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Table of Contents
REVIEW ARTICLE
Year : 2020  |  Volume : 3  |  Issue : 2  |  Page : 41-51

Role of lateral pelvic lymph node dissection in rectal cancer: A systematic review and meta-analysis


1 General Surgical Trainee, Liverpool University Hospitals, Liverpool, Glasgow, Scotland, United Kingdom
2 Queen Elizabeth University Hospital, Glasgow, Scotland, United Kingdom
3 Maidstone and Tunbridge Wells Hospital, United Kingdom
4 James Cook University Hospital, United Kingdom
5 North Tees and Hartlepool NHS Foundation Trust, United Kingdom

Date of Submission14-Sep-2020
Date of Decision02-Dec-2020
Date of Acceptance06-Dec-2020
Date of Web Publication28-Apr-2021

Correspondence Address:
Dr. Ashwin Rajendiran
General Surgical Trainee, Liverpool University Hospitals, Liverpool
United Kingdom
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijcs.ijcs_30_20

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  Abstract 

Introduction: Total Mesorectal excision (TME) is globally accepted as the standard treatment for rectal cancer. Lateral lymph node dissection (LLND) is still an oncological debate among colorectal surgeons and practiced routinely in some centers of the Eastern world (Japan and Korea) based on limited evidence. Aims: This review aims to determine the oncological and survival benefit of adding LLND to standard TME and also the additional morbidity associated. Outcomes Measured: The primary outcomes are local recurrence, 5-year overall survival and disease-free survival. The secondary outcomes are the incidence of urinary and sexual dysfunction. Materials and Methods: A systematic review protocol was followed. A structured search was run across MEDLINE, OVID, and COCHRANE databases. Five articles from three randomized trials were included. Meta-analysis was performed using Revman 5.3™. Results: No difference was noted between TME and TME + LLND for local recurrence (odds ratio [OR] 0.77, 0.44, 1.35), disease-free survival (OR 1.04, 0.81, 1.34), and overall survival (OR 1.05, 0.79, 1.41). The degree of heterogeneity was within acceptable limits. The OR for urinary dysfunction (OR 2.02, 0.45, 9.11) and male sexual dysfunction (OR 3.96, 0.54, 28.82) had wide confidence intervals and significant heterogeneity; the overall effect was not statistically significant. Conclusion: Our study included only randomized controlled trials and noted no difference in the oncological or survival outcomes. Previous reviews have included nonrandomized studies in a desperate attempt to produce evidence for or against LLND. A carefully arranged International controlled trial is necessary to settle this East-West controversy.

Keywords: Extended total mesorectal excision, lateral lymph node dissection, rectal cancer


How to cite this article:
Rajendiran A, Shenoy S, Shalaby A, Viswanath Y K, Shanmugam V. Role of lateral pelvic lymph node dissection in rectal cancer: A systematic review and meta-analysis. Indian J Colo-Rectal Surg 2020;3:41-51

How to cite this URL:
Rajendiran A, Shenoy S, Shalaby A, Viswanath Y K, Shanmugam V. Role of lateral pelvic lymph node dissection in rectal cancer: A systematic review and meta-analysis. Indian J Colo-Rectal Surg [serial online] 2020 [cited 2021 Jul 28];3:41-51. Available from: https://www.ijcrsonweb.org/text.asp?2020/3/2/41/314976


  Introduction Top


The lateral pelvic lymph nodes refer to the lymph nodes along the middle and inferior rectal artery that drain into the obturator, internal iliac and external iliac nodes [Figure 1]. According to the tumor, node, and metastasis staging for rectal cancer, the involvement of internal iliac nodes is considered as regional disease, whereas that of external and common iliac nodes is treated as metastatic disease.[1] In contrast, the Japanese classification considers all of the lateral lymph node (LLN) groups as regional nodes.[2] The advancement in imaging and better interpretation of anatomy has led to the idea of dissecting these lymph glands, especially in the Eastern surgical world where they have been traditionally performing radical procedures for cancers including gastric and oesophageal cancers. This view has been supported by the incidence of local recurrence at the LLN basin.[3] Selected centers in Japan, China, and South Korea perform routine synchronous dissection of LLND along with total mesorectal excision (TME) for rectal cancer. However, there is a lack of proper evidence in the western publications on this topic as these lymph nodes are considered as metastatic disease.
Figure 1: Lymphatic supply of the rectum

