Is endoscopic submucosal dissection an effective treatment for operable patients with clinical submucosal invasive early gastric cancer?

• Introduction
• Methods
• Patients
• Histological assessment
• Follow-up care after ESD
• Statistical analysis
• Results
• Clinical characteristics
• Short-term outcomes
• Long-term outcomes
• Discussion
• References

Background and study aims: Gastrectomy with lymph node dissection is the gold standard curative treatment for clinical submucosal invasive early gastric cancer (cSM EGC), but a relatively small number of operable patients with cSM EGC have undergone endoscopic submucosal dissection (ESD) instead because they refused surgery. The aim of this study was to determine the effectiveness of ESD in these operable patients.

Methods: The therapeutic outcomes of ESD were retrospectively assessed for 38 patients with 38 operable cSM EGC lesions who initially refused surgery at the National Cancer Center Hospital, Tokyo, from January 1999 to December 2008.

Results: The en bloc resection rate was 84.2 % (32 lesions) and the complete (R0) resection rate was 63.2 % (24 lesions). A total of 33 lesions (86.8 %) involved submucosal invasion on pathology. Resection was non-curative in 34 patients (89.5 %), 22 of whom (64.7 %) underwent subsequent gastrectomy after the need for such surgery was carefully explained to them again. The median follow-up period was 73.2 months (range 3 – 115 months). Local recurrence was detected in one patient, distant metastasis in two patients, and both local recurrence and distant metastasis were detected in one patient. None of these four patients with recurrence (10.5 %) had undergone surgery when their recurrent disease was detected and all of them died from gastric cancer. The 5-year cause-specific survival rate for all patients was 91.8 %.

Conclusion: The 5-year cause-specific survival rate for all patients was lower than the previously reported rate of 96.7 % for pathologically submucosal invasive EGC patients after gastrectomy; therefore, ESD appears to have been an ineffective treatment for operable patients with cSM EGC.

Introduction

Endoscopic submucosal dissection (ESD) is currently in widespread use in Japan as an initial treatment for early gastric cancer (EGC), with a negligible risk of lymph node metastasis even in cases involving large and ulcerative lesions [1] [2] [3] [4] [5] [6] [7] [8]. According to the Japanese Gastric Cancer Treatment Guidelines 2010 (version 3), two independent sets of indications are provided for ESD: absolute indications for standard treatment and expanded indications for investigational treatment [1]. Tumors meeting the absolute indications for standard treatment are: a differentiated-type adenocarcinoma without ulcerative findings, of which the depth of invasion is clinically diagnosed as T1a and the diameter is ≤ 2 cm. In addition, the expanded indications for investigational treatment include: tumors clinically diagnosed as T1a and (a) of differentiated-type, no ulcer, > 2 cm in diameter, or (b) of differentiated-type, with ulcerative findings, and ≤ 3 cm in diameter, or (c) of undifferentiated-type, no ulcer, and ≤ 2 cm in diameter.

EGC lesions that are diagnosed endoscopically as probable mucosal cancer are also treated initially by ESD as a diagnostic procedure because there is always the possibility of submucosal invasion given the fact that precise depth of invasion diagnosis is difficult to determine clinically prior to treatment. Therefore, we usually select EGC lesions satisfying the indications for ESD by excluding those EGC lesions with clinical endoscopic findings of probable submucosal deep invasion such as remarkable redness, uneven surface, margin elevation, ulceration, and enlarged folds [9] [10]. Gastrectomy with lymph node dissection is the gold standard curative treatment for these latter lesions that are endoscopically diagnosed as clinical submucosal invasive early gastric cancer (cSM EGC), resulting in an excellent prognosis for these patients [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]. A relatively small number of patients with cSM EGC, however, have undergone ESD for various reasons: ESD is a viable option for treating cSM EGC lesions in patients considered to be inoperable either because they are too sick and/or weak to undergo surgical treatment with general anesthesia due to concomitant diseases and/or because they are older. Other patients with cSM EGC initially refuse surgery despite both the absence of any concomitant disease and being young enough to undergo surgery safely. Such patients prefer to receive ESD despite the lack of clinical evidence as to its effectiveness in treating cSM EGC. The aim of this study, therefore, was to determine the effectiveness of ESD for operable patients with cSM EGC who refuse surgery.

