Abstract
Background
Endoscopic submucosal dissection (ESD) has been widely performed for the treatment of early gastric cancer (EGC). The aim of this study is to examine the effectiveness of ESD in submucosal invasive gastric cancers (SM-GC), with a special focus on patients who underwent non-curative resection.
Methods
Data for 1,246 patients who underwent ESD for treatment of EGC at six medical centers in Daegu-Gyeongbuk, Korea, between February 2003 and May 2010 were collected. After retrospective analysis of ESD databases, 118 patients were enrolled and classified into three groups: (1) EGC with submucosal invasion less than 500 μm (SM1-GC) that met the expanded criteria (EC) (SM1 EC, n = 42); (2) SM1-GC that did not meet the EC (SM1 non-EC, n = 38); and (3) EGC with submucosal invasion greater than 500 μm (SM2-GC, n = 38).
Results
The en bloc and complete resection rates did not differ significantly among the three groups. However, the curative resection rate was significantly better in the SM1 EC group (69.0 %) compared to that in SM1 non-EC and SM2-GC groups (0 % in both cases). Out of a total of 118 patients, 89 (75.4 %) underwent non-curative resection, and cancer recurrence was observed in 9 (9/89, 10.1 %). We analyzed the survival rate in these non-curative patients and the overall survival and disease-free survival did not differ significantly between patients that were treated with additional surgical resection and those that were simply followed up after ESD.
Conclusions
Non-curative resection in SM-GC does not always lead to cancer recurrence. Thus, if additional surgery cannot be performed because of the patient’s unsuitable condition or refusal, a close follow-up with endoscopy can be considered as an alternative for carefully selected patients. Moreover, as the ESD technology continues to evolve, it might be possible to expand the criteria for curative ESD in patients with SM-GC.
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The endoscopic submucosal dissection (ESD) method, which has been developed to enable direct dissection along the submucosal layer using specialized devices, has an advantage over conventional endoscopic mucosal resection (EMR) when it comes to removal of larger or ulcerated early gastric cancer (EGC) lesions in an en bloc manner [1, 2]. Furthermore, ESD allows accurate histological assessment of the resected specimens, which may help prevent residual disease and local recurrence [3–5].
According to the 2010 guidelines of the Japanese Gastric Cancer Association, expanded criteria for the treatment of submucosal invasive gastric cancers (SM-GC) with curative endoscopic resection include a cancer size of 30 mm or less, differentiated-dominant histology, lack of vessel involvement, and submucosal invasion of less than 500 μm (SM1). Outside the clinical trial setting, expert endoscopists usually perform ESD based on these expanded criteria, which are also used to determine the curability and develop the follow-up strategy. However, the prognosis in patients with SM-GCs treated with ESD remains unclear, and the actual feasibility of ESD for SM-GCs is still controversial. In this regard, the probability of lymph node metastases ranges from 10.2 to 22.9 % for SM-GCs [6–10], and, according to some reports, they may occur even in cases of EGC that meet the expanded criteria [11, 12].
The purpose of this study is to determine the feasibility of the ESD for SM-GC by assessing the therapeutic outcomes in patients treated with ESD. Furthermore, with a special focus on non-curative patients, we investigated whether the survival outcomes differed between patients that were treated with additional surgical resection and those that were simply followed up after ESD.
Materials and methods
Patients
A total of 1,246 EGC patients were treated with ESD at six medical centers in Daegu-Gyeongbuk, Korea, between February 2003 and May 2010. We retrospectively reviewed a prospectively maintained database of all patients with EGC treated with ESD. Out of these 1,246 patients, 121 had SM-GC. Three patients who did not attend follow-up appointments after ESD were excluded, and the remaining 118 were enrolled in this study.
We divided the enrolled cases into three groups according to the results of pathologic examination. The first group included cases with submucosal invasion of less than 500 μm (SM1-GC) that met the EC (SM1 EC group, n = 42). The second group contained SM1-GC cases that did not meet the expanded criteria (SM1 non-EC group, n = 38). Finally, cases with submucosal invasion in excess of 500 μm were combined into the third group (SM2-GC group, n = 38) (Fig. 1).
In principle, we recommended that patients with SM2 cancer and those with SM1 cancer who does not meet the expanded criteria should be treated with additional surgical resection. The decision of whether to perform the additional surgery was made based on the condition of the patient and his/her willingness to receive surgery.
This study was approved by the Institutional Review Board of each medical center. Before ESD, all patients provided oral and written informed consent for the procedure.
