JOURNAL OF LAPAROENDOSCOPIC & ADVANCED SURGICAL TECHNIQUES Volume 24, Number 6, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/lap.2013.0572
Endoscopic Submucosal Dissection for Early Gastric Neoplasms in Elderly Patients Yan Zhang, MM,1 Lijiang Huang, MM,2 Lin Li, MD,1 and Feng Ji, MD, PhD1
Abstract
Objective: To retrospectively evaluate the safety and feasibility of endoscopic submucosal dissection (ESD) for the treatment of early gastric cancer (EGC) in elderly patients q75 years of age. Patients and Methods: One hundred seventy-one patients (187 lesions) treated with ESD from January 2010 to September 2013 were enrolled in our study. Subjects were classified into two groups: elderly (age q75 years) or non-elderly (age < 75 years). Clinicopathological characteristics, resectability, curability, complications, rates of local recurrence, and residual disease were evaluated. Association of clinicopathological characteristics of the lesions with immediate bleeding was analyzed. Results: No significant differences in clinical characteristics were observed. The incidences of comorbidity were significantly different between the elderly group and the non-elderly group (P < .001). Of the elderly patients, 54.3% had two or more underlying diseases compared with 18.4% of the non-elderly patients (P < .001). Of the 98.0% of elderly patients and 97.1% of younger patients who received en bloc resection, curative resection reached 94.1% and 96.3%, respectively. Immediate bleeding occurred in 15.2% of the elderly group and 4.8% of the non-elderly group (P = .044). Operation time differed significantly (P = .039). No apparent discrepancy was observed in perforation and delayed bleeding. The differences in the invasion depth were considered between the two groups (P = .001). Logistic regression analysis revealed that the rate of immediate bleeding was associated with invasion depth (P = .003). There were no differences in the follow-up period and rates of local recurrence and residual disease. Conclusions: ESD is safe and feasible for elderly patients in the era of a graying population. Higher risk of immediate bleeding and longer operation time should be concerned. Introduction
E
arly gastric cancer (EGC) is defined as invasive gastric neoplasm that is confined to the mucosa and submucosa, irrespective of lymphatic metastasis. If EGC is treated appropriately, its prognosis of EGC is much better than that of advanced gastric cancer.1,2 Therefore, early diagnosis and proper therapies are urgent. Several preliminary studies have revealed that endoscopic submucosal dissection (ESD) has gradually replaced gastrectomy and endoscopic mucosal resection as a standard treatment for EGC, which allows en bloc resection, precise histological assessment, and low residual disease and local recurrence rate as well as minimal trauma and quick recovery.3–5 However, as the population ages, the number of elderly patients steadily increases. Elderly patients often remain underrepresented in clinical trials. Moreover, patients with advanced age always show declined physiological function 1 2
and worse general conditions compared with younger patients. Preoperative malnutrition and concomitant diseases contribute to higher rates of postoperative complications after surgery. Thus, ESD seems to be a better choice for EGCs in the elderly population. The aim of our present study was to compare the clinical and therapeutic outcomes between the elderly population and the non-elderly population, as well as to assess the safety and effectiveness of ESD in elderly patients 75 years of age and older. In addition, clinical risk factors that might influence on the ESD processing were also evaluated. Patients and Methods Patients and enrollment criteria
From January 2010 to September 2013, in total, 187 EGCs in 171 patients were treated by ESD in The First
Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Department of Gastroenterology, Xiangshan First People’s Hospital, Xiangshan, China.
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Affiliated Hospital, School of Medicine, Zhejiang University (Hangzhou, China) and Xiangshan First People’s Hospital (Xiangshan, China). The study protocol was approved by the Hospital Ethics Committee. Written informed consent statements were obtained from all the participants involved in this study before surgery. Patients and their families were also informed of potential hazards and complications and signed the surgical informed consents. ESD procedures were performed on gastric neoplasms with no nodal metastasis, and patients were enrolled on the basis of the expanded criteria proposed by Gotoda et al.6 as follows: differentiated mucosal cancer without ulcer findings irrespective of tumor size; differentiated mucosal cancer with ulcers of p30 mm in diameter; undifferentiated mucosal cancer without ulcers of p20 mm in diameter; and minute differentiated submucosal cancer (invasion depth, p500 lm) without ulcers of p30 mm in diameter. Endoscopic ultrasound and computed tomography were carried out if there was a possibility of submucosal invasion.
macroscopic type of the EGCs was categorized into the elevated type and the flat/depressed type. The tumor size was divided into three groups: p20 mm, 20–40 mm, and q40 mm. En bloc resection was defined as resection in a single piece instead of piecemeal separation by endoscopy. The resections were deemed curative when the specimens removed were free of tumorous glands in both the lateral and vertical margins and when submucosal invasion was, histopathologically speaking, < 500 lm and neither vascular nor lymphatic metastasis was involved.6,9–11 Resections that did not meet the mentioned criteria were defined as noncurative resections. Other histopathological characteristics, including invasion depth, absence or presence of ulcer findings, lymphatic and vascular metastasis, and tumor involvement, were also assessed. Final pathological diagnoses were classified as lowgrade adenoma, high-grade adenoma, differentiated-type adenocarcinoma, and undifferentiated-type adenocarcinoma (including in situ carcinoma).
ESD technique
Follow-up
Before patients received treatment, preoperative examinations were routinely performed. Patients who took daily anticoagulants or antiplatelet therapy were told to stop medications for 1 week if possible. We chose the most experienced endoscopist from each institution to perform the treatment. All of the patients were sedated by intravenous anesthesia and endotracheal general anesthesia. A typical sequence included marking, injection, precut, incision, submucosal dissection, and wound care. More specifically, several dots were marked 5–10 mm outside the lesion with argon plasma coagulation (APC 300A; ERBE, Tubingen, Germany), and the mixed solution, which includes normal saline solution with 0.002% indigo carmine and 0.001% epinephrine, was injected into the submucosal layer to lift the lesion. A circumferential incision into the mucosa was made by using a hook knife (model KD-620LR; Olympus, Tokyo, Japan). Dissection of the lesion was carried out with an insulation-tipped electrosurgical knife (model KD-610L; Olympus). Finally, the surrounding tissues were removed with a snare. During the procedure, therapeutic and preventive endoscopic hemostasis was applied to bleeding points and visible vessels with an argon knife and hemoclips (model HX-201YR-135; Olympus) as needed. Proton pump inhibitors and agents protecting the stomach were routinely administered after ESD. Bleeding during or after the procedure was defined as bleeding based on clinical evidence with or without the need of endoscopically hemostatic treatment or transfusion. Immediate bleeding was defined as bleeding that occurred during the ESD procedure. Perforation was confirmed by direct observation during the procedure and/or by the presence of free air on an abdominal radiograph or computed tomography scan. Procedure-related mortality was defined as death due to complication within 30 days after the ESD procedure.
Conventional endoscopic examinations with biopsy were conducted at 1, 3, 6, and 12 months after ESD and annually thereafter to assess the healing, residue, and local recurrence of the disease. Contrast-enhanced computed tomography and ultrasound sonography were performed at least once a year to detect the lymphatic and vascular metastasis.