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Standard TME involves dissection of the rectum and the sleeve of perirectal fat with an intact perirectal fascial envelope. For upper rectal tumors, the perirectal fat is transected at least 5 cm below the lower margin, based on Prof. Heald's theory of tumor spread distally along the mesorectum.[4] Interestingly, this standard technique of Mesorectal Excision performed in the western world is described as “limited resection” in Japanese literature.[5]

Synchronous LLN disease among locally advanced rectal tumors is reported in 10%–25%.[6] According to the Japanese Society for Cancer of the Colon and Rectum (JSCCR) data, the incidence of LLN involvement in lower rectal cancers is 16%–23%.[3] Though it appears that the incidence of LLN involvement would vary between the East and the West, El-Khoury et al., in their systematic review, have concluded that it might be the same.[7]

According to the JSCCR cancer registry, patients who had LLND had a better 5-year overall survival than those without LLND (68.9% vs. 62.0%).[3] The 2016 Japanese guideline-recommended lateral node dissection for all tumors situated below the peritoneal reflection and invading beyond the muscularis propria.[8] However, the recent 2019 update mentions this as a level B recommendation based on recent studies that showed no survival benefit in LLND.[3],[9],[10]

The surgeons from the Eastern world support their argument for LLND based on limited available evidence. The Western world is yet to get convinced on this radical approach, especially when more nonsurgical, oncological treatment options are available. Past evidence has shown that more radical surgery has not reflected on overall survival benefit and came with additional morbidity, radical breast surgery, for example.[11] With this controversy in mind, we intended to explore the available evidence to get a high-quality recommendation for and against adding LLND to TME. We analyzed oncological outcomes such as local recurrence, overall survival, and disease-free survival in addition to the morbidity associated with rectal cancer surgery.


  Materials and Methods Top


A systematic review and meta-analysis were performed following the Cochrane Handbook for Systematic Reviews.[12] A systematic search protocol was constructed using the MeSH keywords “lateral lymph node dissection,” “TME,” “local recurrence,” “survival” and their possible variations. The PICO format used can be found in [Appendix 1]. The search was run in three databases, OVID, MEDLINE, and COCHRANE. The latest search was done in May 2020. The bibliographies of the retrieved articles were analyzed for any relevant literature. The Controlled Clinical Trials registry was also searched for any information regarding ongoing trials.



The inclusion criteria were clearly defined and agreed by all the authors. The studies included for the review were (1). Randomized trials comparing TME and TME + LLND (2) Studies that report at least one of the primary and secondary outcomes. In terms of the study design, only randomized trials were included. Nonrandomized trials and retrospective studies were excluded to avoid bias. Studies published in all languages were scrutinized provided the abstract was available in English, and full articles were reviewed using online translator for its relevance to the study.

Preoperative chemotherapy or radiotherapy was not taken as an exclusion criterion in this review. However, sensitivity analysis was done with and without these interventions.

The PRISMA flowchart for the study selection is presented in [Figure 2]. The retrieved articles were assessed for eligibility by AR and SS independently. If the title and abstract were found to be relevant, full articles were obtained to assess the methodological quality, and a decision regarding the inclusion of the article is made. For studies reported across several papers, the largest or the most updated cohort was taken for analysis. Discrepancies in the selection process were resolved by consulting a third author (VS). The reasons for the rejection of the articles by the authors were recorded.
Figure 2: PRISMA 2009 flow diagram

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The studies were analyzed for their validity by AR and SS using the critical appraisal skills program (CASP) questionnaire and COCHRANE Risk of Bias Assessment Tool. The assessment was made by the reviewers individually, and a consensus was reached by discussion. One study was agreed by the authors to be of poor quality.[13] Since the number of trials included in the systemic review was low, this study was included. However, sensitivity analysis was performed with and without this study.

The primary objective of this meta-analysis was to determine whether the addition of LLND to TME for rectal cancer surgery, as compared to TME alone, carries any oncological benefit in terms of local recurrence and survival. The primary outcomes of this review were: (1) local recurrence, (2) 5-year overall survival, (3) disease-free survival. The secondary objective was to ascertain whether additional pelvic lymph node dissection adds the risk of morbidity like urinary and sexual dysfunction.

