Efficacy of the No. 10 lymphadenectomy with spleen preservation on patients with gastric cancer and/or esophagogastric junction adenocarcinoma who underwent total gastrectomy: a systematic review and meta-analysis
Introduction
Gastric cancer is responsible for over one million new cases in 2020, and is listed as the fourth most common malignancy and one of the most common causes of cancer-related death worldwide (1,2). According to the Japanese Gastric Cancer Treatment Guideline (JGCTG) 2010 (version 3), surgery with total gastrectomy and D2 lymph node dissection (LND) is recommended as the standard treatment for patients with advanced upper and middle gastric carcinoma in East Asia (3). The advanced Siewert type II/III adenocarcinoma of the esophagogastric junction (AEG) is suggested with the same treatment with proximal gastric cancer as their anatomical position and biological behavior are quite similar (3).
Nevertheless, whether the No. 10 lymph node (No.10 LN, also known as splenic hilar LN) should be dissected in total gastrectomy remains controversial. The incidence rate of No. 10 lymph node metastasis (LNM) is reported to be 9.0–27.9% in the advanced upper and middle gastric cancers (4-7) and 4.8–15.0% in the Siewert type II/III AEG (8-11). Thus, the No. 10 LND is recommended to be added in the total gastrectomy (12).
However, some studies consider that undergoing the No. 10 LND is unnecessary, for the No. 10 LNM is considered as one of the incurable factors of prognosis and the No. 10 LND does not have a survival benefit (13,14). Shin et al. (15) have reported that patients with the No. 10 LNM have worse survival than patients without the No. 10 LNM and does not gain survival benefit from the No. 10 LND. Recently, the No. 10 LN has been deleted from the definition of D2 LND in total gastrectomy according to the JGCTG 2018 (5th edition) by the Japanese Gastric Cancer Association (16).
The aim of the present study was to perform a systematic review of randomized controlled trials (RCTs) or cohort studies to evaluate the effects of No. 10 LND with spleen preservation on patients with gastric cancer and/or Siewert type II/III AEG who have undergone total gastrectomy. We present the following article in accordance with the PRISMA reporting checklist (17) (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-522/rc).
Methods
Search strategy and selection criteria
The PubMed, Embase, the Cochrane Library, ClinicalTrials.gov and American Society of Clinical Oncology.org (ASCO.org) were searched until January 2022 for relevant citations. A combination of the following terms was used to complete the search: “gastric cancer”, “cardiac carcinoma”, “esophagogastric junction carcinoma”, “No. 10 lymphadenectomy”, “splenic hilar lymphadenectomy”, “No. 10 lymph node”, “splenic hilar lymph node”, and “gastrectomy”. Manual searches included scanning of reference lists in relevant articles. No language restriction was applied.
Eligible trials were RCTs or cohort studies that compared the No. 10 LND with the non-No.10 LND for patients with gastric cancer and/or Siewert type II/III AEG who underwent the total gastrectomy. Moreover, data concerning the survival rate should be reported in studies. Studies were excluded if they met the following criteria: (I) intraoperative evidence of peritoneal dissemination or distant metastasis; (II) combined major organ resection (except necessary organ resection, such as splenectomy or pancreatectomy, because of intraoperative organ injury, the intraoperative detection of invasion of the pancreas or spleen, or to enable the en bloc dissection of evident metastatic No. 10 LNs); (III) incomplete pathological data; (IV) and neoadjuvant therapy.
Study selection
Two authors (MXC, BWX) independently selected literature. A third author (BXK) resolved any discrepancies if the first two authors disagreed. The full text of each potentially eligible study was evaluated for inclusion or exclusion in accordance with the selection criteria of the two independent reviewers (YF and YXK).
Data extraction
Two authors (XLS and YBW) independently extracted the data using predefined data extraction forms. Extracted data included study details, study population characteristics, interventions, and outcomes from each eligible trial. All relevant texts, tables, and figures were reviewed for data extraction. Any disagreement in data extraction was resolved by a third reviewer (YYL).
Quality assessment
The methodological quality of cohort studies was assessed by using of the Newcastle-Ottawa Scale (18). A “star system” was applied in each study in accordance with three broad perspectives: selection of cases (0–4 stars), comparability of groups (0–2 stars), and assessment of outcome (0–3 stars). The quality of each study was graded as either “high quality” (8–9 stars) or “moderate quality” (5–7 stars). The quality of the included RCTs was assessed using the modified Jadad standard. Three items were included in the specified criteria of the RCTs: randomization (0–2 points), dropout or withdrawal (0–1 point), and allocation concealment (0–2 points) (19). A blind approach was discarded in RCTs because of the intrinsic nature of the intervention. Studies that received an Jadad score of 3 or higher were classified as high-quality studies. Two authors (YYL and YXK) independently ranked and assessed each study.
Outcome measures
The primary outcome was overall survival rate that was assessed in the included study. This endpoint was measured over one, three, or five years, depending on the size of the study and the length of the follow-up. The disease-free survival (DFS) rate at each time point, complications and mortality associated with the No. 10 LND were the secondary outcomes.
