Clinical Outcomes in Early Cervical Cancer Patients Treated with Nerve Plane–sparing Laparoscopic Radical Hysterectomy

Original Article

Clinical Outcomes in Early Cervical Cancer Patients Treated with Nerve Plane−sparing Laparoscopic Radical Hysterectomy Dan Zhao, MD, Bin Li, MD, Yating Wang, MD, Shuanghuan Liu, MD, Yanan Zhang, MD, and Guangwen Yuan, MD From the Department of Gynecology Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

ABSTRACT Study Objective: To explore the feasibility of nerve plane−sparing laparoscopic radical hysterectomy (NPS-LRH) as a simplified C1-type surgery for cervical cancer patients and to compare this technique with laparoscopic radical hysterectomy (LRH). Design: A retrospective comparative study. Setting: An academic tertiary hospital affiliated with the Chinese National Cancer Center. Patients: Six hundred fifteen patients with F
ed
eration Internationale de Gyn
ecologie et d’Obst
etrique stage Ib and IIa cervical cancer who underwent laparoscopic radical hysterectomy between January 2010 and December 2017 were enrolled. Among them, 263 patients underwent the NPS-LRH surgery, and 352 patients underwent the LRH surgery. Intraoperative data and postoperative outcomes were compared between the 2 groups. Interventions: NPS-LRH is a simplified type C1 procedure that preserves the ureteral mesentery and its nerve plane, whereas LRH is a type C2 procedure in the Querleu-Morrow surgical classification system. Measurements and Main Results: There were no statistically significant differences in age, body mass index, F
ed
eration Internationale de Gyn
ecologie et d’Obst
etrique stage, tumor differentiation, pathological type, depth of invasion, lymphovascular space invasion, parametrial tissue invasion, lymphatic metastasis, neoadjuvant chemotherapy, or postoperative adjuvant radiotherapy and chemotherapy between the 2 groups. Compared with the LRH group, the NPS-LRH group had a shorter length of operation (238.7 § 53.9 minutes vs 259.8 § 56.6 minutes, p < .01), less intraoperative bleeding (p < .01), more resected lymph nodes (p = .028), shorter duration of urinary catheterization (p < .01), lower incidences of postoperative hydronephrosis (p = .044), less long-term frequent urination (p < .01), less acute urinary incontinence (p < .01), poor bladder sensation (p = .028), and constipation (p = .029). There were no statistically significant differences in the diseasefree survival and overall survival between the 2 groups (p = .769 and .973, respectively). Conclusion: NPS-LRH is a simplified, safe, and feasible type C1 operation that had a shorter length of operation, less intraoperative bleeding, more resected lymph nodes, and better postoperative bladder function compared with the LRH group. Further studies are required to assess its benefits on rectal function and long-term prognosis. Journal of Minimally Invasive Gynecology (2019) 00, 1−10. © 2019 AAGL. All rights reserved. Keywords:

Bladder function; Bowel function; Cervical cancer; C-type operation; Laparoscopy; Querleu-Morrow classification; Prognosis

The authors declare that they have no conflict of interest. Supported by the special fund for “Capital City Clinical Specific Application Study” Z171100001017115, and CAMS Initiative for Innovative Medicine (no. 2017-I2M-2-003). Corresponding author: Bin Li, MD, Department of Gynecology Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, South Panjiayuan Residential, Chaoyang District, Beijing 100021, China. E-mail: [email protected] Submitted February 26, 2019, Revised April 25, 2019, Accepted for publication April 26, 2019. Available at www.sciencedirect.com and www.jmig.org 1553-4650/$ — see front matter © 2019 AAGL. All rights reserved. https://doi.org/10.1016/j.jmig.2019.04.025

Cervical cancer remains a major malignancy that threatens women’s health worldwide, even though this disease is rapidly decreasing because of human papillomavirus (HPV) vaccination in the European and American countries, In China, HPV 2-valent vaccine was approved by China Food and Drug Administration in 2017, becoming the first HPV vaccine approved for cervical cancer prevention in China. The effect of the vaccine has not yet been shown. The number of new cases was approximately 98,900, whereas the number of deaths was 30,500 per year [1]. Radical hysterectomy has been the main treatment for F
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ecologie et d’Obst
etrique

