The efficacy and safety of lateral lymph node dissection for patients with rectal cancer: A systematic review and meta-analysis

Asian Journal of Surgery xxx (xxxx) xxx

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Review Article

The efficacy and safety of lateral lymph node dissection for patients with rectal cancer: A systematic review and meta-analysis Peilan Ma a, 1, Yuan Yuan b, 1, Peijing Yan c, 1, Guohua Chen d, Shixun Ma a, Xiangdong Niu a, Meng Xu a, Kehu Yang c, e, f, g, **, Hui Cai a, * a

General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, Gansu, 730000, China Department of Critical Care Medicine, Gansu Provincial Hospital, Lanzhou, Gansu, 730000, China Institute of Clinical Research and Evidence Based Medicine, Gansu Provincial Hospital, Lanzhou, Gansu, 730000, China d Clinical Medical College, China Medical University, Shenyang, Liaoning, 110000, China e Evidence Based Social Science Research Center, Lanzhou University, Lanzhou, Gansu, 730000, China f Key Laboratory of Evidence Based Medicine and Knowledge Translation of Gansu Province, Lanzhou, Gansu, 730000, China g Evidence Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, 730000, China b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 23 September 2019 Accepted 8 November 2019 Available online xxx

Lateral lymph node metastasis in rectal cancer was first reported in the 1950s, since then, there has been an on-going debate about the value of lateral lymph node dissection (LLND) in the management of rectal cancer. We carried out a systematic review and meta-analysis to evaluate the value of LLND for the patients with rectal cancer. To collect clinical studies for the comparison of LLND and non-LLND in patients with rectal cancer, PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar databases were searched from inception to 2019.A total of 26 studies, including 6865 patients were enrolled. Data processing and statistical analyses were performed using Stata V.15.0 software and Review Manager 5.3 software. Outcome measures included the 5-year survival rate, recurrence rate, perioperative outcomes, urinary function, and male sexual function. Regarding efficacy, our meta-analysis results showed no difference in 5-year disease-free survival rate and local recurrences between the two groups, the Hazard Ratio (HR) and 95% confidence interval (CI) was1.07 and 0.89 to 1.28 (P ¼ 0.496),and the Odds Ratio(OR) and 95% CI were 0.90 and 0.76 to 1.06 (P ¼ 0.208), respectively. Concerning safety, the incidence of urinary dysfunction and male sexual dysfunction was significantly increased in the LLND group (OR ¼ 2.14, 95%CI ¼ 1.21e3.79, P ¼ 0.009), and (OR ¼ 4.19, 95%CI ¼ 1.55e11.33, P ¼ 0.005), respectively. In conclusion, LLND did not improve the long-term prognosis of patients with rectal cancer, and was associated with increased urinary dysfunction and male sexual dysfunction. © 2020 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Keywords: Lateral lymph node dissection Meta-analysis Rectal cancer

1. Introduction In surgical treatment of rectal cancer, total mesorectal excision (TME) has become the international standard procedure.1 TME has reportedly been shown to reduce the overall local recurrence rate

* Corresponding author. 204 Donggang West Road, Lanzhou, Gansu, 730000, China. ** Corresponding author. 199 Donggang West Road, Lanzhou, Gansu, 730000, China. E-mail addresses: [email protected] (K. Yang), caialonteam@163. com (H. Cai). 1 Peilan Ma, Yuan Yuan and Peijing Yan were co-first authors.

to less than 10%.2 However, approximately 10%e25% of patients who underwent TME developed lateral lymph node metastases (including the total iliac lymph nodes, internal iliac lymph nodes and obturator lymph nodes), which were not excised in conventional TME,3e5 and were largely responsible for locoregional recurrence and poor prognosis. Based on the findings mentioned above, Japanese surgeons adopted the technique of lateral lymph node dissection (LLND) as a supplement to traditional rectal surgery, thereby aiming to reduce locoregional recurrence rates and improve cancer-specific survival.6e8 In several Japanese hospitals, TME combined with LLND was recommended as a standard treatment for advanced low rectal cancer by the guidelines of the Japanese Society for Cancer of the Colon and Rectum.9 In contrast,

https://doi.org/10.1016/j.asjsur.2019.11.006 1015-9584/© 2020 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article as: Ma P et al., The efficacy and safety of lateral lymph node dissection for patients with rectal cancer: A systematic review and meta-analysis, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.11.006