Methods

Patients

Among 2880 patients with 3232 EGC lesions who were treated by ESD from January 1999 to December 2008 at the National Cancer Center Hospital (Tokyo, Japan), 68 patients with 69 lesions had been diagnosed with cSM EGC. Of these 68 patients, 30 (31 cSM EGC lesions) were excluded as they were regarded as being inoperable either because they were too sick and/or weak for surgical treatment with general anesthesia due to concomitant disease (e. g. synchronous cancer in another organ, cardiovascular disease, respiratory disease, renal failure, or liver dysfunction) and/or because they were 80 years of age or older; these patients had no alternative other than to be treated by ESD for their cSM EGC. The clinical characteristics, short-term outcomes, and long-term outcomes of ESD performed on the remaining 38 operable patients with 38 cSM EGC lesions who initially refused surgery were retrospectively assessed.

Clinical characteristics including age, sex, tumor location, and macroscopic appearance were assessed. The following short-term outcomes were then evaluated: en bloc resection rate; complete (R0) resection rate; complication rate in cases of bleeding that required hemostasis, bleeding that required a transfusion or perforation; pathological findings from the resected specimens including histological type, depth of invasion, tumor size, existence of lymphatic (ly) and/or venous invasion (v), ulcer findings (UL), and resection margins (horizontal margin [HM] and vertical margin [VM]); and non-curative resection rate. Finally, the long-term outcomes were analyzed including local recurrence and distant metastasis as well as the overall survival and cause-specific survival rates.

The risks and benefits of the ESD procedure were thoroughly explained to every patient and written informed consent was obtained from each of them in accordance with our institutional protocol prior to their treatment by ESD.

Histological assessment

According to the Japanese Gastric Cancer Treatment Guidelines 2010 (version 3) [1], a resection was judged as curative when all of the following conditions were fulfilled: en bloc resection, tumor size ≤ 2 cm, histologically of differentiated-type, pT1a, HM0, VM0, ly(–), v(–). In addition, a resection was considered as curative for a tumor in a case involving the expanded indications when all of the following conditions were fulfilled: (a) tumor size > 2 cm, histologically of differentiated-type, pT1a, UL( – ); or (b) tumor size ≤ 3 cm, histologically of differentiated-type, pT1a, UL( + ); or (c) tumor size ≤ 2 cm, histologically of undifferentiated-type, pT1a, UL( – ); or (d) tumor size ≤ 3 cm, histologically of differentiated-type, pT1b(SM1, < 500 microns from the muscularis mucosae). A resection that did not satisfy any of the above criteria was considered non-curative.

Follow-up care after ESD

Patients with curative resection meeting the absolute indications for ESD were followed up by annual esophagogastroduodenoscopy examinations. Patients who met the expanded indications also underwent abdominal computed tomography or endoscopic ultrasonography examinations every 6 months. Patients with non-curative resections were referred for and frequently consented to additional gastrectomy with lymph node dissection after the need for such surgery was carefully explained to them based on the pathological findings from their ESD specimens. If patients with non-curative resections continued to refuse surgical resection, however, such patients were followed up using the same protocol as for patients with curative resections who met the expanded indications.

Statistical analysis

Survival time was calculated as the interval between the date of the first treatment and the date of death or the last confirmed date of being alive for survivors. Survival curves were calculated using the Kaplan – Meier method with the SPSS for Windows release 6.0 standard computer software statistical package (SPSS Inc., Chicago, Illinois USA, 1993).

Results

Clinical characteristics

The median patient age was 66 years (range 39 – 75 years) and the male/female ratio was 33 /5. The clinical characteristics of the 38 cSM EGC lesions included tumor location of upper third/middle third/lower third of the stomach in 15 /13 /10 patients, respectively, and macroscopic types of 0-IIc/0-I/0-IIa/0-IIa + IIc in 11 /7 /7 /13 patients, respectively.

Short-term outcomes

The en bloc resection rate was 84.2 % (32 lesions) and the complete (R0) resection rate was 63.2 % (24 lesions). The rate of bleeding requiring hemostasis was 18.4 % (seven lesions), and bleeding requiring a transfusion occurred in one patient (2.6 %) who underwent emergency surgery because the bleeding could not be controlled endoscopically. In addition, five patients (13.2 %) experienced perforations, all of which were successfully managed endoscopically without surgical intervention. Pathological characteristics of the 38 cSM EGC lesions included 32 histological intestinal-type cancers (84.2 %; 23 well differentiated, eight moderately differentiated, and one papillary adenocarcinoma) and six histological diffuse-type cancers (15.8 %; five poorly differentiated adenocarcinomas, no signet-ring cell carcinomas, and one mucinous adenocarcinoma). Mucosal/submucosal depth of invasion was present in 5 /33 patients (13.2 %/86.8 %); mean tumour size ± SD was 26.9 ± 15.0 mm and median tumor size was 24 mm (range 9 – 80 mm); lymphatic/venous invasion was positive in 10 /5 patients (26.3 %/13.2 %); ulcer findings were present/absent in 6 /32 patients (15.8 %/84.2 %); and HM/VM was cancer positive in 4 /13 of the 38 patients (10.5 %/34.2 %).