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(FIGO) stage Ib-IIa cervical cancer, and it has a cure rate of more than 80% [2]. However, the pelvic autonomic nerves can be damaged when removing parametrial tissues extensively. The pelvic autonomic nerves consist of the hypogastric nerve (HN), pelvic splanchnic nerve (PSN), and its inferior hypogastric plexus (IHP). These nerves control the bladder, rectal, and sexual functions in women. The main complications after nerve injury are bladder and bowel dysfunction [3,4], with bladder dysfunction being more prominent and accounting for 76% to 85% of the complications [5,6]. The introduction of laparoscopic radical hysterectomy (LRH) brings the advantage of reducing surgical injuries and providing a faster recovery. Despite the technical improvement, 37% of patients still develop postoperative urinary dysfunction, which affects their quality of life [7]. A nerve-sparing radical hysterectomy (NSRH) technique was introduced with the goal of preserving the fine pelvic autonomic nerve structures while resecting the parametrial tissue. Although several early studies have shown that NSRH is feasible, the anatomic landmarks used in the operations were not consistent, and the surgical steps were complicated [8−13]. In 2008, the Querleu-Morrow (Q-M) surgical classification system listed NSRH as a C1-type radical hysterectomy [14], suggesting that type C1 had become the mainstay and should be widely applied. Thus, it is necessary to establish a standardized and simplified C1 procedure. Several anatomic studies have shown that, although the network of pelvic autonomic nerves is complex, these nerves are distributed in parallel within a thin layer of the tissue under the ureter, which is called the pelvic nerve plane [15−18]. Based on these studies, we proposed a new surgical approach in 2011—nerve plane−sparing radical hysterectomy (NPSRH) [19]. In NPSRH, the ureter was used as the key anatomic landmark, whereas the nerve plane under the ureter was preserved. With this technique, there was no need to dissect the detailed nerve structures of HN, PSN, and IHP, which simplifies the procedure considerably. Our pilot study showed that open NPSRH improved postoperative bladder and bowel functions without affecting the prognosis, and it could be performed as a simplified C1 procedure [20,21]. In the current study, we explored the feasibility of nerve plane−sparing laparoscopic radical hysterectomy (NPS-LRH) and compared its outcome with those of conventional laparoscopic radical hysterectomy (LRH).

Materials and Methods Study Design and Participants We conducted a retrospective comparative study in 615 consecutive patients with FIGO stage Ib-IIa cervical cancer between January 2010 and December 2017 who received LRH at the Department of Gynecologic Oncology in the Cancer Hospital of the Chinese Academy of Medical Sciences, Beijing, China. Among them, 263 patients underwent

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NPS-LRH, which was performed by 3 laparoscopic surgeons. The remaining 352 patients underwent LRH surgery by other surgeons who did not master the NPS-LRH technique in the department. Informed consent was obtained from each patient before surgery. The study protocol was approved by the hospital ethics committee. Preoperative Assessment and Treatment For all patients, preoperative biopsies were performed to confirm the pathological diagnosis of cervical cancer. Pelvic examinations were performed by 2 senior gynecologic oncologists to determine the clinical FIGO stages. Imaging studies, including a B-scan ultrasound, chest X-ray, pelvic and abdominal computed tomographic scan, and magnetic resonance imaging, were used to exclude the possibility of parametrial and distant metastases. The preoperative blood tests included routine cell counts, chemistry, and tumor marker tests. In patients with locally advanced cancer (Ib2 and IIa2 stages and cervical tumor size >4 cm), 1 to 2 cycles of preoperative neoadjuvant chemotherapy with paclitaxel combined with platinum (cisplatin or carboplatin) were administered to reduce the tumor size to less than 4 cm before surgery. Surgical Procedures After general anesthesia and intubation, the patient was placed in the Trendelenburg position, and standard disinfection, draping, and urinary catheterization were performed. A CO2 pneumoperitoneum was established with a pressure of 15 mm Hg. A laparoscope was inserted into the peritoneal cavity between the umbilicus and the xiphoid process. Under direct visualization, 3 to 4 trocars of 5 or 12 mm were placed into the peritoneal cavity. Then, pelvic lymphadenectomy was performed. Patients with common iliac lymph node metastasis or locally advanced cancers received abdominal para-aortic lymphadenectomy. Ovarian transposition was performed in young patients. NPS-LRH (Simplified C1 Type) NPS-LRH was characterized by full use of the pelvic intrinsic space during dissection of the parametrial tissues. The ureter was the key anatomic landmark throughout the operation. The entire ureteral mesentery and its extension to the dorsal side (nerve plane) were preserved, and the pelvic autonomic nerve structures were left untouched. These key steps were like the open NPSRH procedure, which we had reported previously [19]. The extent of parametrial resection was based on the C1-type criteria of the Q-M classification of cervical cancer surgery [14]. The dimension of resection was as follows: dorsal parametrium, lateral parametrium (paracervix), and ventral parametrium. The ureter attached to the posterior leaf of the broad ligament was detached laterally together with its dorsal