Data extraction and analysis

Data extraction was done by AR and SS individually and matched for any discrepancy. The following data were extracted: author's name, year of publication, characteristics of the study population, study design, inclusion and exclusion criteria, the number of recruited patients in each group and outcomes. Overall survival at 5 years, disease-free survival, and incidence of local recurrence, urinary dysfunction, and sexual dysfunction were recorded.

The odds ratio (OR) was used as the summary statistic to measure the outcome. OR denoted the odds of an event occurring in the TME + LLND group compared with the TME group. Mantel-Haentzel method was used to combine the OR. All the included studies reported their data as dichotomous variables. OR of <1 favored TME + LLND group. The estimate of OR was considered to be statistically significant when P < 0.05 and the 95% confidence interval did not cross the midline, i.e., did not include the value 1.

Random effects model was used when there was significant heterogeneity among the included studies with I2 of >50%. Begg's Funnel plot was used to determine publication bias. Sensitivity analysis was performed, excluding the low-quality study.[13] Meta-analysis was performed using Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.™ for Macintosh™.


  Results Top


From the structured search, 38 articles relevant to the topic were obtained after the removal of the duplicates [Figure 2]. Of these, 29 were excluded based on the relevance of the abstract. Out of the 9 articles that went on to the 2nd stage of selection, four articles were excluded. One was an interim report of the trial whose primary analysis was already included.[14] Four meta-analyses that included predominantly nonrandomized studies were excluded from the review.[15],[16],[17],[18] One article mentioned “meta-analysis” in the title but was a retrospective study and was excluded.[19] Three non-English articles were non-randomized studies and were excluded.[20],[21],[22] Five articles were included for the systematic review. These articles contained data from three trials [Table 1]. The primary and secondary outcomes (urinary and male sexual dysfunction) from the JCOG 2012 trial were split into three publications.[9],[23],[24] Two studies were randomized trials comparing TME and TME + LLND.[9],[13] One study was an ad-hoc analysis of a randomized controlled trial (RCT) primarily aimed to compare two chemotherapeutic agents for adjuvant treatment of rectal cancer.[10]
Table 1: Articles included after second stage of selection

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Local recurrence

Three studies reported the incidence of local recurrence. A total of 1191 patients were included in the analysis. The pooled result showed no significant difference in the incidence of local recurrence between the two groups. The OR was 0.77 (0.44, 1.35). However, the confidence intervals were wide and the P value of the overall effect was not statistically significant (P = 0.36). I2 was 45%, which shows a moderate degree of heterogeneity between the two studies [Figure 3]. Begg's Funnel plot was symmetric, showing no bias between the studies [Figure 4].
Figure 3: Forrest plot for local recurrence

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Figure 4: Begg's funnel plot for local recurrence showing that publication bias is within limits

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Five-year overall survival

A total of 1191 subjects from the three studies were included. There was no survival benefit noted in the TME + LLND group. The combined OR was 1.05 (0.79, 1.41) and the P value of the overall effect was 0.72 (not significant). There was no significant heterogeneity between the studies (I2 = 17%) [Figure 5]. The funnel plot was symmetric showing no bias between the studies [Figure 6].
Figure 5: Forrest plot for 5-year overall survival

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Figure 6: Begg's funnel plot for overall survival showing that publication bias is within acceptable limits

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Five-year relapse-free survival

No survival benefit was demonstrated for the TME + LLND group. The pooled data from three studies[9],[10],[13] showed a combined OR of 1.04 (0.87, 1.25). The P value of the overall effect was 0.65 (not significant). The I2 statistic was 0% [Figure 7]. The funnel plot was symmetrical showing no bias.
Figure 7: Forrest plot for 5-year disease free survival

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Sensitivity analysis

Out of the three studies included for the meta-analysis, one was found to be of inadequate quality[13] using the CASP questionnaire and Cochrane's ROB tool assessment. To determine its influence on the overall effect, a sensitivity analysis was performed, excluding this study.