ESD methods
The ESD procedure was performed following a standard method. After informed consent was obtained, the ESD was performed under conscious sedation with intravenous midazolam and meperidine by experienced endoscopists who had conducted EMR or EMR-precutting (EMR-P) in more than 100 cases. When necessary the resection margin was determined using chromoendoscopy with indigo carmine or narrow-band imaging (NBI) in addition to conventional white light endoscopy. Next, the area about 5 mm lateral to the lesion was marked with spotty cautery using various endoscopic knives (Olympus, Tokyo, Japan). This was followed by a submucosal injection of hypertonic saline mixed with epinephrine (1:10,000) or glycerol, and sodium hyaluronate to lift the lesion. The endoscope was positioned at the submucosa, and dissection was performed with an endoscopic knife in the caudal direction under direct observation. Resected specimens were stretched with pins and fixed with 10 % formalin solution before delivery to the pathologist.
Histopathological evaluation
For histopathological examination, resected specimens were sectioned perpendicularly at 2-mm intervals. The EGC location was classified as the upper, middle, and lower third of the stomach. The gross type of tumor was determined as elevated, flat, or depressed. Ulcer was defined as a mucosal defect, mucosal deformity, converging fold identified by endoscopy, or submucosal fibrosis. Based on histological findings, tumors were divided into differentiated type adenocarcinoma (well or moderately differentiated tubular adenocarcinoma and papillary adenocarcinoma) and undifferentiated type adenocarcinoma (poorly differentiated adenocarcinoma, signet ring cell carcinoma, and mucinous adenocarcinoma). Tumor involvement in the lateral and deep margins, lymphatic and vascular involvement, tumor size, and the presence or absence of submucosal invasion was assessed. In cases with submucosal infiltration, invasion depth was measured and quantified.
En bloc resection was defined as a resection in a single piece as opposed to a piecemeal resection conducted in multiple pieces. Complete resection was defined as an en bloc or piecemeal lesion resection with complete reconstruction of the lesion by tissues with negative lateral and vertical resection margins and no lymphovascular involvement. In ESD for SM-GCs, curative resection was defined as a resection of differentiated cancer with negative margin, no submucosal invasion deeper than 500 μm, and no lymphovascular involvement.
Follow-up
The patients were followed up with endoscopic examinations and biopsy at 3, 9, and 12 months after ESD, and then annually. To minimize patient dropout, we employed questionnaires or telephone conversations with the patients, particularly with those who missed or postponed follow-up appointments. To detect local recurrence or metachronous cancer, biopsy was done at the treatment-related scar or any suspicious abnormalities. In addition, abdominal computed tomography (CT) and/or positron emission tomography (PET)/CT were performed annually to detect lymph node and distant metastases.
Evaluation of outcomes
The following clinical variables were investigated: patient age, sex, gross tumor type, size, location, ulceration, histologic type, lymphatic invasion, vascular invasion, en bloc resection rate, complete resection rate, curative resection rate, delayed bleeding rate, perforation rate, and local recurrence rate.
We analyzed overall survival and disease-free survival in patients who had undergone non-curative ESD (SM1 EC group with non-curative resection + SM1 non-EC group + SM2-GC group, total n = 89) and were treated with additional surgical resection versus those who were simply followed up after ESD without surgical intervention.
Statistical analysis
Statistical calculations were performed using the SPSS software version 18.0 for Windows (SPSS, Inc., Chicago, IL, USA). Student’s t test was performed for analysis of continuous data. Categorical data analysis was performed using the χ 2 test or Fisher’s exact test. Data for the long-term outcomes were calculated using the Kaplan–Meier method and analyzed by the log-rank test. P values <0.05 were considered statistically significant.
Results
Clinicopathologic features of patients
Of the 118 patients with SM-GCs, 80 had submucosal invasion of less than 500 μm (SM1-GCs), whereas 38 had submucosal invasion greater than 500 μm (SM2-GCs). SM1-GCs were divided into two groups based on whether they met the expanded ESD criteria (42 patients with SM1-GCs, SM1 EC group) or did not satisfy those criteria (38 patients with SM1-GCs, SM1 non-EC group) (Fig. 1).
The clinicopathologic features of the 118 enrolled patients are shown in Table 1. The overall mean age was 66 ± 9.7 years. The most common location of SM-GC was the lower third of the stomach (57 %). Differences in lesion size were observed among the three groups (P < 0.001). Ulcer frequency differed significantly between the SM1 non-EC and SM2-GC groups (P = 0.020). Histologically, differentiated cancer was significantly higher in SM1 EC group compared with the other two groups (P = 0.001). Furthermore, the ratios of lymphatic and vascular invasion were significantly different (P = 0.048 and 0.015, respectively).