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lateral lymph node metastasis was considered a systemic metastatic disease in Western countries. Therefore, it was concluded that there was no general reason to recommend LLND, because of the increase of intraoperative vice injury (injury of blood vessels and nerves) leading to prolonged surgical duration and an increase in blood loss, and even in a series of complications, did not improve the prognosis of patients.8,10 Currently, many clinical control studies11e14 have focused on the relationship between LLND and long-term prognosis of rectal cancer patients. However, due to the small sample size, single center studies and other reasons, different research conclusions were drawn. Meta-analysis was considered a vital tool with good quality evidence.15,16 In a previous meta-analysis,17 it was indicated that LLND did not confer a significant overall oncological advantage, but was associated with poor quality on account of increased urinary and sexual dysfunction. Because only one Randomized Controlled Trial (RCT) was included and the sample size was small, the authors concluded that the value of LLND should be further investigated in the context of RCTs. In addition, the authors suggested that LLND should be compared with preoperative radiotherapy, which has been demonstrated to reduce the yearly risk of local recurrence of rectal cancer by 46% without any significant improvement in overall survival. In recent years, controversy still exists about the value of LLND in the treatment of primary rectal cancer,18e20 and novel original studies on the efficacy and safety of LLND continue to emerge. The Japanese Clinical Oncology Group (JCOG) conducted a phase 3 clinical RCT to compare mesorectal excision (ME) with and without LLND. To provide a more comprehensive conclusion, an evidencebased approach was adopted, and meta-analysis conducted to compare LLND and non-LLND in patients who underwent surgery for the treatment of rectal cancer. Meta-analytical methods were used to assess the efficacy and safety of LLND in patients with rectal cancer. 2. Methods This meta-analysis was designed, conducted, and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement.21,22 In addition, a MeaSurement Tool to Assess Systematic Reviews (AMSTAR 2) was used to assess the methodological quality of this review.23,24 2.1. Search strategy In this study, we electronically searched multiple foreign language databases including PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar for all studies in which LLND was compared with traditional rectal cancer surgery in patients with rectal cancer from inception to July 20, 2019.The following MeSH and main keywords were used: “neoplasm, rectal ”, “rectal tumor”,“rectal cancer”, “lateral lymph node dissection”, “selective lateral lymph node dissection”, “transverse lymph node dissection”, “lateral pelvic lymph node dissection”, “extended lymphadenectomy ”, and “lateral pelvic wall lymph-node dissection”. Based on these MeSH and main keywords, the search was completed, and provided the search strategy (for PubMed) as presented in the supplementary appendix (Item1).

(4) Aggregate information can be shown by relevant statistical criteria such as Hazard Ratio (HR), Odds Ratio (OR), Weighted Mean Difference (WMD). Exclusion criteria were as follows: (1) Document types including reviews, meta-analyses, letters, case reports or conference abstracts, (2) Duplicate or repeat documents (republished article), (3) There were no initial data, (4) The number of research samples were too small (less than 20 cases), (5) Non-human studies. 2.3. Data extraction and quality assessment Two reviewers (PLM and GHC) used a standardized data extraction form to extract the following information from each eligible study: baseline characteristics, contained name of the first author, publication date, country, study type, number of patients enrolled in each group, age, sex, tumor site and staging, neoadjuvant chemoradiotherapy; major outcomes, mention of survival (5-year survival, 5-year disease-free survival); recurrence (total recurreces, local recurrences, distant recurrences); perioperative outcomes (surgical duration, blood loss); adverse events (perioperative complications, perioperative mortality, urinary dysfunction, and male sexual dysfunction). To assess the quality of the included studies, the Cochrane Risk of Bias Tool for RCTs and the NewcastleeOttawa Scale (NOS) criterion for cohort studies were used. Any discrepancy between the two reviewers was resolved by discussion and mutual agreement. If necessary, a third researcher (PJY) was involved. 2.4. Statistical analysis The WMD with a 95% CI was employed to analyze continuous variables, including duration of surgery, blood loss. Simultaneously, dichotomous variables, such as recurrence and adverse events outcomes were evaluated by the OR and 95% CI. In addition, the HR was used as a summary statistical measure for survival outcome (5year survival and 5-year disease-free survival).The statistical index I2 was used to evaluate the heterogeneity among studies. I2>50% indicated a significant heterogeneity among studies, and the random-effect model was used. In other cases, the fixed effects model was used. All statistical values were calculated by 95% CI, and the p-value threshold was set at 0.05, which indicated statistical significance. All data processing and statistical analyses were performed using Review Manager 5.3 software (Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and Stata version 15.0 software (Stata Corporation, College Station, TX, USA). We performed subgroup analysis and sensitivity analysis on outcome indicators with high heterogeneity, and publication bias was tested using the Begg's test and Egger's test. Role of the funding source The funders of the study did not play a role in study design, data collection, data analysis, data interpretation, or writing of the manuscript. The corresponding author had full access to all the data presented in the study and had final responsibility for the decision to submit the manuscript for publication. 3. Results