Histopathological assessment
Resected specimens were sectioned perpendicularly at 2-mm intervals, which facilitated histopathological evaluations. According to the Japanese classification of gastric carcinoma7 and the Vienna classification of gastrointestinal epithelial neoplasia,8 the location was classified by dividing the stomach into three sections: upper third, middle third, and lower third. The
Statistical analysis
All data analyses were conducted with a statistical software package (SPSS version 16.0; SPSS Inc., Chicago, IL). Categorical variables are expressed as an absolute value and a percentage. Continuous variables are expressed as mean – standard deviation values. Statistical analyses were performed using the Mann–Whitney U test and the chi-squared test. The odds ratio and 95% confidence intervals were presented from the logistic regression models to identify risk factors that significantly affected immediate bleeding. P < .05 was considered statistically significant. Results Comparison of clinicopathological parameters of EGC among three different age groups
In total, 171 patients with 187 EGC lesions (Fig. 1) were enrolled in the study. To track down the best dividing point of age cohort in the present study, we divided the patients into the young group (p60 years of age), the younger-elderly group (61–74 years of age), and the older-elderly group (q75 years of age). Table 1 compares the clinicopathological characteristics of EGC treated by ESD among the three groups. The data showed that patients 75 years of age or older were more prone to suffer from comorbidities that often were accompanied by two or more diseases compared with the young and younger-elderly groups. The lesions’ invasion depth differed significantly among the groups, and the olderelderly group underwent a longer operation time in contrast with the other two groups. No significant difference was observed between the young and the younger-elderly groups. Thus we combined the young group with the younger-elderly group as the non-elderly group, and the older-elderly group was renamed as the elderly group in the following study.
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FIG. 1. Endoscopic views of multiple foci from a patient in the elderly group who was 76 years old. (A) A 1.8-cm depressed lesion was observed in the anterior wall of the greater curvature. (B) Endoscopic ultrasound showed the lesion was limited to the mucosal layer. (C) En bloc resection was performed. (D) A 1.5-cm elevated lesion was observed in the posterior wall of the greater curvature in the mucosal layer (white arrow). (E) Endoscopic ultrasound showed the lesion was limited to the mucosal layer. (F) En bloc resection was performed. (G and H) Resected specimens. (I and J) Follow-up endoscopy showed the healed wound 1 week after endoscopic closure. Clinical characteristics of the patients in the elderly and non-elderly groups
Lesion-based clinical characteristics are summarized in Table 2, based on the classification into the following groups: the elderly group (q75 years of age; 46 patients, 51 lesions) and the non-elderly group (< 75 years of age; 125 patients, 136 lesions). The mean ages in the two groups were 79.0 – 3.9 and 59.4 – 8.3 years (P < .001), respectively. There were no significant differences in the female:male ratio (39.4% versus 58.2%), specimen size (2.0 – 1.0 cm versus 1.9 – 1.0 cm), macroscopic type (21/30 versus 65/71), and location between the two groups. There were 11/51 (21.6%) versus 21/136 (15.4%) ulcer-positive lesions, respectively. The prevalence of comorbidities in the elderly group was significantly higher than in the non-elderly group (76.1% [35/46] versus 37.6% [47/125]; P < .001). Hypertension was predominately present in both groups (52.2% versus 32.8%; P = .021), followed by diabetes mellitus, respiratory disease (19.6% versus 7.2%; P = .026), and heart disease, among others. More elderly patients suffered two or more complications than non-elderly patients (54.3% versus 18.4%; P < .001). Therapeutic outcome and complications in the elderly and non-elderly groups
En bloc resection was performed in 98.0% of the advanced patients and 97.1% of the younger patients. The curative resection reached 94.1% and 96.3%, respectively, and there was no significant difference. All elderly patients and 3 non-
elderly patients who had a positive lateral margin with involvement of tumor glands underwent additional surgery and were diagnosed with no tumor residue. The other two nonelderly cases went through repeated ESD treatment. On the whole, both groups could be treated by ESD effectively and safely, as seen in Table 3. However, it is noteworthy that an apparent discrepancy was observed in immediate bleeding between the elderly group and the non-elderly group (15.2% versus 4.8%; P = .044). Delayed bleeding was encountered in 8.7% of the elderly group and 5.6% of the non-elderly group. Most episodes of bleedings could be managed by conservative medical treatment and endoscopic hemostasis with no need of transfusion except for 1 case in the non-elderly group who received additional surgery because of postoperative bleeding. No significant difference in perforation was observed between the two groups. All cases were managed by endoscopic clipping with satisfactory outcome. The mean length of hospital stay after ESD was very short in both groups, and the difference was not significant. Operation time differed significantly as elderly patients needed a longer operation time than non-elderly patients (67.8 – 30.7 minutes versus 47.9 – 20.2 minutes; P = .039). No death was attributed to an ESD-related procedure. Histopathological outcome in the elderly and non-elderly group
The resected specimens were evaluated histopathologically after the ESD procedure (Table 4). The depth of invasion can be classified into three groups—mucosal layer,
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Table 1. Comparison of Clinicopathological Parameters of Early Gastric Cancer Lesions Among Different Age Groups Value
Number of patients Number of lesions Location Upper Middle Lower Anastomosis Presence of comorbidity Hypertension Respiratory disease Having two or more complications En bloc resection Curative resection Immediate bleeding Operation time (minutes) Invasion depth Mucosa Muscularis mucosa Submucosa (SM1) Histological type (intraepithelial neoplasia) Low-grade High-grade Early gastric cancer Differentiated Undifferentiated
Young (p60 years)
Younger-elderly (61–74 years)
Older-elderly (q75 years)
60 63
65 73
46 51
2 (3.2)a 18 (28.6) 40 (63.5) 3 (4.8) 19 (31.7)a 18 (30.0)a 4 (6.7)a 9 (15.0)a 61 (96.8) 61 (96.8) 3 (5.0) 42.6 – 18.3a
7 (9.6) 26 (35.6) 38 (52.1) 2 (2.7) 28 (43.1)b 27 (41.5) 5 (7.7) 14 (21.5)b 71 (97.3) 70 (95.9) 3 (4.6) 50.4 – 21.7b
9 (17.6) 17 (33.3) 24 (47.1) 1 (2.0) 35 (76.1) 24 (52.2) 9 (19.6) 25 (54.3) 50 (98.0) 48 (94.1) 5 (10.9) 67.8 – 30.7
51 (81.0)a 10 (15.9) 2 (3.2)a
60 (82.2)b 8 (11.0) 5 (6.8)b
30 (58.9) 10 (19.6) 11 (21.6)
28 (44.4)a 16 (25.4)
21 (28.7) 16 (21.9)
12 (23.5) 9 (17.6)
8 (12.7)a 11 (17.5)
17 (23.3) 19 (26.0)
17 (33.3) 13 (25.5)
Data are n (%), median, or mean – standard deviation values as indicated. a P < .05 in the non-elderly group compared with the older-elderly group. b P < .05 in the younger-elderly group compared with the older-elderly group.
muscularis mucosa, and submucosal layer—and differed significantly between the elderly and non-elderly groups in that 58.9% versus 81.6% exhibited invaded mucosal layer (P = .001), 19.6% versus 13.2% exhibited invaded muscularis mucosa, and 21.6% versus 5.1% (P = .002) exhibited invaded submucosal layer, respectively. Histological diagnoses included low-grade adenoma, high-grade adenoma, differentiated-type adenocarcinoma, and undifferentiated-type adenocarcinoma (including in situ carcinoma), and there was no significant difference (23.5% versus 36.0%, 17.6% versus 23.5%, 33.3% versus 18.4%, and 25.5% versus 22.1%, respectively) among them. Follow-up outcome
The difference in the follow-up period between the two groups was not significant (Table 4). The mean follow-up time was 27.1 – 12.6 and 27.5 – 11.4 months, respectively. Residual disease and local recurrence rates were low in the two groups. In the elderly group, 3 patients (6.5%) developed local recurrence, and 3 patients were observed to have residual disease and received additional surgery. In the nonelderly group, 3 patients (2.4%) were found to have disease recurrence or residual lesions; all of them were positive in vertical and/or lateral margins and accepted subsequent treatment as mentioned above.
