The Feasibility and Effects in Full Staging Surgery of Endometrial Cancer by Combination of Transumbilical Single-port Laparoscopy and ERAS

Backgrounds group and multi-port laparoscopic group, of which 31 cases and 62 cases in single port laparoscopic group and multi-port laparoscopic group were respectively. ERAS technology was used in the perioperative period of the two groups of patients, and the intraoperative and postoperative patients were compared. The medical records of 62 patients with type I endometrial cancer stage I who underwent open surgery from April 2011 to June 2018 were collected. Survival analysis was performed to compare the survival, mortality and recurrence among single port, multi-port laparoscopic and the open group.


Background
Endometrial Cancer (Endometrial Cancer EC) is the most common disease among female reproductive system malignancies in developed countries and ranks second in China. According to statistics from the National Cancer Center in 2019, the incidence of endometrial cancer in my country is 10.28 per 100,000, and the mortality rate is 1.9 per 100,000. In recent years, its incidence rate has shown a gradual increase trend, and the age of onset has a younger trend [1] .
The treatment of endometrial cancer is based on surgical treatment, and staged surgery is performed according to the patient's condition. The basic surgical procedures include extrafascial doubleattachment surgery, pelvic lymph node dissection, and para-aortic lymph node dissection. The surgical methods include conventional open surgery, vaginal surgery and laparoscopic surgery. With the advancement of laparoscopic technology and the continuous improvement of laparoscopic instruments, the advantages of laparoscopic surgery have become increasingly prominent. A large number of studies have shown that laparoscopic surgery for endometrial cancer has less intraoperative blood loss and faster postoperative recovery compared with open surgery. Therefore, laparoscopic surgery is favored by more and more physicians and patients, and has become one of the preferred methods for comprehensive staging of endometrial cancer [2,3] . Single port laparoscopic surgery (laparo-endoscopic single-site surgery, LESS) is to use the natural scar of the human umbilical to perform surgery, NOTES is the most feasible technology yet [4,5] . Nowadays, transumbilical single port laparoscopy is generally accepted and widely used because of its low dependence on equipment and mature technology and easy mastery.
The concept of enhanced recovery after surgery (ERAS) was rst proposed by Danish surgeon Professor Kehlet in 1997. ERAS refers to a series of perioperative optimization treatment measures based on evidence-based medicine to reduce surgical trauma and stress. Reduce postoperative pain, promote early eating and activities of patients, and accelerate postoperative recovery of patients [6] At present, ERAS has been widely used in gastrointestinal surgery, hepatobiliary surgery, urology, etc., and has been proven to promote gastrointestinal peristalsis, relieve pain and promote postoperative recovery of patients.
In order to study the safety and effects of transumbilical single port laparoscopic endometrial cancer full staging surgery combined with ERAS in the treatment of stage I endometrial cancer, the ERAS concept was applied to the perioperative period of single port laparoscopic endometrial cancer staging surgery to understand whether laparoscopic surgery is a risk factor affecting the prognosis of endometrial cancer. to December 2019 were selected as candidates. Single port laparoscopic group and multi-port laparoscopic group, of which 31 cases and 62 cases in single port laparoscopic group and multi-port laparoscopic group were respectively. ERAS technology was used in the perioperative period of the two groups of patients, and the intraoperative and postoperative patients were compared. The medical records of 62 patients with type I endometrial cancer stage I who underwent open surgery from April 2011 to June 2018 were collected. Survival analysis was performed to compare the survival, mortality and recurrence among single port, multi-port laparoscopic and the open group.

Inclusion criteria
Diagnosed as pathological type I endometrial cancer and veri ed as stage I by surgery; The size of uterus was smaller than 3 months pregnancy; No history of multiple abdominal surgery and repeated episodes of chronic pelvic in ammatory diseases; No serious medical and surgical complications symptoms; No contraindications to surgery, anesthesia and arti cial pneumoperitoneum. The patients were in good conditions with an ECOG score of 0-1.

exclusion criteria
Ages>75 years old with high risk of induction of anesthesia; Patients with severe medical and surgical basic diseases, coagulation dysfunction or receiving therapeutic anticoagulants; Active period of acute infection; A history of secondary abdominal surgery; Patients with suspected multiple tumor metastases; Obese patients (BMI>35kg/m2); Received radiotherapy or chemotherapy in the past; Type endometrial cancer; Other medical or psychological diseases that cannot cooperate to complete this research.