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Clinical Outcomes in Early Cervical Cancer Patients

mesentery (the proximal portion of the nerve plane that contained the HN nerve bundle). The Okabayashi space was exposed on the inner side of the mesoureter. The Douglas pouch was opened, and the rectum was pushed down. The uterosacral ligament was resected at the rectum via the Okabayashi space, without causing any injury to the proximal part of the nerve plane (Fig. 1A). Between the Fig. 1 The key surgical steps during the NPS-LRH procedure. (A) Dorsal parametrium management; the uterosacral ligament was resected at the site medial to the Okabayashi space. The mesentery under the ureter was preserved as the proximal part of the nerve plane in which the HN bundle was contained. (B) Lateral parametrium management; resection was performed at the beginning of the uterine artery. The parametrial lymph tissues were removed around the deep uterine vein. The deep uterine vein and the dorsal side of the PSN were preserved. The HN bundle along the ureter can be seen in the figure. (C) Ventral parametrium management; the ureter and the distal portion of the underlying nerve plane were pushed outward from the paravaginal space to preserve the IHP bladder branch. On the inner side of the nerve plane, the branches of the deep uterine vein, including the uterine tributary, the middle vesical vein, and the inferior vesical vein, were resected. The nerve plane was preserved.

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paravesical space and the pararectal space, the uterine artery and the superficial uterine vein were resected at the level of their origin. All parametrial lymphatic tissues around the deep uterine vein were removed, but the trunk of the deep uterine vein was preserved to avoid injury to the underlying PSN and the medial nerve plane (Fig. 1B). The vesicouterine fold of the peritoneum was opened, and the bladder was pushed down to the level of the upper third vagina. The paravaginal space was dissected. After unroofing the ureter, the ureter and the underlying distal part of the nerve plane (the part of the mesoureter that extends toward the bladder and contained the IHP bladder branch) were pushed laterally via the paravaginal space. On the side medial to the nerve plane, the branches of the deep uterine vein (including the uterine tributary, the middle vesical vein, and the inferior vesical vein) were resected without damaging the distal portion of the nerve plane (Fig. 1C). Finally, based on tumor invasion, the corresponding length of the vagina was amputated. Because the ureter was not separated from the underlying mesentery during the procedure, the entire nerve plane together with the ureter were preserved after extensive removal of the uterus (Fig. 2A and B). LRH (C2 Type) LRH surgery was performed by the other surgeons who did not master the NSRH techniques in the department. LRH, in which there is no preservation of autonomic nerves, is categorized as the C2 type of the Q-M surgical classification [14]. During the LRH procedure, the trunk of the deep uterine vein was resected at its root. The parametrial lymph nodes were not dissected separately, all lateral parametrial tissues were removed together with the deep uterine vein, and the underlying PSN and medial nerve plane were sacrificed. The ureter was completely freed without preserving the nerve plane. Postoperative Adjuvant Therapy Patients with pathological risk factors, such as a special tumor type, lymph node metastasis, parametrial invasion, positive surgical margins, lymphatic vascular invasion, deep stromal invasion of the cervix, and a large tumor size, received postoperative adjuvant therapy. This included concurrent chemoradiotherapy, external beam radiation therapy, brachytherapy, and systemic chemotherapy. External beam radiation therapy combined with platinum-based chemotherapy was the main treatment. Patient Assessment and Follow-up Baseline clinical and pathological characteristics were compared between the NPS-LRH and LRH groups. The intraoperative and postoperative results were used to evaluate the outcome of the procedure. Postoperative bladder and