There was no change in the incidence of local recurrence after excluding this article. The P value for overall effect was 0.22 versus 0.36 when the article was included [Figure 8]. Similarly, no change in the effect was observed for overall survival [Figure 9]. Thus, excluding the low-quality study still did not have any influence on the overall outcome.
Figure 8: Forrest plot for local recurrence without Nagawa, 2001

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Figure 9: Forrest plot for overall survival without Nagawa, 2001

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Urinary dysfunction

A total of 746 patients were analyzed. Oki et al., 2018 have not reported their morbidity data. A random-effects model was performed due to significant heterogeneity (I2 = 82%) among the included studies. No significant difference was noted between the two groups in terms of incidence of urinary dysfunction. Mantel-Haenszel method was used to combine the OR. The combined OR was 2.02 (0.45, 9.11) with very wide confidence intervals. A P value of the overall effect was 0.36, which was not statistically significant [Figure 10].
Figure 10: Forrest plot for urinary dysfunction

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Male sexual dysfunction

Two studies have reported the incidence of male sexual dysfunction after surgery. The International Index of Erectile Function-5 defines male sexual dysfunction as the ratio of patients with symptoms relative to the number of patients who had no erectile dysfunction before the surgery.[25] This was the tool used by Saito et al. The study included only the male patients with normal sexual function before the surgery; the final number of patients analyzed was limited to a small subset of the main study population. The proportion of male patients without sexual dysfunction in the JCOG trial that recruited a total of 701 patients was only 14% and 12% in the TME + LLND and TME groups, respectively.[24]

Data from 78 patients were analyzed. The I2 test was 58% showing significant heterogeneity between the studies. Hence, a random-effects model was carried out. The combined OR was 3.96 (0.54, 28.82) again with significantly wider confidence intervals. The overall effect was not significant (P = 0.17) [Figure 11].
Figure 11: Forrest plot for male sexual dysfunction

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  Discussion Top


The systematic review was carried out to determine the oncological benefit of performing LLN dissection (LLND) along with TME for local recurrence and survival. Secondary outcomes included the incidence of urinary dysfunction and male sexual dysfunction.

The review analyzed three randomized trials reported from 2001 to 2018. Only randomized trials were included and this is one of the main strengths of our study. The review results showed no survival benefit in the TME + LLND group for overall survival and disease-free survival. The rates of local recurrence were also similar between the two groups. The difference in the rate of urinary and male sexual dysfunction did not reach any statistical significance. This is contrary to the results of the meta-analysis done in 2009, which favored TME in terms of the urinary dysfunction and male sexual dysfunction.[16] Similar results were also noted in the meta-analyses done in 2020.[17],[18] Notably, all the previous meta-analyses included predominantly retrospective and non-randomized trials.[15],[16],[17],[18] Our study compared to previous systematic reviews clearly demonstrated the benefit of performing meta-analysis of randomized controlled trials alone. This also showed that increasing the number of patients outside the RCTs did not make any difference to the outcome of the combined analysis methodology.

The reviewers also noted significant factors in the individual studies that can lead to bias. Fujita, 2017 could not conclude the noninferiority of TME alone over TME + LLND. However, the superiority of TME + LLND is not established as this is a noninferiority trial for TME.[9] This study mentions that the randomization is done intraoperatively, and metastatic tumors were excluded from the study. However, in the subsequent sections, it is noted that these ineligible patients were excluded after randomisation.[26] This would affect the internal validity of the trial as these patients should not have been included in the study. The intention to treat policy was not adhered to.

The ad hoc analysis described by Oki, 2016, is from a randomized trial comparing two chemotherapy agents for adjuvant treatment in rectal cancer. There was no randomization involved in terms of the type of surgery the patients received. It was noted that patients who received TME + LLND were significantly younger. Also, all of the patients received one of the two chemotherapeutic agents as adjuvant therapy. The trial failed to conclude any difference in outcome between the two groups.[10] In this trial, adjuvant therapy, a co-intervention is a significant confounding factor causing bias. This also affects the external validity as routine adjuvant chemotherapy for Stage II rectal cancer is not practised in Western countries.[27] Sensitivity analysis excluding this article showed no change in the outcome.

The RCT described by Nagawa et al., 2001 is of inadequate methodical quality and this has been agreed by all the authors. There was no mention of the type of randomization used in the trial. There was no mention of the power calculation in the study, and in our view, the sample size (n = 45) was inadequate for a randomized trial to have a meaningful conclusion and eliminate randomization bias. Nonparametric tests were used to calculate effect size and this questions the precision of the treatment effect. The researchers used endo-anal USS (Ultrasound) to assess the lymph node involvement preoperatively. However, the standard practice is magnetic resonance imaging (MRI) rectum for local staging. All of the patients received neoadjuvant radiotherapy and adjuvant chemotherapy.