Grouping methods
This study was grouped by surgical method, and SMD (standardized difference) was used to verify the matching effect. The patients in the single port laparoscopic group and the multi-port laparoscopic group were matched and grouped according to 1:2. Different surgical methods were used as the dependent variables. Age, body mass index, menopause, gravity and parity, neoadjuvant chemotherapy, tumor tissue grade, surgical methods of hysterectomy, pelvic lymph node dissection, and para-aortic lymph node dissection were used as covariates. After matched grouping, there were 31 cases in the single port laparoscopic group and 62 cases in the multi-port laparoscopic group. In order to reduce the bias caused by different covariates, the SMD of each variable was calculated, such as SMD<0.2, indicating that the equilibrium distribution of covariates among the groups. All cases were supervised by the ethics committee of Guangxi Medical University A liated Cancer Hospital.

Administration in perioperative period
The candidates were administrated in accordance with the ERAS concept. All patients underwent preoperative examinations. And the gynecologists, anesthesiologists and nurses communicated with the patients before the operation about treatment methods and relieved their anxiety. No fasting food and liquid before the operation, 800ml orally took maltodextrin fructose drinks at 24:00 am last night before the surgery, and 400ml orally took maltodextrin fructose drinks at 6:00am in the surgery morning.
Preoperative skin preparation and preoperative antibiotics were used to clean contaminated incisions (class II incisions) and preventive use of antibiotics (conventional use of cefazolin sodium pentahydrate 2g combined with ornidazole 0.5g) with intravenous infusion 30min to 1h before skin incision. If the surgery time was more than3 hours or exceeded twice the half-life of antibiotics or the intraoperative blood loss exceeded 1500ml, the administration should be repeated. Intravenous short-acting anesthetics were applied during the surgery. Keeping a warm environment, raising the temperature of operating room and using a thermal insulation blanket to keep the body temperature at about 36.5 degrees, the incision was in ltrated and anesthetized with local anesthetics after surgery. Besides, the amount of uid input was control to prevent excessive uid. Returning to liquid diet as soon as possible after the surgery. The gastrointestinal function assessment performed by the physician in charge at least three times a day and adjusted diet according to the assessment. Routine analgesia and antiemetic treatment were given after the surgery, and early out-of-bed activity was encouraged. According to the patient's postoperative recovery, the drainage tube and catheter should be removed as soon as possible.
The basic discharge standards included being engaged in a semi-liquid diet,, wounds healing well without signs of infection, pain relieving merely by oral painkillers and moving freely.

Surgery methods
All candidates received extrafascial hysterectomy, adnexectomy and pelvic and paraaortic lymphadenectomy.

Evaluation
Intraoperation evaluation Intraoperation conditions Surgery time; intraoperative blood loss; intraoperative uid infusion; intraoperative blood transfusion rate; decrease in hemoglobin after the operation; number of lymph nodes resection.

Intraoperation complications
Obturator nerve injury; injury to nearby organs during surgery, including intestine, bladder, and ureter during surgery; vascular damage needing repair.

Rapid rehabilitation evaluation
Postoperative hospitalization days; postoperative urinary catheter indwelling time; recovery of gastrointestinal function; abdominal drainage tube indwelling time; postoperative incision pain scores were all based on the international standard Visual Analog Scale (Visual Analog Scale, VAS). The degree of pain is represented by 11 numbers from 0 to 10, 0 means no pain, and 10 represents the most painful. The patients choose one of the 11 numbers from 0-10 to represent the degree of pain according to her own pain level and records it (table1).

Quality of Life
The quality of life was assessed using the Health Survey Brief Table (SF-36), which included physiological functions, physiological functions, physical diseases, general health conditions, energy, social functions, emotional functions, mental health, etc., each with a full score of 100 points, The higher the score, the better the quality of life.

Survival analysis
Mortality, recurrence rate, overall survival (OS: the time interval from the beginning of treatment to death or the end of follow-up) and disease-free survival (DFS: the beginning of treatment to recurrence of the disease or the patient due to progression) time of death).