A total of 34 patients (89.5 %) with 34 lesions underwent non-curative resection: 32 of the lesions were shown pathologically to involve submucosal invasion and two were mucosal cancers that did not meet the indication criteria. Among the 34 non-curative resection patients, 22 of them (64.7 %) underwent subsequent gastrectomy after the need for such surgery was carefully explained to them again. Among the 22 patients who received an additional gastrectomy, six had residual tumors – three with local residual tumors without lymph node metastasis and three with local residual tumors and lymph node metastasis. One other patient had lymph node metastasis only.

Long-term outcomes

During the median follow-up period of 73.2 months (range 3 – 115 months), local recurrence was detected in one patient, distant metastasis in two patients, and both local recurrence and distant metastasis were detected in one patient. All four patients with recurrence (10.5 %) died from gastric cancer as none of them had undergone radical surgery when their recurrent disease was detected. A detailed clinical course for each of the four patients with recurrent disease is shown in [Table 1]. The overall survival curve is shown in [Fig. 1] with a 5-year survival rate of 86.8 %, and the cause-specific survival curve is shown in [Fig. 2] with a 5-year survival rate of 91.8 %.

Discussion

Patients with cSM EGC lesions are usually treated by gastrectomy with lymph node dissection. However, 68 patients with 69 lesions that were diagnosed with cSM EGC underwent ESD at our hospital for various reasons from January 1999 to December 2008. Among these 68 patients, 38 patients with 38 cSM EGC lesions initially refused surgery despite both the absence of any concomitant disease and being young enough to undergo such surgery safely.

In the present study, the complete resection rate of ESD performed on operable patients with cSM EGC lesions was < 70 %, which is considerably lower than our previously published rate of 93 % in a large consecutive series of patients with EGC who underwent ESD with curative intent [5]. Resection was curative in only 10.5 % of the eligible 38 patients with cSM EGC, and thus ESD for cSM EGC did not play an important role as a diagnostic procedure in the present study.

The perforation rate in this series was 13.2 %, which is considerably higher than the previously reported rate of 4 % [5]; however, all five perforation cases in the present study were successfully managed endoscopically. We suspect that the muscle layer was inadvertently perforated during the ESD procedures in these five cases as a result of the precise structure of the gastric wall, particularly the muscle layer, not being fully apparent to the endoscopist due to the existence of submucosal invasion. In addition, the 5-year cause-specific survival rate of 91.8 % was lower than the previously reported rate of 96.7 % for patients with pathological submucosal invasive EGC who underwent gastrectomy [24]. The results of the present study on ESD performed on operable patients with cSM EGC lesions were therefore unsatisfactory, not only in terms of resectability but also with respect to curability. Considering the fact that the mortality rate associated with gastric cancer for patients with cSM EGC following ESD was relatively high, performing ESD on cSM EGC for the sole purpose of diagnosis seems to make little sense because in the present study so few patients with cSM EGC received curative resections from their ESD.

In contrast, gastrectomy with lymph node dissection for EGC has a low operative mortality rate, especially in Japan, of < 1 % and results in an excellent prognosis for patients with cSM EGC. It is therefore suitable for such patients not only in terms of resectability and curability but also with respect to safety [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27]. Considering the fact that in the present study 64.7 % of patients with non-curative resection consented to subsequent gastrectomy after the need for such surgery had been carefully explained to them again, it is essential that we try to persuade patients with cSM EGC that gastrectomy with lymph node dissection is the gold standard curative treatment for cSM EGC and that ESD would probably be an ineffective treatment option from the point of view of both resectability and curability.

In this study, the 5-year cause-specific survival rate for patients with cSM EGC was lower than the rate reported previously for patients with pathological submucosal invasive EGC who underwent gastrectomy. It should be noted, however, that only the percentages themselves were compared and no actual statistical analysis was performed to compare the two rates because the study was merely a retrospective case series rather than a case – control study to compare the 5-year cause-specific survival rates for both procedures conducted during the same time frame. Although it seems reasonable to conclude from the present study that ESD is an ineffective treatment for patients with operable cSM EGC, the results should be interpreted with caution due to this limitation.

