consecutive ESDs that altogether lasted 192 minutes. Intra-abdominal air was detected by a CT scan and treated by abdominal needle decompression without further adverse events.
DISCUSSION Despite the increasing use of endoscopic procedures for the treatment of early GI malignancies, there have been only a few previously published reports on therapeutic outcomes of ESD for EGC in Western countries.27,32 Although it has been speculated that Western institutions could not achieve ESD results comparable to those at Japan institutions,32,33 the findings of this study demonwww.giejournal.org
strate favorable outcomes similar to those achieved at major Japanese institutions. The Western delay in adopting ESD has been attributed to several unfavorable conditions including the perceived scarcity of early-stage lesions.4,34 Despite the recognized high prevalence of gastric cancer in many Latin American countries,35 reports of early diagnosis have in reality been scarce and often rely on autopsy records.36,37 In contrast, this study of a large series of 54 EGC lesions supports in a novel way that early diagnosis is both achievable and sustainable in a Western endoscopy setting. As previously reported by us, use of the SACE method for complete and systematic examination of the upper GI tract in daily practice has made a remarkable difference in our ability to consistently increase the number of accurately diagnosed EGC cases.15,38,39 Precision in depth estimation was also an important consideration in this study because all suspicious lesions were carefully examined for predictors of SM deep invasion by using indigo carmine dye, and those deemed to involve such invasion were precluded from ESD treatment.40,41 This study constitutes the largest series of ESD procedures for differentiated EGC reported in the West. Most of the early cancers (58%) were located in the gastric lesser curvature. A large gastric cancer series in Japan has also identified the lesser curvature as the most-frequent crosssectional position on the circumference.42 Our data also confirm previous findings that located approximately 60% of gastric cancers in the lesser curvature, 30% at the gastroesophageal junction, and 10% in the greater curvature.43 Two lesions preoperatively diagnosed by biopsy as HGD were subsequently determined to be lowgrade dysplasia after ESD. Such misdiagnoses are likely explained by probable inclusion of the HGD portions of the lesions in the preoperative biopsy specimens. In relation to ESD outcomes, the excellent en bloc resection and en bloc tumor-free margin resection rates of 98% and 93%, respectively, compare favorably with the respective 92.7% to 96.1% and 82.6% to 94.5% rates found at Japanese referral institutions.8-10 In this series, 83% of all resections were curative, which is also similar to multicenter Japanese studies reporting curability rates of 73.6% to 85.4%.8,9 The IT-Knife2 is one of the devices available for ESD in the United States and has been used most frequently in the stomach.44 After the short mucosal incision was performed in this series by using a conventional needle-knife, circumferential incision and SM dissection were successfully completed with an IT-Knife2, thereby demonstrating the suitability of using a single knife to perform both steps. Although specific data are not yet available, we believe that 1-knife ESD will considerably reduce the overall cost of procedures for Western centers planning to use ESD for the treatment of EGC. Another key factor for success in this study may have been the participation of an anesthesiologist in all of the procedures because a previous Volume
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TABLE 2. Endoscopic submucosal dissection time in relation to clinicopathological factors
Factors Mean age, y
Lesions (N [ 54) !60 min 66.6
R60 min
P value
68.4
.14
64.4
Sex
.58 Male Female
28 (52%)
11
17
26 (48)
13
13
4 (7)
1
3
.62
22 (41)
14
8
.03*
Location Pyloric channel Antrum Angulus
8 (15)
3
5
.72
Lower third
6 (11)
4
2
.39
Middle third
6 (11)
1
5
.21
Upper third
8 (15)
1
7
.06
Anterior wall
8 (16)
6
2
.20
Lesser curve
29 (58)
10
19
.12
Posterior wall
8 (16)
4
4
1.00
Greater curve
5 (10)
3
2
.65
IIc component
41 (76)
17
24
IIc component
13 (24)
7
6
Macroscopic type
.58
Mean tumor size, mm
.03*
R25
10 (19)
1
9
!25
44 (81)
23
21
Present
13 (24)
0
13
Absent
41 (76)
24
17
Present
6 (11)
2
4
Absent
48 (89)
22
26
!.001*
Fibrosis
Ulcer
.68
*Fisher exact test (2 tailed).
report indicated that sedation administered by an anesthesiologist improved the en bloc resection rate and reduced the procedure time.45 A large ESD series has reported SM fibrosis in 20% of the cases with mild F1 and severe F2 in 62% and 38% of those cases, respectively.29 Similarly, our study revealed SM fibrosis in 24% of the cases with F2 cases accounting for 10 (77%) of the total number of 13 SM fibrosis cases probably due to aggressive or bite-on-bite preoperative biopsy44 as well as the inclusion of 2 local recurrence cases. Currently, there are no preoperative methods for ascertaining fibrosis, so future studies to establish and evaluate techniques for identifying SM fibrosis would be highly beneficial. It has been speculated that ESD procedure times achieved in Japan could not be reproduced in Western 6 GASTROINTESTINAL ENDOSCOPY Volume
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countries,33 but this study has demonstrated that very similar ESD times are, in fact, possible. The median procedure time in this series was 61 minutes, which is similar to the mean time of 60 minutes in 1033 ESDs performed at a Japanese referral center.5 Subgroup analysis revealed ESD times of 60 minutes and longer for lesions with SM fibrosis and lesions 25 mm and larger. A recent study also reported SM fibrosis, larger than tumor size 7 cm2, and upper stomach location were predictors of a longer ESD procedure time.28 Significantly shorter procedure times were also achieved in this study for lesions located in the antrum (P ! .03), which was similar to the findings of a large ESD study conducted in Japan.5 A relatively easier endoscope manipulation by using the direct-view approach is probably the reason for this result. Although several studies have also associated upper stomach location with longer ESD times (O121 minutes),5 such a relationship was not conclusively demonstrated in this study. There were 4 cases of EGC involving the pyloric channel. One ESD resulted in a piecemeal resection and another in a positive horizontal margin; thus, the curative resection rate was only 50% for those 4 cases. ESDs performed for such lesions are particularly challenging due to restricted visualization of the distal resection margin, and the procedures often require the use of retroflexion at the duodenal bulb.46 The findings of a recent series of 24 cases of gastric neoplasia involving the pyloric channel demonstrated the difficulty of such procedures, with positive horizontal margins and perforations occurring in 13% and 8% of the cases, respectively.47 Delayed bleeding occurred after 4 ESDs (7%), which is similar to the results of large Japanese studies reporting delayed bleeding rates of 0.6% to 6%.8,10 Three of the 4 lesions in this series were located in the gastric antrum. Although the exact reason remains unclear, increased antrum peristaltic movement may have contributed, at least to some extent, to delayed bleeding.5 Two of the delayed bleeding cases occurred in chronic renal failure patients. High rates of delayed bleeding and related deaths after ESD have previously been reported because of the tendency of these patients to bleed and their associated vascular comorbidities.48,49 Delayed bleeding also occurred in 1 patient with previously diagnosed liver cirrhosis. After initial endoscopic control, bleeding resumed, requiring surgical intervention and admission to the intensive care unit. The patient eventually died of multiple-organ dysfunction more than 1 month after ESD. This was considered a procedure-related death because it occurred during the patient’s same hospital admission. No other procedure-related deaths occurred in this series. A higher risk of bleeding and postprocedure adverse events is well documented in such patients because of severe clotting impairment and a reduction in their platelet counts.50 There were 2 cases (4%) of a perforation being successfully closed by using endoscopic www.giejournal.org
