# Efficacy and Safety of Radical Resection of RectalCancer Combined with Selective Lateral Lymph Node Dissection in the Treatment of Low Rectal Cancer under Meta-analysis

Authors: Futao Hou; Zhige Yu; Hongxi Chen; Chaowu Chen
Journal: Contrast Media & Molecular Imaging
 (2022)

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## Abstract

Rectal cancer mostly occurs in the middle and low position in China, and many anatomical evidence has confirmed that Lateral Lymph Node Metastasis (LLNM) exists in middle and low rectal cancer. Laparoscopic surgery can penetrate into the pelvic cavity and magnify and narrow the visual field, which is helpful for lymph node dissection and vascular nerve protection, while it has minimally invasive characteristics and is considered to be more suitable for LLND. Relevant articles published from January 2000 to May 2022 are searched using “Rectal cancer, Lateral lymph node dissection, Radical resection of rectal cancer, Low rectal cancer, Laparoscopic therapy, Treatment of rectal cancer” as test terms, analyzed and assessed using Rev Man 5.3 software and Stata software to assess the risk bias of included references, and heterogeneity among each study is evaluated usingQ test and heterogeneity (I2). The experimental results show that there is no heterogeneity among the studies (I2 = 8.46%). The heterogeneity of lymphatic metastasis in the included literature is evaluated, and the results show that there is heterogeneity between the studies (I2 = 52.06%).


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## Body

## 1. Introduction

According to a global cancer statistics report published by Ca in February 2021, colorectal cancer mortality and morbidity rank second and third among all cancers, respectively, and have an increasing trend year by year. In China, rectal cancer mostly occurs in middle and low rectal cancer, and a large number of anatomical evidence has confirmed the presence of lateral lymph node metastasis (LLNM) in middle and low rectal cancer [1]. According to two Japanese multicenter studies, the incidence of LLNM in low rectal cancer is about 13.3% to 20.1%, and LLNM is indeed one of the main causes of local recurrence in advanced low rectal cancer. However, there has been controversy regarding the treatment modalities for LLNM. In 1982, a British professor first proposed the concept of total mesorectal excision (TME). TME can reduce the local recurrence rate after rectal cancer surgery. Subsequently, radical surgery for rectal cancer is gradually completed based on this principle. Currently, Western guidelines for the treatment of rectal cancer also tend to combine neoadjuvant chemoradiotherapy (nCRT) [2]. The main reason may be that mesorectal excision (ME) cannot meet the requirements of radical resection for rectal cancer with positive lateral lymph nodes in the lateral space (internal iliac artery and its external branches) and intermediate space (internal iliac artery and its two sides, anterior branches, pelvic wall fascia), and can only completely remove mesenteric lymph nodes in the medial space (posterior pelvic visceral fascia and anterior Denonvilliers fascia) [3]. Therefore, lateral lymph node dissection (LLND) is necessary.It is innovatively included in the current domestic and foreign literature research on radical resection of rectal cancer combined with LLND in the treatment of low rectal cancer. The meta-analysis system is used to evaluate the efficacy of combined therapy for low rectal cancer, in order to evaluate the efficacy and safety of combined therapy for low rectal cancer, and to provide evidence for clinical treatment.The rest of this paper is organized as follows: Section2 discusses the related work, followed by focusing on data extraction and statistical methods in Section 3. The heterogeneity evaluation and meta-analysis are discussed in Section 4. Section 5 concludes the paper with the summary.