2.2. Inclusion and exclusion criteria 3.1. Studies retrieved and characteristics Inclusion criteria were as follows:(1) Original data were available in the literature, (2) The original literature included a comparison between LLND with non-LLND for rectal cancer, (3) The objects, design, and statistical methods of the studies were similar,

The electronic retrieval initially identified 1433 studies. A total of 587 duplicate articles were excluded and 808 unrelated articles were excluded after reading the titles and abstracts. Subsequently,

Please cite this article as: Ma P et al., The efficacy and safety of lateral lymph node dissection for patients with rectal cancer: A systematic review and meta-analysis, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.11.006

Kim11 Nagawa27 Yano25 Fujita28 Kusters26 Saito29 Georgiou12 Fujita30 Ito31 Enker32 Michelassi33 Hojo10 Michelassi34 Moreira35 Suzuki36 Shirouzu37 Watanabe38 Fujita18 Maeda39 Col40 Matsuoka41 Hasdemir13 Kyo42 Kobayashi14 Matsuda43 Park44

mean±sd=mean LLND non  LLND

Year

Type

PatientsðnÞ LLND non  LLND

Age(year) -

2007 2001 2007 2012 2009 2016 2017 2017 2018 1986 1988 1989 1992 1994 1995 2001 2002 2003 2003 2005 2005 2005 2006 2009 2018 2018

Prospective RCT Prospective RCT Prospective RCT Prospective RCT RCT Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective

176 23 39 351 324 171 17 351 351 192 64 192 17 95 60 303 75 204 65 24 15 24 15 784 32 80

59 ± 10 59.1 ± 10.1 NR 61(54e67) 58(11) 61(55e66) 57(40e71) 61(26e75) 61(26e75) NR NR NR 67(46e80) 58(35e64) 61(27e86) NR NR 57(10) 56(28e76) 52.2 ± 13.5 63(37e77) 52.2 ± 13.5 NR NR 64(39e76) 57.8 ± 11.9

First author

309 22 70 350 755 172 24 350 350 220 73 245 10 83 132 155 40 42 12 146 42 160 22 488 13 281

55 ± 10 60.1 ± 8.8 NR 62(55e68) 64(11) 62(56e69) 66(39e81) 62(26-75 62(26e75) NR NR NR 71(52e86) 63(38e79) 52(21e85) NR NR 64(12) 59(46e84) 57.7 ± 12.9 63(34e87) 57.7 ± 12.9 NR NR 68(40e79) 61 ± 10.5

GenderðM=FÞ LLND non  LLND

Neoadjuvant therapy

120/56 17/6 NR 236/115 215/109 171/0 11/6 236/115 236/115 103/89 NR NR 9/8 59/36 37/23 NR 57/18 133/71 44/21 NR 12/3 NR 15/0 507/277 24/8 46/34

176/0 23/0 2/37 0/351 0/324 0/171 12/5 0/351 0/351 39/153 0/64 0/192 NR NR 0/60 NR 53/22 0/204 NR NR 0/15 NR 0/15 0/784 32/0 80/0

191/118 16/6 NR 236/114 478/277 172/0 17/7 236/114 236/114 128/92 NR NR 7/3 44/39 87/45 NR 26/14 24/18 6/6 NR 27/15 NR 22/0 296/192 9/4 198/83

LLND

ðyes=noÞ non  LLND

309/0 22/0 0/70 0/350 379/376 0/172 19/5 0/350 0/351 54/166 0/73 0/245 NR NR 0/132 NR 25/15 0/42 NR NR 0/42 NR 0/22 0/488 13/0 281/0

Tumor location

Dukes' stage

NOS score

a.b.c a.b a.b a.b a.b. a.b. NR a.b a.b a.b.c. a.b.c. a.b a.b.c. a.b a.b.c. a a.b a.b a.b a.b a.b a.b.c. a.b a.b a.b a.b

B.C B.C. NR B.C A.B.C B.C NR B.C B.C A.B.C B.C A.B.C A.B.C A.B.C B.C A.B.C B.C B.C A.B.C NR A.B.C A.B.C.D A.B.C A.B.C B.C B.C

8 RCT 8 RCT 8 RCT 8 RCT RCT 7 8 8 6 7 7 8 9 7 7 8 8 8 6 8 8 8

P. Ma et al. / Asian Journal of Surgery xxx (xxxx) xxx

Please cite this article as: Ma P et al., The efficacy and safety of lateral lymph node dissection for patients with rectal cancer: A systematic review and meta-analysis, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.11.006

Table 1 The baseline characteristics of the included studies.