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clips with no further adverse events. The lesions were located in the pyloric channel and the posterior wall of the antrum. This result is similar to the findings at major Japanese referral centers that have reported perforation rates of 3.6% to 4.7%.9,10 One patient who underwent 2 consecutive ESDs lasting a total of 192 minutes experienced transmural air leakage that was successfully managed conservatively by using needle decompression.51 The lengthy procedure time and prolonged muscle layer exposure from the first ESD ulcer could explain such air leakage in the absence of any evidence of an actual perforation. In a previous series of 33 patients, prolonged procedure time was identified as a cause of transmural air leakage, with all such cases successfully treated conservatively.25 Efforts to undertake ESD procedures without proper training could result in unacceptably high noncurative resection and adverse event rates. The favorable outcomes achieved in this study are due at least in part to the formalized step-by-step training received by the participating endoscopist. In fact, such a gradual process with particular emphasis on EGC diagnosis followed by observing and assisting in ESDs performed on patients together with practice on animal models and, finally, performing small antrum ESDs has been shown to be an effective method for attaining an ESD level of proficiency that fosters a high en bloc resection rate.52 Ideally, this specialized training should be carried out at recognized centers in which a high volume of ESD procedures are performed and led by highly experienced endoscopists. No long-term outcome data are available yet, but we are currently gathering survival data for analysis and further comparison with the results reported by endoscopists in Japan. Another limitation of the study is that the ESD outcomes represent the experience of an individual expert endoscopist and may not necessarily be extrapolated to other Western endoscopy settings. In conclusion, our experience has demonstrated that favorable therapeutic outcomes of ESD for EGC can be achieved in a Western endoscopy setting when such procedures are performed by an expert endoscopist after proper specialized training. The en bloc resection, en bloc tumorfree margin resection, and curative resection rates as well as the ESD procedure times and adverse event rates reported here were comparable to the outcomes previously reported in multicenter studies conducted by major Japanese institutions. Given the important potential impact that ESD could have on favorable patient outcomes in the future, the necessity of establishing high endoscopic examination standards for the accurate detection of EGC and developing appropriate professional training programs constitute major challenges to the widespread acceptance of ESD for the treatment of EGC in an increasing number of Western countries. www.giejournal.org
Therapeutic outcomes of gastric ESD in a western setting
REFERENCES 1. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol 2006;12:354-62. 2. A snapshot of stomach cancer. Incidence and mortality. Available at: www.cancer.gov/researchandfunding/snapshots. Accessed September 22, 2014. 3. Murillo R, Piñeros M, Hernández G. Atlas de mortalidad por cáncer en Colombia. Bogotá, Colombia: Instituto Nacional de Cancerología; Instituto Geográfico Agustín Codazzi; 2004. 4. Piñeros M, Pardo C, Gamboa O, et al. Atlas de mortalidad por cáncer en Colombia. Instituto Nacional de Cancerología; Instituto Geográfico Agustín Codazzi; 2010. 5. Oda I, Gotoda T, Hamanaka H, et al. Endoscopic submucosal resection for early gastric cancer: technical feasibility, operation time and complications from a large consecutive series. Digest Endosc 2005;17:54-8. 6. Isotomo H, Shikuwa S, Yamaguchi N, et al. Endoscopic submucosal dissection for early gastric cancer: a large-scale feasibility study. Gut 2009;58:331-6. 7. Gotoda T, Kaltenbach T, Soetikno R. Is en bloc resection essential for endoscopic resection of GI neoplasia? Gastrointest Endosc 2008;67: 805-7. 8. Oda I, Saito D, Tada M, et al. A multicenter retrospective study of endoscopic resection for early gastric cancer. Gastric Cancer 2006;9:262-70. 9. Sugimoto T, Okamoto M, Mitsuno Y, et al. Endoscopic submucosal dissection is an effective and safe therapy for early gastric neoplasms: a multicenter feasible study. J Clin Gastroenterol 2012;46:124-9. 10. Hotta K, Oyama T, Akamatsu T, et al. A comparison of outcomes of endoscopic submucosal dissection (ESD) For early gastric neoplasms between high-volume and low-volume centers: multi-center retrospective questionnaire study conducted by the Nagano ESD Study Group. Intern Med 2010;49:253-9. 11. Henry ZH, Yeaton P, Shami VM, et al. Meshed capillary vessels found on narrow-band imaging without optical magnification effectively identifies colorectal neoplasia: a North American validation of the Japanese experience. Gastrointest Endosc 2010;72:118-26. 12. Canales OM, Miyagui J, Takano J, et al. Usefulness of the Exera magnifying NBI system for differential diagnosis of small colorectal polyps using the Sano-Emura classification in Peru [abstract]. Gastrointest Endosc 2011;73:AB438. 13. Wang AY, Emura F, Oda I, et al. Endoscopic submucosal dissection with electrosurgical knives in a patient on aspirin therapy (with video). Gastrointest Endosc 2010;72:1066-71. 14. Vargas G, Chavez M, Sanchez V, et al. Tratamiento endoscópico de cancer gástrico temprano mediante Disección Endoscópica Sub-Mucosa (DES) usando el IT-Knife 2. Rev Gastroenterol Perú 2012;32:297-302. 15. Emura F, Gralnek I, Sano Y, et al. Improving early detection of gastric cancer: a novel systematic alphanumeric-coded endoscopic approach. Rev Gastroenterol Perú 2013;33:52-8. 16. Chang CC, Chen SH, Lin CP, et al. Premedication with pronase or Nacetylcysteine improves visibility during gastroendoscopy: an endoscopist-blinded, prospective, randomized study. World J Gastroenterol 2007;13:444-7. 17. Chang WK, Yeh MK, Hsu HC, et al. Efficacy of simethicone and N-acetylcysteine as premedication in improving visibility during upper endoscopy. J Gastroenterol Hepatol 2014;29:769-74. 18. Sano Y, Saito Y, Kuan-I F, et al. Efficacy of magnifying chromoendoscopy for the differential diagnosis of colorectal lesions. Dig Endosc 2005;17:105-16. 19. Choi J, Kim SG, Im JP, et al. Comparison of endoscopic ultrasonography and conventional endoscopy for prediction of depth of tumor invasion in early gastric cancer. Endoscopy 2010;42:705-13. 20. Japanese Gastric Cancer Association. Japanese Classification of Gastric Carcinoma - 2nd English Edition. Gastric Cancer 1998;1:10-24. 21. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 2003;58(6 Suppl):S3-43.
