Comparison of the efficacy and safety of total laparoscopic hysterectomy without and with uterine manipulator combined with pelvic lymphadenectomy for early cervical cancer

Some studies have reported that the prognosis of total laparoscopic hysterectomy (TLH) for early‐stage cervical cancer (CC) is worse than that of open surgery. And this was associated with the use of uterine manipulator or not. Therefore, this study retrospectively analyzes the efficacy and safety of TLH without uterine manipulator combined with pelvic lymphadenectomy for early‐stage CC.


INTRODUCTION
Cervical cancer (CC) is one of the most common cancers in women and the second life-threatening cancer after breast cancer.Infection of high-risk human papilloma virus (HPV) is the leading cause of CC. 1 According to statistics, there were about 600 000 new cases of CC globally in 2020, including about 340 000 deaths and with a mortality rate as high as more than 50%. 2 More terribly, patients with CC in developing countries have a higher mortality rate, accounting for more than 85% worldwide. 3,4pen radical hysterectomy combined with pelvic lymphadenectomy is the earliest surgery applied to treat CC. 3 With the advancement of science and technology, laparoscopic radical surgery for CC was debuted in 1992. 5It is reported that compared with traditional laparotomy, laparoscopic surgery is characterized with advantages such as less intraoperative blood loss, clear anatomical field, small incision, faster postoperative recovery, and better postoperative quality of life. 6Therefore, laparoscopic surgery has been widely applied in treating early CC serving as the preferred choice for both doctors and patients.However, Laparoscopic Approach to Cervical Cancer (LACC) trail have proposed that, relative to traditional laparotomy, patients receiving laparoscopic surgery have a higher recurrence rate and a lower disease-free survival rate. 7The results of this high-level clinical study have astounded gynecologic oncologists worldwide.Most of scholars believe that this may be related to the use of uterine manipulator in laparoscopic surgery. 8,9Uterine manipulator, a device used in total or subtotal hysterectomy, is mainly organically composed of central guide rod, cervical fixator, and fornix cup.Uterine manipulator can lift the uterus and facilitate the complete resection of the cervix during surgery. 10The application of a uterine manipulator in abdominal hysterectomy can reduce vaginal shortening, reported by a study. 11However, according to a retrospective analysis, the absence of a uterine manipulator can reduce related complications and avoid ureteral injury. 12Currently, the efficacy and safety of uterine manipulator are still controversial.Therefore, 58 patients with CC (clinical stage IB1-IIA1) who consecutively underwent radical hysterectomy in Meizhou People's Hospital (Huangtang Hospital) were selected in this study first.Then, we investigated the efficacy and safety of total laparoscopic hysterectomy (TLH) without uterine manipulator combined with pelvic lymphadenectomy for patients with early CC through retrospectively analyzing their clinical data.Briefly speaking, the objective of this study was to provide a theoretical basis for the treatment of patients with early CC in clinical practice.

Study subjects
Fifty-eight patients with CC in IB1-IIA1 stage clinically who consecutively received radical hysterectomy from December 2018 to March 2020 in Meizhou People's Hospital (Huangtang Hospital) were selected.The selected patients were divided into the no uterine manipulator group (n = 26) and uterine manipulator group (n = 32) according to whether applying uterine manipulator.
Inclusion criteria and exclusion criteria 13 were shown as follows.Patients were included in this study if they (1) aged 18 years or older; (2) were confirmed to suffer from CC histologically; (3) had tumor types such as squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma; (4) were identified as IB1-IIA1 stage clinically and pathologically.The patients were excluded as long as they (1) did not undergo preoperative imaging or pathological assessment with guidance of a standardized protocol; (2) had any history of invasive tumors except CC; (3) had received chemotherapy or radiotherapy previously.After that, the data such as age, body mass index (BMI), histological subtype, clinical and pathological stage, tumor size, and number of pelvic/paraaortic lymph node transplants were collected from the included patients.By the way, this study had been approved by the Ethics Committee of Meizhou People's Hospital (Huangtang Hospital) (Ethics No.: 2021-C-02).Inform consent was obtained from all patients.