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Fig. 2 (A) The appearance of the left pelvic cavity after NPS-LRH surgery showing that the outer surface of the nerve plane was preserved as a thin layer connected to the proximal part of the ureter with parallel nerve bundles. The PSN below the deep uterine vein (DUV) was completely preserved. (B) The pelvic appearance after NPS-LRH surgery showing that the overall preserved inner surface of the nerve plane was a thin layer connected to the structure under the ureter with internal parallel nerve bundles. IIA = internal iliac artery; Ur = ureter; U = uterus; B = bladder; R = rectum; U-S Lig = uterosacral ligament; UA = uterine artery; PLN = parametrial lymph node; IVV = inferior vesical vein; MVV = middle vesical vein; BB = bladder branch of the inferior hypogastric plexus; PSN = pelvic splanchnic nerve; HN = hypogastric nerve; NP = nerve plane.

2 years. Evaluations included gynecologic examination, the vaginal stump ThinPrep cytologic test (Hologic Inc., Marlborough, MA), serum tumor markers, ultrasound, and a chest X-ray. If indicated, contrast-enhanced computed tomographic imaging, magnetic resonance imaging, and positron emission tomography−computed tomographic were performed to rule out recurrence or metastasis. All of these were standardized between the 2 study groups. Statistical Analysis Statistical analysis was performed with SPSS 16.0 software (SPSS Inc., Chicago, IL). Continuous data are presented as a mean § standard deviation, and they were compared using the t test if they had a normal distribution. Otherwise, the Mann-Whitney U test was applied for continuous data with nonnormal distribution. Categoric data are presented as proportions, and they were compared using chi-square analysis; p < .05 was considered to indicate a statistically significant difference. Survival analysis was performed using the log-rank test. Results

bowel functions were assessed to evaluate the autonomic nerve function. Satisfactory short-term bladder function recovery was defined as an adequate sensation of bladder filling, subjective satisfaction with urination, and residual urine <100 mL after Foley catheter removal. The catheter was removed firstly on the 7th day for all patients after the operation. Portable ultrasound was used to measure the residual urine. The catheter was inserted and kept for another 5 to 7 days until the patients reached the standard of bladder function recovery. Satisfactory short-term bowel function recovery was based on the postoperative passage of gas. Long-term bladder and bowel functions were evaluated by appointed doctors during office visits or though telephone using a standardized questionnaire at 12 months after the surgery. The questionnaire included 7 questions on frequent urination, urge incontinence and stress incontinence, loss of bladder sensation, straining to urinate, diarrhea, and constipation. Patients were followed up every 3 months for the first 2 years and then every 6 months after

The baseline clinical and pathological characteristics of the NPS-LRH and LRH groups are shown in Table 1. There were no statistically significant differences in age, body mass index, FIGO stage, tumor differentiation, pathological type, tumor stage, lymphatic vascular invasion, parametrial tissue invasion, lymphatic metastasis, preoperative neoadjuvant chemotherapy, postoperative adjuvant radiotherapy, or postoperative adjuvant chemotherapy between the 2 groups. The intraoperative and postoperative outcomes in the NPS-LRH and LRH groups are shown in Table 2. The NPS-LRH group had a significantly shorter operating time and a significantly less amount of blood loss than the LRH group (238.7 § 53.9 minutes vs 259.8 § 56.6 minutes and 113.3 § 98.2 mL vs 174.4 § 126.7 mL, respectively; both p < .01). Also, patients in the NPS-LRH group had a greater number of resected lymph nodes (32.8 § 11.1 vs 30.8 § 10.4, p = .028). There was no significant difference in the incidences of intraoperative and postoperative complications between the 2 groups, except that the incidence of hydronephrosis in the NPS-LRH group was lower than that in the LRH group (2.3% vs 6.0%, p = .044). The duration of postoperative catheterization in the NPS-LRH group was shorter than that in the LRH group (10.2 § 8.8 days vs 16.0 § 16.2 days, p < .01). There were no differences in the postoperative return of bowel function and the length of stay between the 2 groups. The bladder and bowel function were investigated at 1 year after the surgery. A total of 206 patients in the NPSLRH group and 327 patients in the LRH group were followed up for more than 1 year, and they completed the survey questionnaires. The results are shown in Table 3. The