Statistical analysis
A meta-analysis of outcomes by combining various studies was performed using the Review Manager (RevMan) software, version 5.3.5 (The Cochrane Collaboration, Software Update, Oxford). The effect measures of interest were odds ratio (OR) and mean difference with 95% confidence interval (CI). The statistical heterogeneity was assessed using chi-square (χ2) and I2 tests. I2 <25%, 25%≤ I2 ≤50%, and I2 >50% reflected small, moderate, and large inconsistencies, respectively. Sub-group analyses or sensitivity analyses was undertaken to attempt to explain heterogeneities if existed. The ability to conduct subgroup analyses depended on whether the required information was reported in the included studies. The location of tumor was considered for possible subgroup analysis. Sensitivity analyses were carried out only in high quality trials to avoid errors caused by poor quality studies. The publication bias was performed using the Begg’s funnel plots and Egger's tests if the number of included studies was more than 10 (20,21). P<0.05 was considered significant.
Results
Selection of trials
From the 656 citations identified using database searches, 18 duplicate studies and 623 reviews, case reports, letters, editorials, and irrelevant articles were excluded (Figure 1). Furthermore, 7 out of the 15 remaining trials with potential relevance were excluded from the study after reading the full text. One study referred to the posterior No. 10 LND (22); and six studies did not reveal sufficient outcome information to perform analysis (23-28). Finally, eight retrospective cohort studies involving 4,131 patients were included in the study (14,29-35).
Among the included studies, 1,929 patients were in the No. 10+ group (No. 10 LND was conducted for patients with gastric cancer and/or Siewert type II/III AEG who underwent the total gastrectomy) and 2,202 patients were in the No. 10− group (No. 10 LND was not conducted for patients with gastric cancer and/or Siewert type II/III AEG who underwent total gastrectomy). For the study by Park et al. (14), only the data of arms fulfilled the included criteria and were extracted for meta-analysis. In the study of Bian et al. (30), although the data fulfilled the included criteria was limited in the patients with negative No. 4s LNs, we performed a sensitivity analysis and found the result be influenced slightly by the confinement of patients with negative No. 4s LNs. Thus, we included this study for meta-analysis. The average age of patients was 58.9 years, and 74.8% of the patients were male (Table 1). The percentages of TNM stages I–IV of the tumors were 11.0%, 25.7%, 59.5%, and 3.8%, respectively, for patients with the No. 10 LND, and 16.1%, 25.9%, 54.3%, and 3.7%, respectively, for patients without the No. 10 LND. The mean tumor size of gastric cancer and/or Siewert type II/III AEG was 5.9 cm. The mean duration of follow-up was 70.7 months.
Table 1
Study | Year | Country | Study type | Arms | Sample size (n) | Sex, M/F (n) | Age (year) | Tumor size (cm) | Tumor location (upper third and AEG/middle third/lower third/entire and linitisplastica) | Pathological differentiation (differentiated/undifferentiated) | TNM stage† (I/II/III/IV) | Follow-up duration (month) |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Bian | 2016 | China | Retrospective | No. 10+‡ | 260 | 185/75 | NC | NC | NC | 39/221 | 5/59/196/0 | 62 |
No. 10−§ | 243 | 170/73 | NC | NC | NC | 48/195 | 6/58/179/0 | 62 | ||||
Huang | 2017 | China | Retrospective | No. 10+ | 198 | 155/43 | 61.9 | 6.1 | 80/75/0/43 | NC | 9/49/140/0 | 60 |
No. 10− | 198 | 154/44 | 61.1 | 5.9 | 83/80/0/35 | NC | 15/45/138/0 | 60 | ||||
Lin | 2021 | China | Retrospective | No. 10+ | 354 | 280/74 | 62.3 | 5.3 | 161/122/0/71 | 275/79 | 61/90/203/0 | 60 |
No. 10− | 354 | 286/68 | 63.1 | 5.3 | 155/146/0/53 | 289/65 | 73/85/196/0 | 60 | ||||
Liu | 2021 | China | Retrospective | No. 10+ | 237 | 165/72 | 58.0 | 6.8 | 148/60/19/10 | 68/169 | 20/44/156/17 | 91.2 |
No. 10− | 237 | 172/65 | 58.1 | 7.0 | 138/64/22/13 | 68/169 | 20/34/163/20 | 91.2 | ||||
Lv | 2016 | China | Retrospective | No. 10+ | 293 | 241/52 | NC | 4.9 | 293/0/0/0 | NC | 52/87/154/0 | 47 |
No. 10− | 401 | 335/66 | NC | 4.9 | 401/0/0/0 | NC | 81/104/216/0 | 47 | ||||
Oh | 2021 | Korea | Retrospective | No. 10+ | 288 | 194/94 | 56.1 | 7.5 | NC | 88/200 | NC | 60 |
No. 10− | 288 | 198/90 | 56.1 | 7.5 | NC | 89/199 | NC | 60 | ||||
Park | 2019 | Korea | Retrospective | No. 10+ | 79 | 58/21 | 55.5 | NC | NC | NC | 22/57/0/0 | 93.3 |
No. 10− | 248 | 168/80 | 55.1 | NC | NC | NC | 100/148/0/0 | 93.3 | ||||
Yang | 2014 | China | Retrospective | No. 10+ | 220 | 163/57 | NC | NC | 104/64/41/11 | 35/185 | 12/35/128/45 | 89.5 |
No. 10− | 233 | 166/67 | NC | NC | 64/85/51/33 | 25/208 | 14/22/146/51 | 96 |
†, TNM stage was according to seventh American Joint Committee on Cancer staging system for gastric cancer; ‡, No. 10 lymph node dissection; §, non-No. 10 lymph node dissection. M/F, male/female; AEG, adenocarcinoma of the esophagogastric junction; TNM, tumor-node-metastasis; NC, not clear.