Operation methods
In the no uterine manipulator group, patients were given conventional laparoscopic hysterectomy without uterine manipulator and pelvic lymphadenectomy. 14Specifically, the patient received general anesthesia in a supine position, followed by routine disinfection and draping for establishment of artificial pneumoperitoneum.Next, a figureof-eight suture was given at the fundus of the uterine, with the coils reserved.The coils were clamped with needle holders, and the direction of the uterus was controlled according to the need of the operation.Subsequently, lymph nodes were dissected, the artery and vein beside the uterus were ligated and cut off, and the posterior vaginal wall was routinely freed.Next, the ligaments around the uterus were separated, the uterus was freed, and the paravaginal tissues and rectal ligaments were cut off.After incision of the vagina, the uterus was removed and the sample was collected.In the uterine manipulator group, patients received laparoscopically assisted pelvic lymphadenectomy + hysterectomy treatment. 15To be specific, after general anesthesia, patient's body was adjusted to a dorsal lithotomy position (Trendelenburg position).Upon the end of preoperative preparation, laparoscopic "three-port method" was used to send surgical instruments to the patient's abdominal cavity.Under the help of surgical instruments, the artificial pneumoperitoneum was established.After that, laparoscopy was employed to observe the pelvic and abdominal cavity.If there was an adhesive structure, surgical instruments were used for a separation.Upon the removal of uterus using harmonic scalpel, the peritoneum between the uterus and bladder was incised and pelvic lymph nodes were dissected.After the completion of lymph node dissection, the bleeding of the pelvic cavity was stopped through taking some hemostatic measures.Later, the pelvic cavity was washed, and a drainage tube was placed.Finally, the incision was sutured, and the operation was ended up.

Outcome measures
1. Hemoglobin changes, operation time, intraoperative bleeding, blood transfusion, number of pelvic nodules, and anal exhaust time were compared between the two groups.2. Intraoperative and postoperative complications were compared between the two groups.3. The comparison of the recurrence rate, 1-year survival rate and metastasis were performed between the two groups.

Statistical analysis
Statistical software SPSS 22.0 was employed for data analysis.Measurement data were expressed as mean ± standard deviation, and t test was used for comparison between the two groups; enumeration data were expressed as n (%), chisquare test or Fisher exact test was used for comparison among groups.Additionally, Kaplan-Meier curve was utilized for survival analysis, and log-rank method for comparing survival distributions from two samples.p < 0.05 indicated a statistically significant difference.

Clinical baseline characteristics of the two group patients
As shown in

Comparison of intraoperative and postoperativerelated indicators between the two groups
The operation time of the no uterine manipulator group was significantly longer than that of the uterine manipulator group (191.23 ± 44.26 min vs. 168.88± 25.85 min, p = 0.020).Referring to the changes in hemoglobin levels during the perioperative period, the blood loss was significantly larger (72.69 ± 33.65 mL vs. 55.62 ± 20.31 mL, p = 0.020) in the no uterine manipulator group than that in the uterine manipulator group.However, there was no notable difference in hemoglobin change, blood transfusion rate, number of pelvic nodules, and anal exhaust time between the two groups (p > 0.05) (Table 2).

Comparison of intraoperative and postoperative complications between the two groups
As shown in Note: Measurement data were expressed as (mean ± SD); enumeration data were expressed as n (%).Abbreviation: BMI, body mass index.
lymphocyst (12.5%) was higher.In the no uterine manipulator group, complications were diagnosed from 15 patients, among them, the probabilities of bladder dysfunction (23.1%) and urinary retention (15.4%) were higher.The differences in the occurrence of complications between the two groups were not significant ( p > 0.05).Port site 0 (0) 0 (0) --Note: "-" indicated no exact value; enumeration data were expressed as n (%).