Follow up
All patients were followed up in outpatient clinics and telephone with every 3 months in the rst and second years after surgery. The main follow-up contents included gynecological physical examination, abdominal and pelvic imaging examination, and related laboratory examinations of tumor biomarkers to decide whether to perform chest, abdomen, and pelvic CT further. From the third year, the follow-up would be conducted every six months. And from the fourth year on, the follow-up would be conducted once a year.
Statistical analysis SPSS22.0 statistical software was used for statistical analysis. If the measurement data obeys the normal distribution or approximately accorded with normal distribution, the mean ± standard deviation was used to describe the data and the independent sample t test was used for the comparison between groups. While the measurement data was consistent with the skewness distribution, the median (interquartile) number interval to describe the data, and the Wilcoxon test was used for comparison between groups. Categorical data was described by percentages, and comparison between groups is by chi-square test or Fisher's test. The p value less than 0.05 was considered to be signi cant. SMD (standardized difference) was used to verify the balance of general data that SMD<0.2 indicating the ideal matching effect. And the smaller the SMD, the better the balance between groups.
Survival analysis was performed by R 3.6.1 software (https://www.r-project.org/). The Kaplan-Meier method was used to compare OS between groups. The Cox proportional hazard regression model was used to analyze the relationship between surgical methods and OS and PFS, and the hazard ratio (HR) and its corresponding 95% con dence interval (CI) were calculated. The p value less than 0.05 was considered to be signi cant.

Clinical characteristics
All clinical characteristics of single port and multiple-port laparoscopy groups were balance and comparable (table 3).

Intraoperation
The single port group was compared with the multiple-port group in terms of operation time, intraoperative blood loss, intraoperative uid infusion, and intraoperative blood transfusion rate. The differences were statistically signi cant (P 0.05). However, the change of hemoglobin in the single port group before and after the surgery, the number of pelvic and para-aortic lymph nodes resection, intraoperative complications were no signi cantly different. See Table 4.

ERAS
The postoperative conditions of single port laparoscopic group were signi cantly better than the multiport laparoscopic group. The time of water and food intake, atus, urinary catheter and abdominal drainage tube indwelling, hospital stay were signi cantly shorter in single port laparoscopic group. And pain score for 24 hours after surgery group was lower in single port laparoscopic group (Table 5).

Complications
There was 1 case of pelvic infection in the single port laparoscopic group. While there were 4 cases suffering complications in the multi-port laparoscopic group, including 2 cases of intestinal obstruction, 1 case of lymphatic leakage, and 1 case of urinary tract infection. But there was no signi cant difference between two groups in terms of the incidence of postoperative complications.