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22. Gotoda T, Iwasaki M, Kusano C, et al. Endoscopic resection of early gastric cancer treated by guideline and expanded National Cancer Centre criteria. Br J Surg 2010;97:868-71. 23. Uraoka T, Fujii T, Saito Y, et al. Effectiveness of glycerol as a submucosal injection for EMR. Gastrointest Endosc 2005;61:736-40. 24. Ono H, Hasuike N, Inui T, et al. Usefulness of a novel electrosurgical knife, the insulation- tipped diathermic knife-2, for endoscopic submucosal dissection of early gastric cancer. Gastric Cancer 2008;11: 47-52. 25. Onogi F, Araki H, Ibuka T, et al. “Transmural air leak”: a computed tomographic finding following endoscopic submucosal dissection of gastric tumors. Endoscopy 2010;42:441-7. 26. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer 2011;14:113-23. 27. Pimentel-Nunes P, Mourâo F, Veloso N, et al. Long-term follow-up after endoscopic resection of gastric superficial neoplastic lesions in Portugal. Endoscopy 2014;46:933-40. 28. Lu ZS, Yang YS, Feng D, et al. Predictive factors of endoscopic submucosal dissection procedure time for gastric superficial neoplasia. World J Gastroenterol 2012;18:7009-14. 29. Higashimaya M, Oka S, Tanaka S, et al. Outcome of endoscopic submucosal dissection for gastric neoplasm in relationship to endoscopic classification of submucosal fibrosis. Gastric Cancer 2013;16:404-10. 30. Gotoda T, Yanagisawa A, Sasako M, et al. Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at two large centers. Gastric Cancer 2000;3:219-25. 31. Kitamura T, Tanabe S, Koizumi W, et al. Argon plasma coagulation for early gastric cancer: technique and outcome. Gastrointest Endosc 2006;63:48-54. 32. Schumacher B, Charton JP, Nordmann T, et al. Endoscopic submucosal dissection of early gastric neoplasia with a water jet-assisted knife: a Western, single-center experience. Gastrointest Endosc 2012;75: 1166-74. 33. Neuhaus H. ESD around the world: Europe. Gastrointest Endosc Clin N Am 2014;24:295-311. 34. Iacopini F, Bella A, Costamagna G, et al. Stepwise training in rectal and colonic endoscopic submucosal dissection with differentiated learning curves. Gastrointest Endosc 2012;76:1188-96. 35. Llorens P. Gastric cancer in Chile. Gastrointest Endosc 1999;49:408-11. 36. Adrada JC, Calambás FH, Díaz JE, et al. The socio-demographic and clinical characteristics in gastric cancer population in the department of Cauca, Colombia. Rev Col Gastroenterol 2008;23:2009-14. 37. Henao FJ, Rojas OA, Mejía AF, et al. Extension de la lindadenectomía para el tratamiento quirúrgico del adenocarcinoma gástrico en el Hospital Universitario San Ignacio: cohorte prospectiva con análisis de supervivencia. Rev Col Cirugía 2001;16:65-71.
