Improved Oncologic Outcomes Following Laparoscopic Surgery for Small T4 Colon Cancer : A Multi-center Comparative Study

Background: Laparoscopic surgery for T4 colon cancer may be safe in selected patients. Based on the theory that small tumor size might preoperatively predict a good laparoscopic surgery outcome, we herein compare the clinicopathologic and oncologic outcomes of open and laparoscopic surgery in small T4 colon cancer. Methods: In a retrospective multicenter study, we reviewed the data of 449 patients, including 117 patients with tumors ≤ 4 cm, who underwent T4 colon cancer surgery between January 2014 and December 2017. We compared the clinicopathologic and 3-year oncologic outcomes between the laparoscopic and open surgery groups. Results: Blood loss, length of hospital stay, and postoperative morbidity were lower in the laparoscopic group than in the open group (86 mL vs. 278 mL, p < 0.001; 10.0 days vs. 12.5 days, p = 0.003; and 18.0% vs. 29.5%, p = 0.005, respectively). There were no intergroup differences in overall survival (OS) and 3-year disease-free survival (DFS; 87.8% vs. 83.2%, p = 0.117; 69.5% vs. 68.1%, p = 0.408, respectively). Among patients with tumors of size ≤ 4 cm, blood loss was lower in the laparoscopic surgery group than in the open group (80 mL vs. 208 mL, p = 0.001); despite no statistical difference observed in the 3-year OS (84.4% vs 78.7%, p = 0.442), the laparoscopic group had a better 3-year DFS (73.8% vs. 46.0%, p = 0.004). Conclusions: Laparoscopic surgery showed similar outcomes to open surgery in T4 colon cancer patients, and may have favorable short-term oncologic outcomes in patients with small T4 tumors.


Background
Approximately 10-20% of patients with colon cancer are diagnosed with T4 colon cancer [1][2][3]. R0 resection is essential for curative surgery in T4 colon cancer, although R0 resection is not easily achieved in case of tumor invasion into the adjacent organs or structures. Several meta-analyses and randomized controlled trials have reported that laparoscopic surgery is non-inferior to open surgery for colon cancer [4][5][6][7]. However, in T4 colon cancer, the feasibility of laparoscopic surgery with regard to the oncologic outcome remains debatable. In addition, treatment guidelines recommend an open approach for pT4 colon cancer.
Several recent studies have reported that laparoscopic surgery for T4 colon cancer showed better shortterm outcomes, such as less intraoperative blood loss and shorter hospital stay, than open surgery as well as non-inferiority in oncologic outcomes [8][9][10]. However, the exact clinical conditions wherein laparoscopic surgery for T4 colon cancer is feasible or harmful, with regard to the oncologic outcomes, need to be ascertained. Studies have reported that a technical di culty during laparoscopic surgery could threaten oncological safety, while tumor size is a factor that is known to in uence the technical di culty associated with tumor resection [11,12].
In T4 colon cancer, a laparoscopic approach seems to be superior in regard to clinical outcomes in cases where the tumor is easy to access or handle, such as with a small invasive tumor. However, large-sized tumors are more di cult to resect laparoscopically, which may increase the risk of tumor spillage.
However, there is scant evidence of the comparative outcomes of open and laparoscopic surgery with respect to the tumor size in T4 colon cancer.
In this study, we investigated the hypothesis that small tumors may in uence the preoperative prediction of a good outcome following a laparoscopic approach, and evaluated the clinicopathologic and oncologic outcomes of open and laparoscopic surgery in small T4 colon cancer patients.

Patient characteristics
A retrospective chart review and analysis of multicenter data were undertaken, including data of patients diagnosed with pathologic T4 colon cancer who underwent curative surgery at three institutions between January 2014 and December 2017. Rectal cancer was de ned as cancer in which the lower margin of the tumor was located within 15 cm above the anal verge, and patients with rectal cancer were excluded from this study. Moreover, patients with stage T1-3 colon cancer, histological diagnosis indicating cancer other than adenocarcinoma, palliative surgery, in ammatory bowel disease, and hereditary colon cancer were excluded.
The patient characteristics and perioperative outcomes were analyzed, including age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) score, preoperative carcinoembryonic antigen (CEA) level, location, operative time, blood loss, intraoperative transfusion, length of hospital stay, and postoperative morbidity. The pathologic features that were analyzed included tumor size, T stage, nodal status, angio-lymphatic invasion, venous invasion, perineural invasion, adjacent organ resection, and R0 resection. The oncologic outcome included the 3-year disease-free survival (DFS) and overall survival (OS) as the primary outcomes. The tumor size was measured on the basis of the long diameter of the tumor in the pathologic specimen. Patients with ASA scores 1 or 2 and 3 or 4 were included in the same group for analysis. The tumor location was divided into the right (from cecum to transverse colon) and left (from splenic exure to sigmoid colon) sides. The nodal status was classi ed as the absence (N0) or presence (N+) of metastatic regional lymph node(s).
All study procedures were conducted in accordance with the principles of the Declaration of Helsinki of 1964 and its later amendments. This study was approved by the institutional review board of the National Cancer Center, Korea (NCC2020-0166), and the need for informed consent was waived due to the retrospective study design.