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Table 1 Clinical and Pathological Characteristics

Age (y) BMI (kg/m2 FIGO stage, n (%) IB1 IB2 IIA1 IIA2 Grade, n (%) 1 2 3 Unknown Histologic type, n (%) Squamous cell carcinoma Nonsquamous cell carcinoma LVSI, n (%) Yes No The depth of invasion, n (%) ≤1/2 >1/2 Parametrial involvement, n (%) Yes No Lymph node metastasis, n (%) Yes No Neoadjuvant chemotherapy, n (%) Yes No Postoperative radiation, n (%) Yes No Postoperative chemotherapy, n (%) Yes No

NPS-LRH (n = 263) 44.7 § 8.9 24.3 § 3.4

LRH (n = 352) 44.5 § 8.8 24.1 § 3.7

174 (66.2) 44 (16.7) 22 (8.4) 23 (8.7)

262 (74.4) 41 (11.6) 33 (9.4) 16 (4.5)

16 (6.1) 88 (33.5) 126 (47.9) 33 (12.5)

23 (6.5) 125 (35.5) 163 (46.3) 41 (11.6)

197 (74.9) 66 (25.1)

250 (71.0) 102 (29.0)

103 (39.2) 160 (60.8)

114 (32.4) 238 (67.6)

161 (61.2) 102 (38.8)

236 (67.0) 116 (33.0)

1 (0.4) 262 (99.6)

2 (0.6) 350 (99.4)

43 (16.3) 220 (83.7)

45 (12.8) 307 (87.2)

61 (23.2) 202 (76.8)

63 (17.9) 289 (82.1)

124 (47.1) 139 (52.9)

148 (42.0) 204 (58.0)

111 (42.2) 152 (57.8)

160 (45.5) 192 (54.5)

p Value .818 .517 .472

.975

.326

.097

.161

.821

.267

.129

.239

.463

BMI = body mass index; LRH = laparoscopic radical hysterectomy; FIGO = F
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ecologie et d’Obst
etrique; LVSI = lymphovascular space invasion; NPS-LRH = nerve plane−sparing laparoscopic radical hysterectomy.

NPS-LRH group had a significantly lower incidence of frequent urination and incidence of urge incontinence than the LRH group (9.2% vs 17.4% and 1.5% vs 6.7%, respectively; both p < .01). However, the incidence of stress urinary incontinence was comparable between the 2 groups (8.2% vs 9.2%, p = .692). In addition, the NPS-LRH group had a lower proportion of patients with poor bladder sensation (0.8% vs 4.6%, p = .028). Also, the NPS-LRH group had a slight lower incidence of straining to urinate although it did not reach statistical significance (11.2% vs 17.1%, p = .062). There was no difference in the incidence of diarrhea (2.4% vs 6.1%, p = .078), but the incidence of constipation was significantly lower in the NPS-LRH group than in the LRH group (4.9% vs 10.7%, p = .029). Twenty-eight patients were lost in the follow-up period. The median follow-up of the 256 patients in the NPS-LRH group was 28 months (range, 6−66 months). Nine patients

had local pelvic recurrences, and 10 had distant metastases. The median follow-up in 331 patients in the LRH group was 33 months (range, 8−100 months). Fifteen of these 331 patients had local recurrences, and 8 had distant metastases. As shown in Figure 3A and 3B, there were no significant differences in the disease-free survival and overall survival between the 2 groups (p = .769 and p = .973, respectively). Discussion Currently, NSRH has been classified as a type C1 surgery based on the new Q-M classification although the steps of a type C1 of surgery are not standardized [14,22]. The characteristic of a type C1 surgery is to meticulously separate the detailed pelvic autonomic nerves from surrounding parametrial tissue [8−13]. In fact, the pelvic autonomic

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Table 2 Intraoperative and Postoperative outcomes

Operative time (min) (mean § SD) Blood loss (mL) (mean § SD) Blood transfusion rate, % Number of nodes resected (SD) Intraoperative complications, n (%) Vascular injury Bowel injury Neurologic injury Urinary injury Postoperative complications, n (%) Pelvic infection Hydronephrosis Lymphocyst Edema of the lower extremity Bowel obstruction Vaginal cuff cleavage Urinary tract fistula formation Length of the hospital stay (days) (mean § SD) Duration of catheterization (days) (mean § SD) Time to passage of gas through the anus (d) (mean § SD)