Clinical outcomes of ESD for SM-GCs
The outcomes of the ESD are shown in Table 2. The en bloc resection rates did not differ significantly among SM1 EC (85.7 %), SM1 non-EC (94.7 %), and SM2-GC (97.4 %) groups. Furthermore, the complete resection rate was not significantly better for the SM1 EC group (81 %) than for SM1 non-EC group (81.6 %) or SM2-GCgroup (71.1 %). In contrast, the curative resection rate was significantly higher for the SM1 EC group compared to SM1 non-EC and SM2-GC groups (69, 0, and 0 %, respectively).
There was no statistically significant difference among the 3 groups in the delayed bleeding rate, perforation rate, or local tumor recurrence rate.
Clinical courses after ESD for SM-GCs
The summary of the clinical courses after ESD is shown in Fig. 2. During the median follow-up period of 40 months (range 3–99), local recurrences were observed in 10.2 % (12/118) of the patients. Out of a total of 118 patients, 32 underwent preventive operation after ESD. Among these patients, 4 individuals from the SM1 EC group underwent additional surgery even though their ESD had achieved curative resection. Because these surgeries were performed before 2010, the absolute indication was applied at that time. According to the absolute ESD criteria, submucosal invasion was an indication for surgery. Postoperative histologic findings in 28 patients who underwent non-curative ESD are shown in Table 3.
Additional surgical resection was performed for 19 % of the patients (8/42) in the SM1 EC group. For these 8 patients (4: curative resection, 4: non-curative resection), no lymph node metastasis or residual cancer were detected in the postoperative histologic findings. Thirty-four patients (81 %) in the SM1 EC group were followed up after ESD without surgery, and local recurrence was found in 5 patients (5/34, 14.7 %). Among these patients, 4 underwent re-ESD, whereas the remaining patient who had undergone non-curative resection refused further treatment (additional surgery or re-ESD). He died from gastric cancer (total f/u period: 60 months, Table 4).
Out of a total of 38 patients in the SM1 non-EC group, 6 underwent preventive operation after ESD. Among 32 patients who were followed up after ESD without surgery, local recurrence was observed in 2 cases, and these patients underwent therapeutic operation. All 8 patients who underwent additional surgery survived and did not have recurrence. Although 5 patients died after ESD in the SM1 non-EC group, the reasons were underlying diseases (2 cases of lung cancer, 1 case of pancreatic cancer, 1 case of pneumonia, and 1 case of cardiac arrest).
Additional surgical resection was performed for 47.4 % (18/38) of the patients in the SM2-GC group. Histological evaluation of the postoperative specimens revealed that there were no lymph node metastasis or residual cancer in 12 of these patients (12/18, 66.7 %). In three patients (3/18, 16.7 %) histology revealed perigastric lymph node metastasis, and one of them died of recurrent gastric cancer 33 months after the surgery (total f/u period: 37 months, Table 4). Among 20 patients in the SM2-GC group who refused surgery for the reasons such as old age, underlying disease, etc., and were followed up after ESD, local recurrence was observed in three cases, and one patient died of multiple metastasis (total f/u period: 41 months, Table 4). The remaining 17 SM2-GC patients (17/20, 85 %) survived and did not have recurrence, even though no additional surgery was performed.
Survival outcomes after ESD for SM-GCs
We analyzed the overall survival and disease-free survival in patients who had undergone non-curative ESD (SM1 EC group with non-curative resection + SM1 non-EC group + SM2-GC group, total n = 89) depending on whether preventive operation was performed. They were divided into two groups: patients who were treated with additional surgical resection (n = 28) and those who were followed up after ESD without additional surgery (n = 61). The overall and disease-free survival rates did not differ significantly between these two groups (Fig. 3a, b). Although the P values did not show statistical significance, there was a trend of poorer survival outcomes in patients who were not treated with additional surgery.
Discussion
In response to the rapid development of the ESD treatment approaches, expanded criteria for applicability of endoscopic resection in EGC have recently been proposed [13]. Despite the widespread use of these criteria, the clinical outcomes have not been fully evaluated. Our study divided patients into three groups: SM1 EC, SM1 non-EC, and SM2-GC. With respect to the technical outcome of ESD for SM-GCs, the differences in en bloc and complete resection rates were not statistically significant among these three groups. Likewise, no difference was observed in the delayed bleeding and perforation rates. In the case of non-curative ESD, the overall survival and disease-free survival did not differ significantly between the patients that were treated with additional surgical resection and those who were simply followed up after ESD.
