1 Introduction

Surgery is the mainstay treatment for rectal cancer [1]. Recently, with the development of minimally invasive techniques for rectal cancer, laparoscopic surgery has been gradually used to treat rectal tumors because of its advantages of less trauma, less intraoperative bleeding, and faster postoperative recovery [2, 3]. However, according to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for the diagnosis and treatment of rectal cancer, laparoscopic surgery is currently only recommended for rectal cancer clinical trials. Large-scale clinical trials such as CLASICC [4], COLOR II [5], and LASRE [6] have published relevant results, which suggest that laparoscopic rectal cancer surgeries have similar short- and long-term outcomes compared to open surgeries. However, two studies, ACOSOG Z6051 [7] and ALaCaRT [8], revealed that laparoscopic surgery had a higher positive rate of circumferential resection margin (CRM) (laparoscopic group vs. open group = 12.1% vs 7.7%) and lower R0 resection rate (laparoscopic vs. open, 87% vs. 92%) than conventional open surgery. Therefore, the use of laparoscopy in the treatment of rectal cancer remains controversial, and further evidence-based medical evidence is required. Under this premise, our study is a prospective multi-center clinical trial conducted by the Beijing Municipal Science and Technology Commission, integrating several mature hospitals that perform laparoscopic surgery and open surgery for rectal cancer. Herein, we evaluated the short-term outcomes of laparoscopic surgery for rectal cancer by comparing the efficacy and safety of open and laparoscopic surgeries for rectal cancer.

2 Materials and methods

2.1 Participants and data collection

This study was initiated by the Cancer Hospital of the Chinese Academy of Medical Sciences, and 10 medical centers across the country completed the patient recruitment. This study adopted a multi-center, open-label, non-randomized concurrent control method, and the enrollment period was from January 2017 to December 2018. The inclusion criteria were as follows: ① pathologically diagnosed adenocarcinoma; ② tumor lower edge distance from the dentate line ≤ 15 cm; ③ patient age 18–80 years; ④ no invasion of adjacent tissues or organs; ⑤ no distant organ metastasis; ⑥ body mass index (BMI) ≤ 34 kg/m2; ⑦ ECOG score ≤ 3. The following patients were excluded: ① Patients with American Society of Anesthesiologists classification grade > III; ② Patients who had undergone multiple abdominal operations or extensive abdominal adhesions in the past; ③ Patients with a history of a malignant tumor within 5 years; ④ Patients requiring emergency surgery, such as acute intestinal obstruction, gastrointestinal perforation, etc. ⑤ Patients with T1 rectal cancer who met the criteria for transanal local excision; ⑥ Patients with familial adenomatous polyposis, Lynch syndrome-related rectal cancer, and active inflammatory bowel disease.

This study was approved by the Chinese Academy of Medical Sciences Cancer Hospital and the ethics committees of the participating hospitals. Beijing Qihuang Pharmaceutical Co., Ltd. has been entrusted with conducting quality monitoring and progress review of this project. All enrolled patients signed an informed consent form before surgery.

2.2 Procedures

A strict selection of surgeons was performed before the study was conducted, and each surgeon was required to have at least 30 years of experience in laparoscopic and open surgery for rectal cancer. All patients underwent rectal magnetic resonance imaging and/or intrarectal ultrasonography, chest, abdomen, pelvic computed tomography, and other related examinations to improve the preoperative diagnosis and clinical staging. Baseline data and related information were obtained for patients who underwent neoadjuvant therapy. Both groups underwent routine preoperative preparation.