## 2. Related Work

Currently, Western countries placed less emphasis on nCRT, while routine implementation of LLND is lower. The main reason is that western scholars believed that the tumor effect of LLND was uncertain and the incidence of complications was high. The development of surgery in Japan was based on anatomical studies. As early as the 1970s, LLND was started during surgery for low rectal cancer. To date, LLND has been recognized by most Japanese surgeons as a routine procedure for surgical treatment of low rectal cancer [4]. The guidelines clearly stated that when rectal tumors had lower borders below peritoneal recurrence and involved muscle, LLND should be performed even if no LLNM was found preoperatively or intraoperatively [5]. It has been shown that lymphatic drainage from the rectum could be divided into three main routes. The superior approach extended from the superior rectal artery to the inferior mesenteric artery; laterally along the middle rectal artery to the internal iliac and obturator foramina; and the descending route extended to the inguinal lymph nodes. Upper and lateral pathways were important for lymphatic spread [6–8].The local recurrence rate in the bilateral atlanto-occipital group was significantly lower than that in the unilateral atlanto-occipital group, and the local control was better. Lateral lymph nodes such as iliac bone and obturator foramen were not within the scope of TME lymph node dissection, and patients undergoing TME surgery still had the risk of tumor lymph node metastasis. Because of its special anatomical location, the metastasis rate of pelvic lateral lymph nodes in low rectal cancer could reach 10%–25%. This route of lymph node metastasis was considered to be the cause of postoperative local recurrence in patients with rectal cancer and the reason that the local recurrence rate of low rectal cancer was higher than that of middle and upper low rectal cancer. The aim of LLND was to remove these potentially metastatic lymph nodes, thereby controlling local recurrence and even improving long-term survival [9]. Urinary function and subjective sexual function scores were not significantly different compared to the individual groups. Recent evidence from Western countries suggested that neoadjuvant chemoradiotherapy (nCRT) combined with TME might not be sufficient to treat some patients with advanced low rectal cancer, while LLND might reduce local recurrence rates. More and more scholars believed that accurate grasp of surgical indications for LLND could bring survival benefits. Moreover, some domestic scholars have also proposed individualized and selective LLND strategies. Laparoscopic surgery could penetrate the pelvic cavity, enlarge, and narrow the visual field, and facilitate lymph node dissection and vascular neuroprotection. In addition, it had the characteristics of minimally invasive and was considered more suitable for the realization of LLND [10–12].


## 3. Data Extraction and Statistical Methods

The Cochrane Library, PubMed, MEDLINE, EBSCO, Science Direct, and China National Knowledge Infrastructure (CNKI) databases are searched by computer to collect domestic and foreign literature on airway stent implantation for airway stenosis [13, 14]. Relevant literature published from January 2000 to May 2022 are searched using “Rectal cancer, Lateral lymph node dissection, Radical resection of rectal cancer, Low rectal cancer, Laparoscopic therapy, Treatment of rectal cancer” as test terms, and all database searches use a combination of subject headings and free words, which are appropriately adjusted according to the specific database. The search strategy is determined by multiple presearches. Professional journals are manually searched to avoid omissions, and the subjects of searching the literature are people.The search process uses subject headings combined with free words for multiple searches to obtain references that can be included, and then the search engine is used to trace each article [15–17]. The quality of the included articles is assessed using Rev Man 5.3 software provided by the Cochrane collaboration.The inclusion criteria are as follows: (1) Patients undergoing low rectal cancer treatment. (2) Radical resection of rectal cancer combined with LLND is compared with non-LLND treatment. (3) CT2/3/4 or CN + disease without distant metastasis. (4) The study results contain efficacy or safety endpoints, including overall response, complete response (CR), partial response (PR), and adverse events (AE).The exclusion criteria are as follows: (1) The sample size of the study is less than 5 patients. If the sample size is too small, there will be bias and insufficient power. (2) Prospective studies are preferred to be included in retrospective studies in order to improve the level of evidence as much as possible. Randomized controlled trials have not been included due to different outcome measures. (3) Conference abstracts, case reports, reviews, communication articles, clinical experience reports with incomplete information, and animal or cell experiments. (4) The literature lacks complete information and the data are vague or unextractable.Literature screening and data extraction are independently performed by two professionals using a unified Microsoft Excel, cross-checked, and included in the final results, and discrepancies are resolved by discussion [18]. The main extracted data are as follows: (1) General data information of the included studies are title, first author, and publication years. (2) Basic characteristics of the study subjects are number of cases, patient age, and gender. (3) Survival time after treatment, complications, and other indicators. (4) Key elements of bias risk evaluation are randomization method, whether to implement blinding, allocation concealment. (5) Outcome indicators and outcome measurement data such as CR, PR, and safety outcome AE.The quality of the included articles is evaluated using the quality assessment of diagnostic accuracy studies criteria recommended by Cochrane for treatment trials. The quality of the included original literature is evaluated according to each evaluation indicator, and each study is evaluated according to “conformity,” “non-conformity,” and “uncertainty.”Rev Man 5.3 software and Stata software are used, odds ratio (OR) is used as the effect index for dichotomous variables, and mean difference (MD) is used as the effect index for continuous variables, and point estimates and their 95% CI are given for each effect index [19]. Heterogeneity among the included study results is analyzed by X2 test (test level α = 0.1), and heterogeneity is quantitatively judged in combination with I2. If there is no statistically significant difference in heterogeneity among the study results, a fixed-effect model is used for meta-analysis. If there is a statistically significant difference in heterogeneity, a random-effect model is used for meta-analysis, and subgroup analysis is used to explore the possible source of heterogeneity. The test level of meta-analysis is set as α = 0.05. Forest plots and Summary Receiver Operating Characteristic (SROC) curves are plotted, and asymmetric linear regression of funnel plots is plotted [20]. Funnel plots for different treatment measures are used to test for potential publication bias and sensitivity analysis are performed [21].