Cosmetic effect of incision
Transumbilical single port laparoscopic surgery took advantage of the skin folds of the umbilical to conceal the incision to the greatest extent. The appearance of the umbilical restored to the preoperative state in 3 months after the surgery, as shown in Figure 1 and Figure 2. Patients in the single port group were more satis ed with the cosmetic effect of the postoperative incision (Table 6).  The physical function, physical pain and vitality of the single port laparoscopic group were signi cantly better than that of the multi-port laparoscopic group. But there was no signi cant difference in physical roles, general health status, social function, emotional roles, and mental health between the two groups, see Table 7.
The in uence of prognosis among different surgery methods clinical data Comparing the general information of the patients, there was no signi cant difference in age, pregnancy, menopause, BMI, pelvic lymph node dissection, and para-aortic lymph node dissection among the three groups (P>0.05); while the three groups of patients had signi cant differences in stages and differentiation (P<0.05). The three groups of patients had a good balance in terms of age, pregnancy and childbirth, and para-aortic lymph node dissection, with SMD<0.2; but the balance of variables such as BMI, FIGO staging, and tumor differentiation slightly worse with SMD>0.2. So, the multivariate COX regression models analysis were conducted to control the in uence of confounding factors (Table 8).
Table8.Comparison of general features among three groups of patients The median follow-up time in the single port laparoscopic group was 13 months, and 1 case died and 2 cases recurred. While the median follow-up time in the multi-port laparoscopic group was 20 months, 2 cases died, and 2 cases recurred. And the median follow-up time in the open surgery group was 66 months a total of 7 cases died and 4 cases recurred. The mortality and recurrence rate among three groups was no signi cantly different (Table 9).  Figure 3A. The 1-year DFS of patients in single port, multiple-port laparoscopic groups, and open surgery group were 93.5%, 94.7%, and 91.7%, respectively, and there was no signi cant difference among the groups (P=0.759), as shown in Figure 3B.  [7] rst reported a comprehensive staging operation for endometrial cancer under LESS. It is believed that single port laparoscopic surgery is safe and feasible in the treatment of gynecological malignant tumors This study selected 93 patients with type I endometrial cancer stage I for a prospective randomized controlled study to compare the clinical effects of single port laparoscopy and multiple-port laparoscopy.
The results showed that compared with the multiple-port laparoscopic group, the differences of medium transfusion volume and intraoperative blood transfusion rate were signi cant different in single port laparoscopic group (P<0.05). Although the intraoperative blood loss of the single port laparoscopic group was slightly more than that of multiple-port laparoscopic group (100ml vs 90ml) (P=0.044), the intraoperative blood transfusion rate was lower than that of the multiple-port laparoscopic group (0% vs 1.61%) (P=0.000). It resulted that the change of hemoglobin before and after the surgery was not signi cantly different between single port and multi-port laparoscopic groups (P>0.05). Meanwhile, the intraoperative and postoperative complications did not increase in single port laparoscopic group, which was consistent with the research conducted by Chambers [8] , verifying the safety and feasibility of single port laparoscopy technology in full staging surgery of endometrial carcinoma. However, the surgery time of the single port laparoscopic group (283min) was signi cantly longer than that of the multi-port laparoscopic group (180min) (P 0.001), so the intraoperative uid infusion volume (2400ml) of the single port laparoscopic group was signi cantly more than that of the multi-port laparoscopic group (1900ml) (P=0.011). This might be due to the lack of experiences. Although our team had carried out multi-port laparoscopic gynecological malignant tumor surgery for many years, it was in the year of 2018 that the single port laparoscopic endometrial cancer staging surgery was carried out. In 2017, Barnes et al. [9] retrospectively analyzed 110 cases of single port laparoscopic endometrial cancer comprehensive staging surgeries, and compared the last 30 cases with the rst 20 cases in the study cohort. The results indicated that after the rst 20 surgeries, the surgeries time, intraoperative blood loss and complication rate decreased signi cantly. Moreover, the limitations of the equipment that the unique "chopsticks effect" of single port laparoscopy contributed to longer surgery time at some extent [10,11] . Generally, the application of conventional laparoscopic surgical instruments was di cult in single port laparoscopy, which leads to prolonged surgery time. If we made improvements to the equipment, the lens could be replaced with a smaller one, and the instrument could be replaced with a long or short instruments, which were able to reduce the di culty of the surgery and shorten the surgery time.
In addition, the number of lymph node dissection is an important indicator to evaluate the effect of surgery, and the surgery of endometrial cancer includes pelvic lymph node dissection±para-aortic lymph node dissection. The effect of different surgical methods can be evaluated by counting the number of lymph nodes. There was no statistically signi cant difference between the pelvic lymph nodes (13.39±7.36 vs 14.05±7.64) and para-aortic lymph nodes (3.00 (0.50, 5.50) vs 4.00 (2.00, 7.00)) dissected in the single port laparoscopic group and the porous group (P>0.05), suggesting that single-port laparoscopic surgery can also achieve the effect of multi-port laparoscopic surgery in cleaning lymph nodes.