Qualitative analysis of studies
As Table 2 shows, among the eight cohort studies, 7 were of high quality (14,29,30,32-35), and 1 was of moderate quality (31).
Table 2
Study | Selection | Comparability | Outcome | Score | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 2 | 3 | 4 | 5A | 5B | 6 | 7 | 8 | ||||
Bian 2016 | *† | * | * | * | * | * | * | * | * | *********‡ | ||
Huang 2017 | * | * | * | * | * | * | * | * | * | ********* | ||
Lin 2021 | * | * | * | * | * | * | * | * | * | ********* | ||
Liu 2021 | * | * | * | * | * | * | * | * | * | ********* | ||
Lv 2016 | * | * | * | * | * | * | * | ******* | ||||
Oh 2021 | * | * | * | * | * | * | * | * | * | ********* | ||
Park 2019 | * | * | * | * | * | * | * | * | ******** | |||
Yang 2014 | * | * | * | * | * | * | * | * | * | ********* |
1, representativeness of the exposed cohort; 2, non-exposed cohort drawn from the same community; 3, ascertainment of exposure; 4, outcome of interest not present at start of study; 5A, comparability of cohorts on the basis of tumor categories; 5B, comparability of cohorts on the other factors; 6, assessment of outcomes; 7, follow-up long enough for outcomes to occur; 8, adequacy of follow up of cohorts; †, each star represents if an individual criterion within the subsection was fulfilled; ‡, score for study quality. The quality of each included cohort study was graded as either “high quality” (8–9 stars) or “moderate quality” (5–7 stars).
Survival rate
Overall survival rate
The meta-analysis results showed that the No. 10 LND significantly improved the 3- [eight studies (14,29-35) reported this data, OR =0.71, 95% CI: 0.62–0.81, P<0.00001; heterogeneity: I2 =39%, P=0.12 for χ2] and 5-year [eight studies (14,29-35) reported this data, OR =0.66, 95% CI: 0.58–0.75, P<0.00001; heterogeneity: I2 =24%, P=0.23 for χ2] survival rates but not the 1-year survival rate [eight studies (14,29-35) reported this data, OR =0.91, 95% CI: 0.75–1.11, P=0.36; heterogeneity: I2 =53%, P=0.04 for χ2; Figure 2].
Survival rate of patients with gastric cancer after surgical resection with total gastrectomy
The pooled meta-analysis results demonstrated that the No. 10 LND significantly improved the 3- [six studies (14,30,32-35) reported this data, OR =0.76, 95% CI: 0.65–0.90, P=0.001; heterogeneity: I2 =32%, P=0.19 for χ2] and 5-year [seven studies (14,29,30,32-35) reported this data, OR =0.70, 95% CI: 0.60–0.82, P<0.00001; heterogeneity: I2 =13%, P=0.33 for χ2] survival rates but not the 1-year survival rate [six studies (14,30,32-35) reported this data, OR =0.95, 95% CI: 0.74–1.21, P=0.67; heterogeneity: I2 =61%, P=0.02 for χ2; Figure 3A].
Survival rate of patients with gastric cancer and type III AEG after surgical resection with total gastrectomy
The overall survival rates in patients with the No. 10 LND were significantly higher than those in patients without the No. 10 LND after 3 [seven studies (14,30-35) reported this data, OR =0.72, 95% CI: 0.57–0.90, P=0.004; heterogeneity: I2 =54%, P=0.04 for χ2], and 5 years [eight studies (14,29-35) reported this data, OR =0.64, 95% CI: 0.53–0.79, P<0.0001; heterogeneity: I2 =49%, P=0.06 for χ2], but not 1 year [seven studies (14,30-35) reported this data, OR =0.92, 95% CI: 0.62–1.37, P=0.69; heterogeneity: I2 =63%, P=0.01 for χ2; Figure 3B].