Risk factors associated with immediate bleeding
In this study, the immediate bleeding rate was significantly high. Consequently, we further investigated relevant risk factors using logistic regression analysis. Univariate analysis and multivariate analysis revealed that invasion depth was the sole significant contributor to immediate bleeding (mucosa versus submucosa, odds ratio = 54.565, P = .003) (Table 5). Discussion
Life expectancy has dramatically increased because of improvement of life conditions and progress of medical and health care. It has been reported that aging population has accounted for 14.3% of the population in China by 2012, reaching 1.94 hundred million. ESD, as a safe and minimally invasive technique invented in Japan, has been gradually and successfully carried out in China since its invention. Our present study demonstrates that ESD is indeed safe and effective for elderly patients in China. First, there were no significant differences in clinicopathological characteristics except a higher rate of comorbidities compared with nonelderly patients. Second, the data demonstrate that ESD can be carried out in elderly patients safely as well as in nonelderly people. Third, both age groups received effective treatments with low rates of residual disease and local recurrence.
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Table 2. Clinical Characteristics of the Patients Value Elderly group Number of patients Number of lesions Age (years) Gender (female/male) Size p20 mm 20–40 mm q40 mm Location Upper Middle Lower Macroscopic type Elevated Flat/depressed Combined ulcer Presence of comorbidity Hypertension Diabetes mellitus Heart disease Respiratory disease Suffer from other tumors Antiplatelet agents used Having two or more complications
75–89 13/33 0.2–5.0 35 12 4
Non-elderly group
46 51 (79.0 – 3.9) (39.4) (2.0 – 1.0 cm) (68.6) (23.5) (7.8)
125 136 28–73(59.4 – 8.3) 46/79 (58.2) 0.1–7.0 (1.9 – 1.0 cm) 98 (72.1) 28 (20.6) 10 (7.4)
P
< .001 NS NS
NS 9 (17.6) 17 (33.3) 25 (49.0)
9 (6.6) 44 (32.4) 83 (61.0) NS
21 30 11/51 35 24 10 8 9 7 4 25
(41.2) (58.8) (21.6) (76.1) (52.2) (21.7) (17.4) (19.6) (15.2) (8.7) (54.3)
65 71 21/136 47 41 19 13 9 11 6 23
(47.8) (52.2) (15.4) (37.6) (32.8) (15.2) (10.4) (7.2) (8.8) (4.8) (18.4)
NS < .001 .021 NS NS .026 NS NS < .001
Data are n, n (%), or mean – standard deviation values as indicated. NS, not significant.
Table 3. Therapeutic Outcomes and Complications of the Patients Value Elderly group
Non-elderly group
P
En bloc resection 50 (98.0) 132 (97.1) NS Curative resection 48/51 (94.1) 131/136 (96.3) NS Horizontal ( + ) 2 (3.9) 5 (3.7) Vertical ( + ) 1 (2.0) 0 (0) Immediate bleeding 7 (15.2) 6 (4.8) .044 Delayed bleeding 4 (8.7) 7 (5.6) NS Perforation 1 (2.2) 5 (4) NS Length of stay (days) 10.4 – 4.8 11.2 – 3.6 NS Operation time 67.3 – 24.2 47.9 – 20.2 .039 (minutes) Follow-up surgery 6 5 NS Complication 3 2 related Noncurative 3 3 resection Immediate death 0 0 Data are n, n (%), or mean – standard deviation values as indicated. NS, not significant.
In our study, comparison of clinicopathological characteristics among the young group, younger-elderly group, and older-elderly group implied that advanced age is often accompanied by comorbidities. Patients 75 years of age or older were more prone to suffer from two or more diseases compared with the young and younger-elderly groups, and they had a deeper invasion depth and longer ESD operation time, which showed significant differences in the cohort. No significant difference was observed between the young and the younger-elderly group. We inferred that 75 years old seemed like a reasonable dividing point. In addition, Kakushima et al.12 reported that individuals 65–74 years of age have signs of aging, whereas the majority of them keep a relatively healthy figure that can function well to live a normal life. Regarding elderly patients 75 years old of age or older with unspecific clinical symptoms at early stages, they often show declines in physical conditions and have higher incidences of underlying disease, which impair overall quality of life and hamper recovery after operation. Consequently, elderly patients (75 years old of age or older) are a high-risk population for gastric cancer, and we should pay attention to choosing the appropriate treatment of advanced age with EGC. We then compared the clinicopathological parameters between the elderly group and the non-elderly group treated with ESD. No significant differences in tumor size, location, macroscopic type, and combination with ulcer or without were observed between the two groups. Of note is that 76.1%
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Table 4. Histological Parameters of the Patients Value
Invasion depth Mucosa Muscularis mucosa Submucosa (SM1) Histological type Low-grade intraepithelial neoplasia High-grade intraepithelial neoplasia Differentiated EGC Undifferentiated EGC Residual or recurrence Follow-up period (months)
Elderly patients
Non-elderly patients
30 (58.9) 10 (19.6) 11 (21.6)
111 (81.6) 18 (13.2) 7 (5.1)
12 (23.5)
49 (36.0)
.001 .001 NS .002 NS NS
9 (17.6)
32 (23.5)
NS
17 (33.3) 13 (25.5) 3 (6.5) 27.1 – 12.6
25 (18.4) 30 (22.1) 3 (2.4) 27.5 – 11.4
.029 NS NS NS
P
Data are n (%) or mean – standard deviation values as indicated. EGC, early gastric cancer; NS, not significant.