Comparison of postoperative recurrence and survival rate between the two groups
As shown in Table 4, a median follow-up of 6 months (range: 0-12 months) was performed on the two group patients.There was no significant difference in the 1-year disease-free survival (DFS) rate (86.4% vs. 84.6%)and overall survival (OS) rate (93.6% vs. 88.3%) between the two groups (p > 0.05) (Figure 1 and Table 4).The recurrence rate was 15.4% in the no uterine manipulator group and 9.4% in the uterine manipulator group.Additionally, seven patients in the uterine manipulator group suffered from distant metastases (involving the brain, lung, liver, and intra-abdominal cavity); five patients in the no uterine manipulator group presented with distant metastases (two cases of metastases in the lung, one in the brain, one in the bone, and one in the abdominal cavity).Both group patients did not occur port site metastasis.Overall, there was no significant difference in the recurrence rate and distant metastasis between the two groups (p > 0.05).

DISCUSSION
Compared with traditional laparotomy, the application rate of laparoscopic surgery in the treatment of early CC is higher owing to a variety of advantages such as less intraoperative bleeding, small incision, quick healing, and less postoperative complications. 16One study noted that the number of patients treated with minimally invasive radical hysterectomy decreased from 64.9% to 30.4% after the release of the LACC trial. 17In comparison with traditional open surgery, laparoscopic surgery exhibits a higher recurrence rate and a lower tumor-free survival rate. 7However, some studies suggest that intraoperative application of uterine manipulators may be associated with clinical outcomes and prognosis of patients with early CC receiving laparoscopic surgery. 18,19At present, the efficacy and safety of uterine manipulators in laparoscopic surgery still remain controversial.Therefore, the efficacy and safety of laparoscopic surgery without uterine manipulator on patients with early CC were explored in this study.In this research, there were no significant differences in postoperative complication rates, postoperative recurrence rates, and 1-year overall survival between TLH without uterine manipulator combined with pelvic lymphadenectomy and conventional laparoscopic surgery with uterine manipulator.Such finding further confirmed the feasibility of hysterectomy without uterine manipulator.
In this study, the clinical data of 58 patients with early CC were divided into no uterine manipulator group and uterine manipulator group, with mean ages of 49.08 ± 11.69 and 52.72 ± 8.87 years, respectively.Previous studies have reported that the most common onset age of CC in China ranges from 45 to 54 years, consistent with the result in this study. 20An epidemiological study of CC in China showed that the ratio of squamous cell carcinoma to adenocarcinoma was 10.6:1 in patients with early CC. 21In this paper, the ratio of squamous cell carcinoma to adenocarcinoma was 8.3:1, which was lower than that reported in previous studies, suggesting that the incidence of adenocarcinoma is increasing.Endocervical adenocarcinoma is prevalent adenocarcinoma not prone to be detected in the early stage.The increased incidence of adenocarcinoma in this study indirectly illustrated the improved diagnostic level of CC in our hospital.
The outcome measures of patients were further compared between the two group in this study.The results showed much longer operation time of patients in the no uterine manipulator group than in the uterine manipulator group.Patients in the no uterine manipulator group had a longer operation time because they needed to undergo figure-of-eight suture at the fundus of the uterine.According to previous studies, the duration of most laparoscopic CC surgeries is 150-200 min.The duration of surgery in both groups in this study is consistent with previous reports. 22,23Moreover, we also observed that the blood loss of patients in the no uterine manipulator group was significantly higher than that in the uterine manipulator group.Although the blood transfusion rate was also slightly higher, the difference was not significant.Laparoscopically assisted pelvic lymphadenectomy and hysterectomy did not affect the surgical field, and the bleeding point could be accurately positioned when the bleeding occurred.Therefore, the blood loss and blood transfusion rate of patients in the uterine manipulator group were relatively low.There was no significant difference in hemoglobin change, number of pelvic nodules and anal exhaust time between the two groups.Hence, the two operation methods had no adverse effect on the recovery of postoperative gastrointestinal function in F I G U R E 1 Disease-free survival in the no uterine manipulator group and uterine manipulator group.patients. 24,25In addition, the probability of urinary retention was higher in both groups, and the incidence of bladder dysfunction reached 23.1% in the no uterine manipulator group.Some researchers have pointed out that laparoscopic radical surgery can affect the pelvic floor of patients, and usually, doctors will prolong the indwelling time of urinary catheter to ensure that patients can urinate normally.Nevertheless, the indwelling of urinary catheter is an invasive procedure, which will stimulate the urethra of patients, 26 weaken the reflex of micturition, and increase the risk of bladder dysfunction. 27Fortunately, assessment of the urination of patients and remove indwelling catheters as early as possible may reduce the risk of postoperative bladder dysfunction. 28he follow-up was also carried out for the recurrence and survival rates of the patients.To be specific, the 1-year DFS rate (86.4% vs. 84.6%)and OS rate (93.6% vs. 88.3%)were not significantly different between the two groups.In a meta-analysis including six observational studies, minimally invasive radical hysterectomy without uterine manipulator had a lower recurrence-free survival rate than open radical hysterectomy. 29Besides, the study by Nica et al. claimed that the use of uterine manipulator in patients with early CC undergoing minimally invasive radical hysterectomy was not an independent factor associated with their recurrence rates, 30 generally consistent with our results.Furthermore, some other researchers have stated that the use of uterine manipulator will bring tumor cells into the uterine cavity, which may increase the risk of postoperative recurrence. 31Therefore, conventional laparoscopically assisted extensive hysterectomy without uterine manipulator was performed in this study.The implement of measures like figure-of-eight suture at the fundus of the uterine and needle holder clamping coil in the no uterine manipulator group greatly avoided the destruction of tumor tissue or cells caused by surgery and reduced the recurrence rate of patients as much as possible.
TLH without uterine manipulator + pelvic lymphadenectomy further improves the laparoscopic operation.Specifically, it preserves the advantages of laparoscopic surgery and prolongs the survival of patients.This study was one of the few retrospective studies that analyzed the efficacy and safety of TLH without uterine manipulator combined with pelvic lymphadenectomy relative to conventional laparoscopic surgery with uterine manipulator.Our research provided a data support for the application of TLH without uterine manipulator + pelvic lymphadenectomy in early-stage CC.However, due to the limitations of retrospective analysis, the sample size of this study was small.The weight of evidence for the above findings needs to be strengthened and gradually improved in subsequent studies.
In summary, there is no significant difference in the efficacy and safety between TLH without uterine manipulator + pelvic lymphadenectomy and traditional laparoscopic surgery.Therefore, despite higher feasibility of TLH without uterine manipulator + pelvic lymphadenectomy in the treatment of patients with early CC, the negative effects brought by the operation time and blood loss during surgery need to be taken into consideration.Next, a randomized controlled study with multiple samples will be carried out to further validate the feasibility of TLH without uterine manipulator + pelvic lymphadenectomy for patients with early-stage CC.For oncologists, the principles of standardized oncology treatment are the foundation.Therefore, the problems encountered during surgery should be analyzed objectively and comprehensively.Continuous improvement not only make surgery safer and more effective but also make it bring more benefits to patients.