LLND: lateral lymph node dissection; non-LLND: non-lateral lymph node dissection; NR: not reported. RCT: randomised controlled trial; a: low rectum; b:mid-rectum; c:upper rectum.

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Fig. 1. Study identification and selection flow chart.

Fig. 2. Quality assessment of 5 RCTs. RCTs ¼ randomized controlled trials. Risk of bias summary (A) and Risk of bias graph (B).

12 studies were excluded from 38 potentially eligible studies by reading the full articles. Finally, 26 studies10e14,18,25e44 were included, which involved 6865 patients (LLND group ¼ 3171; nonLLND group ¼ 3694).There were 5 RCTs, 4 prospective nonrandomized studies and 17 retrospective cohort studies in which LLND was compared with non-LLND for rectal cancer. Baseline characteristics of the included studies are summarized in Table 1. Quality evaluation of all cohort studies was conducted using the NOS scale, and the results ranged from 6 to 9 stars, indicating that

in general, the quality of the method was good (Table 1). The screening flow chart of the included studies is presented in Fig. 1.The quality evaluation of the 5 RCTs is presented in Fig. 2, which showed that the overall quality of the 5 RCTs was good. 3.2. Meta-analysis results All results were arbitrated by subgroup of the study type (RCT or non-RCT). Meta-analysis results are shown in Table 2.

Please cite this article as: Ma P et al., The efficacy and safety of lateral lymph node dissection for patients with rectal cancer: A systematic review and meta-analysis, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.11.006

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Table 2 Result of meta-analysis and subgroup analysis by preoperative chemoradiotherapy of LLND compared with non-LLND for rectal cancer. NO of study Outcome indicators 5-year survival Study type RCT 2 non-RCT 6 5-year disease-free survival Study type RCT 2 non-RCT 5 Total recurrences Study type RCT 1 non-RCT 8 Local recurrences Study type RCT 2 non-RCT 16 Distant recurrences Study type RCT 1 non-RCT 11 Surgical duration Study type RCT 3 non-RCT 7 Preoperative chemoradiotherapy yes 4 no 4 NR 2 Blood loss Study type RCT 3 non-RCT 5 Preoperative chemoradiotherapy yes 4 no 4 Perioperative complications Study type RCT 2 non-RCT 8 Perioperative mortality Study type RCT 1 non-RCT 4 Urinary dysfunction Study type RCT 2 non-RCT 6 Preoperative chemoradiotherapy yes 2 no 4 NR 3 Sexual dysfunction Study type RCT 2 non-RCT 3

PatientsðnÞ LLND non  LLND

HR/OR/WMD(95% CI)

P value

374 1288

372 1284

1.23(0.84,1.80) 1.13(0.82,1.58)

0.288 0.455

0.23 248.48

0.0% 98%

0.628 <0.001

374 724

372 690

1.07(0.85,1.36) 1.08(0.81,1.45)

0.559 0.595

0.06 7.32

0.0% 45.4%

0.813 0.120

23 917

22 708

1.53(0.43,5.40) 0.98(0.79,1.23)

0.508 0.885

0.00 3.33

e 0.0%

e 0.853

374 2596

372 2851

0.64(0.39,1.05) 0.94(0.79,1.12)

0.077 0.512

0.85 23.92

0.0% 37.3%

0.356 0.066

23 1345

22 1904

1.59(0.38,6.63) 1.11(0.87,1.41)

0.526 0.407

0.00 13.41

e 25.4%

e 0.202

545 573

544 911

107.20(101.59,112.81) 88.81 (50.13,127.49)

<0.001 <0.001

3.47 57.77

42.4% 89.6%

0.176 <0.001

152 918 48

340 809 306

88.84(58.56,119.12) 90.69(66.94,114.45) 104.00(85.36,122.64)

<0.001 <0.001 <0.001

2.26 92.75 0.00

0.0% 96.8% 0.0%

0.520 <0.001 1.000

545 525

544 605

254.46(221.54,287.38) 318.52(-73.76,710.80)