of the elderly patients had an accompanying comorbidity, compared with the non-elderly group. The morbidity rates of hypertension and respiratory diseases were higher in the advanced age group than in the younger patients, and 54.3% of the elderly patients suffered from two or more underlying diseases. Higher rates of comorbidity result in impaired immunity and declined tolerance of gastrectomy, and that is why ‘‘watch and see’’ policy is always adopted for patients 80 years of age or older instead of surgery,13 which will shorten life expectancy and decrease the overall survival. As the data indicated, there was no significant difference in histological type, but the difference in the depth of invasion between the two groups should not be ignored. The ratio of
lesions infiltrating into the submucosa was higher in the elderly patients than in the non-elderly group. We infer that atypical symptoms delayed patients’ visit time, and that is why many elderly patients did not receive a diagnosis until the late stage. In this study, ESD was performed safely. We found a low rate of procedure-associated complications, such as delayed bleeding and perforation, between the two groups, similar to those in other reports.14–16 Although a higher rate of immediate bleeding was encountered in the elderly patients, most of the bleeding episodes could be managed by conservative medical treatment and endoscopic hemostasis with no need of transfusion. No death related to the ESD procedure occurred in either group. Surgical mortality was 3.0%, and inhospital mortality reached 6.7% after gastrectomy in previous studies.17 Therefore, clinical results suggest that the ESD technique achieves a safe resection in the elderly group as well as in the non-elderly group. When it comes to the risk of immediate bleeding, there have been few reports.18,19 Jang et al.18 considered that younger age and more proximal location of the lesions correlated with significant bleeding. Jeon et al.19 reported that the tumor histology was the only factor that was statistically significantly associated with bleeding. In the present series, logistic regression analysis revealed that invasion depth was the significant contributor to immediate bleeding and that high older age was not an independent predictor of bleeding. Because the lesions invaded to the submucosal layer, it may be rather difficult to remove them completely, leading to more frequent bleeding during the procedure. As mentioned above, the ratio of lesions infiltrating into the submucosa is higher in the elderly patients than in the non-elderly group. This may explain why more elderly patients suffer from immediate bleeding compared with non-elderly people. Moreover, the operation time differed a lot among the two groups as in a previous report.20 This can be explained by the fact that elderly patients often have accompanying severe underlying diseases, which increases the patients’ intolerance
Table 5. Association of Clinicopathological Characteristics of the Lesions with Immediate Bleeding Univariate analysis Characteristic Tumor size < 20 mm 20–40 mm > 40 mm Invasion depth Mucosa Muscularis mucosa Submucosa (SM1) Histological type Low-grade intraepithelial neoplasia High-grade intraepithelial neoplasia Differentiated EGC Undifferentiated EGC Hypertension Respiratory disease Presence of comorbidity Having two or more complications
Multivariate analysis
OR (95% CI)
P
1 (reference) 2.395 (0.714–8.030) 1.629 (0.182–14.591)
.157 .663
1 (reference) 1.864 (0.353–9.835) 7.885 (2.112–29.436)
.463 .002
1 (reference) 3.437 (0.804–14.696) 2.366 (0.497–11.261) 0.000 1.409 (0.328–3.355) 1.300 (0.274–6.465) 0.949 (0.305–2.949) 0.471 (0.100–2.211)
.096 .279 .998 .936 .724 .927 .340
CI, confidence interval; EGC, early gastric cancer; OR, odds ratio.
OR (95% CI)
P
1 (reference) 16.055 (0.957–269.374) 54.565 (3.791–785.293)
.054 .003
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to the procedure and the physicians’ technical difficulty. In addition, invasion of the submucosa layer and high frequency of bleeding during the procedure may prolong the operation time. We should pay attention to a high frequency of bleeding and subsequent longer procedure time, which may be followed by unnecessary complications, higher blood loss, and increased risk of delayed bleeding, perforation, and wound infection. Given this, we emphasize that ESD treatment is a safe and minimal invasive method that could be performed in elderly patients by carefully monitoring bleeding and controlling operation time. In terms of therapeutic effect and survival, elderly patients achieved the same clinical outcomes as non-elderly patients. En bloc resection and curative resection rates were high, and the residual disease and local recurrence rates were very low in the two groups. Patients with positive vertical/lateral margins received additional surgery and/or repeated ESD and were diagnosed with no tumor residue. The mean length of stay was not apparently significantly different in elderly patients in comparison with non-elderly patients. This implies that ESD is an effective treatment not only for younger patients but also for patients of advanced age, as has been found in other published reports.11,14,17 Unfortunately, there are several limitations in the design of our study. It is a retrospective analysis with patient selection bias. We tried to enroll the patients based on the Japanese criteria21 to solve the problem. Other limitations are our short follow-up period and small numbers of patients. Long-term observation and a larger group of patients are warranted. In conclusion, ESD is a safe and effective treatment of EGC in elderly patients. Compared with gastrectomy and endoscopic mucosal resection, it allows curative resection and provides accurate histological assessment, low local recurrence, and high quality of life, and the 3-year and 5-year survival rates were similar between ESD and surgery,22 although elderly patients have a higher incidence of immediate bleeding and need a longer operation time.
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Disclosure Statement
No competing financial interests exist.
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from early gastric cancer: Estimation with a large number of cases at two large centers. Gastric Cancer 2000;3: 219–225. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011;14:101–112. Schlemper RJ, Riddell RH, Kato Y, Borchard F, Cooper HS, Dawsey SM, Dixon MF, Fenoglio-Preiser CM, Fle´jou JF, Geboes K, Hattori T, Hirota T, Itabashi M, Iwafuchi M, Iwashita A, Kim YI, Kirchner T, Klimpfinger M, Koike M, Lauwers GY, Lewin KJ, Oberhuber G, Offner F, Price AB, Rubio CA, Shimizu M, Shimoda T, Sipponen P, Solcia E, Stolte M, Watanabe H, Yamabe H. The Vienna classification of gastrointestinal epithelial neoplasia. Gut 2000;47: 251–255. 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–S43. Hirasawa K, Kokawa A, Oka H, Yahara S, Sasaki T, Nozawa A, Morimoto M, Numata K, Taguri M, Morita S, Maeda S, Tanaka K. Risk assessment chart for curability of early gastric cancer with endoscopic submucosal dissection. Gastrointest Endosc 2011;74:1268–1275. Hirasaki S, Tanimizu M, Nasu J, Shinji T, Koide N. Treatment of elderly patients with early gastric cancer by endoscopic submucosal dissection using an insulated-tip diathermic knife. Intern Med 2005;44:1033–1038. Kakushima N, Fujishiro M, Kodashima S, Muraki Y, Tateishi A, Yahagi N, Omata M. Technical feasibility of endoscopic submucosal dissection for gastric neoplasms in the elderly Japanese population. J Gastroenterol Hepatol 2007;22:311–314. Etoh T, Katai H, Fukagawa T, Sano T, Oda I, Gotoda T, Yoshimura K, Sasako M. Treatment of early gastric cancer in the elderly patient: Results of EMR and gastrectomy at a national referral center in Japan. Gastrointest Endosc 2005; 62:868–871. Toyokawa T, Fujita I, Morikawa T, Okamoto A, Miyasaka R, Watanabe K, Horii J, Gobaru M, Terao M, Murakami T, Tomoda J. Clinical outcomes of ESD for early gastric neoplasms in elderly patients. Eur J Clin Invest 2011;41: 474–478. Goto O, Fujishiro M, Oda I, Kakushima N, Yamamoto Y, Tsuji Y, Ohata K, Fujiwara T, Fujiwara J, Ishii N, Yokoi C, Miyamoto S, Itoh T, Morishita S, Gotoda T, Koike K. A multicenter survey of the management after gastric endoscopic submucosal dissection related to postoperative bleeding. Dig Dis Sci 2012;57:435–439. Kim BJ, Chang TH, Kim JJ, Min BH, Lee JH, Son HJ, Rhee PL, Rhee JC, Kim KM, Park CK. Efficacy and safety of endoscopic submucosal dissection for early gastric cancer in patients with comorbid diseases. Gut Liver 2010; 4:186–191. Hsu JT, Liu MS, Wang F, Chang CJ, Hwang TL, Jan YY, Yeh TS. Standard radical gastrectomy in octogenarians and nonagenarians with gastric cancer: Are short-term surgical results and long-term survival substantial? J Gastrointest Surg 2012;16:728–737. Jang JS, Choi SR, Graham DY, Kwon HC, Kim MC, Jeong JS, Won JJ, Han SY, Noh MH, Lee JH, Lee SW, Baek YH, Kim MJ, Jeong DS, Kim SK. Risk factors for immediate and delayed bleeding associated with endoscopic submucosal dissection of gastric neoplastic lesions. Scand J Gastroenterol 2009;44:1370–1376.