## 4. Heterogeneity Evaluation and Meta-analysis

### 4.1. Search Results and Basic Information of Literature

258 articles are obtained by searching the database, 41 repeated publications are first removed, 56 articles are removed for ineligibility, and 30 articles are removed for other reasons, and the remaining 128 articles are preliminarily selected. By reading the abstracts and titles, 54 articles are excluded and 74 remained. 30 research reports and review articles are excluded, leaving 44. All remaining articles are read fully, excluding 18 articles with incorrect study types. 15 articles are excluded due to incomplete or unobtainable treatment results required. 3 articles are not human subjects, and 8 articles are finally included in the meta-analysis. Figure1 is the flow chart of literature search. It is clearly evident from Figure 1 that it shows a flow diagram of the retrieving literature.Figure 1
Flow chart of literature search.The basic information of the literature is extracted by reading the contents of the literature. In 8 included literature [19–21], a comparison of the two treatment methods is used, in which 831 patients are included in LLND + ME for low rectal cancer and 971 patients are included in non-LLND for low rectal cancer. In addition, among the 8 included literature, the sample size varies from 41 to 701. Eight articles describe the process of treating low rectal cancer by LLND + ME in detail, and record the changes of various indicators of patients before and after treatment, as well as the complications and morbidity caused by LLND + ME in the treatment of low rectal cancer. The quality evaluation is performed on the 8 included literature, and the results show that 6 literature (75%) have grade A, 1 literature (12.5%) has grade B, and 1 literature (12.5%) has grade C. Table 1 shows the basic information of included literature. It is clearly evident from Table 1 that the basic characteristics of the included articles are enough.Table 1
Basic information of included literature.
AuthorYearTreatment methodCaseAkiyoshi [11]2014LLND + ME38Fujita [12]2017LLND + ME351Georgiou [13]2017LLND + ME17Lee [14]2019LLND + ME37Matsuda [15]2018LLND + ME32Ogura [16]2017LLND + ME107Oki [17]2019LLND + ME215Yang [18]2020LLND + ME34Figure2 shows risk bias evaluation plot for references generated by Rev Man 5.3 software. It is clearly evident from Figure 2 that the random sequence generation is in low risk of bias.Figure 2
Risk bias evaluation plot for references generated by Rev Man 5.3 software.Figure3 shows the summary chart of reference risk bias. It is clearly evident from Figure 3 that “+” indicates low risk, “−” indicates high risk, and “ ” indicates unclear.Figure 3
Summary chart of reference risk bias.


### 4.2. Heterogeneity Evaluation Results

The heterogeneity of survival rate is evaluated in the included literature. The results show that the heterogeneity of low rectal cancer among the studies is low (I2 = 24.20%). The heterogeneity of treatment complications in the included literature is evaluated. The results show that there is no heterogeneity among the studies (I2 = 8.46%). The heterogeneity of lymphatic metastasis in the included literature is evaluated, and the results show that there is heterogeneity among the studies (I2 = 52.06%). In order to further verify whether there is heterogeneity between the data of the two examination methods, and to compare the differences in the indicators of different treatment methods, a random-effect model is required for pooled analysis.