DFS rate
Overall DFS rate
The meta-analysis showed significant differences between the two groups, and the result favored the No. 10+ group with 1- [five studies (30-33,35) reported this data, OR =0.76, 95% CI: 0.61–0.93, P=0.008; heterogeneity: I2 =0, P=0.61 for χ2], 3- [five studies (30-33,35) reported this data, OR =0.69, 95% CI: 0.60–0.81, P<0.00001; heterogeneity: I2 =0%, P=0.55 for χ2], and 5-year [five studies (30-33,35) reported this data, OR =0.66, 95% CI: 0.56–0.76, P<0.00001; heterogeneity: I2 =5%, P=0.38 for χ2] DFS rates (Figure 4).
DFS rate of patients with gastric cancer after surgical resection with total gastrectomy
Results showed that the No. 10 LND was associated with a significant improvement in the 1- [four studies (30,32,33,35) reported this data, OR =0.79, 95% CI: 0.62–0.99, P=0.04; heterogeneity: I2 =0%, P=0.54 for χ2], 3- [four studies (30,32,33,35) reported this data, OR =0.72, 95% CI: 0.60–0.85, P=0.0002; heterogeneity: I2 =0%, P=0.47 for χ2], and 5-year [four studies (30,32,33,35) reported this data, OR =0.70, 95% CI: 0.59–0.83, P<0.0001; heterogeneity: I2 =0%, P=0.62 for χ2] DFS rates (Figure 5A).
DFS rate of patients with gastric cancer and type III AEG after surgical resection with total gastrectomy
The DFS rate in the No. 10+ group was significantly higher after 1 [five studies (30-33,35) reported this data, OR =0.72, 95% CI: 0.55–0.93, P=0.01; heterogeneity: I2 =30%, P=0.22 for χ2], 3 [five studies (30-33,35) reported this data, OR =0.66, 95% CI: 0.53–0.82, P=0.0001; heterogeneity: I2 =43%, P=0.14 for χ2], and 5 years [five studies (30-33,35) reported this data, OR =0.61, 95% CI: 0.46–0.80, P=0.0004; heterogeneity: I2 =67%, P=0.02 for χ2] than that in the No. 10− group (Figure 5B).
Safety
The most frequent side effects correlated with the No. 10 LND that were reported in the trials were iatrogenic spleen injury, intraoperative blood loss, pancreas-related complications, and peritoneal bleeding. The pooled meta-analysis results demonstrated that there was no significant difference between the two groups in the complications with grade I-II [five studies (31-35) reported this data, OR =1.20, 95% CI: 0.96–1.51, P=0.12; heterogeneity: I2 =10%, P=0.35 for χ2], complications with grade III-IV [five studies (31-35) reported this data, OR =1.30, 95% CI: 0.91–1.85, P=0.16; heterogeneity: I2 =21%, P=0.28 for χ2], and mortality [five studies (29,30,32-34) reported this data, OR =1.59, 95% CI: 0.52–4.87, P=0.42; heterogeneity: I2 =0%, P=0.72 for χ2, Figure 6].
Discussion
This systematic review shows that the No. 10 LND with spleen preservation can significantly improve the overall survival and the DFS rates of patients with gastric cancer and/or Siewert type II/III AEG who have undergone the total gastrectomy.
Given the special anatomical position of the spleen and various complicated splenic hilum vessels, the exposure and the vascularization of splenic vessels are difficult to perform. Moreover, pancreas-related complications and bleeding may be present. Thus, surgeons have preferred splenectomy to facilitate the No. 10 LND for the total gastrectomy in previous years (36,37). However, the total gastrectomy combined with the resection of spleen is reported to result in higher morbidity, larger blood loss, and could not show a superiority on survival rates compared with that of splenic preservation (38,39). Moreover, the loss of the antitumor and the anti-infection functions of the spleen’s immunologic effect is a negative effect for patients with splenectomy. Sano et al. (40,41) have compared the prognosis of patients with splenectomy and spleen preservation (without intentional No. 10 dissection); found that the 5-year overall survival rates of two arms are 75.1% and 76.4%, respectively (P>0.05); and confirmed the noninferiority of the spleen preservation. However, this study was limited to patients with upper gastric cancer without invasion to the greater curvature. Regarding proximal gastric cancer invading the greater curvature, one retrospective study in Japan reported that no significant survival benefit was observed in the splenectomy group comparing with spleen preservation (without intentional No. 10 dissection) group [5-year OS rate of 63.7% vs. 73.6% and 5-year relapse-free survival (RFS) rate of 60.2% vs. 67.3%], and splenectomy was associated with a higher morbidity rate (30.2% vs. 13.3%) (42). Yang et al. (43) have conducted a meta-analysis and found that splenectomy did not increase 5-year overall survival rate but had significantly higher incidence of postoperative complications. For the above reasons, the laparoscopic spleen-preserving No. 10 LND is first reported by Huang et al. and has been gradually accepted and adopted by an increasing number of surgeons as a technically safe and feasible procedure (44).