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38. Emura F, Mejia J, Mejia M, et al. Effectiveness of systematic chromoendoscopy for diagnosis of early cancer and gastric premalignant lesions. Results of two consecutive screening campaigns in Colombia (20062007). Rev Col Gastroenterol 2010;25:19-30. 39. Emura F, Baron TH, Gralnek IM. The pharynx: examination of an area too often ignored during upper endoscopy. Gastrointest Endosc 2013;78: 143-9. 40. Yamada T, Sugiyama H, Ochi D, et al. Risk factors for submucosal and lymphovascular invasion in gastric cancer looking indicative for endoscopic submucosal dissection. Gastric Cancer 2014;17:692-6. 41. Oda I, Abe S, Kusano C, et al. Correlation between endoscopic macroscopic type and invasion depth for early esophagogastric junction adenocarcinomas. Gastric Cancer 2011;14:22-7. 42. Maruyama K, Gunvén P, Okabayashi K, et al. Lymph node metastases of gastric cancer. General pattern in 1931 patients. Ann Surg 1989;210:596-602. 43. Cancer of the stomach. In: Mehta A, Bansal SC, eds. Diagnosis and management of cancer. New Delhi (India): Jaypeee Brothers Medical Publishers; 2004. p. 351-72. 44. Draganov PV, Gotoda T, Chavalitdhamrong D, et al. Techniques of endoscopic submucosal dissection: application for the Western endoscopist? Gastrointest Endosc 2013;78:677-88. 45. Park CH, Min JH, Yoo YC, et al. Sedation methods can determine performance of endoscopic submucosal dissection in patients with gastric neoplasia. Surg Endosc 2013;27:2760-7. 46. Park JC, Kim JH, Youn YH, et al. How to manage pyloric tumours that are difficult to resect completely with endoscopic resection: comparison of the retroflexion vs. forward view technique. Dig Liver Dis 2011;43:958-64. 47. Lim CH, Park JM, Park CH, et al. Endoscopic submucosal dissection of gastric neoplasia involving the pyloric channel by retroflexion in the duodenum. Dig Dis Sci 2012;57:148-54. 48. Numata N, Oka S, Tanaka S, et al. Clinical outcomes of endoscopic submucosal dissection for early gastric cancer in patients with chronic kidney disease. J Gastroenterol Hepatol 2013;28:1632-7. 49. Goto O, Fujishiro M, Kodashima S, et al. Feasibility of endoscopic submucosal dissection for patients with chronic renal failure on hemodialysis. Dig Endosc 2010;22:45-8. 50. Repici A, Pagano N, Hassan C, et al. Endoscopic submucosal dissection of gastric neoplastic lesions in patients with liver cirrhosis: a systematic review. J Gastrointest Liver Dis 2012;21:303-7. 51. Baron TH, Wong Kee Song LM, Zielinski MD, et al. A comprehensive approach to the management of acute endoscopic perforations (with videos). Gastrointest Endosc 2012;76:838-59. 52. Oda I, Odagaki T, Suzuki H, et al. Learning curve for endoscopic submucosal dissection of early gastric cancer based on trainee experience. Dig Endosc 2012;24(Suppl 1):129-32.
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Therapeutic outcomes of endoscopic submucosal dissection of differentiated early gastric cancer in a Western endoscopy setting (with video) Fabian Emura, MD, PhD, FASGE,1,2,3,5 Juan Mejía, MD,1 Alberto Donneys, EcE,2 Orlando Ricaurte, MD,4 Luis Sabbagh, MD,5 Luis Giraldo-Cadavid, MD, FCCP,6 Ichiro Oda, MD,7 Yutaka Saito, MD, PhD,7 Camilo Osorio, MD2,3 Bogotá, Colombia; Tokyo, Japan
Background: Large multicenter gastric cancer endoscopic submucosal dissection (ESD) studies conducted at major Japanese institutions have reported en bloc resection, en bloc tumor-free margin resection, and curative resection rates of 92.7% to 96.1%, 82.6% to 94.5%, and 73.6% to 85.4%, respectively, with delayed bleeding and perforation rates of 0.6% to 6.0% and 3.6% to 4.7%, respectively. Although ESD is currently an alternative treatment in some countries, particularly in Asia, it remains uncertain whether ESD therapeutic outcomes in Western endoscopy settings can be comparable to those achieved in Japan. Objective: To evaluate the ESD therapeutic outcomes for differentiated early gastric cancer (EGC) in a Western endoscopy setting. Design/Setting: Consecutive case series performed by an expertly trained Western endoscopist. Patients: Fifty-three patients with 54 lesions. Interventions: ESD for early gastric cancers (T1) satisfying expanded inclusion criteria. Main Outcome Measurements: En bloc resection, en bloc tumor-free margin resection, and curative resection rates were 98%, 93%, and 83%, respectively. The delayed bleeding rate was 7%, and the perforation rate was 4%. Results: The mean patient age was 67 years, and the mean tumor size was 19.8 mm, with 54% of the lesions located in the lesser curvature. The median procedure time was 61 minutes, with ESD procedures 60 minutes or longer associated with submucosal fibrosis (P! .001) and tumor size 25 mm or larger (P Z .03). In every ESD procedure, both circumferential incision and submucosal dissection were performed by using a single knife. Two of the 4 delayed bleeding cases required surgery, and all perforations were successfully managed by using endoscopic clips. Limitation: Long-term outcome data are currently unavailable. Conclusion: ESD for differentiated EGC resulted in favorable therapeutic outcomes in a Western endoscopy setting comparable to those achieved at major Japanese institutions. (Gastrointest Endosc 2015;-:1-8.)
Abbreviations: EGC, early gastric cancer; ESD, endoscopic submucosal dissection; HGD, high-grade dysplasia; SACE, systematic alphanumeric coded endoscopy; SM, submucosal. DISCLOSURE: This work was supported in part by a grant-in-aid for the Comprehensive Strategy to Control Cancer in the Americas from the Emura Foundation for the Promotion of Cancer Research. All authors disclosed no financial relationships relevant to this article. Copyright ª 2015 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2015.03.1960 Received October 4, 2014. Accepted March 13, 2015.
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Current affiliations: Advanced Gastrointestinal Endoscopy, EmuraCenter LatinoAmerica (1), Emura Foundation for the Promotion of Cancer Research (2), Division of Gastroenterology and Endoscopy, Universidad de La Sabana (3), Department of Pathology, Universidad Nacional de Colombia, (4), Centro de Exploraciones Digestivas, Clínica Universitaria Colombia (5), Department of Internal Medicine, Universidad de La Sabana, Bogotá DC, Colombia (6), Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan (7). Reprint requests: Fabian Emura, MD, PhD, FASGE, Advanced Gastrointestinal Endoscopy, EmuraCenter LatinoAmerica, Calle 134 No. 7-83, Oficina 341, Edificio Altos del Bosque, Bogotá DC, Colombia. If you would like to chat with an author of this article, you may contact Dr Emura at [email protected].