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19. Jeon SW, Jung MK, Cho CM, Tak WY, Kweon YO, Kim SK, Choi YH. Predictors of immediate bleeding during endoscopic submucosal dissection in gastric lesions. Surg Endosc 2009;23:1974–1979. 20. Chung IK, Lee JH, Lee SH, Kim SJ, Cho JY, Cho WY, Hwangbo Y, Keum BR, Park JJ, Chun HJ, Kim HJ, Kim JJ, Ji SR, Seol SY. Therapeutic outcomes in 1000 cases of endoscopic submucosal dissection for early gastric neoplasms: Korean ESD Study Group multicenter study. Gastrointest Endosc 2009;69:1228–1235. 21. Oda I, Odagaki T, Suzuki H, Nonaka S, Yoshinaga S. Learning curve for endoscopic submucosal dissection of early gastric cancer based on trainee experience. Dig Endosc 2012;24(Suppl 1):129–132. 22. Chiu PW, Teoh AY, To KF, Wong SK, Liu SY, Lam CC, Yung MY, Chan FK, Lau JY, Ng EK. Endoscopic sub-
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mucosal dissection (ESD) compared with gastrectomy for treatment of early gastric neoplasia: a retrospective cohort study. Surg Endosc 2012;26:3584–3591.
Address correspondence to: Feng Ji, MD, PhD Department of Gastroenterology The First Affiliated Hospital College of Medicine Zhejiang University 79 Qingchun Road Hangzhou, 310003, Zhejiang Province China E-mail: [email protected]
Endoscopic Submucosal Dissection for Early Gastric Neoplasms in Elderly Patients Yan Zhang, MM,1 Lijiang Huang, MM,2 Lin Li, MD,1 and Feng Ji, MD, PhD1
Abstract
Objective: To retrospectively evaluate the safety and feasibility of endoscopic submucosal dissection (ESD) for the treatment of early gastric cancer (EGC) in elderly patients q75 years of age. Patients and Methods: One hundred seventy-one patients (187 lesions) treated with ESD from January 2010 to September 2013 were enrolled in our study. Subjects were classified into two groups: elderly (age q75 years) or non-elderly (age < 75 years). Clinicopathological characteristics, resectability, curability, complications, rates of local recurrence, and residual disease were evaluated. Association of clinicopathological characteristics of the lesions with immediate bleeding was analyzed. Results: No significant differences in clinical characteristics were observed. The incidences of comorbidity were significantly different between the elderly group and the non-elderly group (P < .001). Of the elderly patients, 54.3% had two or more underlying diseases compared with 18.4% of the non-elderly patients (P < .001). Of the 98.0% of elderly patients and 97.1% of younger patients who received en bloc resection, curative resection reached 94.1% and 96.3%, respectively. Immediate bleeding occurred in 15.2% of the elderly group and 4.8% of the non-elderly group (P = .044). Operation time differed significantly (P = .039). No apparent discrepancy was observed in perforation and delayed bleeding. The differences in the invasion depth were considered between the two groups (P = .001). Logistic regression analysis revealed that the rate of immediate bleeding was associated with invasion depth (P = .003). There were no differences in the follow-up period and rates of local recurrence and residual disease. Conclusions: ESD is safe and feasible for elderly patients in the era of a graying population. Higher risk of immediate bleeding and longer operation time should be concerned. Introduction
E
arly gastric cancer (EGC) is defined as invasive gastric neoplasm that is confined to the mucosa and submucosa, irrespective of lymphatic metastasis. If EGC is treated appropriately, its prognosis of EGC is much better than that of advanced gastric cancer.1,2 Therefore, early diagnosis and proper therapies are urgent. Several preliminary studies have revealed that endoscopic submucosal dissection (ESD) has gradually replaced gastrectomy and endoscopic mucosal resection as a standard treatment for EGC, which allows en bloc resection, precise histological assessment, and low residual disease and local recurrence rate as well as minimal trauma and quick recovery.3–5 However, as the population ages, the number of elderly patients steadily increases. Elderly patients often remain underrepresented in clinical trials. Moreover, patients with advanced age always show declined physiological function 1 2
and worse general conditions compared with younger patients. Preoperative malnutrition and concomitant diseases contribute to higher rates of postoperative complications after surgery. Thus, ESD seems to be a better choice for EGCs in the elderly population. The aim of our present study was to compare the clinical and therapeutic outcomes between the elderly population and the non-elderly population, as well as to assess the safety and effectiveness of ESD in elderly patients 75 years of age and older. In addition, clinical risk factors that might influence on the ESD processing were also evaluated. Patients and Methods Patients and enrollment criteria
From January 2010 to September 2013, in total, 187 EGCs in 171 patients were treated by ESD in The First
Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Department of Gastroenterology, Xiangshan First People’s Hospital, Xiangshan, China.
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Affiliated Hospital, School of Medicine, Zhejiang University (Hangzhou, China) and Xiangshan First People’s Hospital (Xiangshan, China). The study protocol was approved by the Hospital Ethics Committee. Written informed consent statements were obtained from all the participants involved in this study before surgery. Patients and their families were also informed of potential hazards and complications and signed the surgical informed consents. ESD procedures were performed on gastric neoplasms with no nodal metastasis, and patients were enrolled on the basis of the expanded criteria proposed by Gotoda et al.6 as follows: differentiated mucosal cancer without ulcer findings irrespective of tumor size; differentiated mucosal cancer with ulcers of p30 mm in diameter; undifferentiated mucosal cancer without ulcers of p20 mm in diameter; and minute differentiated submucosal cancer (invasion depth, p500 lm) without ulcers of p30 mm in diameter. Endoscopic ultrasound and computed tomography were carried out if there was a possibility of submucosal invasion.
macroscopic type of the EGCs was categorized into the elevated type and the flat/depressed type. The tumor size was divided into three groups: p20 mm, 20–40 mm, and q40 mm. En bloc resection was defined as resection in a single piece instead of piecemeal separation by endoscopy. The resections were deemed curative when the specimens removed were free of tumorous glands in both the lateral and vertical margins and when submucosal invasion was, histopathologically speaking, < 500 lm and neither vascular nor lymphatic metastasis was involved.6,9–11 Resections that did not meet the mentioned criteria were defined as noncurative resections. Other histopathological characteristics, including invasion depth, absence or presence of ulcer findings, lymphatic and vascular metastasis, and tumor involvement, were also assessed. Final pathological diagnoses were classified as lowgrade adenoma, high-grade adenoma, differentiated-type adenocarcinoma, and undifferentiated-type adenocarcinoma (including in situ carcinoma).