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The primary outcome of this study was the comparison of oncologic outcomes, including 3-year OS and 3-year DFS, between the laparoscopic and open surgery groups for small T4 colon cancer. The secondary outcome was the R0 resection rate. The OS was de ned as the time from surgery to death, and the DFS was de ned as the time from surgery to any recurrence, a second cancer, or death. R0 resection was de ned as the absence of cancer cells, when evaluated microscopically, at the primary tumor site after resection.

Statistical analysis
Data are reported as mean and standard deviation (SD) for continuous variables, and as frequency (%) for categorical variables. The comparison of the variables between the open and laparoscopic groups was performed by using the independent t-test and chi-square test or Fisher's exact test. Survival curves were analyzed by using the Kaplan-Meier method, and the intergroup differences were compared using the log-rank test. A p-value < 0.05 was considered to indicate a signi cant difference. Patients in the laparoscopy group had higher BMI (22.0 kg/m 2 vs. 23.7 kg/m 2 , p < 0.001) and a lower proportion of patients in this group had an ASA score greater than 2 (14.1% vs. 4%, p < 0.001) than in the open group. The proportions of blood loss (278 mL vs. 86 mL, p < 0.001) and postoperative transfusion (12.8% vs. 0.7%, p < 0.001) were lower in the laparoscopy group. Moreover, patients in the laparoscopy group had a shorter hospital stay (12.5 days vs. 10.0 days, p = 0.003) and a lower postoperative morbidity (29.5% vs. 18%, p = 0.005) ( Table 1).  Outcomes of small T4 colon cancer Table 3 shows the clinical characteristics and perioperative outcomes of patients with tumor size ≤ 4 cm.

Patient characteristics
The laparoscopy group had higher BMI (22.3 kg/m 2 vs. 23.9 kg/m 2 , p = 0.026) and less blood loss (208 mL vs. 80 mL, p = 0.03). Other variables did not differ signi cantly between the two study groups. Table 4 presents the pathologic features and oncologic outcomes of patients with tumor size ≤ 4 cm.

Discussion
Although the safety of laparoscopic surgery for colon cancer had been demonstrated in several studies [4][5][6][7], the safety of this surgical approach is controversial in T4 colon cancer. Several studies have suggested that a laparoscopic approach in T4 colon cancer may be feasible in some patients. Few studies have provided useful indications for laparoscopic surgery in T4 colon cancer. Klaver et al. [2] reported that laparoscopic surgery for T4a tumors might be safe. However, the pathologic features would not be helpful in determining the indication of laparoscopic surgery preoperatively. Park et al. [13] found the laparoscopic approach to be feasible for left-sided T4 colon cancer. Nevertheless, a useful predictor is still necessary to preoperatively determine the safety of laparoscopic surgery for T4 cancer.
In this study, the clinicopathologic and oncologic outcomes of laparoscopic surgery for T4 colon cancer were generally comparable to those of open surgery. The laparoscopic approach, especially for small T4 tumors, showed better 3-year DFS than did open surgery.
A previous study has reported that malignant cells are intraoperatively exfoliated from the tumor during resection and spread to the peritoneal surface and portal vein system. This can be prevented by minimizing tumor manipulation, e.g., through a laparoscopic approach [14]. As did our study, Lacy et al. showed better cancer-related survival with laparoscopic colectomy than open surgery for non-metastatic colon cancer in a randomized clinical trial [15]. When laparoscopic surgery is conducted by a wellexperienced surgeon, tumor spillage and spread may be prevented in some patients.
As the tumor size increases, some technical challenges arise with regard to laparoscopic surgery, because it reduces the working space, narrows the operative visual eld, increases bleeding, and makes the tumor di cult to remove. Moreover, larger tumors increase the risk of tumor spillage, thereby increasing peritoneal seeding or trocar-site recurrence. Our data shows that the 3-year OS and DFS rates in patients with tumor size > 4 cm were not signi cantly different between the two groups (84.4% vs. 89.2%, p = 0.17; 73.8% vs. 68.0%, p = 0.625, respectively). This suggests that the laparoscopic approach is more feasible in patients with small tumor than in those with larger tumors.
Laparoscopic surgery is better than open surgery in regard to the perioperative outcome. In previous studies comparing laparoscopic and open surgery in T4 colon cancer, laparoscopic surgery was associated with less intraoperative blood loss [1,16,17], which has been proven to be a predictor of longterm survival [18,19]. Some studies have shown that hospital stays are shorter in patients who undergo laparoscopic surgery [20,21]. In this study, the laparoscopic group patients had less intraoperative blood loss and shorter hospital stays than the open surgery group patients.
In previous studies of T4 colon cancer, the conversion rate from laparoscopic to open surgery was reported to be in the range of 7.1-28.2% [3]. Converted patients have high postoperative morbidity and adverse effects on long-term oncologic outcomes [22]. In the present study, the overall conversion rate was 7%, and the conversion rate for patients with tumor size ≤ 4 cm was 2.3%. The low conversion rate might be responsible for the better oncologic outcomes of laparoscopic surgery. This study was approved by the institutional review board of the National Cancer Center, Korea (NCC2020-0166). The need for informed consent was waived due to the retrospective study design.

Consent for publication:
We simply extracted data and did not involve the private information of patients.
Availability of data and materials: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.