The two groups of patients underwent either open surgery or laparoscopic-assisted surgery. All surgeons were selected according to the relevant criteria and participated in both surgery groups. The surgical technique for open surgery nvolves several key steps. ①Abdominal incision: The surgeon makes an incision in the abdomen, usually along the midline or to one side, to access the colon and rectal area. ② Mobilization of the colon: The surgeon mobilizes the colon, detaching it from the abdominal wall and surrounding structures to provide access to the rectum. ③Identification and isolation of the rectum: The surgeon identifies the rectum and isolates it from the surrounding tissues and organs. This may involve dividing or ligating blood vessels and other structures. ④Rectal resection: This may be performed using a variety of techniques, including sharp dissection, electrocautery, or stapling. ⑤Anastomosis: The surgeon creates an anastomosis between the remaining rectum or colon and the healthy tissue. The type of anastomosis used may depend on the location and extent of the tumor, as well as the surgeon's preference and experience. ⑥Closure of incision: The surgeon closes the abdominal incision using sutures. The surgical key steps were as following: ①Placement of ports: The surgeon makes several small incisions in the abdomen and inserts trocars to provide access for laparoscopic instruments and a camera. These ports are usually placed in the lower abdomen, and one may be placed in the upper abdomen for better visualization. ②Identification and mobilization of the colon and rectum: The surgeon identifies the colon and rectum and mobilizes them by dividing the ligaments that attach them to the abdominal wall and other structures. ③Rectal resection: The surgeon removes the affected portion of the rectum using laparoscopic instruments. ④Anastomosis: The type of anastomosis used may depend on the location and extent of the tumor, as well as the surgeon's preference and experience. Hand-sewn or stapled anastomoses may be used. ⑤Closure of incisions: The surgeon closes the small incisions using sutures. In both groups, the mesorectum was excised according to the principle of total mesorectal excision (TME). For patients who underwent anal sphincter preservation, the distal margin of the tumor was > 2 cm from the tumor. Next, tumor resection and digestive tract reconstruction were performed. The gastrointestinal reconstruction approaches included anterior rectal resection (conventional anastomosis, lower anastomosis, and ultralow anastomosis), combined abdominoperineal resection, and Hartmann's procedure.

The laparoscopic surgery group followed the same TME surgery principle as the open surgery group. A small incision in the lower abdomen was made for specimen removal. In cases of difficulty in the operation, such as severe abdominal adhesions, or serious complications during surgery, the laparoscopic operation was terminated and converted to laparotomy. Patients were closely observed after surgery, clinically relevant events and indicators were recorded, and pathological results were evaluated. Close follow-up and regular monitoring of the survival of enrolled patients were also ensured. One year after surgery, the patients' defecation function, urination function, sexual function, and quality of life were regularly evaluated quantitatively according to the requirements of the corresponding scales.

2.3 Statistical analysis

Different statistical analysis methods were selected depending on the data type. Descriptive statistics were used to calculate the number of cases, mean, standard deviation, median, and maximum values. The differences in related indicators between groups were compared using independent samples t-test, chi-square test, Fisher's exact test, and ANOVA, and survival analysis of each group was performed using the Kaplan–Meier method and COX regression analysis. Statistical analysis was performed using R software 4.2.1. The statistical significance test in this study was two-sided, and statistical significance was set at P < 0.05.

3 Results

A total of 3,073 patients were successfully enrolled and underwent surgery. The baseline information is shown in Table 1. According to the intraoperative situation, 1,761 patients underwent laparoscopic surgery, and the remaining 1,312 patients underwent conventional open surgery. There were no significant differences between the two groups regarding age, sex, BMI, distance from the lower tumor margin to the dentate line, tumor location, preoperative neoadjuvant therapy, and preoperative CEA and CA199 levels.

Table 1 Basic information of patients
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As shown in Table 2, there was no statistical difference between the two groups in tumor differentiation, N stage, lymph vessel invasion, nerve invasion, vascular invasion, and positive rate of circumferential resection margins. The proportion of tumors with a maximum diameter > 5 cm (χ2 = 0.089, P = 0.018) and the proportion of T4 stage tumors (χ2 = 0.478, P < 0.001) were higher in the open surgery group than in the laparoscopic group. Regarding the number of lymph nodes harvested, the laparoscopic group had a higher proportion of > 12 lymph nodes (χ2 = 0.248, P < 0.001) than the open surgery group. No statistical difference was observed between the two groups in terms of postoperative hospital stay, intraoperative blood loss, time to pass first flatus, the time of first mobility, time to first liquid food intake, and anal sphincter preservation rate (Table 3). However, the laparoscopic surgery group had better outcomes in terms of operation time (t = 6.750, P < 0.001) and postoperative pain scores (t = 0.896, 0.63, 0.964, and 0.989 on postoperative days 1, 2, and 3, respectively, all P < 0.001).

Table 2 Pathology-related results
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Table 3 Perioperative indicators
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Furthermore, we analyzed the perioperative complications in all patients. As shown in Table 4, the incidence of grades 2–4 adverse reactions in the two groups were 12.5% and 14.6%, respectively, with no statistical difference (χ2 = 0.061, P = 0.105). However, the wound infection rate was lower in the laparoscopic group (χ2 = 0.19, P < 0.001) than in the open surgery group, while the rates of wound dehiscence, abdominal infection, lung infection, sepsis, postoperative bleeding, cardiac-related complications, urinary system-related complications, dysuria, anastomotic leakage, intestinal obstruction, postoperative return to the intensive care unit, and 28-day mortality were not statistically different between both groups.

