Laparoscopic surgical challenge for T4a colon cancer

Abstract For patients with T4a colon cancer, the risk of peritoneal dissemination after surgery remains unclear. Seven hundred and eleven patients with T3 or T4a colon cancer, 80 years of age or younger, underwent curative resection (open surgery in 512 and laparoscopic surgery in 199) at the four Jikei University hospitals between 2006 and 2012. Their risk factors for peritoneal dissemination after surgery were evaluated retrospectively. Number of lymph node metastases, postoperative liver metastases and postoperative peritoneal dissemination events in the T4a group were significantly greater than the number in the T3 group. Peritoneal dissemination after surgery developed in four patients (0.7%) in the T3 group and in six patients (5%) in the T4a group. Risk factors for peritoneal dissemination consisted of macroscopic type (P = 0.016), serosal invasion (P = 0.017) and number of lymph node metastases (P = 0.009) according to the Cox proportional hazards regression model. However, tumor diameter and surgical approach (laparoscopic vs open) were not significant factors for peritoneal dissemination. There were no significant differences between the postoperative relapse‐free survival rates for each surgical approach within the T3 or T4a group. Because of comparable postoperative peritoneal dissemination in T3 and T4a colon cancer by the surgical approach (laparoscopic or open), laparoscopic surgery for patients with T4a colon cancer seems justified.


| INTRODUCTION
In the early 1990s, laparoscopic surgery for early-stage cancer was considered feasible in Japan, but it was not known whether an adequate extent of lymph node dissection for more advanced cases could be achieved by laparoscopic procedures. 1 In the Japanese Society for Cancer of the Colon and Rectum Guidelines 2010, 2 laparoscopic surgery is suitable for D2, D1 or D0 resection of colon and RS cancer and is strongly indicated for the treatment of cStage 0 to cStage I disease. However, according to the national survey conducted by the Japanese Society of Endoscopic Surgery (JSES), 3 the percentage of more advanced cancers (T2 or higher) accounting for the procedure has increased to over 50% of the total cases. Although many patients with T4 colon cancer are included in those cases, the risk of peritoneal dissemination after surgery remains unclear. The aim of this retrospective study was to evaluate the validity of laparoscopic surgery for patients with T4a colon cancer.

| Statistical analysis
Continuous variables were expressed as mean and range. Wilcoxon rank-sum test was used for comparison of continuous variables and the chi-squared test was used for comparison of categorical data.
Postoperative relapse-free survival rates were examined by the Kaplan-Meier method and log-rank analysis. Variables affecting peritoneal dissemination after surgery were analyzed using the Cox proportional hazards regression. A P-value of less than.05 was considered to indicate significance. All data were analyzed with the computer program IBM SPSS Statistics, version 22.0 (IBM Japan, Ltd, Tokyo, Japan).

| Comparison of patient characteristics between T3 and T4a
Between patients with T4a disease and patients with T3 disease, no significant difference was identified in age, gender, tumor location, macroscopic type of tumor, tumor diameter, and pathological type ( Table 1). The groups of patients did differ significantly in surgical approach, operation time, intraoperative bleeding, lymph node metastasis, and postoperative recurrence rates of peritoneal dissemination and liver metastasis (Table 1). Median follow-up period was 78 months (range 36-130 months). Frequency of peritoneal dissemination after surgery was less than one percent for patients with T3 and five percent for those with T4a (Table 1).
3.2 | Comparison of patient postoperative relapsefree survival rate between T3 and T4a The 5-year relapse-free survival rates were 90.5% for patients with T3 and 72.6% for patients with T4a (Fig. 1). There was a significant difference in postoperative relapse-free survival rates between T3 and T4a according to log-rank analysis (P < 0.001).

| Comparison between open and laparoscopic surgery in patients with T3
Between patients with T3 who received open surgery and laparoscopic surgery, no significant differences were identified in age, gender, macroscopic type of tumor, pathological type, lymph node metastasis and postoperative recurrence rates or sites, whereas significant differences were achieved in tumor location, operation time, intraoperative bleeding, tumor diameter, and pathological type (  (Fig. 2). There was no significant difference in postoperative relapse-free survival rate between the two groups by log-rank analysis (P = 0.338).

| Comparison between open and laparoscopic surgery in patients with T4a
Between patients with T4 who received open surgery and patients who received laparoscopic surgery, no significant differences were found in age, tumor location, operation time, macroscopic type of tumor, tumor diameter, pathological type, lymph node metastasis and postoperative recurrence rate or site (Table 3), whereas significant differences were identified in gender and intraoperative bleeding ( Table 3). Intraoperative blood loss in the open surgery group was significantly greater than in the laparoscopic surgery group.

| Comparison of postoperative relapse-free survival rate of patients with T4a between open and laparoscopic surgery
The 5-year relapse-free survival rate of patients with T4a was 81.8% for patients who underwent laparoscopic surgery and 71.5% for patients who underwent open surgery (Fig. 3), showing no significant difference by log-rank analysis (P = 0.389).

| Cox proportional hazards regression for peritoneal dissemination after surgery
To determine the variables affecting peritoneal dissemination after surgery, 11 variables (age, gender, tumor location, operative time, intraoperative blood loss, macroscopic type, tumor diameter, pathological type, serosal invasion, number of lymph node metastases, and surgical approach) were analyzed using the Cox proportional hazards regression, because the stage identifies depth of tumor and number of lymph node metastases. Only three factors, macroscopic type (P = 0.016), serosal invasion (P = 0.017) and number of lymph node metastases (P = 0.009), were independent contributing factors to peritoneal dissemination after surgery (Table 4).

| DISCUSSION
Although liver metastasis is the most frequent recurrence pattern after surgery in patients with colon cancer, peritoneal dissemination accounted for 16% of all patients with recurrence, for which serosal invasion may correlate with peritoneal dissemination. 5   In our study, peritoneal dissemination after surgery developed in six patients with T4a (5%), which was very low compared to the previous reports evaluated more than 10 years ago. 5,7 Cox proportional hazards regression analysis demonstrated serosal invasion and number of lymph node metastases to be the independent contributing factors for peritoneal dissemination after surgery, whereas the surgical approach failed to demonstrate a significant difference in the postoperative relapse-free survival rate in the T4a group.
Whether we chose laparoscopic or open surgery for the T4a group, the surgical outcome was the same. Therefore, laparoscopic surgery for patients with T4a colon cancer seems justified.
A large number of controlled studies and meta-analyses have shown that laparoscopic surgery is associated with less pain, early recovery of bowel transit and shorter hospital stay compared to open surgery. [8][9][10][11][12] Furthermore, a subset analysis of a randomized trial showed a lower recurrence rate and better survival in patients with stage III colon cancer undergoing laparoscopic surgery compared with open surgery. [13][14][15][16][17] In those studies, no additional procedure to cover serosal invasion to prevent the detachment of cancer cells to the peritoneal cavity was used during surgery in either approach.
In conclusion, laparoscopic surgery for patients with T4a colon cancer seems justified because patients with T3 and T4a had comparable postoperative peritoneal dissemination and other recurrences such as liver or lung metastasis.

CONFLI CTS OF INTEREST
Authors declare no conflicts of interest for this article.