NPS-LRH (n = 263) 238.7 § 53.9 113.3 § 98.2 2.3 32.8 § 11.1

LRH (n = 352) 259.8 § 56.6 174.4 § 126.7 4.3 30.8 § 10.4

1 (0.4) 2 (0.8) 2 (0.8) 1 (0.4)

3 (0.9) 2 (0.6) 4 (1.1) 4 (1.1)

9 (3.4) 6 (2.3) 31 (11.8) 18 (6.8) 3 (1.1) 1 (0.8) 0 (0.0) 12.7 § 4.6 10.2 § 8.8 1.95 § 0.23

17 (4.8) 21 (6.0) 55 (15.6) 26 (7.4) 5 (1.4) 2 (0.6) 2 (0.6) 13.2 § 5.5 16.0 § 16.2 1.98 § 0.29

p Value <.01 <.01 .262 .028 .803 .844 .968 .613 .514 .044 .220 .899 .972 .844 .574 .246 <.01 .167

LRH = laparoscopic radical hysterectomy; NPS-LRH = nerve plane−sparing laparoscopic radical hysterectomy; SD = standard deviation.

nervous system is difficult to identify and separate completely from the adjacent venous plexus in parametrium. Some surgeons have used special equipment, such as a nerve electrical stimulation device [23], ultrasonic aspirator [24], and water jet [25], to perform the operation. In recent years, laparoscopic surgery has been applied in C1 operation. The magnification visualization of laparoscopy can facilitate the recognition of the autonomic nerves, and the uterine manipulation can help to develop the pelvic spaces. However, the operation still requires complicated steps to meticulously dissect the autonomic nerves from the surrounding venous structure [26−31]. Bogani et al [29] pointed out that laparoscopic C1 surgery has high technical requirements and relies on a specialized surgical team, which has made this technique difficult to be widely adopted. Therefore, it is important to establish a simplified C1 procedure that is easily performed.

Fujii et al [11] found that the HN and the PSN merged into the IHP bladder branch at the parametrium, thus creating a sagittal planar structure that was named "the nerve plane." From an anatomic standpoint, Yabuki et al [16] pointed out that the nerve plane was the extension from the ureteral mesentery to the bladder, which mainly contained the IHP structure that controlled the bladder. Yamaguchi et al [17] found that some HN bundles were distributed around the ureter, and they did not merge into the IHP. Instead, they ran into the trigone of the bladder directly along the nerve plane and caused sympathetic dominant innervation of the bladder. On the other hand, Touboul [18] and Kraima et al [32] found a close connection between the pelvic autonomic nerves and the ureter, and they believed that some of the nerves from the IHP also innervate the ureter. All of these studies suggested that the pelvic autonomic nerves were distributed underneath the ureter, including not

Table 3 Bladder and Rectal Function 1 Year after Surgery

Frequent urination Urge incontinence Stress incontinence Loss of bladder sensation Straining to urinate Diarrhea Constipation

NPS-LRH (n = 206), n (%) 19 (9.2) 3 (1.5) 17 (8.2) 2 (0.8) 23 (11.2) 5 (2.4) 10 (4.9)

LRH = laparoscopic radical hysterectomy; NPS-LRH = nerve plane−sparing laparoscopic radical hysterectomy.

LRH (n = 327), n (%) 57 (17.4) 22 (6.7) 30 (9.2) 15 (4.6) 56 (17.1) 20 (6.1) 35 (10.7)

p Value <.01 <.01 .692 .028 .062 .078 0.029

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Fig. 3 (A) Progression-free survival (percent). (B) Overall survival (percent).