In conclusion, ESD appears to be an ineffective treatment for operable patients with cSM EGC based on the results of the present study. If such patients who initially refuse surgery despite both the absence of any concomitant disease and being young enough to safely undergo the highly recommended gold standard curative surgical treatment, it would be better not to perform ESD, except for those cases where submucosal deep invasion is unclear. Instead, we should strongly advise these patients as to the absolute clinical necessity of performing a gastrectomy with lymph node dissection.

Competing interests: None.

Acknowledgment

We wish to express our appreciation to Christopher Dix for his assistance in editing this manuscript.

• References

• 1 Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer 2011; 14: 113-123
  CrossrefPubMedSearch in Google Scholar
• 2 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: 219-225
  CrossrefPubMedSearch in Google Scholar
• 3 Ono H, Kondo H, Gotoda T et al. Endoscopic mucosal resection for treatment of early gastric cancer. Gut 2001; 48: 225-229
  CrossrefPubMedSearch in Google Scholar
• 4 Gotoda T, Kondo H, Ono H et al. A new endoscopic mucosal resection procedure using an insulation-tipped electrosurgical knife for rectal flat lesions. Gastrointest Endosc 1999; 50: 560-563
  CrossrefPubMedSearch in Google Scholar
• 5 Oda I, Gotoda T, Hamanaka H et al. Endoscopic submucosal dissection for early gastric cancer: technical feasibility, operation time and complications from a large consecutive series. Dig Endosc 2005; 17: 54-58
  CrossrefPubMedSearch in Google Scholar
• 6 Yamamoto H, Kawata H, Sunada K et al. Successful one-piece resection of large superficial tumors in the stomach and colon using sodium hyaluronate and small-caliber-tip transparent hood. Endoscopy 2003; 35: 690-694
  Thieme ConnectPubMedSearch in Google Scholar
• 7 Oyama T, Kikuchi Y. Aggressive endoscopic mucosal resection in the upper GI tract – Hook knife EMR method. Minim Invas Ther Allied Technol 2002; 11: 291-295
  PubMedSearch in Google Scholar
• 8 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: 868-871
  CrossrefPubMedSearch in Google Scholar
• 9 Ono H, Yoshida S. Endoscopic diagnosis of the depth of cancer invasion for gastric cancer. Stomach and Intestine (abstract in English) 2001; 36: 334-340
  PubMedSearch in Google Scholar
• 10 Sano T, Okuyama Y, Kobori O et al. Early gastric cancer endoscopic diagnosis of depth of invasion. Dig Dis Sci 1990; 35: 1340-1344
  CrossrefPubMedSearch in Google Scholar
• 11 Gotoda T, Sasako M, Ono H et al. Evaluation of the necessity for gastrectomy with lymph node dissection for patients with submucosal invasive gastric cancer. Br J Surg 2001; 88: 444-449
  CrossrefPubMedSearch in Google Scholar
• 12 Okamura T, Tsujitani S, Korenaga D et al. Lymphadenectomy for cure in patients with early gastric cancer and lymph node metastasis. Am J Surg 1988; 155: 476-480
  CrossrefPubMedSearch in Google Scholar