Table 4 Perioperative complications
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The median follow-up time for all patients was 25 months (interquartile range: 15–34 months). At the last follow-up on December 31, 2021, 302 (9.8%) patients had died, and 1,046 (34.0%) had disease progression, including 568 patients (32.3%) in the laparoscopic surgery group and 459 patients (35.0%) in the open surgery group. The hazard ratio (HR) for 3-year recurrence-free survival after laparoscopic surgery compared to open surgery was 1.089 (95% confidence interval (CI) = 0.962–1.232, P = 0.170, Fig. 1A). Recurrence after R0 resection occurred in 97 (17%) patients in the laparoscopic group and 87 (19%) in the open surgery group. Of these patients, 233 (41%) in the laparoscopic group and 211 (46%) in the open surgery group were diagnosed with liver metastases, 91 (16%) in the laparotomy group and 60 (13%) in the open surgery group were diagnosed with peritoneal metastases, and 164 (29%) in the laparoscopic group and 156 (34%) in the laparotomy group were diagnosed with lung metastases. Multivariate analysis suggested that intraoperative blood loss, T and N stages, nerve invasion, and postoperative sepsis were independent prognostic factors for disease-free survival. Intraoperative blood loss > 100 mL (HR = 1.284, 95% CI = 1.011–1.629, P = 0.041), T3-T4 (HR = 1.295, 95% CI = 1.128–1.488, P < 0.001), lymph node-positive (HR = 1.170, 95% CI = 0.1.019–1.342, P = 0.024), positive for nerve invasion (HR = 1.194, 95% CI = 1.021–1.397, P = 0.027) and postoperative sepsis (HR = 2.057, 95% CI = 1.167–3.624, P = 0.013) tended to indicate a poor prognosis (Fig. 1B). In the DFS subgroup analysis, we observed no significant differences between the two subgroups in terms of sex (men vs. women), age (≤ 60 years vs. > 60 years), tumor location (high, middle, and low), intraoperative blood loss (≤ 100 mL vs. > 100 mL), T stage (T1-T3 vs. T4), N stage (N0 vs. N1-N2), and preoperative CEA and CA199 levels (Fig. 1C). In the study, nearly 30 factors were included in the multivariate analysis, which may cause multicollinearity problems. To avoid this issue, we first performed the univariate analysis cox analysis on the above factors. Next, the factors with statistical differences were subjected to multivariate analysis (as shown in Table S1). The results are consistent with the previous method.

Fig. 1
figure 1

A Kaplan–Meier curve for comparison of disease-free survival (DFS). HR = hazard ratio. B Multivariate analyses of clinicopathological characteristics and potential risk factors with disease-survival in the study. C Subgroup analysis of patient's postoperative disease-free survival

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To further evaluate the quality of life of the two groups after surgery, the Wexner score, IPSS score, and LARS score were used to evaluate defecation function, voiding function and sexual function, respectively, in the two groups. As shown in Table 5, there were no statistically significant differences in the three scores between the two groups.

Table 5 Quality of life 1 year after operation
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4 Discussion

Recently, with the continuous promotion and advancement of the concept of minimally invasive surgery, several patients are more willing to undergo laparoscopic surgery [9,10,11]. This study was designed as a non-randomized concurrent control study, and after meeting the inclusion and exclusion criteria, the study participants were enrolled according to the intention of both doctors and patients. Finally, 3,073 cases were included. There were no statistical differences in neoadjuvant therapy or other parameters used for subsequent analysis. In terms of pathology, the proportion of both tumors with a maximum diameter of more than 5 cm and T4 stage was higher in the open group than in the laparoscopic group.

For tumors with larger volumes and deeper local infiltration, open surgery is more convenient for exposing the operating area and aiding the surgeons, making the surgeons willing to choose open surgery in this study. However, from the subsequent subgroup analysis, we observed that for rectal cancer with a maximum tumor diameter of > 5 cm or a T4 stage, there was no significant difference in the 3-year DFS between the laparoscopic surgery and laparotomy groups. This finding also suggests the feasibility of laparoscopic surgery in large rectal tumors or deep infiltration cases. Regarding lymph node dissection, the proportion of lymph nodes with more than 12 lymph nodes harvested in the laparoscopic group was higher. This may be related to the magnifying effect of laparoscopy [12]. Compared with traditional open surgery, laparoscopy can display the tissue structure more clearly and is more conducive for lymph node dissection [13].