ESD technique
Follow-up
Before patients received treatment, preoperative examinations were routinely performed. Patients who took daily anticoagulants or antiplatelet therapy were told to stop medications for 1 week if possible. We chose the most experienced endoscopist from each institution to perform the treatment. All of the patients were sedated by intravenous anesthesia and endotracheal general anesthesia. A typical sequence included marking, injection, precut, incision, submucosal dissection, and wound care. More specifically, several dots were marked 5–10 mm outside the lesion with argon plasma coagulation (APC 300A; ERBE, Tubingen, Germany), and the mixed solution, which includes normal saline solution with 0.002% indigo carmine and 0.001% epinephrine, was injected into the submucosal layer to lift the lesion. A circumferential incision into the mucosa was made by using a hook knife (model KD-620LR; Olympus, Tokyo, Japan). Dissection of the lesion was carried out with an insulation-tipped electrosurgical knife (model KD-610L; Olympus). Finally, the surrounding tissues were removed with a snare. During the procedure, therapeutic and preventive endoscopic hemostasis was applied to bleeding points and visible vessels with an argon knife and hemoclips (model HX-201YR-135; Olympus) as needed. Proton pump inhibitors and agents protecting the stomach were routinely administered after ESD. Bleeding during or after the procedure was defined as bleeding based on clinical evidence with or without the need of endoscopically hemostatic treatment or transfusion. Immediate bleeding was defined as bleeding that occurred during the ESD procedure. Perforation was confirmed by direct observation during the procedure and/or by the presence of free air on an abdominal radiograph or computed tomography scan. Procedure-related mortality was defined as death due to complication within 30 days after the ESD procedure.
Conventional endoscopic examinations with biopsy were conducted at 1, 3, 6, and 12 months after ESD and annually thereafter to assess the healing, residue, and local recurrence of the disease. Contrast-enhanced computed tomography and ultrasound sonography were performed at least once a year to detect the lymphatic and vascular metastasis.
Histopathological assessment
Resected specimens were sectioned perpendicularly at 2-mm intervals, which facilitated histopathological evaluations. According to the Japanese classification of gastric carcinoma7 and the Vienna classification of gastrointestinal epithelial neoplasia,8 the location was classified by dividing the stomach into three sections: upper third, middle third, and lower third. The
Statistical analysis
All data analyses were conducted with a statistical software package (SPSS version 16.0; SPSS Inc., Chicago, IL). Categorical variables are expressed as an absolute value and a percentage. Continuous variables are expressed as mean – standard deviation values. Statistical analyses were performed using the Mann–Whitney U test and the chi-squared test. The odds ratio and 95% confidence intervals were presented from the logistic regression models to identify risk factors that significantly affected immediate bleeding. P < .05 was considered statistically significant. Results Comparison of clinicopathological parameters of EGC among three different age groups
In total, 171 patients with 187 EGC lesions (Fig. 1) were enrolled in the study. To track down the best dividing point of age cohort in the present study, we divided the patients into the young group (p60 years of age), the younger-elderly group (61–74 years of age), and the older-elderly group (q75 years of age). Table 1 compares the clinicopathological characteristics of EGC treated by ESD among the three groups. The data showed that patients 75 years of age or older were more prone to suffer from comorbidities that often were accompanied by two or more diseases compared with the young and younger-elderly groups. The lesions’ invasion depth differed significantly among the groups, and the olderelderly group underwent a longer operation time in contrast with the other two groups. No significant difference was observed between the young and the younger-elderly groups. Thus we combined the young group with the younger-elderly group as the non-elderly group, and the older-elderly group was renamed as the elderly group in the following study.
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FIG. 1. Endoscopic views of multiple foci from a patient in the elderly group who was 76 years old. (A) A 1.8-cm depressed lesion was observed in the anterior wall of the greater curvature. (B) Endoscopic ultrasound showed the lesion was limited to the mucosal layer. (C) En bloc resection was performed. (D) A 1.5-cm elevated lesion was observed in the posterior wall of the greater curvature in the mucosal layer (white arrow). (E) Endoscopic ultrasound showed the lesion was limited to the mucosal layer. (F) En bloc resection was performed. (G and H) Resected specimens. (I and J) Follow-up endoscopy showed the healed wound 1 week after endoscopic closure. Clinical characteristics of the patients in the elderly and non-elderly groups
Lesion-based clinical characteristics are summarized in Table 2, based on the classification into the following groups: the elderly group (q75 years of age; 46 patients, 51 lesions) and the non-elderly group (< 75 years of age; 125 patients, 136 lesions). The mean ages in the two groups were 79.0 – 3.9 and 59.4 – 8.3 years (P < .001), respectively. There were no significant differences in the female:male ratio (39.4% versus 58.2%), specimen size (2.0 – 1.0 cm versus 1.9 – 1.0 cm), macroscopic type (21/30 versus 65/71), and location between the two groups. There were 11/51 (21.6%) versus 21/136 (15.4%) ulcer-positive lesions, respectively. The prevalence of comorbidities in the elderly group was significantly higher than in the non-elderly group (76.1% [35/46] versus 37.6% [47/125]; P < .001). Hypertension was predominately present in both groups (52.2% versus 32.8%; P = .021), followed by diabetes mellitus, respiratory disease (19.6% versus 7.2%; P = .026), and heart disease, among others. More elderly patients suffered two or more complications than non-elderly patients (54.3% versus 18.4%; P < .001). Therapeutic outcome and complications in the elderly and non-elderly groups
En bloc resection was performed in 98.0% of the advanced patients and 97.1% of the younger patients. The curative resection reached 94.1% and 96.3%, respectively, and there was no significant difference. All elderly patients and 3 non-