A

B

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only the autonomic nerves for the bladder but also the nerves for the ureter. The ureter and the nerve plane should be preserved together to maintain the integrity of nerve structures. Furthermore, the ureter itself can be the most prominent anatomic landmark during radical hysterectomy surgery. This was the rationale of the NPS-LRH procedure proposed in the current study. Compared with the currently reported laparoscopic C1 procedure, the NPS-LRH procedure confers the following 3 improvements: 1. The uterosacral ligaments were divided at the site medial to the Okabayashi space in the management of dorsal parametrium. The mesentery under the ureter was preserved as the proximal part of the nerve plane, which contained the HN bundles. 2. In the management of the lateral parametrium, only the parametrial lymphatic tissue around the deep uterine vein was removed. The trunk of the deep uterine vein was kept intact. This approach not only reduced the damage to the underlying PSN, but also it avoided the destruction of the nerve plane from resection and turnover of the trunk of the deep uterine vein. 3. When dissecting the ventral parametrium, the uterine and the bladder tributary of the deep uterine vein were resected medial to the ureter. This approach could preserve the distal part of the nerve plane under the ureter and keep the IHP bladder branch intact. Thus, NPSLRH avoided the complicated procedures of dissecting the detailed autonomic nerve structures from the adjacent venous plexus in parametrium; therefore, the surgery was simplified in the current study. The proposed NPS-LRH technique was based on the open NPSRH procedure that we had established earlier [19], but it was less time-consuming, mainly because of the application of laparoscopy. Compared with other laparoscopic C1 studies, NPS-LRH also had a relatively shorter operative time [33]. We have performed 263 NPS-LRH operations. As we know, this is currently the largest sample of laparoscopic C1 surgery. Nowadays, 3 laparoscopic surgeons have mastered the NPS-LRH technique and have developed 3 specialized surgical teams in our hospital. Therefore, we think this simplified procedure can be applied in other centers as well. In the current study, the NPS-LRH group had less bleeding and a shorter operative time than the LRH group. This might be because NPS-LRH preserved the trunk of the deep uterine vein and avoided deep pelvic bleeding, thus shortening the time of hemostasis. In a recent study by Jiang et al [34], the same treatment of deep uterine veins was proposed. The authors believed that preserving the trunk of the deep uterine vein was beneficial for hemostasis, and it also reduced the possibility of PSN injury. In our study, the incidence of postoperative hydronephrosis was significantly reduced in the NPS-LRH group. It has been reported that the

incidence of hydronephrosis after radical resection of cervical cancer was 22% to 46% [35]. In addition to adhesion and compression, intraoperative ureteral denervation was also 1 of the main causes of hydronephrosis. NPS-LRH did not separate the ureter from the mesentery; thus, it preserved certain autonomic nerve structures that innervate the ureter, which might explain the lower incidence of postoperative hydronephrosis in the NPS-LRH group. In our study, the duration of postoperative catheterization was significantly shorter in the NPS-LRH group than in the LRH group. Other studies have suggested that laparoscopic C1 surgery can promote the postoperative recovery of short-term urinary function [27,30,34]. However, Roh et al [36] suggested that the evaluation of long-term urinary function can assess the effects of C1 surgery more accurately because the full recovery of urinary function usually takes approximately 1 year after radical surgery. Several studies have evaluated the improvement in long-term urinary function after laparoscopic C1 surgery, but the evaluation criteria were not consistent [30,31,34,37]. The current study chose questionnaires on autonomic innervation related to the urinary symptoms, including frequent urination and urinary incontinence associated with sympathetic nerves, as well as symptoms of bladder sensation and difficulty in emptying associated with parasympathetic nerves. NPS-LRH improved all of these symptoms, which could be because of the complete preservation of the autonomic nervous structure that controls the bladder in the nerve plane. Other studies have confirmed the role of laparoscopic C1 surgery in improving long-term bladder function, but they have confirmed its role mainly in improving parasympathetic innervation function. However, the improvement in urinary function from sympathetic innervation was not significant [34,37]. Yamaguchi et al [17] found that some HN bundles reached the bladder directly, but they did not merge into the IHP bladder branch. NPS-LRH specifically preserved this part of the sympathetic nerve within the plane and thus its alleviated symptoms of frequent urination and urge urinary incontinence. However, the improvement in stress urinary incontinence was not adequate, probably because the supporting structure of the pelvic floor tissue was affected during extensive resection of the parametrial tissue. A meta-analysis of studies with small sample sizes showed that, in addition to improving postoperative bladder function, laparoscopic C1 surgery also had a benefit on bowel and sexual function [33]. In the current study, the postoperative recovery time for the passage of gas was short in both the NPS-LRH and LRH groups, with no difference between the 2 groups. This could be related to the fast recovery of bowel function after laparoscopic surgery. With respect to long-term bowel function, NPS-LRH significantly reduced the symptom of constipation, which was consistent with other studies [29,37]. However, the symptom of diarrhea did not improve significantly, which might be caused by postoperative radiotherapy. The NPS-LRH procedure mainly preserved the autonomic nervous

Zhao et al.