In this study, the significant benefit of the No. 10 LND is observed, which is similar to the result reported by Huang et al. (32). Several reasons can account for the decreased mortality. First, the No. 10 LNM is closely linked with the prognosis of patients (15,45). Shin et al. (15) have reported that the 5-year survival rate for patients in the hilar node metastasis group (11.04%) is significantly lower than that in the non-metastasis group (51.57%, P<0.001). Takayama et al. (45) have also reported that the prognosis of patients with positive No. 10 LNs is significantly worse than that of patients with negative No. 10 LNs. Although the No. 10 LND with splenectomy is demonstrated to have no superiority in terms of safety and prognosis over the non-No. 10 LND, many studies have verified that the spleen-preserving No. 10 LND, whether in the laparoscopic or the open form, is safe (46,47). Yang et al. (29) have reported that no spleen-preserving LND-related complication, such as intraperitoneal hemorrhage or pancreatic leakage, has occurred in the two groups, except one patient from the 10D+ group who has experienced intraoperative splenic injury. Zheng et al. (26) have conducted a prospective multicenter study to evaluate the technical safety and feasibility of laparoscopic spleenpreserving No. 10 LND for 242 patients with total gastrectomy. Results show that the major complication rate is 3.3% (8/242), but No. 10 LND-related complications are not observed (26). Thus, without morbidity and mortality, the spleen‑preserving No. 10 LND may bring increased dissection of the positive No. 10 LNs and possibly favorable prognosis. Zheng et al. (26) have reported that the average numbers of laparoscopic spleenpreserving No. 10 LND and metastases are 2.4 and 0.1, respectively, and the rate of the No. 10 LNM is 8.1% among patients with advanced gastric cancer (18/223). Second, the No. 10 LNM is found to be significantly associated with positive No. 4s LN in several studies (30,48,49). Bian et al. (30) have found that the negative predictive efficacy of No. 4s LN status for no metastasis to No. 10 LN is 98.09%. Aoyagi et al. (48) have reported that Nos. 4sa and 4sb LNM are significant parameters for the No. 10 LNM (P<0.001 and P=0.006, respectively) with a logistic regression analysis. Besides, No. 4s LNs are found be upstream of No. 10 LNs (50). Thus, based on the above, the status of negative No. 4s LN may be an indicator for predicting no metastasis to No. 10 LN, and No. 10 LND may gain survival benefits for the patients with No. 4s metastasis. If No. 4s LNs are identified as positive by using intraoperative visualization or pathological examination, the No. 10 LND may be recommended. Third, the greater curvature is found as the common tumor location in patients with No. 10 LNM (38.5%) followed by posterior wall (27.8%), and encircling involvement (22.8%) (4). The serosa-negative tumors located at the lesser curvature and anterior wall are observed with no No. 10 LNM (4). Watanabe et al. (51) have found that the incidence of the No. 10 LNM is 15.9% in patients with tumors invading the greater curvature from a retrospective data of 421 patients’ outcomes after the total gastrectomy for proximal advanced gastric cancer, and the index to estimate the benefit from the No. 10 LND is 5.6, indicating a certain survival benefit. The greater curvature invasion is verified to be a risk factor of the No. 10 LNM, and therefore it had clinical significance of No. 10 LND for these patients with advanced gastric cancer invading the greater curvature line (38,51). Maezawa et al. (52) have found the substantially higher T1 of the No. 10 LN than the other regional nodes, such as Nos. 8a, 11p, and 11d, in locally advanced proximal gastric cancer invading the greater curvature. Authors recommend the No. 10 LND as a part of the D2 dissection for proximal gastric cancer invading the greater curvature (52).
The meta-analyses show that the DFS rates for patients with the No. 10 LND have significantly better prognosis compared with those for patients without the No. 10 LND. Three studies are not included in the meta-analyses because of insufficient data (14,29,34). However, Park et al. (14) have observed a RFS rate and found no difference in the RFS rates between the two groups. The DFS rate, which is closely correlated to relapse and distant metastasis, generally denotes the length of time the patient survives without any signs or symptoms after primary treatment for a cancer (53). The presence of the No. 10 LNM is one of the independent predictors of distant metastasis after the R0 surgical resection, indicating that the non-No. 10 LND patients with potentially positive No. 10 LN have a high risk for the presence of distant LNM and therefore a lower DFS, but a limited risk for the presence of relapse in situ (6). Thus, the relative effect of the No. 10 LND may be less remarkable for RFS than DFS.
Considering the discrepancies of Siewert type II AEG, Siewert type III AEG, and stomach cancer, subgroup analysis according to the location of tumor are performed. The results of subset analyses showed that the survival and DFS rates of the patients with gastric cancer are consistent with those of the patients with gastric cancer and/or type II/III AEG. Results indicate that the tumor, whether located in the stomach or below 1 centimeter above the esophagogastric junction, is not crucial in the prognosis of patients. The finding maybe because the biological behavior and the anatomical position of the Siewert type II/III AEG are quite similar to those of advanced proximal gastric cancer, which has a similar prognosis while the total gastrectomy and the D2 lymphadenectomy are performed (54). The subgroup analyses on the tumor of gastric cancer and/or Siewert type III AEG indicate that the No. 10 LND significantly improves the overall survival and the DFS rates of patients with gastric cancer and/or the Siewert type III AEG who have undergone total gastrectomy. However, the validity of meta-analysis may be affected by significant heterogeneity and limited sample sizes. The subset analyses according to tumor size, tumor stage, and degree of pathological differentiation are not conducted because of insufficient information. The result of meta-analysis of safety in trials comparing No. 10 LND versus non-No. 10 LND indicates that No. 10 LND is a safe way for patients with gastric cancer and/or Siewert type II/III AEG who have undergone total gastrectomy.