<0.001 0.112

5.18 65.75

61.4% 93.9%

0.075 <0.001

152 918

340 809

192.12(-161.45,545.70) 318.69(247.60,389.78)

0.287 <0.001

5.77 27.99

48% 89.3%

0.123 <0.001

374 617

372 789

1.44(1.00,2.07) 1.22(0.91,1.63)

0.051 0.176

0.03 6.29

0.0% 0.0%

0.862 0.506

351 648

350 639

3.00(0.12,73.89) 0.81(0.33,1.98)

0.502 0.643

0.00 1.71

e 0.0%

e 0.635

374 391

372 748

2.02(0.45,9.11) 2.32(1.27,4.24)

0.360 0.006

5.46 9.10

81.7% 45.1%

0.019 0.105

103 909 104

303 200 967

2.58(0.89,7.48) 1.80(0.97,3.35) 2.21(0.50,9.84)

0.081 0.064 0.297

2.05 9.04 7.82

51.1% 66.8% 74.4%

0.153 0.029 0.020

194 272

194 279

3.96(0.54,28.82) 5.17(1.33,20.16)

0.174 0.018

2.36 2.63

57.7% 24.0%

0.124 0.228

c2

Heterogeneity I2 p  value

LLND: lateral lymph node dissection; non-LLND: non-lateral lymph node dissection; RCT: randomised controlled trial; non-RCT: non-randomised controlled trial; NR: not reported; HR: hazard ratio; OR: odds ratio; WMD: weighted mean difference.

3.3. Survival meta-analysis results Eight of the twenty-six included studies11e14,27,30,32,35 reported results of 5-year survival (Fig. 3A). No significant differences were observed between the LLND group and non-LLND group: RCTs subgroup (HR ¼ 1.23, 95% CI ¼ 0.84e1.80, P ¼ 0.288), non-RCTs subgroup (HR ¼ 1.13, 95% CI ¼ 0.82e1.58, P ¼ 0.455). However, severe homogeneity was observed in the non-RCTs subgroup (c2 ¼ 248.48, I2 ¼ 98%, P < 0.001). Seven studies11e13,18,27,30,36 reported 5-year disease-free survival (Fig. 3B).The data indicated that there were no significant

differences: RCTs subgroup (HR ¼ 1.07, 95%CI ¼ 0.85e1.36, P ¼ 0.559), non-RCTs subgroup (HR ¼ 1.08, 95% CI ¼ 0.81e1.45, P ¼ 0.595). Moderate between-study heterogeneity was observed in the non-RCTs subgroup (c2 ¼ 7.32, I2 ¼ 45.4%, P ¼ 0.120). 3.4. Recurrent meta-analysis results In nine studies,12,18,25,27,35,36,38,41,43 total recurrences were reported. Fig. 4A shows the pooled analysis, which indicated no differences between the two groups: RCT subgroup (OR ¼ 1.53, 95% CI ¼ 0.43e5.40, P ¼ 0.508), non-RCTs subgroup (OR ¼ 0.98, 95%

Please cite this article as: Ma P et al., The efficacy and safety of lateral lymph node dissection for patients with rectal cancer: A systematic review and meta-analysis, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.11.006

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Fig. 3. 5-year survival (A) and 5-year disease-free survival (B) for all patients and by study type subgroups. Square indicate point estimate of each study. Size of square indicates relative contribution of each study. Solid horizontal line represents 95% CI of each study. Diamond indicates pooled HR value.

CI ¼ 0.79e1.23, P ¼ 0.885). The results of the homogeneity test showed no homogeneity between the two groups (c2 ¼ 3.33, I2 ¼ 0.0%, P ¼ 0.853). Data of local recurrences were extracted from eighteen studies,10e14,18,25e27,30,32,33,35e38,41,43 including 6193 patients. No significant differences were observed between the two groups: RCTs subgroup (OR ¼ 0.64, 95%CI ¼ 0.39e1.05, P ¼ 0.077), non-RCTs

subgroup (OR ¼ 0.94, 95% CI ¼ 0.79e1.12, P ¼ 0.512), however moderate heterogeneity was observed in the non-RCTs subgroup (c2 ¼ 23.92, I2 ¼ 37.3%, P ¼ 0.066, Fig. 4B). Data on distant recurrences were reported in twelve studies.11e13,18,26,27,35,37,38,41,43,44 Overall, we detected no significant benefit of LLND for low rectal cancer when compared with the nonLLND group, the differences did not reach statistical significance:

Please cite this article as: Ma P et al., The efficacy and safety of lateral lymph node dissection for patients with rectal cancer: A systematic review and meta-analysis, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.11.006

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RCT subgroup (OR ¼ 1.59, 95%CI ¼ 0.38e6.63, P ¼ 0.526), non-RCTs subgroup (OR ¼ 1.11, 95% CI ¼ 0.87e1.41, P ¼ 0.407) with minor heterogeneity in the non-RCTs subgroup (c2 ¼ 13.41, I2 ¼ 25.4%, P ¼ 0.202, Fig. 4C). 3.5. Perioperative meta-analysis results Ten studies10,12,13,18,27,29,32,42e44 assessing the duration of surgery included a total of 2573 patients. When compared with the non-LLND group, an increase in surgical duration (Fig. 5A) was observed in the LLND group: RCTs subgroup (WMD ¼ 107.20,95% CI ¼ 101.59e112.81, P < 0.001), non-RCTs subgroup(WMD ¼ 88.81, 95%CI ¼ 50.13e127.49, P < 0.001). Moreover significant heterogeneity was observed in the non-RCTs subgroup (c2 ¼ 57.77, I2 ¼ 89.6%, P < 0.001). Data on blood loss during surgery were acquired from eight studies,10,12,18,27,29,31,43,44 and the pooled results (Fig. 5B) showed a significant difference favoring non-LLND: RCTs subgroup (WMD ¼ 254.46, 95%CI ¼ 221.54e287.38, P < 0.001), non-RCTs subgroup (WMD ¼ 318.52, 95%CI ¼ 73.76e710.80, P ¼ 0.112), with a severe heterogeneity in the non-RCTs subgroup (c2 ¼ 65.75, I2 ¼ 93.9%,P < 0.001). Results of the subgroup analysis of the above two outcome indicators are presented in Table 2. 3.6. Adverse events meta-analysis results When compared with the non-LLND group, the assembled data from ten studies10,12,18,27,28,34,36,41,43,44 involving 2652 patients showed that the increase of perioperative complications was not statistically significant(Fig. 6A): RCTs subgroup (OR ¼ 1.44, 95% CI ¼ 1.00e2.07, P ¼ 0.051), non-RCTs subgroup (OR ¼ 1.22, 95% CI ¼ 0.91e1.63, P ¼ 0.176), with no heterogeneity between-studies. Data of perioperative mortality was obtained from ten studies,10e12,18,27,28,32,34,36,38 and the results (Fig. 6B) showed no significant differences between the two groups: RCT subgroup (OR ¼ 3.00, 95%CI ¼ 0.12e73.89, P ¼ 0.502), non-RCTs subgroup (OR ¼ 0.81, 95%CI ¼ 0.33e1.98, P ¼ 0.643), with no heterogeneity. Urinary dysfunction was reported in nine studies.10,27,28,31,39e42,44 The incidence of dysuria was more prevalent to postoperative patients in the LLND group (Fig. 6C), and differences were statistically significant in the non-RCTs subgroup (OR ¼ 2.32, 95%CI ¼ 1.27e4.24, P ¼ 0.006), however, a greater heterogeneity was detected between studies in the RCTs subgroup (c2 ¼ 5.46, I2 ¼ 81.7%, P ¼ 0.019). The occurrence of male sexual dysfunction was reported in five studies10,27,29,39,42 in which 939 male patients were investigated. The statistically significant results (Fig. 6D) showed that sexual dysfunction was more universal in postoperative patients in the LLND group:RCTs subgroup (OR ¼ 3.96, 95%CI ¼ 0.54e28.82, P ¼ 0.174), non-RCTs subgroup (OR ¼ 5.17, 95%CI ¼ 1.33e20.16, P ¼ 0.018), with moderate heterogeneity (c2 ¼ 2.36, I2 ¼ 57.7%, P ¼ 0.124). 3.7. Publication bias A funnel plot based on the LLND was generated to assess publication bias (Fig. 7).No publication bias was observed: Begg,s tests (z ¼ 0.91, P ¼ 0.363) and Egger,s tests(t ¼ 0.57,P ¼ 0.579). Fig. 4. Total recurrence (A), local recurrence (B), and distant recurrence (C) for all patients and by study type subgroups. Square indicate point estimate of each study. Size of square indicates relative contribution of each study. Solid horizontal line represents 95% CI of each study. Diamond indicates pooled OR value.