### 4.3. Meta-analysis of Disease-free Survival

For 8 articles on LLND + ME combination therapy versus non-LLND for low rectal cancer, the impact of treatment on disease-free survival is analyzed. Figure4 shows the forest plot for disease-free survival. It is clearly evident from Figure 4 that taking the OR as the outcome measure, the disease-free survival analysis of 8 LLND + ME combination therapy and non-LLND therapy obtains degree of freedom (df) = 8.64, I2 = 24.20%, P = 0.28, and the OR for patient survival is calculated using a fixed-effect model due to low heterogeneity among the study groups. Meta-analysis reveals that patients treated with LLND + ME have better survival than those treated with non-LLND, with an OR of 0.26 and a 95% confidence interval (CI) of (−0.05, 0.57).Figure 4
Forest plot for disease-free survival.Figure5 shows the Galbraith heterogeneity test plot for disease-free survival. It is clearly evident from Figure 5 that the heterogeneity test is performed for the data on the effect of disease-free survival.Figure 5
Galbraith heterogeneity test plot for disease-free survival.Figure6 shows the Labbe heterogeneity test plot for disease-free survival. It is clearly evident from Figure 6 that the data are tenable and have reference similarity among each study.Figure 6
Labbe heterogeneity test plot for disease-free survival.Figure7 shows the assessment plot of bias risk for disease-free survival. It is clearly evident from Figure 7 that the included literature has good stability.Figure 7
Assessment plot of bias risk for disease-free survival.


### 4.4. Meta-analysis of Total Complications

For 8 articles on LLND + ME combination therapy versus non-LLND for low rectal cancer, the impact of treatment on overall complications is analyzed. Figure8 shows the forest plot of total complications. It is clearly evident from Figure 8 that taking OR as the outcome measure, the analysis of total complications in 8 LLND + ME combined treatment versus non-LLND treatment obtains df = 6.68, I2 = 8.46%, P = 0.46. Meta-analysis finds that patients treated with LLND + ME have fewer complications than those treated with non-LLND, with an OR of -0.24 and a 95% CI of (−0.56, 0.07), suggesting that LLND + ME is more effective than common treatment and can reduce complications.Figure 8
Forest plot of total complications.Figure9 shows the Galbraith heterogeneity test plot for total complications. It is clearly evident from Figure 9 that the heterogeneity results of each study are very concentrated.Figure 9
Galbraith heterogeneity test plot for total complications.Figure10 shows the Labbe heterogeneity test plot for total complications. It is clearly evident from Figure 10 that the data among each study are valid and had reference similarity.Figure 10
Labbe heterogeneity test plot for total complications.Figure11 shows the risk of bias assessment plot for total complications. It is clearly evident from Figure 11 that the results of the applied analysis model have no significant change, indicating that the included literature have good stability.Figure 11
Risk of bias assessment plot for total complications.


### 4.5. Meta-analysis of Lymph Node Metastasis

For 8 articles on LLND + ME combination therapy versus non-LLND for low rectal cancer, the effect of treatment on lymph node metastasis in patients is analyzed. Figure12 shows the risk of bias assessment plot for total complications. It is clearly evident from Figure 12 that using OR as an outcome measure, analysis of lymph node metastasis in 8 LLND + ME combined treatment versus non-LLND treatment obtains df = 14.67, I2 = 52.06%, and P = 0.04, with heterogeneity among studies. Meta-analysis finds that lymph node metastasis is less in patients treated with LLND + ME than in patients treated with non-LLND, with an OR of -0.59 and 95% CI of (−1.03, −0.14), suggesting that LLND + ME combined treatment is more effective than common treatment and can reduce lymph node metastasis.Figure 12
Forest plot for lymph node metastasis.Figure13 shows the Galbraith heterogeneity test plot for lymph node metastasis. It is clearly evident from Figure 13 that the heterogeneity results of each study are very concentrated.Figure 13
Galbraith heterogeneity test plot for lymph node metastasis.Figure14 shows the Labbe heterogeneity test plot for lymph node metastases. It is clearly evident from Figure 14 that the data are tenable and have reference similarity among each study.Figure 14
Labbe heterogeneity test plot for lymph node metastases.Figure15 shows the risk of bias assessment for lymph node metastasis. It is clearly evident from Figure 15 that the results of the applied analysis model show no significant change, indicating that the included literature has good stability.Figure 15
Risk of bias assessment for lymph node metastasis.