The current study has several potential limitations. First, there are important heterogeneities among studies. Sensitivity and subgroup analyses have failed to eliminate the significance. There are many differences across studies that serve as sources of heterogeneity, including variation in sample sizes, variation in the baseline of tumor characteristics (e.g., tumor differentiation, stage, and size), and length of follow-up period. Second, the publication bias may exist because of the relatively limited database. The quality of the current study may be influenced by none of the available RCTs included. We speculate that the reason may be that for surgeons, performing surgical intervention with randomized and blinded ways is a difficult and unethical task. Nevertheless, the meta-analyses of well-designed non-RCTs are demonstrated to have similar accuracy to RCTs (55). There may be duplicate patients due to several overlaps in terms of institution and operation year, in which the patients underwent total gastrectomy (29,31-34). However, we failed to eliminate the duplicate data because of the insufficient reported information in the included studies. Nevertheless, we conducted sensitivity analyses of the studies that may have contained duplicate patients to verify the stability of the results. The analysis results indicated that the survival outcomes in this study are slightly influenced by potential duplicate patients. Besides, there may exist potentially confounding selection bias from the non-No. 10 LND group introduced by the retrospective nature of the included studies, because it is difficult to analyze and draw a conclusion regarding the No. 10 LN metastasis and staging without lymphadenectomy. The improved comprehensive approach of imaging diagnosis, intraoperative diagnosis on LN metastasis and staging can be expected in the future (56). In addition, the chemotherapy is a prognostic factor of patients with gastric cancer and/or Siewert type II/III AEG who have undergone the total gastrectomy. Hence, patients who have received postoperative chemotherapy during the period of the clinical researches may influence the results. Therefore, the results of current study should be interpreted cautiously.
Conclusions
The No. 10 LND with spleen preservation is a safe approach to improve the survival of patients with gastric cancer and/or Siewert type II/III AEG who have undergone total gastrectomy. Further high-quality prospective trials are urgently needed to verify this outcome.
Acknowledgments
Funding: This study was funded by
Footnote
Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-522/rc
Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-522/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-522/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Joshi SS, Badgwell BD. Current treatment and recent progress in gastric cancer. CA Cancer J Clin 2021;71:264-79. [Crossref] [PubMed]
- Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
- Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2010 (ver. 3). Gastric Cancer 2011;14:113-23. [Crossref] [PubMed]
- Sasada S, Ninomiya M, Nishizaki M, et al. Frequency of lymph node metastasis to the splenic hilus and effect of splenectomy in proximal gastric cancer. Anticancer Res 2009;29:3347-51. [PubMed]
- Nashimoto A, Yabusaki H, Matsuki A. The significance of splenectomy for advanced proximal gastric cancer. Int J Surg Oncol 2012;2012:301530. [Crossref] [PubMed]
- Zhu GL, Sun Z, Wang ZN, et al. Splenic hilar lymph node metastasis independently predicts poor survival for patients with gastric cancers in the upper and/or the middle third of the stomach. J Surg Oncol 2012;105:786-92. [Crossref] [PubMed]
- Guner A, Hyung WJ. Advantages of Splenic Hilar Lymph Node Dissection in Proximal Gastric Cancer Surgery. J Gastric Cancer 2020;20:19-28. [Crossref] [PubMed]
- Kakeji Y, Yamamoto M, Ito S, et al. Lymph node metastasis from cancer of the esophagogastric junction, and determination of the appropriate nodal dissection. Surg Today 2012;42:351-8. [Crossref] [PubMed]
- Goto H, Tokunaga M, Sugisawa N, et al. Value of splenectomy in patients with Siewert type II adenocarcinoma of the esophagogastric junction. Gastric Cancer 2013;16:590-5. [Crossref] [PubMed]
- Hasegawa S, Yoshikawa T, Rino Y, et al. Priority of lymph node dissection for Siewert type II/III adenocarcinoma of the esophagogastric junction. Ann Surg Oncol 2013;20:4252-9. [Crossref] [PubMed]
- Kurokawa Y, Takeuchi H, Doki Y, et al. Mapping of Lymph Node Metastasis From Esophagogastric Junction Tumors: A Prospective Nationwide Multicenter Study. Ann Surg 2021;274:120-7. [Crossref] [PubMed]
- Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011;14:101-12. [Crossref] [PubMed]
- Galizia G, Lieto E, De Vita F, et al. Modified versus standard D2 lymphadenectomy in total gastrectomy for nonjunctional gastric carcinoma with lymph node metastasis. Surgery 2015;157:285-96. [Crossref] [PubMed]
- Park SH, Son T, Seo WJ, et al. Prognostic Impact of Extended Lymph Node Dissection versus Limited Lymph Node Dissection on pN0 Proximal Advanced Gastric Cancer: a Propensity Score Matching Analysis. J Gastric Cancer 2019;19:212-24. [Crossref] [PubMed]
- Shin SH, Jung H, Choi SH, et al. Clinical significance of splenic hilar lymph node metastasis in proximal gastric cancer. Ann Surg Oncol 2009;16:1304-9. [Crossref] [PubMed]
- Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2018 (5th edition). Gastric Cancer 2021;24:1-21.
- Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. J Clin Epidemiol 2021;134:178-89. [Crossref] [PubMed]
- Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available online: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm
- Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12. [Crossref] [PubMed]
- Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34. [Crossref] [PubMed]
- Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088-101. [Crossref] [PubMed]
- Lin JX, Huang CM, Zheng CH, et al. Is it necessary to dissect the posterior lymph nodes along the splenic vessels during total gastrectomy with D2 lymphadenectomy for advanced gastric cancer? Eur J Surg Oncol 2017;43:2357-65. [Crossref] [PubMed]
- Yang K, Lu ZH, Zhang WH, et al. Comparisons Between Different Procedures of No. 10 Lymphadenectomy for Gastric Cancer Patients With Total Gastrectomy. Medicine (Baltimore) 2015;94:e1305. [Crossref] [PubMed]
- Ji X, Fu T, Bu ZD, et al. Comparison of different methods of splenic hilar lymph node dissection for advanced upper- and/or middle-third gastric cancer. BMC Cancer 2016;16:765. [Crossref] [PubMed]
- Wang JB, Liu ZY, Chen QY, et al. Short-term efficacy of robotic and laparoscopic spleen-preserving splenic hilar lymphadenectomy via Huang's three-step maneuver for advanced upper gastric cancer: Results from a propensity score-matched study. World J Gastroenterol 2019;25:5641-54. [Crossref] [PubMed]
- Zheng CH, Xu YC, Zhao G, et al. Safety and feasibility of laparoscopic spleen-preserving No. 10 lymph node dissection for locally advanced upper third gastric cancer: a prospective, multicenter clinical trial. Surg Endosc 2020;34:5062-73. [Crossref] [PubMed]
- Zheng C, Xu Y, Zhao G, et al. Outcomes of Laparoscopic Total Gastrectomy Combined With Spleen-Preserving Hilar Lymphadenectomy for Locally Advanced Proximal Gastric Cancer: A Nonrandomized Clinical Trial. JAMA Netw Open 2021;4:e2139992. [Crossref] [PubMed]
- Zhong Q, Chen QY, Xu YC, et al. Reappraise role of No. 10 lymphadenectomy for proximal gastric cancer in the era of minimal invasive surgery during total gastrectomy: a pooled analysis of 4 prospective trial. Gastric Cancer 2021;24:245-57. [Crossref] [PubMed]
- Yang K, Zhang WH, Chen XZ, et al. Survival benefit and safety of no. 10 lymphadenectomy for gastric cancer patients with total gastrectomy. Medicine (Baltimore) 2014;93:e158. [Crossref] [PubMed]
- Bian S, Xi H, Wu X, et al. The Role of No. 10 Lymphadenectomy for Advanced Proximal Gastric Cancer Patients Without Metastasis to No. 4sa and No. 4sb Lymph Nodes. J Gastrointest Surg 2016;20:1295-304. [Crossref] [PubMed]
- Lv CB, Huang CM, Zheng CH, et al. Should Splenic Hilar Lymph Nodes be Dissected for Siewert Type II and III Esophagogastric Junction Carcinoma Based on Tumor Diameter?: A Retrospective Database Analysis. Medicine (Baltimore) 2016;95:e3473. [Crossref] [PubMed]
- Huang CM, Chen T, Lin JX, et al. The effects of laparoscopic spleen-preserving splenic hilar lymphadenectomy on the surgical outcome of proximal gastric cancer: a propensity score-matched, case-control study. Surg Endosc 2017;31:1383-92. [Crossref] [PubMed]
- Lin JX, Wang ZK, Huang YQ, et al. Clinical Relevance of Splenic Hilar Lymph Node Dissection for Proximal Gastric Cancer: A Propensity Score-Matching Case-Control Study. Ann Surg Oncol 2021;28:6649-62. [Crossref] [PubMed]
- Liu K, Chen XZ, Zhang YC, et al. The value of spleen-preserving lymphadenectomy in total gastrectomy for gastric and esophagogastric junctional adenocarcinomas: A long-term retrospective propensity score match study from a high-volume institution in China. Surgery 2021;169:426-35. [Crossref] [PubMed]
- Oh YJ, Kim DH, Eom BW, et al. Is Splenic Hilar Lymph Node Dissection Without Splenectomy Essential for Proximal Advanced Gastric Cancer? Ann Surg Oncol 2021;28:8952-61. [Crossref] [PubMed]
- Nakata K, Nagai E, Ohuchida K, et al. Technical feasibility of laparoscopic total gastrectomy with splenectomy for gastric cancer: clinical short-term and long-term outcomes. Surg Endosc 2015;29:1817-22. [Crossref] [PubMed]