4. Discussion The results of this meta-analysis showed that LLND did not provide significant survival benefits for patients with rectal cancer. Furthermore, a prolonged surgical duration resulted in more intraoperative blood loss and an increased incidence of

Please cite this article as: Ma P et al., The efficacy and safety of lateral lymph node dissection for patients with rectal cancer: A systematic review and meta-analysis, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.11.006

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Fig. 5. Surgical duration (A), blood loss (B) for all patients and by study type subgroups. Square indicate point estimate of each study. Size of square indicates relative contribution of each study. Solid horizontal line represents 95% CI of each study. Diamond indicates pooled WMD value.

postoperative urinary dysfunction and male sexual dysfunction. The results of sensitivity analysis were stable, indicating that these results were reliable. When we conducted subgroup analysis by research type (RCT or non-RCT), 5-year survival rate, surgical duration, blood loss, urinary dysfunction and sexual dysfunction showed significant

heterogeneity, which may be related to study design, ethnic differences, inconsistent measurement methods and different reporting methods. Regarding blood loss, only one of all the included studies12 showed a decrease (by 100 ml) in the LLND group. Patients in the LLND group were younger than patients in the non-LLND group, therefore, age may be an influencing factor;

Please cite this article as: Ma P et al., The efficacy and safety of lateral lymph node dissection for patients with rectal cancer: A systematic review and meta-analysis, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.11.006

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however, this will need to be further verified. In addition, high heterogeneity of surgical duration, blood loss, and urinary dysfunction were related to preoperative chemoradiotherapy. This was probably due because preoperative chemoradiotherapy45 reduced the tumor stage, at the same time affecting the blood supply and cell metabolism of local tissues, thereby causing inflammatory edema in local tissues and an increased surgical duration and intraoperative blood loss. Regarding urination and sexual function, radiation therapy has demonstrated to adversely affect urination and sexual function,46 and this was also reflected in our conclusion results. One27 of all included studies showed high heterogeneity, and all patients in this study underwent preoperative chemoradiotherapy. In patients with rectal cancer, it was important to consider postoperative local recurrence, which was related to lateral node involvement.36,47,48 To demonstrate whether LLND could benefit patients with rectal cancer, the JCOG conducted a phase 3 clinical RCT to compare ME with and without LLND. Main endpoints, including 5-year recurrence-free survival, overall survival, and local-relapse-free survival showed a difference favoring the LLND group. The local recurrence rates were 7.4% and 12.6% in the ME with LLND and ME alone groups, respectively (P ¼ 0.024).30 The pattern of relapsevaried from region to region. In Japan, it was mainly the lateral pelvis and in the Netherlands the central pelvis was involved. Moreover, in a South Korea study,49 it was reported that lateral pelvic recurrence was the main pattern of recurrence (83%), while in a Swedish trial50 it was shown that lateral pelvic recurrence was not the main pattern of recurrence (6%).Therefore, a region-by-region analysis of pelvic lateral lymph node metastasis may be necessary. Western scholars advocated TME surgery combined with chemoradiotherapy for the treatment of rectal cancer. However, Ishihara et al51 found that, even after receiving neoadjuvant therapy, the local recurrence rate of rectal cancer patients without LLND was 8.4% within 5 years after surgery, while patients with combined LLND did not show local recurrence. These findings suggested that neoadjuvant therapy may not be effective in removing all positive lymph nodes and should be supplemented by surgical dissection to consolidate the efficacy. Thus, this conclusion will need to be supported by clinical studies in major cases. The significant increase of urinary and male sexual dysfunction in the LLND group of our meta-analysis was as expected. In the past, several studies10,27,39e42,44 reported that LLND can increase the incidence of urinary dysfunction and male sexual dysfunction after surgery. However, a RCT31 conducted by JCOG reported that LLND did not associate with a significant increase in the incidence of urinary dysfunction. Urinary dysfunction was associated with tumor location(lower rectum) and blood loss(>500 ml).It was confirmed that only blood loss was independently predictive of early urinary dysfunction.Sexual dysfunction was a prevalent postoperative complication as previously demonstrated for primary rectal cancer after LLND,27,42,52 as autonomic nerves in the region were at high risk or were sacrificed to achieve optimal oncological outcomes. In an RCT29 by JCOG, it was shown that the incidence of sexual dysfunction was associated with increased age. Multifactorial analysis was conducted and it was concluded that LLND may not increase the incidence of sexual dysfunction in men after surgery and that an age over 56 was the only risk factor.

