Clinical impact of D3 lymph node dissection with left colic artery (LCA) preservation compared to D3 without LCA preservation: Exploratory subgroup analysis of data from JCOG0404

Abstract Aim We investigated the clinical impact of D3 lymph node dissection preserving left colic artery (LCA) compared to D3 without LCA preservation using data from JCOG0404. LCA preservation is expected to maintain adequate blood supply, which is effective in preventing anastomotic leakage, intestinal paralysis, and bowel obstruction. Whether D3 with LCA preservation (Group A) improves clinical outcomes following resection of sigmoid colon cancer compared to D3 without LCA preservation (Group B) is unclear. Methods Procedure type was identified from photographs of the surgical field collected for central surgical review in JCOG0404. Clinical outcomes were compared between each procedure. Results Among the 1057 randomized patients in JCOG0404, 631 patients receiving sigmoid colectomy or anterior resection were included in the subgroup analysis. Group A comprised of 135 patients and Group B of 496 patients. Patient backgrounds did not differ between groups. Median operative time, blood loss, anastomotic leakage, and intestinal paralysis were not remarkably different (Group A vs Group B: 185 vs 186 minutes, 60 vs 50 mL, 3.0% vs 5.0%, and 2.2% vs 3.8%). More overall postoperative complications occurred in Group B than Group A (21.6% vs 9.6%, P = .022). Five‐year relapse‐free survival (RFS) and overall survival (OS) tended to be better in Group A than Group B (RFS: 83.7% and 80.5%, HR 0.80 [95% CI 0.51‐1.26], OS: 96.3% and 91.1%, HR 0.41 [95% CI 0.19‐0.89]). Conclusions Short‐ and long‐term outcomes tend to be better in Group A than Group B, indicating that preservation of LCA could be an alternative treatment.


| INTRODUC TI ON
The Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer recommend D3 lymph node dissection for clinical stage II/III colorectal cancer. 1 Still now, during curative resection of sigmoid colon and rectosigmoid colon cancer, it is unclear whether D3 lymph node dissection with the left colic artery (LCA) preservation is beneficial compared to D3 without LCA preservation in terms of clinical outcomes.
Choosing whether D3 lymph node dissection with or without LCA preservation depends on a surgeon's preference. LCA preservation is expected to maintain adequate blood supply, which prevents anastomotic leakage. There is a need to determine whether LCA preservation improves clinical short-and long-term outcomes.
JCOG0404 was a randomized controlled trial (RCT) conducted by the Colorectal Cancer Study Group of the Japan Clinical Oncology Group (JCOG) to confirm the non-inferiority of laparoscopic surgery (LAP) compared to open surgery (OP) for patients with stage II/III colon cancer in terms of overall survival (OS). The surgical treatment of these two groups with or without LCA preservation in the present study required D3 dissection equivalent to complete mesocolic excision with central vascular ligation. 2 JCOG0404 enrolled more than 1000 patients, making it one of the largest RCTs for patients with colon cancer requiring D3 dissection in Japan. Although non-inferiority of LAP with D3 dissection to OP for OS could not be confirmed in terms of OS, OS in both groups was similar and better than expected, and laparoscopic D3 surgery could be an acceptable treatment option for patients with stage II or III colon cancer.
At present, there are few reports about the clinical impact of D3 with LCA preservation. We aimed to investigate the clinical impact of D3 lymph node dissection with LCA preservation compared to D3 without LCA preservation by exploratory analyses using the data from JCOG0404. To the best of our knowledge, this is the first study to evaluate the clinical effects of D3 lymph node dissection with or without LCA preservation from collected data of Japanese large-scale RCT. The details of the JCOG0404 study have been reported elsewhere. 3,4 The data of patients who received assigned sigmoidectomy and anterior resection in JCOG0404 were used in this exploratory analysis.