## 4.1. Search Results and Basic Information of Literature

258 articles are obtained by searching the database, 41 repeated publications are first removed, 56 articles are removed for ineligibility, and 30 articles are removed for other reasons, and the remaining 128 articles are preliminarily selected. By reading the abstracts and titles, 54 articles are excluded and 74 remained. 30 research reports and review articles are excluded, leaving 44. All remaining articles are read fully, excluding 18 articles with incorrect study types. 15 articles are excluded due to incomplete or unobtainable treatment results required. 3 articles are not human subjects, and 8 articles are finally included in the meta-analysis. Figure1 is the flow chart of literature search. It is clearly evident from Figure 1 that it shows a flow diagram of the retrieving literature.Figure 1
Flow chart of literature search.The basic information of the literature is extracted by reading the contents of the literature. In 8 included literature [19–21], a comparison of the two treatment methods is used, in which 831 patients are included in LLND + ME for low rectal cancer and 971 patients are included in non-LLND for low rectal cancer. In addition, among the 8 included literature, the sample size varies from 41 to 701. Eight articles describe the process of treating low rectal cancer by LLND + ME in detail, and record the changes of various indicators of patients before and after treatment, as well as the complications and morbidity caused by LLND + ME in the treatment of low rectal cancer. The quality evaluation is performed on the 8 included literature, and the results show that 6 literature (75%) have grade A, 1 literature (12.5%) has grade B, and 1 literature (12.5%) has grade C. Table 1 shows the basic information of included literature. It is clearly evident from Table 1 that the basic characteristics of the included articles are enough.Table 1
Basic information of included literature.
AuthorYearTreatment methodCaseAkiyoshi [11]2014LLND + ME38Fujita [12]2017LLND + ME351Georgiou [13]2017LLND + ME17Lee [14]2019LLND + ME37Matsuda [15]2018LLND + ME32Ogura [16]2017LLND + ME107Oki [17]2019LLND + ME215Yang [18]2020LLND + ME34Figure2 shows risk bias evaluation plot for references generated by Rev Man 5.3 software. It is clearly evident from Figure 2 that the random sequence generation is in low risk of bias.Figure 2
Risk bias evaluation plot for references generated by Rev Man 5.3 software.Figure3 shows the summary chart of reference risk bias. It is clearly evident from Figure 3 that “+” indicates low risk, “−” indicates high risk, and “ ” indicates unclear.Figure 3
Summary chart of reference risk bias.


## 4.2. Heterogeneity Evaluation Results

The heterogeneity of survival rate is evaluated in the included literature. The results show that the heterogeneity of low rectal cancer among the studies is low (I2 = 24.20%). The heterogeneity of treatment complications in the included literature is evaluated. The results show that there is no heterogeneity among the studies (I2 = 8.46%). The heterogeneity of lymphatic metastasis in the included literature is evaluated, and the results show that there is heterogeneity among the studies (I2 = 52.06%). In order to further verify whether there is heterogeneity between the data of the two examination methods, and to compare the differences in the indicators of different treatment methods, a random-effect model is required for pooled analysis.


## 4.3. Meta-analysis of Disease-free Survival

For 8 articles on LLND + ME combination therapy versus non-LLND for low rectal cancer, the impact of treatment on disease-free survival is analyzed. Figure4 shows the forest plot for disease-free survival. It is clearly evident from Figure 4 that taking the OR as the outcome measure, the disease-free survival analysis of 8 LLND + ME combination therapy and non-LLND therapy obtains degree of freedom (df) = 8.64, I2 = 24.20%, P = 0.28, and the OR for patient survival is calculated using a fixed-effect model due to low heterogeneity among the study groups. Meta-analysis reveals that patients treated with LLND + ME have better survival than those treated with non-LLND, with an OR of 0.26 and a 95% confidence interval (CI) of (−0.05, 0.57).Figure 4
Forest plot for disease-free survival.Figure5 shows the Galbraith heterogeneity test plot for disease-free survival. It is clearly evident from Figure 5 that the heterogeneity test is performed for the data on the effect of disease-free survival.Figure 5
Galbraith heterogeneity test plot for disease-free survival.Figure6 shows the Labbe heterogeneity test plot for disease-free survival. It is clearly evident from Figure 6 that the data are tenable and have reference similarity among each study.Figure 6
Labbe heterogeneity test plot for disease-free survival.Figure7 shows the assessment plot of bias risk for disease-free survival. It is clearly evident from Figure 7 that the included literature has good stability.Figure 7
Assessment plot of bias risk for disease-free survival.