Fig. 6. Perioperative complications (A), perioperative mortality (B), urinary dysfunction(C), male sexual dysfunction (D) for all patients and by study type subgroups. * Perioperative mortality involved 10 studies, 5 of which had zero number of events, so they were not expressed in the figure Square indicate point estimate of each study. Size of square indicates relative contribution of each study. Solid horizontal line represents 95% CI of each study. Diamond indicates pooled OR value.

Please cite this article as: Ma P et al., The efficacy and safety of lateral lymph node dissection for patients with rectal cancer: A systematic review and meta-analysis, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.11.006

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P. Ma et al. / Asian Journal of Surgery xxx (xxxx) xxx

Finally, the data used in this study were all from published studies, thereby lacking gray literature, such as thematic reports, unpublished data, government reports, and other evidence from traditional or non-traditional literature sources. 5. Conclusion The results of this meta-analysis showed that LLND increased the incidence of postoperative urinary dysfunction and male sexual dysfunction, but did not improve the long-term prognosis of the patients with rectal cancer. Therefore, LLND should be carefully carried out. In addition, a randomized trial comparing LLND with neoadjuvant chemoradiotherapy might be expected to further demonstrate the value of LLND in the management of rectal cancer. Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors. Funding/support This study was supported by Natural Science Foundation of Gansu Province, China (Grant No.18JR3RA052), and National Key Research and Development Program (Grant No 2018YFC1311500). Contributors

Fig. 7. Beggs's funnel plot(A)and Egger's funnel plot(B)for assessing publication bias of local recurrences.

However, patients who underwent preoperative chemoradiotherapy were excluded in this RCT. However, this RCT does not consider the role of preoperative chemoradiotherapy. In another clinical trial,53 involving preoperative chemoradiotherapy and lymph nodes size will help identify appropriate indications for effective use of selective LLND. When compared with previous similar meta-analysis,17 this study included more research literatures, especially RCT. Therefore, a more detailed subgroup analysis of outcome indicators with high heterogeneity was performed. However, our study has several limitations: First, the included original research objects were mostly from Japan, and the representative sample size was relatively low. Furthermore, the surgical criteria for Japanese rectal cancer patients were different from those in other countries and regions. They did not depend on tumor staging, but according to the recommendation of the Japanese Research Society for Cancer of the Colon and Rectum9: all patients with rectal cancer would undergo LLND, and therefore, the results cannot be reliably extrapolated. Second, the included studies were completed in different clinical centers, and during treatment, the evaluation method of outcome indicators had a great relationship with surgical proficiency, subjective expectation, and the nature and location of the patient's tumor, which resulted in inevitable bias. Moreover, there were differences in the study design, inclusion criteria, and surgical procedures of surgeons, which may have affected the accuracy of the results. Third, this study was a secondary study, and it was impossible to control the differences among the original studies included in the experimental design, inclusion criteria and surgical operation, which may have affected the reliability of the results.

Conception and design of the study: Hui Cai and Kehu Yang. Studies selection: Peilan Ma, Yuan Yuan and Peijing Yan. Data extraction: Peilan Ma, Peijing Yan and Guohua Chen. Statistical analyses: Peilan Ma, Yuan Yuan, Shixun Ma, Meng Xu. Conceptualization: Peijing Yan, Xiangdong Niu. Data curation: Peijing Yan, Shixun Ma. Methodology: Peilan Ma, Yuan Yuan, Guohua Chen. Software: Peilan Ma, Guohua Chen, Xiangdong Niu. Supervision: Hui Cai and Kehu Yang. Writing e original draft: Peilan Ma. Writing e review and editing: Hui Cai. All authors were involved in the decision to submit for publication. Declaration of competing interest The authors declared no conflicts of interest. Acknowledgements The authors thank the DaVinci Surgery System Database (DSSD, www.davincisurgerydatabase.com) and Kehu Yang (Institution of Clinical Research and Evidence Based Medicine, Gansu Provincial Hospital) for their help and support regarding the methodology and meta-analysis process. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.asjsur.2019.11.006. References 1. Nagtegaal ID, van de Velde CJ, Marijnen CA, et al. Low rectal cancer: a call for a change of approach in abdominoperineal resection. J Clin Oncol. 2005;23: 9257e9264.

Please cite this article as: Ma P et al., The efficacy and safety of lateral lymph node dissection for patients with rectal cancer: A systematic review and meta-analysis, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.11.006

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Please cite this article as: Ma P et al., The efficacy and safety of lateral lymph node dissection for patients with rectal cancer: A systematic review and meta-analysis, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.11.006