In 2012, Fagotti et al. [12] retrospectively analyzed 100 patients with endometrial cancer undergoing single port laparoscopic surgery. The mean of pelvic lymph node dissections was 16 , which was similar to the results of this study. Although there is no signi cant difference in the dissection of the lymph nodes adjacent to the abdominal aorta, the number of lymph nodes was relatively less. These were likely caused by the position of the para-aortic lymph nodes was higher, and the laparoscopic exposure was not enough, especially for some obese patients, resulting more di cult to clean the para-aortic lymph nodes. Besides, pro ciency in surgical technique exerted a certain in uence. With the improvement of surgical skills and the pro ciency in the application of single-port instruments, the number of lymph nodes dissected by single-port laparoscopic surgery in the abdominal aortic lymph node dissection will increase, which is similar to the domestic case report of Sun Dawei [13] .
In terms of cosmetic effects, the transumbilical single port laparoscope uses a 1.5-3cm incision in the natural recess of the umbilical channel as the surgical approach. The postoperative incision was sutured with absorbable sutures, and the umbilical skin folds could be maximized. Compared with the multipleport laparoscopic group, the patient satisfaction is signi cantly improved.
Application of ERAS in single port laparoscopic endometrial staging surgery Although there are no obvious requirements for minimally invasive surgical incisions in the rapid rehabilitation (ERAS) surgical concept, transumbilical single port laparoscopic surgery (LESS) has only one incision on the abdominal wall with a smaller incision than that of multi-port laparoscopic surgery. If combined with perioperative ERAS, patients should bene t more. Although there is few research on LESS combined with ERAS at home and abroad, the development of colorectal and other surgery has become mature.
In 2012, Ge Haiying et al. [14] published a case analysis of 5 patients with rectal cancer combining ERAS with single port laparoscopy. The 5 patients had little postoperative pain, the postoperative hospital stay was 6 days, and there were no surgery complications. No recurrence or metastasis was found during the 12-month follow-up. In 2016, Chapman et al. [15] used a retrospective case-control study to take laparoscopic or robot-assisted gynecological tumor surgery patients who received ERAS perioperative man-agement and care as the research subjects. The analysis found that who received minimally invasive surgery (laparoscopic or laparoscopic surgery or robot-assisted surgery) for gynecological cancer patients recover faster. The imple-mentation of the ERAS route during the perioperative period can shorten the re-covery time and reduce overall hospitalization costs, immune function damage, and damage to in ammatory factors [16] .
According to the previous studies, LESS combined with ERAS can shorten the postoperative recovery time of patients. For the patients with gynecological malignant tumors, rapid postoperative recovery is conducive to early implementation of postoperative adjuvant treatment. In the comprehensive staging surgery of endometrial cancer, domestic and foreign literature believed that traditional endoscopic technology combined with ERAS was safer and more effective [17,18] . But there were few studies related to LESS combined with ERAS. In this study, the results suggested that single port laparoscopic combined with ERAS group patients recovered better than that of multi-port laparoscopic combined with ERAS group. In general, single port laparoscopy combined with ERAS can not only promote the recovery of patients after surgery, shorten the hospital stay, but also relieve wound pain. Also, this study conducted a survey of the quality of life of SF-36 in patients 3 months after surgery. The scores of each index of the two groups of patients were above 80 points, indicating that the quality of life after laparoscopy combined with ERAS was ideal for both single port and multi-port laparoscopic groups. The scores of physical function, physical pain, and vitality of the single port laparoscopic group are higher than those of the multi-port laparoscopic group, indicating that the single port combined with ERAS has more advantages in the quality of life of patients after surgery.
The in uence of surgical methods on the prognosis of endometrial cancer There are many factors that affect the prognosis of endometrial cancer, but whether the choice of surgical methods will affect the prognosis has always been a hotspot. Janda et al. [19]  This study was based on a prospective randomized controlled study (31 cases in the single port laparoscopic group and 62 cases in the porous group), combined with 62 patients with type I endometrial cancer stage I who had undergone open surgery for survival analysis. The 1-year overall survival of patients with single port, multi-port laparoscopic groups and open surgery group were 96.8%, 98.4%, and 91.5%, respectively, but there was no signi cant difference among the groups, so were the disease-free survival and overall survival. Subsequent univariate and multivariate COX regression analysis showed that the surgical method was not associated with DFS and OS, indicating that the surgical method was not an independent risk factor affecting the prognosis of endometrial cancer, and laparoscopic surgery would not increase the risk of prognosis, which was consistent with those reported in the literature.
In summary, single port laparoscopic surgery for stage I endometrial cancer staging is safe and feasible, and the cosmetic effect is satisfactory. ERAS technology combined with single-port laparoscopic endometrial cancer staging surgery has obvious advantages in the perioperative period. At the same time, it was con rmed that the single port laparoscopic technique did not affect the prognosis of endometrial cancer. However, this study was a single-center study, and the sample size was small, and the follow-up time was not long enough, which might have a certain impact on the results. In the future, multi-center prospective studies should be carried out to make the observation time can be extended to make the results more convincing. This retrospective study protocol was approved by the Ethics Committee of Guangxi Medical University a liated Cancer Hospital. Of note, the requirement to obtain informed consent was waived because of the retrospective nature of this study, and all sensitive information, including the identi cation of patients, medical institutions, and medical practitioners, was made anonymous.

Abbreviations
Consent for publication I understand that the information will be published without my/my child or ward's/my relative's name attached, but that full anonymity cannot be guaranteed.

Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.