## 4.4. Meta-analysis of Total Complications

For 8 articles on LLND + ME combination therapy versus non-LLND for low rectal cancer, the impact of treatment on overall complications is analyzed. Figure8 shows the forest plot of total complications. It is clearly evident from Figure 8 that taking OR as the outcome measure, the analysis of total complications in 8 LLND + ME combined treatment versus non-LLND treatment obtains df = 6.68, I2 = 8.46%, P = 0.46. Meta-analysis finds that patients treated with LLND + ME have fewer complications than those treated with non-LLND, with an OR of -0.24 and a 95% CI of (−0.56, 0.07), suggesting that LLND + ME is more effective than common treatment and can reduce complications.Figure 8
Forest plot of total complications.Figure9 shows the Galbraith heterogeneity test plot for total complications. It is clearly evident from Figure 9 that the heterogeneity results of each study are very concentrated.Figure 9
Galbraith heterogeneity test plot for total complications.Figure10 shows the Labbe heterogeneity test plot for total complications. It is clearly evident from Figure 10 that the data among each study are valid and had reference similarity.Figure 10
Labbe heterogeneity test plot for total complications.Figure11 shows the risk of bias assessment plot for total complications. It is clearly evident from Figure 11 that the results of the applied analysis model have no significant change, indicating that the included literature have good stability.Figure 11
Risk of bias assessment plot for total complications.


## 4.5. Meta-analysis of Lymph Node Metastasis

For 8 articles on LLND + ME combination therapy versus non-LLND for low rectal cancer, the effect of treatment on lymph node metastasis in patients is analyzed. Figure12 shows the risk of bias assessment plot for total complications. It is clearly evident from Figure 12 that using OR as an outcome measure, analysis of lymph node metastasis in 8 LLND + ME combined treatment versus non-LLND treatment obtains df = 14.67, I2 = 52.06%, and P = 0.04, with heterogeneity among studies. Meta-analysis finds that lymph node metastasis is less in patients treated with LLND + ME than in patients treated with non-LLND, with an OR of -0.59 and 95% CI of (−1.03, −0.14), suggesting that LLND + ME combined treatment is more effective than common treatment and can reduce lymph node metastasis.Figure 12
Forest plot for lymph node metastasis.Figure13 shows the Galbraith heterogeneity test plot for lymph node metastasis. It is clearly evident from Figure 13 that the heterogeneity results of each study are very concentrated.Figure 13
Galbraith heterogeneity test plot for lymph node metastasis.Figure14 shows the Labbe heterogeneity test plot for lymph node metastases. It is clearly evident from Figure 14 that the data are tenable and have reference similarity among each study.Figure 14
Labbe heterogeneity test plot for lymph node metastases.Figure15 shows the risk of bias assessment for lymph node metastasis. It is clearly evident from Figure 15 that the results of the applied analysis model show no significant change, indicating that the included literature has good stability.Figure 15
Risk of bias assessment for lymph node metastasis.


## 5. Conclusion

The relevant literature of radical resection of rectal cancer combined with LLND is screened and included in the meta-analysis in order to investigate the efficacy of LLND + ME and non-LLND. Meta-analysis confirms that LLND + ME treatment is effective. Of course, certain defects are inevitable, the categories of stents in the clinical trials included in the study are not uniform, and there is no complete uniform standard for AE rating indicators. Because there are few randomized controlled trials and the outcome indicators are different, they are not included in this meta-analysis, and the level of evidence has been reduced. The subsequent study will collect more indicators, compare the differences between different treatment methods in detail, and provide more accurate reference for clinical treatment.



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