elderly patients who had a positive lateral margin with involvement of tumor glands underwent additional surgery and were diagnosed with no tumor residue. The other two nonelderly cases went through repeated ESD treatment. On the whole, both groups could be treated by ESD effectively and safely, as seen in Table 3. However, it is noteworthy that an apparent discrepancy was observed in immediate bleeding between the elderly group and the non-elderly group (15.2% versus 4.8%; P = .044). Delayed bleeding was encountered in 8.7% of the elderly group and 5.6% of the non-elderly group. Most episodes of bleedings could be managed by conservative medical treatment and endoscopic hemostasis with no need of transfusion except for 1 case in the non-elderly group who received additional surgery because of postoperative bleeding. No significant difference in perforation was observed between the two groups. All cases were managed by endoscopic clipping with satisfactory outcome. The mean length of hospital stay after ESD was very short in both groups, and the difference was not significant. Operation time differed significantly as elderly patients needed a longer operation time than non-elderly patients (67.8 – 30.7 minutes versus 47.9 – 20.2 minutes; P = .039). No death was attributed to an ESD-related procedure. Histopathological outcome in the elderly and non-elderly group
The resected specimens were evaluated histopathologically after the ESD procedure (Table 4). The depth of invasion can be classified into three groups—mucosal layer,
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Table 1. Comparison of Clinicopathological Parameters of Early Gastric Cancer Lesions Among Different Age Groups Value
Number of patients Number of lesions Location Upper Middle Lower Anastomosis Presence of comorbidity Hypertension Respiratory disease Having two or more complications En bloc resection Curative resection Immediate bleeding Operation time (minutes) Invasion depth Mucosa Muscularis mucosa Submucosa (SM1) Histological type (intraepithelial neoplasia) Low-grade High-grade Early gastric cancer Differentiated Undifferentiated
Young (p60 years)
Younger-elderly (61–74 years)
Older-elderly (q75 years)
60 63
65 73
46 51
2 (3.2)a 18 (28.6) 40 (63.5) 3 (4.8) 19 (31.7)a 18 (30.0)a 4 (6.7)a 9 (15.0)a 61 (96.8) 61 (96.8) 3 (5.0) 42.6 – 18.3a
7 (9.6) 26 (35.6) 38 (52.1) 2 (2.7) 28 (43.1)b 27 (41.5) 5 (7.7) 14 (21.5)b 71 (97.3) 70 (95.9) 3 (4.6) 50.4 – 21.7b
9 (17.6) 17 (33.3) 24 (47.1) 1 (2.0) 35 (76.1) 24 (52.2) 9 (19.6) 25 (54.3) 50 (98.0) 48 (94.1) 5 (10.9) 67.8 – 30.7
51 (81.0)a 10 (15.9) 2 (3.2)a
60 (82.2)b 8 (11.0) 5 (6.8)b
30 (58.9) 10 (19.6) 11 (21.6)
28 (44.4)a 16 (25.4)
21 (28.7) 16 (21.9)
12 (23.5) 9 (17.6)
8 (12.7)a 11 (17.5)
17 (23.3) 19 (26.0)
17 (33.3) 13 (25.5)
Data are n (%), median, or mean – standard deviation values as indicated. a P < .05 in the non-elderly group compared with the older-elderly group. b P < .05 in the younger-elderly group compared with the older-elderly group.
muscularis mucosa, and submucosal layer—and differed significantly between the elderly and non-elderly groups in that 58.9% versus 81.6% exhibited invaded mucosal layer (P = .001), 19.6% versus 13.2% exhibited invaded muscularis mucosa, and 21.6% versus 5.1% (P = .002) exhibited invaded submucosal layer, respectively. Histological diagnoses included low-grade adenoma, high-grade adenoma, differentiated-type adenocarcinoma, and undifferentiated-type adenocarcinoma (including in situ carcinoma), and there was no significant difference (23.5% versus 36.0%, 17.6% versus 23.5%, 33.3% versus 18.4%, and 25.5% versus 22.1%, respectively) among them. Follow-up outcome
The difference in the follow-up period between the two groups was not significant (Table 4). The mean follow-up time was 27.1 – 12.6 and 27.5 – 11.4 months, respectively. Residual disease and local recurrence rates were low in the two groups. In the elderly group, 3 patients (6.5%) developed local recurrence, and 3 patients were observed to have residual disease and received additional surgery. In the nonelderly group, 3 patients (2.4%) were found to have disease recurrence or residual lesions; all of them were positive in vertical and/or lateral margins and accepted subsequent treatment as mentioned above.
Risk factors associated with immediate bleeding
In this study, the immediate bleeding rate was significantly high. Consequently, we further investigated relevant risk factors using logistic regression analysis. Univariate analysis and multivariate analysis revealed that invasion depth was the sole significant contributor to immediate bleeding (mucosa versus submucosa, odds ratio = 54.565, P = .003) (Table 5). Discussion
Life expectancy has dramatically increased because of improvement of life conditions and progress of medical and health care. It has been reported that aging population has accounted for 14.3% of the population in China by 2012, reaching 1.94 hundred million. ESD, as a safe and minimally invasive technique invented in Japan, has been gradually and successfully carried out in China since its invention. Our present study demonstrates that ESD is indeed safe and effective for elderly patients in China. First, there were no significant differences in clinicopathological characteristics except a higher rate of comorbidities compared with nonelderly patients. Second, the data demonstrate that ESD can be carried out in elderly patients safely as well as in nonelderly people. Third, both age groups received effective treatments with low rates of residual disease and local recurrence.
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Table 2. Clinical Characteristics of the Patients Value Elderly group Number of patients Number of lesions Age (years) Gender (female/male) Size p20 mm 20–40 mm q40 mm Location Upper Middle Lower Macroscopic type Elevated Flat/depressed Combined ulcer Presence of comorbidity Hypertension Diabetes mellitus Heart disease Respiratory disease Suffer from other tumors Antiplatelet agents used Having two or more complications
75–89 13/33 0.2–5.0 35 12 4
Non-elderly group
46 51 (79.0 – 3.9) (39.4) (2.0 – 1.0 cm) (68.6) (23.5) (7.8)
125 136 28–73(59.4 – 8.3) 46/79 (58.2) 0.1–7.0 (1.9 – 1.0 cm) 98 (72.1) 28 (20.6) 10 (7.4)
P
< .001 NS NS
NS 9 (17.6) 17 (33.3) 25 (49.0)
9 (6.6) 44 (32.4) 83 (61.0) NS
21 30 11/51 35 24 10 8 9 7 4 25
(41.2) (58.8) (21.6) (76.1) (52.2) (21.7) (17.4) (19.6) (15.2) (8.7) (54.3)
65 71 21/136 47 41 19 13 9 11 6 23
(47.8) (52.2) (15.4) (37.6) (32.8) (15.2) (10.4) (7.2) (8.8) (4.8) (18.4)
NS < .001 .021 NS NS .026 NS NS < .001
Data are n, n (%), or mean – standard deviation values as indicated. NS, not significant.
Table 3. Therapeutic Outcomes and Complications of the Patients Value Elderly group
Non-elderly group
P
En bloc resection 50 (98.0) 132 (97.1) NS Curative resection 48/51 (94.1) 131/136 (96.3) NS Horizontal ( + ) 2 (3.9) 5 (3.7) Vertical ( + ) 1 (2.0) 0 (0) Immediate bleeding 7 (15.2) 6 (4.8) .044 Delayed bleeding 4 (8.7) 7 (5.6) NS Perforation 1 (2.2) 5 (4) NS Length of stay (days) 10.4 – 4.8 11.2 – 3.6 NS Operation time 67.3 – 24.2 47.9 – 20.2 .039 (minutes) Follow-up surgery 6 5 NS Complication 3 2 related Noncurative 3 3 resection Immediate death 0 0 Data are n, n (%), or mean – standard deviation values as indicated. NS, not significant.