• 13 Korenaga D, Haraguchi M, Tsujitani S et al. Clinicopathological features of mucosal carcinoma of the stomach with lymph node metastasis in eleven patients. Br J Surg 1986; 73: 431-433
  CrossrefPubMedSearch in Google Scholar
• 14 Iriyama K, Asakawa T, Koike H et al. Is extensive lymphadenectomy necessary for surgical treatment of intramucosal carcinoma of the stomach?. Arch Surg 1989; 124: 309-311
  CrossrefPubMedSearch in Google Scholar
• 15 Inoue K, Tobe T, Kan N et al. Problems in the definition and treatment of early gastric cancer. Br J Surg 1991; 78: 818-821
  CrossrefPubMedSearch in Google Scholar
• 16 Maehara Y, Orita H, Okuyama T et al. Predictors of lymph node metastasis in early gastric cancer. Br J Surg 1992; 79: 245-247
  CrossrefPubMedSearch in Google Scholar
• 17 Sano T, Kobori O, Muto T. Lymph node metastasis from early gastric cancer: endoscopic resection of tumour. Br J Surg 1992; 79: 241-244
  CrossrefPubMedSearch in Google Scholar
• 18 Tsuchiya A, Kikuchi Y, Ando Y et al. Lymph node metastases in gastric cancer invading the submucosal layer. Eur J Surg Oncol 1995; 21: 248-250
  CrossrefPubMedSearch in Google Scholar
• 19 Hanazaki K, Wakabayashi M, Sodeyama H et al. Clinicopathologic features of submucosal carcinoma of the stomach. J Clin Gastroenterol 1997; 24: 150-155
  CrossrefPubMedSearch in Google Scholar
• 20 Kitamura K, Yamaguchi T, Taniguchi H et al. Analysis of lymph node metastasis in early gastric cancer: rationale of limited surgery. J Surg Oncol 1997; 64: 42-47
  CrossrefPubMedSearch in Google Scholar
• 21 Nakamura K, Ueyama T, Yao T et al. Pathology and prognosis of gastric carcinoma. Findings in 10000 patients who underwent primary gastrectomy. Cancer 1992; 70: 1030-1037
  CrossrefPubMedSearch in Google Scholar
• 22 Shimizu S, Tada M, Kawai K. Early gastric cancer: its surveillance and natural course. Endoscopy 1995; 27: 27-31
  Thieme ConnectPubMedSearch in Google Scholar
• 23 Sue-Ling HM, Johnston D, Martin IG et al. Gastric cancer: a curable disease in Britain. BMJ 1993; 307: 591-596
  CrossrefPubMedSearch in Google Scholar
• 24 Sasako M, Kinoshita T, Maruyama K. Prognosis of early gastric cancer. Stomach and Intestine (abstract in English) 1993; 28: 139-146
  PubMedSearch in Google Scholar
• 25 Maruyama K, Sasako M, Kinoshita T et al. Effectiveness of systematic lymph node dissection in gastric cancer surgery. In: Nishi M, Ichikawa H, Nakajima T, et al. eds. Gastric cancer. Berlin: Springer; 1993
  CrossrefSearch in Google Scholar
• 26 Yano H, Monden T, Kinuta M et al. The usefulness of laparoscopy-assisted distal gastrectomy in comparison with that of open distal gastrectomy for early gastric cancer. Gastric Cancer 2001; 4: 93-97
  CrossrefPubMedSearch in Google Scholar
• 27 Kitano S, Shiraishi N, Uyama I. Japanese Laparoscopic Surgery Study Group et al. A multicenter study on oncologic outcome of laparoscopic gastrectomy for early cancer in Japan. Ann Surg 2007; 245: 68-72
  CrossrefPubMedSearch in Google Scholar