Clinical Outcomes in Early Cervical Cancer Patients

structure that controls the bladder. Further studies are required to determine whether it can improve the bowel function. Postoperative sexual dysfunction could be caused by the shortened vagina, the side effects of radiotherapy, decreased ovarian function, and psychological factors. The recovery of sexual function requires more than just preservation of the pelvic autonomic nerves. Therefore, the current study did not include a survey on sexual function. It has been a major concern whether C1 surgery can affect the oncologic outcome. Two meta-analyses with large sample sizes have shown that C1 surgery did not affect the prognosis [38,39]. The only randomized controlled trial with a small sample size reported by Roh et al [36] found that there was no significant difference in the 10-year disease-free survival when comparing open C1 with C2 surgery. Currently, there is no multicenter randomized controlled trial with a large sample size to evaluate the efficacy of C1 surgery, especially for the laparoscopic approach, mainly because of the technical difficulties. The updated version of the 2017 Q-M classification emphasizes that type C1 surgery is the mainstay, whereas type C2 surgery is only indicated if the autonomic nerves could not be preserved for anatomic reasons [22]. Our proposed NPS-LRH surgery simplified the surgical procedure of the type C1 operation and has a certain application prospect. Because NPS-LRH preserves an extra thin layer tissue of nerve plane in the parametrium, it raises a concern of radicality. Even so, resection of the ventral and dorsal parametria in NPS-LRH strictly followed the Q-M type C1 standard. In the lateral parametrium, lymphatic tissue around the deep uterine vein was removed completely, although the trunk of the deep uterine vein was preserved. The number of lymph nodes resected in the NPS-LRH group was more than that in the LRH group. The reason may be attributed to the separate parametrial lymph node dissection, which increased lymph node harvesting by pathologists. The mean follow-up length is not enough to draw a definitive conclusion, but the disease-free survival and overall survival between the 2 groups were comparable, suggesting that NPS-LRH might not compromise the radicality. Recently, the results of the Laparoscopic Approach to Cervical Cancer trial and Surveillance, Epidemiology, and End Results studies were published in the New England Journal of Medicine [40,41], which showed that minimally invasive surgery was associated with a higher risk of death than open surgery among women who underwent radical hysterectomy for early-stage cervical cancer. However, the reasons for this differential effect on survival are not clear from their work. It may be related to surgeon experience, uterine manipulators, and CO2 pneumoperitoneum. The laparoscopic technique was widely applied in our center before the Laparoscopic Approach to Cervical Cancer and Surveillance, Epidemiology, and End Results studies were published. Our study did not intend to clarify the superiority of the surgical approach in terms of the oncologic outcome.

9

The purpose of the study was to investigate the feasibility of our modified C1 radical hysterectomy and compare the outcomes with type C2 surgery. Although it is not encouraged in cervical cancer at present, the laparoscopic technique is beneficial for C1 radical hysterectomy in terms of visualization, precise dissection, and hemostasis. That is not the key point we emphasis in the article. The modified C1 technique we proposed in the article can be also applied to open surgery. The limitations of the current study are as follows: (1) this was a retrospective study, which is subject to bias; (2) the evaluation of postoperative bladder and bowel functions were not comprehensive, and currently there is no standard criterion for reference; and (3) NPS-LRH was a new procedure developed in recent years, and, thus, patients had a relatively short follow-up period. Despite these limitations, the current study has improved the surgical techniques of type C1 operation and has been evaluated in a large number of patients with respect to surgical safety, postoperative quality of life, and prognosis. This study is valuable for further development of C1 surgery.

Conclusion NPS-LRH was feasible and safe while avoiding the complicated steps of dissecting the detailed pelvic autonomic structure and simplifying the laparoscopic type C1 procedure. In addition to the overall improvement in postoperative bladder function, NPS-LRH reduced the occurrence of hydronephrosis and constipation. This procedure also seems to be more favorable in terms of blood loss and operative time.

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