Table 1
, a total of 58 patients with CC were enrolled and divided into no uterine manipulator group and uterine manipulator group.There were 26 patients in the no uterine manipulator group, including 22 cases (84.6%) of squamous cell carcinoma, 3 cases (11.5%) of adenocarcinoma, and 1 case (3.8%) of squamous adenocarcinoma, with a mean age of 49.08 ± 11.69 years and a mean BMI of 25.30 ± 1.95 kg/m 2 .The uterine manipulator group consisted of 32 patients, with a mean age of 52.72 ± 8.87 years and a mean BMI of 26.09 ± 1.73 kg/m 2 , including 28 cases (87.5%) of squamous cell carcinoma, 3 cases (9.4%) of adenocarcinoma, and 1 case (3.1%) of squamous adenocarcinoma.There was no statistical difference in age, BMI, histological subtype, clinical and pathological stage, tumor size, and number of lymph node transplants between the two groups (p > 0.05).Therefore, the general information of the two groups was comparable.

Table 3
, a total of 17 patients in the uterine manipulator group suffered from complications, of which the probability of urinary retention (15.6%) and T A B L E 1 Comparison of general information between groups.
Comparison of results between the two groups.Comparison of complications between the two groups.
T A B L E 2Note: "-" indicated no exact value; enumeration data were expressed as n (%).T A B L E 4Comparison of recurrence and survival rate between the two groups.