| Endpoints and statistical considerations
Adverse events were evaluated according to CTCAE 3.0.
Postoperative mortality and morbidity were respectively defined as death from any cause and any grade 1 or higher adverse event including anastomotic leakage, paralytic ileus, bowel obstruction, and wound complication within 30 days after surgery. The background characteristics of the patients underwent D3 with LCA preservation were compared with those without LCA preservation.
Wilcoxon rank-sum test for continuous variables and Fisher's exact test for categorical variables were performed to compare the two procedures. We used the Cox proportional hazard model to estimate the hazard ratio (HR) for overall survival (OS) and relapse-free  [Correction added on 30 March 2020, after the first online publication: "for OS and RFS" has been included in the above paragraph.]  cStageII [Correction added on 30 March 2020, after the first online publication: "OR" has been amended to "Odds ratio" in the column heading, and a new entry has been added under the sub-heading BMI] differences in sex, clinical stage, tumor location, or proportion of laparoscopic surgery between the two groups (Table 1). Table 2 shows the operative findings. There were no significant differences in operation time or blood loss between the two groups.

| RE SULTS
However, the number of harvested nodes in Group B was significantly higher than in Group A. Table 3 Figure 3B). The HR for Group A was 0.83 (95% CI, 0.53-1.31) by multivariable analysis (Table 5). with LCA preservation, on the other hand, the advantage is maintenance of the blood supply, which helps to prevent anastomotic leakage and intestinal paralysis. Its disadvantages include the possibility of spillage of micrometastatic cells because of skeletonization of the LCA and the requirement of a more complicated procedure with longer operation time than that without LCA preservation. 6 In previous reports of retrospective studies of sigmoid colon and rectal cancer that compared D3 with LCA preservation to D3 without LCA preservation, Yasuda et al reported that there were no significant differences in terms of short-and long-term outcomes between the two procedures. 7 In addition, Sekimoto et al showed that there were no differences in terms of short-term outcomes including operation time, blood loss, and number of harvested lymph nodes between the two procedures. 8 However, several reports showed that precise staging was performed by D3 without preservation of the LCA. 9,10 Even now, there is still no consensus on the level of arterial ligation in sigmoid and rectosigmoid colon cancer. To the best of our knowledge, the present study is first to show the clinical outcomes of D3 with LCA preservation compared to D3 without LCA preservation from large-scale data collected in a multi-institutional RCT. The present study demonstrated LCA preservation might be a beneficial factor for better short-term outcomes.

| D ISCUSS I ON
The present study revealed that, in terms of postoperative complications, short-term outcomes were better in patients undergoing D3 with LCA preservation than D3 without LCA preservation. Although it is generally considered that D3 with LCA preservation is a more complicated technique requiring longer operation time than D3 without LCA preservation, the present study found no significant differences in terms of operation time and blood loss. This is why the present study did not need to take into consideration the surgical learning curve as a potential risk factor because of the study chair of JCOG0404 certified surgeons at each participating institution according to the aforementioned criteria. In terms of the lower incidence of overall complications and wound complications in Group A, we speculated that preserving the LCA enabled preservation of the autonomic nerves, drainage vein, and the immune system as well as the LCA, which might be associated with lower incidence of anastomotic leakage, paralytic ileus, bowel obstruction, and wound complication. There are a few limitations in this study. First, this study is an exploratory subgroup analysis of data from a RCT. Thus, the decision to perform procedures with or without preservation of the LCA depended on physician preference, which were almost decided by institutional policy and might affect clinical outcomes. Second, the number of pathological T3 or less (ss or shallower) tumors in Group A was significantly higher than that in Group B (88.9% vs 80.4%, P = .023, data was not shown), although there were no significant differences in terms of pathological N status between the two groups. Therefore, comparability might not be maintained even though multivariable analysis showed similar HR compared with univariable analysis. Thus, further investigation is necessary to precisely evaluate the usefulness of D3 lymph node dissection with LCA preservation.
In conclusion, our analysis for stage II/III sigmoid and rectosigmoid colon cancer found that short-and long-term outcomes were better in D3 dissection with preservation of the LCA than D3 dissection without preservation of the LCA. We concluded that D3 lymph node dissection with preservation of the LCA could be an alternative treatment for D3 lymph node dissection.

ACK N OWLED G M ENTS
This study was supported in part by the National Cancer Center