Corresponding author

• References

• 1 Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer 2011; 14: 113-123
  CrossrefPubMedSearch in Google Scholar
• 2 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: 219-225
  CrossrefPubMedSearch in Google Scholar
• 3 Ono H, Kondo H, Gotoda T et al. Endoscopic mucosal resection for treatment of early gastric cancer. Gut 2001; 48: 225-229
  CrossrefPubMedSearch in Google Scholar
• 4 Gotoda T, Kondo H, Ono H et al. A new endoscopic mucosal resection procedure using an insulation-tipped electrosurgical knife for rectal flat lesions. Gastrointest Endosc 1999; 50: 560-563
  CrossrefPubMedSearch in Google Scholar
• 5 Oda I, Gotoda T, Hamanaka H et al. Endoscopic submucosal dissection for early gastric cancer: technical feasibility, operation time and complications from a large consecutive series. Dig Endosc 2005; 17: 54-58
  CrossrefPubMedSearch in Google Scholar
• 6 Yamamoto H, Kawata H, Sunada K et al. Successful one-piece resection of large superficial tumors in the stomach and colon using sodium hyaluronate and small-caliber-tip transparent hood. Endoscopy 2003; 35: 690-694
  Thieme ConnectPubMedSearch in Google Scholar
• 7 Oyama T, Kikuchi Y. Aggressive endoscopic mucosal resection in the upper GI tract – Hook knife EMR method. Minim Invas Ther Allied Technol 2002; 11: 291-295
  PubMedSearch in Google Scholar
• 8 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: 868-871
  CrossrefPubMedSearch in Google Scholar
• 9 Ono H, Yoshida S. Endoscopic diagnosis of the depth of cancer invasion for gastric cancer. Stomach and Intestine (abstract in English) 2001; 36: 334-340
  PubMedSearch in Google Scholar
• 10 Sano T, Okuyama Y, Kobori O et al. Early gastric cancer endoscopic diagnosis of depth of invasion. Dig Dis Sci 1990; 35: 1340-1344
  CrossrefPubMedSearch in Google Scholar
• 11 Gotoda T, Sasako M, Ono H et al. Evaluation of the necessity for gastrectomy with lymph node dissection for patients with submucosal invasive gastric cancer. Br J Surg 2001; 88: 444-449
  CrossrefPubMedSearch in Google Scholar
• 12 Okamura T, Tsujitani S, Korenaga D et al. Lymphadenectomy for cure in patients with early gastric cancer and lymph node metastasis. Am J Surg 1988; 155: 476-480
  CrossrefPubMedSearch in Google Scholar
• 13 Korenaga D, Haraguchi M, Tsujitani S et al. Clinicopathological features of mucosal carcinoma of the stomach with lymph node metastasis in eleven patients. Br J Surg 1986; 73: 431-433
  CrossrefPubMedSearch in Google Scholar
• 14 Iriyama K, Asakawa T, Koike H et al. Is extensive lymphadenectomy necessary for surgical treatment of intramucosal carcinoma of the stomach?. Arch Surg 1989; 124: 309-311
  CrossrefPubMedSearch in Google Scholar
• 15 Inoue K, Tobe T, Kan N et al. Problems in the definition and treatment of early gastric cancer. Br J Surg 1991; 78: 818-821
  CrossrefPubMedSearch in Google Scholar
• 16 Maehara Y, Orita H, Okuyama T et al. Predictors of lymph node metastasis in early gastric cancer. Br J Surg 1992; 79: 245-247
  CrossrefPubMedSearch in Google Scholar
• 17 Sano T, Kobori O, Muto T. Lymph node metastasis from early gastric cancer: endoscopic resection of tumour. Br J Surg 1992; 79: 241-244
  CrossrefPubMedSearch in Google Scholar
• 18 Tsuchiya A, Kikuchi Y, Ando Y et al. Lymph node metastases in gastric cancer invading the submucosal layer. Eur J Surg Oncol 1995; 21: 248-250
  CrossrefPubMedSearch in Google Scholar
• 19 Hanazaki K, Wakabayashi M, Sodeyama H et al. Clinicopathologic features of submucosal carcinoma of the stomach. J Clin Gastroenterol 1997; 24: 150-155
  CrossrefPubMedSearch in Google Scholar
• 20 Kitamura K, Yamaguchi T, Taniguchi H et al. Analysis of lymph node metastasis in early gastric cancer: rationale of limited surgery. J Surg Oncol 1997; 64: 42-47
  CrossrefPubMedSearch in Google Scholar
• 21 Nakamura K, Ueyama T, Yao T et al. Pathology and prognosis of gastric carcinoma. Findings in 10000 patients who underwent primary gastrectomy. Cancer 1992; 70: 1030-1037
  CrossrefPubMedSearch in Google Scholar
• 22 Shimizu S, Tada M, Kawai K. Early gastric cancer: its surveillance and natural course. Endoscopy 1995; 27: 27-31
  Thieme ConnectPubMedSearch in Google Scholar
• 23 Sue-Ling HM, Johnston D, Martin IG et al. Gastric cancer: a curable disease in Britain. BMJ 1993; 307: 591-596
  CrossrefPubMedSearch in Google Scholar
• 24 Sasako M, Kinoshita T, Maruyama K. Prognosis of early gastric cancer. Stomach and Intestine (abstract in English) 1993; 28: 139-146
  PubMedSearch in Google Scholar
• 25 Maruyama K, Sasako M, Kinoshita T et al. Effectiveness of systematic lymph node dissection in gastric cancer surgery. In: Nishi M, Ichikawa H, Nakajima T, et al. eds. Gastric cancer. Berlin: Springer; 1993
  CrossrefSearch in Google Scholar
• 26 Yano H, Monden T, Kinuta M et al. The usefulness of laparoscopy-assisted distal gastrectomy in comparison with that of open distal gastrectomy for early gastric cancer. Gastric Cancer 2001; 4: 93-97
  CrossrefPubMedSearch in Google Scholar
• 27 Kitano S, Shiraishi N, Uyama I. Japanese Laparoscopic Surgery Study Group et al. A multicenter study on oncologic outcome of laparoscopic gastrectomy for early cancer in Japan. Ann Surg 2007; 245: 68-72
  CrossrefPubMedSearch in Google Scholar