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BACKGROUND
Endoscopist’s training background
Gastric cancer ranks as the most common malignant tumor in East Asia, Eastern Europe, and parts of Latin America.1 Although the incidence and mortality have decreased in the United States over the past 35 years, it is estimated that the disease will be diagnosed in approximately 21,600 Americans and that 10,990 will die of the disease in 2014.2 As in many other Latin American countries, gastric cancer is the main cause of cancer-related deaths in Colombia, with an estimated 7700 new cases every year, with the majority of those cases diagnosed at an advanced stage.3,4 Key factors in reducing mortality and morbidity, respectively, are early diagnosis and curative endoscopic treatment. Endoscopic submucosal dissection (ESD) was pioneered by Japanese endoscopists and revolutionized the management of early gastric cancer (ECG). ESD has a low risk of lymphnode metastasis and is widely accepted as a minimally invasive, safe, and curative procedure.5,6 En bloc resection is the major advantage of ESD over conventional EMR because it facilitates precise histological assessment, reduces tumor recurrence, and provides higher curability rates.7 Large multicenter gastric cancer ESD studies at major Japanese institutions have reported en bloc resection rates of 92.7% to 96.1%,8,9 en bloc tumor-free margin resection rates of 82.6% to 94.5%,8,9 and curative resection rates of 73.6% to 85.4%.9,10 Those studies have also reported delayed bleeding rates of 0.6% to 6%5,10 and perforation rates of 3.6% to 4.7%.5,10 Although ESD is currently an alternative treatment for EGC in some countries, particularly in Asia, it is still uncertain whether therapeutic outcomes of ESD when performed by suitably trained Western endoscopists are comparable to those achieved at major Japanese institutions. The aim of this study, therefore, was to assess the therapeutic outcomes of ESD for differentiated EGC in a Western endoscopy setting located in Bogotá, Colombia.
MATERIAL AND METHODS Patients and institutions A total of 54 differentiated EGCs in 53 consecutive patients were treated in Bogotá by ESD at either the EmuraCenter LatinoAmerica or Clínica Universitaria Colombia from October 2007 to September 2014. The EmuraCenter has served as a reference facility since 2007, where highly qualified local and Japanese endoscopists have provided training in specific endoscopic techniques such as narrowband imaging,11 magnifying colonoscopy,12 ESD,13,14 and systematic alphanumeric coded endoscopy (SACE).15 Informed consent was obtained from all patients, and the study was approved by the respective institutional review boards. An anesthesiologist administered either intravenous sedation with midazolam and/or propofol or general anesthesia. 2 GASTROINTESTINAL ENDOSCOPY Volume
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The Western endoscopist participating in this series (F.E.) was formally trained at the National Cancer Center Hospital in Tokyo, Japan, for 2 years (2003-2005) in a gastroenterology and endoscopy practice focused on therapeutic procedures. His ESD training consisted of a stepby-step approach encompassing upper GI endoscopy with an emphasis on EGC diagnosis and ESD indications, diagnostic and therapeutic colonoscopy, observing and assisting in more than 300 ESD procedures, performing at least 25 successful ESDs on ex vivo porcine models, and then performing ESDs on gastric lesions under the close supervision of highly experienced endoscopists.
Diagnosis of EGC Endoscopic examination was indicated for both symptomatic patients and screening purposes. SACE was routinely used for diagnosis.15 A mixture of Nacetylcysteine to dissolve the overlying superficial mucus and polydimethylsiloxane to remove saliva bubbles was administered 20 minutes before the endoscopy examination.16,17 Chromoendoscopy was performed to clearly distinguish the margins of the lesions by using a 0.25% solution of indigo carmine dye injected directly into the working channel of the endoscope with a 20-mL disposable syringe.18 For all referral cases, an additional preoperative evaluation was conducted for endoscopic confirmation of the margins and to determine the appropriate ESD strategy to be used on each patient. All lesions were considered to be early cancers also referred to as T1 cancers because they were confined to the mucosa or submucosa based on both endoscopic findings and subsequent pathological analysis. Each lesion demonstrated either differentiated adenocarcinoma or high-grade dysplasia (HGD). EUS was used to estimate the depth of invasion in selected cases.19 The location was divided into the pyloric channel, antrum, angulus, lower third, middle third, and upper third according to a classification proposed by Emura et al.15 The cross-sectional position on the circumference was divided into the anterior wall, lesser curvature, posterior wall, and greater curvature.20 If a lesion extended beyond a particular wall or curvature, its cross-sectional position was based on the location of the larger portion of the lesion. Macroscopic types were determined based on the Paris classification.21
Indications for ESD All lesions satisfied the expanded indications criteria proposed by the National Cancer Center Hospital guidelines for ESD.22
ESD technique Procedures were performed by using an Olympus GIF H180 video endoscope (Olympus Optical Co, Ltd, Tokyo, www.giejournal.org
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Japan), a standard video endoscope system (EVIS EXERA II; Olympus), and an ERBE ICC-200 (ERBE Elektromedizin GmBH, Tübingen, Germany) frequency generator. Marking around the lesions was performed by using a conventional needle-knife. A mixture of normal saline solution, indigo carmine dye, and epinephrine was then injected into the submucosal (SM) layer with Glycerol (Chugai Pharmaceutical Co, Tokyo, Japan)23 used in selected cases. After making a mucosal cut, a circumferential mucosal incision separated the lesion from the underlying healthy tissue followed by SM dissection by using an IT-Knife2 (KD-611L; Olympus) (Video 1, available online at www.giejournal.org).24 A soft, straight, and transparent attachment (D-201-11304; Olympus) to facilitate observation of the SM layer was used during ESDs, primarily for treating lesions located in the gastric body. A grasper forceps (Coagrasper; Olympus) was used for bleeding control and hemostasis, whereas endoscopic clips (EZ Clip HX-610-135L; Olympus) were used for bleeding control and closure of perforations. After retrieval, specimens were pinned on Styrofoam for pathological analysis (Fig. 1). All patients were maintained with intravenous isotonic solution and omeprazole infusion with no nourishment orally during the first 12 to 24 hours after ESD. If there were no adverse events, liquids were initiated at 12 to 24 hours and soft foods at 36 to 48 hours.