- Csendes A, Burdiles P, Rojas J, et al. A prospective randomized study comparing D2 total gastrectomy versus D2 total gastrectomy plus splenectomy in 187 patients with gastric carcinoma. Surgery 2002;131:401-7. [Crossref] [PubMed]
- Toriumi T, Terashima M. Disadvantages of Complete No. 10 Lymph Node Dissection in Gastric Cancer and the Possibility of Spleen-Preserving Dissection J Gastric Cancer 2020;20:1-18. Review. [Crossref] [PubMed]
- Kinoshita T, Okayama T. Is splenic hilar lymph node dissection necessary for proximal gastric cancer surgery? Ann Gastroenterol Surg 2020;5:173-82. [Crossref] [PubMed]
- Sano T, Sasako M, Mizusawa J, et al. Randomized Controlled Trial to Evaluate Splenectomy in Total Gastrectomy for Proximal Gastric Carcinoma. Ann Surg 2017;265:277-83. [Crossref] [PubMed]
- Sano T, Yamamoto S, Sasako M, et al. Randomized controlled trial to evaluate splenectomy in total gastrectomy for proximal gastric carcinoma: Japan clinical oncology group study JCOG 0110-MF. Jpn J Clin Oncol 2002;32:363-4. [Crossref] [PubMed]
- Ohkura Y, Haruta S, Shindoh J, et al. Efficacy of prophylactic splenectomy for proximal advanced gastric cancer invading greater curvature. World J Surg Oncol 2017;15:106. [Crossref] [PubMed]
- Yang K, Zang ZY, Niu KF, et al. The Survival Benefit and Safety of Splenectomy for Gastric Cancer With Total Gastrectomy: Updated Results. Front Oncol 2021;10:568872. [Crossref] [PubMed]
- Huang CM, Chen QY, Lin JX, et al. Huang's three-step maneuver for laparoscopic spleen-preserving No. 10 lymph node dissection for advanced proximal gastric cancer. Chin J Cancer Res 2014;26:208-10. [PubMed]
- Takayama T, Wakatsuki K, Matsumoto S, et al. Prognostic significance of splenic hilar nodal involvement in proximal third gastric carcinoma. Hepatogastroenterology 2011;58:647-51. [PubMed]
- Oh SJ, Hyung WJ, Li C, et al. The effect of spleen-preserving lymphadenectomy on surgical outcomes of locally advanced proximal gastric cancer. J Surg Oncol 2009;99:275-80. [Crossref] [PubMed]
- Mou TY, Hu YF, Yu J, et al. Laparoscopic splenic hilum lymph node dissection for advanced proximal gastric cancer: a modified approach for pancreas- and spleen-preserving total gastrectomy. World J Gastroenterol 2013;19:4992-9. [Crossref] [PubMed]
- Aoyagi K, Kouhuji K, Miyagi M, et al. Prognosis of metastatic splenic hilum lymph node in patients with gastric cancer after total gastrectomy and splenectomy. World J Hepatol 2010;2:81-6. [Crossref] [PubMed]
- Ikeguchi M, Kaibara N. Lymph node metastasis at the splenic hilum in proximal gastric cancer. Am Surg 2004;70:645-8. [PubMed]
- Takahashi T, Sawai K, Hagiwara A, et al. Type-oriented therapy for gastric cancer effective for lymph node metastasis: management of lymph node metastasis using activated carbon particles adsorbing an anticancer agent. Semin Surg Oncol 1991;7:378-83. [Crossref] [PubMed]
- Watanabe M, Kinoshita T, Enomoto N, et al. Clinical Significance of Splenic Hilar Dissection with Splenectomy in Advanced Proximal Gastric Cancer: An Analysis at a Single Institution in Japan. World J Surg 2016;40:1165-71. [Crossref] [PubMed]
- Maezawa Y, Aoyama T, Yamada T, et al. Priority of lymph node dissection for proximal gastric cancer invading the greater curvature. Gastric Cancer 2018;21:569-72. [Crossref] [PubMed]
- National Cancer Institute. NCI Dictionary of Cancer Terms. Available online: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/disease-free-survival
- Mönig SP, Collet PH, Baldus SE, et al. Splenectomy in proximal gastric cancer: frequency of lymph node metastasis to the splenic hilus. J Surg Oncol 2001;76:89-92. [Crossref] [PubMed]
- Abraham NS, Byrne CJ, Young JM, et al. Meta-analysis of well-designed nonrandomized comparative studies of surgical procedures is as good as randomized controlled trials. J Clin Epidemiol 2010;63:238-45. [Crossref] [PubMed]
- Lee S, Song JH, Choi S, et al. Fluorescent lymphography during minimally invasive total gastrectomy for gastric cancer: an effective technique for splenic hilar lymph node dissection. Surg Endosc 2022;36:2914-24. [Crossref] [PubMed]