CRM involvement is an important predictor of local recurrence after rectal surgery [2, 14]. There was no significant difference in the CRM positivity rate (0.9% vs. 1.0%) between the two groups in this study. The CRM positive rate after laparoscopic surgery in this study was 0.9%, similar to the LASRE (1.8%) and COREAN studies (2.9%), and was significantly lower than that of ALaCaRT (7.0%), COLOR II (10%), ACOSOG Z6051 (12.1%), and CLASICC studies (16.0%) [4, 6, 7, 15]. Compared with other studies, the CRM-positive rate in this study was relatively low, which may be related to the intentional enrollment pattern of this study—patients suspected to be CRM-positive before surgery were not included in this study [16]. Nonetheless, our results suggest that there was no statistical difference in the CRM positivity rate between the two surgery types, similar to that obtained in the LASRE and COLOR II trials for low rectal cancer. These results further suggest that the application of laparoscopic techniques in rectal cancer surgery is feasible.

Regarding the perioperative period, the laparoscopic group was superior to the laparoscopic group in terms of operative time and postoperative pain. However, some differences in operation time were reported in previous studies [10, 17]. This may be because of the relatively small incision length in the laparoscopic surgery group, which shortened the abdominal closure time. In addition, the exposure of the operative field of view in the laparoscopic group was more sufficient and convenient for skilled operators to operate continuously while accelerating the operation process [15]. At the same time, the patients in the open surgery group had larger tumor volumes and deeper local infiltration, which also affected the operation time to a certain extent [18]. Postoperative pain reduction in the laparoscopic group was also attributed to the small incision in the laparoscopic group. This includes patients with external transverse and internal longitudinal incisions and natural orifice specimen extraction surgery [12]. The advantages of this type of incision are more evident in terms of perioperative complications. The incidence of incision infection after laparoscopic surgery was lower than that after laparotomy. However, there were no statistically significant differences in other perioperative complications between the two groups.

In this study, the DFS of the two groups at 3 years postoperatively was analyzed, and the results showed no statistical difference. Subgroup analysis performed in this study showed that there were no statistically significant differences in sex, age, rectal tumor location, T4 stage, lymph node metastasis, and relatively large tumors between the laparoscopic surgery and open surgery groups. The T4 rectal cancers involved in this study were mainly rectal cancers with relatively high locations, excluding T4b. Compared with the exclusion of T4 rectal cancer in most previous studies, the results of this study suggest the possibility of laparoscopic surgery for T4 rectal cancer [19, 20]. In addition, multivariate analysis revealed that intraoperative blood loss, T and N stages, nerve invasion, and postoperative sepsis were independent prognostic factors for disease-free survival. In order to reduce the impact of the difference in the proportion of T stages and tumor size in the two groups on the statistical results, we performed a subgroup analysis on the T stages and tumor size. As shown in Fig. 1C, in the T1-T3 vs T4 groups and maximum tumor diameter of ≤ 5 cm vs > 5 cm, there were no statistical differences in DFS between the two surgical methods. Moreover, since sepsis can be treated with medical intervention, it is suggested that the location of the sepsis be identified as soon as possible after surgery to provide timely anti-infective treatment. This may improve the prognosis of rectal cancer patients. Another strength of this study was the evaluation of the patient's function 1 year postoperatively. The results showed no statistical difference in defecation function, urination function, and sexual function between the two groups of patients with rectal cancer, which further suggests the feasibility of the popularization and application of laparoscopic surgery [21, 22].

This study has several limitations. First, a non-randomized contemporaneous comparison method was adopted to conduct research in this study. Despite improved patient compliance, the level of evidence-based medicine remains relatively low. Nevertheless, through the inclusion of more than 3,000 patients, the participation of 10 centers in China, and the participation of nearly 100 surgeons with experience in colorectal surgery, the reliability of this result can be guaranteed to a certain extent. Second, the follow-up endpoint of this study was 3-year disease-free survival. The study participants need to be followed up for a longer period, and the data will be summarized and analyzed at the corresponding time to obtain further results.