Adverse events and postprocedure course Delayed bleeding was defined as clinical evidence of bleeding by hematemesis or melena occurring any time from ESD completion to 30 days after the procedure that required subsequent endoscopic treatment.5 A perforation determination was made by direct endoscopic observation of any gastric wall disruption during the ESD. Intra-abdominal transmural air leakage was defined as a small amount of focal free air close to the stomach identified by a plain abdominal CT scan without any evidence of a perforation occurring during the ESD.25 Procedure-related mortality was defined as any death occurring within 30 days of an ESD or during the same hospital stay.5,27
Pathological analysis Specimens were immediately fixed in 10% formalin and embedded in paraffin. Serial slices of 2 mm were then stained with hematoxylin and eosin. Tumor size, specimen size, ulceration, grade of differentiation, depth of invasion, lymphovascular invasion, and tumor margins were assessed by expert GI pathologists according to the Japanese gastric cancer guidelines (version 3).26
Therapeutic outcomes definitions An en bloc resection was defined as a single-piece resection in contrast to a piecemeal resection, which was defined as a resection in multiple pieces. All piecemeal resections were considered to be noncurative resections. An en bloc tumor-free margin resection was defined as a www.giejournal.org
Therapeutic outcomes of gastric ESD in a western setting
single-piece resection in which both the vertical and horizontal margins of the resected specimen were free of tumor cells for a distance greater than 1 mm from the lesion’s edge. A curative resection was achieved when all of the following conditions were fulfilled: an en bloc resection with negative horizontal and vertical margins and no lymphovascular invasion and one of the following: (1) a mucosal cancer without ulceration regardless of tumor size; (2) a mucosal cancer 3 cm or smaller with ulceration; or (3) a minute SM (SM1, !500 mm from the muscularis mucosa) cancer 3 cm or smaller in size.22 A noncurative resection was defined as a resection that did not satisfy all of these criteria. Procedure time was measured from the first circumferential marking until complete removal of the lesion.28 SM fibrosis was defined as the presence of hard yellowish tissue assessed under white-light chromoendoscopy and classified as mild fibrosis (F1) or severe fibrosis (F2).29 A 1-knife ESD was defined as the use of a single knife for both circumferential incision and SM dissection. Multiple-knife ESD was defined as using more than 1 knife for both the circumferential incision and SM dissection procedural steps. A hybrid ESD was defined as the technique in which the circumferential incision was made by using a knife followed by a snare resection.
Statistical analysis Data were analyzed by using the IBM SPSS version 20 (IBM Corporation, Armonk, NY). Qualitative variables were evaluated by the Fisher exact test and quantitative variables by Student t test or the Mann-Whitney U test. For all statistical tests, a 2-tailed P value !.05 was considered significant.
RESULTS Clinicopathological characteristics The mean patient age was 67 years (range 45-89 years), and the male:female ratio was 1.1:1. Lesions were located in the pyloric channel, antrum, angulus, lower third, middle third, and upper third in 7%, 41%, 15%, 11%, 11%, and 15% of the cases, respectively. Regarding crosssectional position on the circumference, most of the 50 lesions, exclusive of the 4 lesions involving the pyloric channel, were located in the lesser curvature (58%, 29/ 50) followed by the anterior (16%, 8/50) and posterior (16%, 8/50) walls and then the greater curvature (10%, 5/ 50). Macroscopically, there were 30 (55%) IIa þ IIc, 10 (18%) IIa, 7 (13%) IIc, 4 (7%) IIc-Is, and 3 (5%) Is lesions. The total presence of a IIc component was 76% (41/54). Thirty-three cases (61%) were diagnosed at our institutions with 21 (39%) referral cases.
Histological analysis The mean specimen size was 45.9 mm, and the mean tumor size was 19.8 mm. All lesions were T1 cancers. Volume
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Figure 1. ESD technique. A, IIa þ IIc lesion 25 mm in diameter located on the antrum posterior wall. B, Indigo carmine dye spraying clearly shows the lesion’s margin and superficial erosion. C, Marking around the lesion. D, Submucosal injection and mucosal cut. E, Circumferential incision with an ITKnife2 separating the tumor from the underlying healthy tissue. F, Submucosal dissection. G, Total exposure of the muscle layer was accomplished in 25 minutes (Video 1, available online at www.giejournal.org) H, The lesion is fixed before immersion in formaldehyde. Histopathological analysis revealed a well-differentiated adenocarcinoma invading the SM1 layer (300 mm). Ulcer, lymphovascular invasion, and margins were negative.
Well-differentiated adenocarcinoma and HGD were identified in 37 (68%) and 15 (28%) of the lesions, respectively. Two lesions (4%) diagnosed preoperatively as HGD by biopsy were subsequently diagnosed as low-grade dysplasia after ESD. Based on depth of invasion, 46 lesions (85%) were intramucosal, 2 (4%) were SM1, and 6 (11%) invaded deeply into the SM layer (SM2, R500 mm from the muscularis mucosa), with 2 of the latter lesions also demonstrating lymphovascular invasion. Ulceration was detected in 11% (6/54) of the lesions. Overall assessments of curability and clinicopathological characteristics are shown in Table 1.
ESD outcomes En bloc and piecemeal resections resulted in 98% (53/ 54) and 2% (1/54) of the cases, respectively. The lone lesion with a piecemeal resection involved the pyloric channel. En bloc tumor-free margin resection and curative resection rates were 93% (50/54) and 83% (45/54), respectively. Of the 9 noncurative resection cases, 5 of the lesions involved SM2 invasion, 3 lesions had positive horizontal margins, and 1 lesion was both SM2 invasive and had a positive horizontal margin. Surgery was recommended for those patients with SM2 invasion and additional argon plasma coagulation treatment for patients with positive horizontal margins.30,31 SM fibrosis was observed in 24% (13/54) of the cases, with 3 mild F1 cases and 10 severe cases classified as F2. The median ESD procedure time was 61 minutes, and ESD times 60 minutes or longer were significantly associated with SM fibrosis (P ! .001) and tumor size of 25 mm or larger (P Z .03), whereas procedure times for lesions located in the antrum were signif4 GASTROINTESTINAL ENDOSCOPY Volume
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icantly shorter in duration (P ! .03). Overall assessments of ESD procedure times and clinicopathological characteristics are shown in Table 2. A single IT-Knife2 was used for both circumferential incision and SM dissection in each ESD case, so all procedures were considered to be a 1knife ESD. There were no multiple-knife or hybrid ESDs performed in this series.