A recent study reported a significant difference in the complete resection rate between tumors that met the expanded SM1 criteria (93.2 %) and those that did not meet the expanded SM1 criteria (74.2 %) [14]. In contrast, our data do not show such a difference (81.0 vs. 81.6 %). This disagreement might have originated from technical improvements in the ESD procedure which enabled deep submucosal dissection and could result in complete resection even in the case of deep submucosal invasive cancer.
Among the reports describing the outcomes of ESD for EGCs [15–22], the study of Gotoda et al. [16]. found no significant difference in the overall survival between the cases of EGCs that met the guideline criteria and those that met the expanded criteria. However, long-term outcomes for SM1-GCs versus SM2-GCs were not reported in that study. In another study, the authors compared post-ESD outcomes among the cases of SM1-GC that met the expanded ESD criteria, those that did not, and SM2-GC cases [14]. The disease-specific survival did not significantly differ between patients that were simply followed up after ESD and those that were treated with additional surgical resection. However, one limitation of the above study is that it was conducted at a single center. In our multi-center study, we focused on the patients who underwent non-curative resection (SM1 EC group with non-curative resection + SM1 non-EC group + SM2-GC group, total n = 89). We compared the overall and disease-free survival rates between two groups: patients who were treated with additional surgical resection after ESD (n = 28), and those who were followed up after ESD without surgery (n = 61). Although the overall and disease-free survival rates did not differ significantly between these two groups, our data revealed a tendency of poorer survival outcomes in non-curative and non-operative patients. Among 61 patients who were simply followed up after ESD, 7 patients recurred (7/61, 11.5 %) during the follow-up period, and two patients died (2/61, 3.3 %) of gastric cancer. Because of this considerable recurrence rate, we strongly recommend that additional surgery should be performed for patients who undergo non-curative resection of SM-GC. Nevertheless, non-curative resection of SM-GC does not always lead to cancer-related problems. According to our postoperative histologic findings in 28 patients who had undergone non-curative ESD, 18 (18/28, 64.3 %) had neither residual cancer nor lymph node metastasis. Moreover, among the patients in the SM2-GC group who were followed up after ESD without surgery (n = 20), only three (3/20, 15 %) recurred. Therefore, if the condition of a patient (age, underlying disease, etc.) does not permit additional surgery or the patient refuses it, a close follow-up with endoscopy can be considered as an alternative approach for carefully selected individuals.
Our study has several limitations. First, its retrospective design introduces a potential for selection bias. To minimize this bias, we included almost all patients with EGC treated with ESD identified in the database. Our results are meaningful given that it would be difficult to conduct a prospective study on this topic in real clinical environment. Second, because of the multi-center design, the ESD procedures were performed by several endoscopists. Therefore, we cannot exclude the possibility that some differences may have existed in criteria for indication of ESD, the way the procedure was conducted, and histopathological diagnoses. Third, owing to the small sample size and relatively short follow-up periods, our results could be different from those obtained in larger, long-term studies. Further research is needed to assess the appropriate depth of submucosal invasion for successful ESD in SM-GC patients.
In conclusion, although additional surgery is strongly recommended for patients who undergo non-curative resection of SM-GC, a close follow-up with endoscopy can be considered as an alternative in selected cases complicated with multiple comorbidities or high operative risks. As the ESD technology continues to evolve, more SM-GC patients may benefit from ESD, which will further reduce the need for additional surgery in the future.
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Disclosures
Drs. Jun Young Choi, Seong Woo Jeon, Kwang Bum Cho, Kyung Sik Park, Eun Soo Kim, Chang Keun Park, Yun Jin Chung, Joong Goo Kwon, Jin Tae Jung, Eun Young Kim, Kyeong Ok Kim, Byung Ik Jang, Si Hyung Lee, Jeong Bae Park, Chang Hun Yang have no conflicts of interest or financial ties to disclose.
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Choi, J.Y., Jeon, S.W., Cho, K.B. et al. Non-curative endoscopic resection does not always lead to grave outcomes in submucosal invasive early gastric cancer. Surg Endosc 29, 1842–1849 (2015). https://doi.org/10.1007/s00464-014-3874-2
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DOI: https://doi.org/10.1007/s00464-014-3874-2