Thus with the different types of neo-adjuvant and adjuvant treatment used, the study population of these three studies are significantly different from one another and it is hard to derive conclusions from the meta-analysis of the outcomes. The meta-analysis by Yang et al. comparing nCRT (Neo adjuvant Chemo Radiotherapy) + TME and nCRT + TME + LLND looked at eight studies representing 1896 patients. They concluded that nCRT + TME + LLND had a longer operating time and increased rate of urinary dysfunction. No difference was noted in other outcomes.[28]

Also, it is interesting to note that the Japanese have a slightly different way of processing the TME specimen. The lymph nodes in the mesorectum are dissected and examined in the fresh specimen before they were fixed. This potentially disrupts the CRM, and thus, pathological CRM involvement cannot be ascertained. Only the area of the mesorectum macroscopically involved by the tumor was examined by the pathologists.[9] Thus, the comments about the quality of the mesorectum are significantly prone to bias.

The pattern of local recurrence following rectal cancer surgery was found to be different in different geographical groups. Kusters et al. from the Netherlands focussed on the local recurrence following three different modes of treatment in the Western and Eastern population. They included TME, TME + RT (Dutch data) and TME + LLND (Japan data).[Table 2] illustrates their main outcome data. This data are obviously open for discussion considering the method used for the data analysis. However, there seems to be no need for additional LLND in order to avoid local recurrence. The radiotherapy arm had the least of the recurrences among the three groups.[29]
Table 2: Summary of findings of Kusters et al

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The central pelvis was the common site of local recurrence in the Dutch group, whereas in the JCOG 2012 trial based in Japan, the most common site of recurrence was the lateral pelvis.[29] Fujita et al., 2017, have shown that 30%–40% of the patients who received preoperative chemo-radiotherapy and proceeded for extended lymph node dissection showed pathological LLN metastasis.[9] The incidence of lateral recurrence in the Dutch TME group was 24% of all the local recurrence.[9] However, the lateral recurrence rate from a Swedish study was reported to be 6%.[30] This mandates further research into the variation of local recurrence in different regions of the world. This also raises the question of whether there is any variation in tumor behavior between the eastern and western parts of the world or this is to do with the way they are recorded.

Several authors have reported selective LLND based on preoperative criteria, which included lymph node size. The size cut-off has varied from 6 mm to 10 mm between authors.[31],[32],[33] Apart from size, MRI characteristics and response to chemoradiotherapy have also been used as indications for selective LLND.[34],[35] Selective LLND and the standard criteria to define lateral nodal involvement is still an area of debate.

With few systematic reviews (including the current publications) and randomized controlled trials conducted, to date, there is no significant advantage in prophylactic LLND in terms of survival and recurrence. However, performing LLND is associated with prolonged operating time and increased blood loss. The real burden of LLN metastasis also needs to be assessed globally as there are significant discrepancy in reporting the LLN positivity between East and West.

This study also has its limitations. The main drawback is the number of included trials. Performing trials comparing the two procedures is also difficult as LLND is not routinely performed in Western countries. Second, most of the evidence available regarding LLND at present are from countries such as Japan, South Korea, and China. Those surgeons are known for their radical surgical approach for cancer management. Our study raises the question of the benefit for radical surgery in rectal cancer management, given that we are moving more toward local excision with adjuvant treatment for organ preservation.[36] The results from the meta-analysis might not be completely relatable to the Western population. The included studies have not reported the incidence of female sexual dysfunction. Ideally, it would have been more relevant to analyze both male and female sexual dysfunction after LLND.


  Conclusion Top


With the available up-to-date search evidence, there was no significant difference observed between the TME and TME + LLND groups for local recurrence and survival. The claimed additional morbidity of urinary and sexual dysfunction in the TME + LLND group was not statistically significant. Thus, TME + LLND is considered equally safe as TME alone in terms of the complication rate, but it does not confer any additional oncological benefit except prolonged operating time and increased blood loss. The real oncological benefit of additional LLND to the worldwide accepted standard TME practice must be debated in the context of the modern adjuvant/neoadjuvant treatment options and also the gaining popularity of organ-preserving approach. The actual burden of LLN involvement also varies geographically, and the risks versus benefits need to be carefully considered. A properly conducted multinational trial is the need of the hour before changing the current practice.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]
 
 
    Tables

  [Table 1], [Table 2]



 

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