Adverse events Delayed bleeding was observed in 7% (4/54) of the cases, with 3 of the 4 cases involving patients having associated comorbidities. Chronic renal failure was previously diagnosed in 1 such patient who experienced delayed bleeding 4 hours after ESD. Neither removal of a large blood clot at the ESD site for bleeding source location nor the use of epinephrine sclerotherapy was effective; therefore, surgical control was successfully performed on the patient. Another chronic renal failure patient underwent successful endoscopic treatment by epinephrine sclerotherapy for delayed bleeding on the fifth postprocedure day after hemodialysis. The third such patient had liver cirrhosis, and bleeding was initially controlled endoscopically but resumed after 12 hours, requiring surgical intervention. This particular patient was then admitted to intensive care and died on postprocedure day 33 because of multiple-organ dysfunction secondary to liver cirrhosis. The patient without any associated comorbidities experienced bleeding 20 hours after ESD that was successfully treated with endoscopic clips and epinephrine sclerotherapy. Perforation occurred in 4% (2/54) of the cases, with 1 affected lesion located in the antrum posterior wall and the other lesion located in the pyloric channel, which www.giejournal.org
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TABLE 1. Curative resection in relations to clinicopathological factors
Factors Mean age, y
Lesions (N [ 54) Curative Noncurative P value 66.6
62.5
67.4
28 (52%)
23
5
26 (48)
22
4
4 (7)
2
2
.13
Antrum
22 (41)
21
1
.07
Angulus
8 (15)
6
2
.61
Lower third
6 (11)
6
0
.57
Middle third
6 (11)
5
1
1.00
Upper third
8 (15)
5
3
.12
Anterior wall
8 (16)
8
0
.33
Lesser curve
29 (58)
23
6
.48
Posterior wall
8 (16)
8
0
.33
Greater curve
5 (10)
4
1
1.00
IIc component
41 (76)
33
8
No IIc component
13 (24)
12
1
Sex
.20 1.00
Male Female Location Pyloric channel
Macroscopic type
.42
Mean tumor size, mm
1.00
R25
16 (30)
13
3
!25
38 (70)
32
6
Ulcer
.57
Present
6 (11)
4
2
Absent
48 (89)
41
7
required performing an extended ESD up to the duodenal bulb to facilitate achieving a negative horizontal margin. Successful closure by using endoscopic clips was performed in both perforation cases. One instance of transmural air leakage without any evidence of a perforation occurring during or after endoscopic treatment was observed in a patient who underwent 2 consecutive ESDs that altogether lasted 192 minutes. Intra-abdominal air was detected by a CT scan and treated by abdominal needle decompression without further adverse events.
DISCUSSION Despite the increasing use of endoscopic procedures for the treatment of early GI malignancies, there have been only a few previously published reports on therapeutic outcomes of ESD for EGC in Western countries.27,32 Although it has been speculated that Western institutions could not achieve ESD results comparable to those at Japan institutions,32,33 the findings of this study demonwww.giejournal.org
strate favorable outcomes similar to those achieved at major Japanese institutions. The Western delay in adopting ESD has been attributed to several unfavorable conditions including the perceived scarcity of early-stage lesions.4,34 Despite the recognized high prevalence of gastric cancer in many Latin American countries,35 reports of early diagnosis have in reality been scarce and often rely on autopsy records.36,37 In contrast, this study of a large series of 54 EGC lesions supports in a novel way that early diagnosis is both achievable and sustainable in a Western endoscopy setting. As previously reported by us, use of the SACE method for complete and systematic examination of the upper GI tract in daily practice has made a remarkable difference in our ability to consistently increase the number of accurately diagnosed EGC cases.15,38,39 Precision in depth estimation was also an important consideration in this study because all suspicious lesions were carefully examined for predictors of SM deep invasion by using indigo carmine dye, and those deemed to involve such invasion were precluded from ESD treatment.40,41 This study constitutes the largest series of ESD procedures for differentiated EGC reported in the West. Most of the early cancers (58%) were located in the gastric lesser curvature. A large gastric cancer series in Japan has also identified the lesser curvature as the most-frequent crosssectional position on the circumference.42 Our data also confirm previous findings that located approximately 60% of gastric cancers in the lesser curvature, 30% at the gastroesophageal junction, and 10% in the greater curvature.43 Two lesions preoperatively diagnosed by biopsy as HGD were subsequently determined to be lowgrade dysplasia after ESD. Such misdiagnoses are likely explained by probable inclusion of the HGD portions of the lesions in the preoperative biopsy specimens. In relation to ESD outcomes, the excellent en bloc resection and en bloc tumor-free margin resection rates of 98% and 93%, respectively, compare favorably with the respective 92.7% to 96.1% and 82.6% to 94.5% rates found at Japanese referral institutions.8-10 In this series, 83% of all resections were curative, which is also similar to multicenter Japanese studies reporting curability rates of 73.6% to 85.4%.8,9 The IT-Knife2 is one of the devices available for ESD in the United States and has been used most frequently in the stomach.44 After the short mucosal incision was performed in this series by using a conventional needle-knife, circumferential incision and SM dissection were successfully completed with an IT-Knife2, thereby demonstrating the suitability of using a single knife to perform both steps. Although specific data are not yet available, we believe that 1-knife ESD will considerably reduce the overall cost of procedures for Western centers planning to use ESD for the treatment of EGC. Another key factor for success in this study may have been the participation of an anesthesiologist in all of the procedures because a previous Volume
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TABLE 2. Endoscopic submucosal dissection time in relation to clinicopathological factors
Factors Mean age, y
Lesions (N [ 54) !60 min 66.6
R60 min
P value
68.4
.14
64.4
Sex
.58 Male Female
28 (52%)
11
17
26 (48)
13
13
4 (7)
1
3
.62
22 (41)
14
8
.03*
Location Pyloric channel Antrum Angulus
8 (15)
3
5
.72
Lower third
6 (11)
4
2
.39
Middle third
6 (11)
1
5
.21
Upper third
8 (15)
1
7
.06
Anterior wall
8 (16)
6
2
.20
Lesser curve
29 (58)
10
19
.12
Posterior wall
8 (16)
4
4
1.00
Greater curve
5 (10)
3
2
.65
IIc component
41 (76)
17
24
IIc component
13 (24)
7
6
Macroscopic type
.58
Mean tumor size, mm
.03*
R25
10 (19)
1
9
!25
44 (81)
23
21
Present
13 (24)
0
13
Absent
41 (76)
24
17
Present
6 (11)
2
4
Absent
48 (89)
22
26
!.001*
Fibrosis
Ulcer
.68
*Fisher exact test (2 tailed).