In our study, comparison of clinicopathological characteristics among the young group, younger-elderly group, and older-elderly group implied that advanced age is often accompanied by comorbidities. Patients 75 years of age or older were more prone to suffer from two or more diseases compared with the young and younger-elderly groups, and they had a deeper invasion depth and longer ESD operation time, which showed significant differences in the cohort. No significant difference was observed between the young and the younger-elderly group. We inferred that 75 years old seemed like a reasonable dividing point. In addition, Kakushima et al.12 reported that individuals 65–74 years of age have signs of aging, whereas the majority of them keep a relatively healthy figure that can function well to live a normal life. Regarding elderly patients 75 years old of age or older with unspecific clinical symptoms at early stages, they often show declines in physical conditions and have higher incidences of underlying disease, which impair overall quality of life and hamper recovery after operation. Consequently, elderly patients (75 years old of age or older) are a high-risk population for gastric cancer, and we should pay attention to choosing the appropriate treatment of advanced age with EGC. We then compared the clinicopathological parameters between the elderly group and the non-elderly group treated with ESD. No significant differences in tumor size, location, macroscopic type, and combination with ulcer or without were observed between the two groups. Of note is that 76.1%
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Table 4. Histological Parameters of the Patients Value
Invasion depth Mucosa Muscularis mucosa Submucosa (SM1) Histological type Low-grade intraepithelial neoplasia High-grade intraepithelial neoplasia Differentiated EGC Undifferentiated EGC Residual or recurrence Follow-up period (months)
Elderly patients
Non-elderly patients
30 (58.9) 10 (19.6) 11 (21.6)
111 (81.6) 18 (13.2) 7 (5.1)
12 (23.5)
49 (36.0)
.001 .001 NS .002 NS NS
9 (17.6)
32 (23.5)
NS
17 (33.3) 13 (25.5) 3 (6.5) 27.1 – 12.6
25 (18.4) 30 (22.1) 3 (2.4) 27.5 – 11.4
.029 NS NS NS
P
Data are n (%) or mean – standard deviation values as indicated. EGC, early gastric cancer; NS, not significant.
of the elderly patients had an accompanying comorbidity, compared with the non-elderly group. The morbidity rates of hypertension and respiratory diseases were higher in the advanced age group than in the younger patients, and 54.3% of the elderly patients suffered from two or more underlying diseases. Higher rates of comorbidity result in impaired immunity and declined tolerance of gastrectomy, and that is why ‘‘watch and see’’ policy is always adopted for patients 80 years of age or older instead of surgery,13 which will shorten life expectancy and decrease the overall survival. As the data indicated, there was no significant difference in histological type, but the difference in the depth of invasion between the two groups should not be ignored. The ratio of
lesions infiltrating into the submucosa was higher in the elderly patients than in the non-elderly group. We infer that atypical symptoms delayed patients’ visit time, and that is why many elderly patients did not receive a diagnosis until the late stage. In this study, ESD was performed safely. We found a low rate of procedure-associated complications, such as delayed bleeding and perforation, between the two groups, similar to those in other reports.14–16 Although a higher rate of immediate bleeding was encountered in the elderly patients, most of the bleeding episodes could be managed by conservative medical treatment and endoscopic hemostasis with no need of transfusion. No death related to the ESD procedure occurred in either group. Surgical mortality was 3.0%, and inhospital mortality reached 6.7% after gastrectomy in previous studies.17 Therefore, clinical results suggest that the ESD technique achieves a safe resection in the elderly group as well as in the non-elderly group. When it comes to the risk of immediate bleeding, there have been few reports.18,19 Jang et al.18 considered that younger age and more proximal location of the lesions correlated with significant bleeding. Jeon et al.19 reported that the tumor histology was the only factor that was statistically significantly associated with bleeding. In the present series, logistic regression analysis revealed that invasion depth was the significant contributor to immediate bleeding and that high older age was not an independent predictor of bleeding. Because the lesions invaded to the submucosal layer, it may be rather difficult to remove them completely, leading to more frequent bleeding during the procedure. As mentioned above, the ratio of lesions infiltrating into the submucosa is higher in the elderly patients than in the non-elderly group. This may explain why more elderly patients suffer from immediate bleeding compared with non-elderly people. Moreover, the operation time differed a lot among the two groups as in a previous report.20 This can be explained by the fact that elderly patients often have accompanying severe underlying diseases, which increases the patients’ intolerance
Table 5. Association of Clinicopathological Characteristics of the Lesions with Immediate Bleeding Univariate analysis Characteristic Tumor size < 20 mm 20–40 mm > 40 mm Invasion depth Mucosa Muscularis mucosa Submucosa (SM1) Histological type Low-grade intraepithelial neoplasia High-grade intraepithelial neoplasia Differentiated EGC Undifferentiated EGC Hypertension Respiratory disease Presence of comorbidity Having two or more complications
Multivariate analysis
OR (95% CI)
P
1 (reference) 2.395 (0.714–8.030) 1.629 (0.182–14.591)
.157 .663
1 (reference) 1.864 (0.353–9.835) 7.885 (2.112–29.436)
.463 .002
1 (reference) 3.437 (0.804–14.696) 2.366 (0.497–11.261) 0.000 1.409 (0.328–3.355) 1.300 (0.274–6.465) 0.949 (0.305–2.949) 0.471 (0.100–2.211)
.096 .279 .998 .936 .724 .927 .340
CI, confidence interval; EGC, early gastric cancer; OR, odds ratio.
OR (95% CI)
P
1 (reference) 16.055 (0.957–269.374) 54.565 (3.791–785.293)
.054 .003
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to the procedure and the physicians’ technical difficulty. In addition, invasion of the submucosa layer and high frequency of bleeding during the procedure may prolong the operation time. We should pay attention to a high frequency of bleeding and subsequent longer procedure time, which may be followed by unnecessary complications, higher blood loss, and increased risk of delayed bleeding, perforation, and wound infection. Given this, we emphasize that ESD treatment is a safe and minimal invasive method that could be performed in elderly patients by carefully monitoring bleeding and controlling operation time. In terms of therapeutic effect and survival, elderly patients achieved the same clinical outcomes as non-elderly patients. En bloc resection and curative resection rates were high, and the residual disease and local recurrence rates were very low in the two groups. Patients with positive vertical/lateral margins received additional surgery and/or repeated ESD and were diagnosed with no tumor residue. The mean length of stay was not apparently significantly different in elderly patients in comparison with non-elderly patients. This implies that ESD is an effective treatment not only for younger patients but also for patients of advanced age, as has been found in other published reports.11,14,17 Unfortunately, there are several limitations in the design of our study. It is a retrospective analysis with patient selection bias. We tried to enroll the patients based on the Japanese criteria21 to solve the problem. Other limitations are our short follow-up period and small numbers of patients. Long-term observation and a larger group of patients are warranted. In conclusion, ESD is a safe and effective treatment of EGC in elderly patients. Compared with gastrectomy and endoscopic mucosal resection, it allows curative resection and provides accurate histological assessment, low local recurrence, and high quality of life, and the 3-year and 5-year survival rates were similar between ESD and surgery,22 although elderly patients have a higher incidence of immediate bleeding and need a longer operation time.
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Disclosure Statement
No competing financial interests exist.
15.
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Address correspondence to: Feng Ji, MD, PhD Department of Gastroenterology The First Affiliated Hospital College of Medicine Zhejiang University 79 Qingchun Road Hangzhou, 310003, Zhejiang Province China E-mail: [email protected]