report indicated that sedation administered by an anesthesiologist improved the en bloc resection rate and reduced the procedure time.45 A large ESD series has reported SM fibrosis in 20% of the cases with mild F1 and severe F2 in 62% and 38% of those cases, respectively.29 Similarly, our study revealed SM fibrosis in 24% of the cases with F2 cases accounting for 10 (77%) of the total number of 13 SM fibrosis cases probably due to aggressive or bite-on-bite preoperative biopsy44 as well as the inclusion of 2 local recurrence cases. Currently, there are no preoperative methods for ascertaining fibrosis, so future studies to establish and evaluate techniques for identifying SM fibrosis would be highly beneficial. It has been speculated that ESD procedure times achieved in Japan could not be reproduced in Western 6 GASTROINTESTINAL ENDOSCOPY Volume
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countries,33 but this study has demonstrated that very similar ESD times are, in fact, possible. The median procedure time in this series was 61 minutes, which is similar to the mean time of 60 minutes in 1033 ESDs performed at a Japanese referral center.5 Subgroup analysis revealed ESD times of 60 minutes and longer for lesions with SM fibrosis and lesions 25 mm and larger. A recent study also reported SM fibrosis, larger than tumor size 7 cm2, and upper stomach location were predictors of a longer ESD procedure time.28 Significantly shorter procedure times were also achieved in this study for lesions located in the antrum (P ! .03), which was similar to the findings of a large ESD study conducted in Japan.5 A relatively easier endoscope manipulation by using the direct-view approach is probably the reason for this result. Although several studies have also associated upper stomach location with longer ESD times (O121 minutes),5 such a relationship was not conclusively demonstrated in this study. There were 4 cases of EGC involving the pyloric channel. One ESD resulted in a piecemeal resection and another in a positive horizontal margin; thus, the curative resection rate was only 50% for those 4 cases. ESDs performed for such lesions are particularly challenging due to restricted visualization of the distal resection margin, and the procedures often require the use of retroflexion at the duodenal bulb.46 The findings of a recent series of 24 cases of gastric neoplasia involving the pyloric channel demonstrated the difficulty of such procedures, with positive horizontal margins and perforations occurring in 13% and 8% of the cases, respectively.47 Delayed bleeding occurred after 4 ESDs (7%), which is similar to the results of large Japanese studies reporting delayed bleeding rates of 0.6% to 6%.8,10 Three of the 4 lesions in this series were located in the gastric antrum. Although the exact reason remains unclear, increased antrum peristaltic movement may have contributed, at least to some extent, to delayed bleeding.5 Two of the delayed bleeding cases occurred in chronic renal failure patients. High rates of delayed bleeding and related deaths after ESD have previously been reported because of the tendency of these patients to bleed and their associated vascular comorbidities.48,49 Delayed bleeding also occurred in 1 patient with previously diagnosed liver cirrhosis. After initial endoscopic control, bleeding resumed, requiring surgical intervention and admission to the intensive care unit. The patient eventually died of multiple-organ dysfunction more than 1 month after ESD. This was considered a procedure-related death because it occurred during the patient’s same hospital admission. No other procedure-related deaths occurred in this series. A higher risk of bleeding and postprocedure adverse events is well documented in such patients because of severe clotting impairment and a reduction in their platelet counts.50 There were 2 cases (4%) of a perforation being successfully closed by using endoscopic www.giejournal.org
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clips with no further adverse events. The lesions were located in the pyloric channel and the posterior wall of the antrum. This result is similar to the findings at major Japanese referral centers that have reported perforation rates of 3.6% to 4.7%.9,10 One patient who underwent 2 consecutive ESDs lasting a total of 192 minutes experienced transmural air leakage that was successfully managed conservatively by using needle decompression.51 The lengthy procedure time and prolonged muscle layer exposure from the first ESD ulcer could explain such air leakage in the absence of any evidence of an actual perforation. In a previous series of 33 patients, prolonged procedure time was identified as a cause of transmural air leakage, with all such cases successfully treated conservatively.25 Efforts to undertake ESD procedures without proper training could result in unacceptably high noncurative resection and adverse event rates. The favorable outcomes achieved in this study are due at least in part to the formalized step-by-step training received by the participating endoscopist. In fact, such a gradual process with particular emphasis on EGC diagnosis followed by observing and assisting in ESDs performed on patients together with practice on animal models and, finally, performing small antrum ESDs has been shown to be an effective method for attaining an ESD level of proficiency that fosters a high en bloc resection rate.52 Ideally, this specialized training should be carried out at recognized centers in which a high volume of ESD procedures are performed and led by highly experienced endoscopists. No long-term outcome data are available yet, but we are currently gathering survival data for analysis and further comparison with the results reported by endoscopists in Japan. Another limitation of the study is that the ESD outcomes represent the experience of an individual expert endoscopist and may not necessarily be extrapolated to other Western endoscopy settings. In conclusion, our experience has demonstrated that favorable therapeutic outcomes of ESD for EGC can be achieved in a Western endoscopy setting when such procedures are performed by an expert endoscopist after proper specialized training. The en bloc resection, en bloc tumorfree margin resection, and curative resection rates as well as the ESD procedure times and adverse event rates reported here were comparable to the outcomes previously reported in multicenter studies conducted by major Japanese institutions. Given the important potential impact that ESD could have on favorable patient outcomes in the future, the necessity of establishing high endoscopic examination standards for the accurate detection of EGC and developing appropriate professional training programs constitute major challenges to the widespread acceptance of ESD for the treatment of EGC in an increasing number of Western countries. www.giejournal.org
Therapeutic outcomes of gastric ESD in a western setting
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