What Do Risks Exist After Minimally Invasive Surgery in Patients With Stage IA1-IIA1 Cervical Cancer

Objective: To investigate the risks of patients with stage IA1-IIA1 cervical cancer after laparoscopic hysterectomy, and whether adjuvant radiotherapy is necessary. Patients and Methods: From January 2013 to December 2016, we retrospectively analyzed 221 patients with cervical cancer of stage IA1-IIA1. Sixty-two patients were treated with laparoscopic hysterectomy and adjuvant radiotherapy (group A), 115 patients only underwent open surgery (group B) and 44 patients received laparoscopic hysterectomy alone (group C). Local recurrence-free survival (cid:0) LRFS) was the primary outcome, distant metastasis free survival (DMFS) and overall survival (OS) rates were secondary outcomes in the study. Results: The median follow-up time was 58.33 months (range, 56.91-59.76 months) for all the patients. Three groups were balanced in terms of baseline characteristics. The 3-year LRFS rates were 98.4% in group A, 97.4% in group B, and 86.4% in group C, respectively. The LRFS rates of group A and B surpassed group C ( group A vs. B, p=0.634; group A vs. C, p=0.011; group B vs. C, p=0.006). In subgroup analysis of stage IB1-IB3 disease, the 3-year LRFS was 100% in group A , 98.8 % in group B and 83.1% in group C, the 3-year OS rates were 100% in group A, 98.9% in group B, 91.5% in group C. The 3-year LRFS and OS rates on group A and B were signicantly superior to group C ( p<0.05 ). No benets of adjuvant radiotherapy were observed in patients with stage IA and IIA1 cervical cancer. Conclusions: There is a risk of local failure in laparoscopic hysterectomy for early stage cervical cancer. Adjuvant radiotherapy can reduce the risk of recurrence and improve local control for women with early cervical cancer and bring survival benets for patients with stage IB disease after minimally invasive hysterectomy. towards improved overall survival was noted (HR = 0.70, 90%CI = 0.45 to 1.05, p = 0.074) after a long-term follow-up (12 years) (21). These results proposed the establishment of Sedlis criteria. However, laparoscopic hysterectomy for cervical cancer has not been fully carried out at that time, whether this standard is applicable to patients undergoing laparoscopic hysterectomy requires a further investigation. In a comparative study initiated by Eun-Ju Lee et al. (22),disease-free survival were compared between patients underwent laparoscopic radical hysterectomy (LRH) and radical abdominal hysterectomy(RAH). With a median follow-up time of 78 months for the LRH group and 75 months for the RAH group. There was no signicant difference in the 5-year disease-free survival rates between the groups (90.5% and 93.3% for LRH and RAH, respectively, p = 0.918).

radiotherapy were observed in patients with stage IA and IIA1 cervical cancer.
Conclusions: There is a risk of local failure in laparoscopic hysterectomy for early stage cervical cancer.
Adjuvant radiotherapy can reduce the risk of recurrence and improve local control for women with early cervical cancer and bring survival bene ts for patients with stage IB disease after minimally invasive hysterectomy.

Introdution
According to National Comprehensive Cancer Network (NCCN) clinical guidelines, postoperative adjuvant radiotherapy is generally not required for stage IA1 ~ IB cervical cancer patients if there are no risk factors (such as lymph-node involvement, nerve invasion, and large tumor). Recently, A recent study by Ramirez, a highly noteworthy phase III study, was published in the October 2018 New England journal of medicine, which found that the 4.5-year disease-free survival and 3-year tumor-free survival in the minimally invasive surgery group were signi cantly lower than those in the open surgery group, and the risk of death or recurrence in the minimally invasive group was 3.74 times higher than that in the open surgery group (1). A retrospective study by Melame et al. had similar results. It can be speculated that minimally invasive surgery may bring the risk of local recurrence (2). Therefore, We speculate that minimally invasive hysterectomy for early cervical cancer carries a risk of local failure, it is worth studying whether additional postoperative radiotherapy is needed for these patients with minimally invasive surgery.

Methods
From January 2013 to December 2016, a total of 221 patients with early-stage squamous-cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of cervical cancer admitted to our institution. The clinical data of eligible patients with stage IA1-IIA1 cervical cancer were retrospectively analyzed. All patients had an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1. Exclusion criteria included a history or contraindication to radiotherapy; the advanced stage cervical cancer; absence of severe mental disorders or severe diseases of heart, liver, lung, kidney; the existence of high-risk factors (lymph-node involvement, parauterine invasion, and positive vaginal resection margin). Patients were also excluded if the postoperative pathologic risk factors meet the Sedlis Criteria of the latest version of NCCN Guidelines (Version 1.2020). According to different treatment approaches, patients were assigned to different groups. The rst group underwent laparoscopic hysterectomy combined with postoperative radiotherapy (group A, n = 61), the second group only received open surgery (group B, n = 115), and the third group received laparoscopic hysterectomy alone (group C, n = 44). The median age was 47 years . Patients were re-staged based upon International Federation of Gynecology and Obstetrics (2018 FIGO) Surgical Staging of Cancer of the Cervix Uteri(2018). Enrolled patients underwent open surgery or laparoscopic hysterectomy. The patients who received post-operative radiotherapy were treated with 45 to 50 Gy in 95% PTV of expansion based on the tumor bed and high-risk lymph node drainage area delivered over 4 to 5 weeks at 1.8 to 2 Gy per fraction in 4 weeks following the surgical resection,which were carried out by intensity modulated radiotherapy (IMRT). SPSS 24.0 statistical software was used for data analysis. The primary outcome was 3-year LRFS. The secondary endpoints were 3-year OS and 3-year DMFS.. Survival rates were used to caculate by the Kaplan-Meier method. Cox regression analysis was used to estimate prognostic factors. And the statistically signi cant P value was a two-tailed P value less than 0.05.

Subgroups analysis
In exploratory subgroup analysis of the different stages, we compared the LRFS, DMFS and OS rates across the subgroup of stage IA disease, the subgroup of stage IB1-IB3 disease and the subgroup of stage IIA1 disease, respectively.
In subgroup of stage IA disease, there was one patients (6.2%) encountered recurrence and death from cervical cancer in group B, the 3-year LRFS and OS rates were both 93.8%. There were not any recurrences and death occurred in group A and group C. There was no statistically signi cant between-group difference on 3-year LRFS and OS (group A vs. B, p = 0.540, group B vs. C, p = 0.576

Discussion
In the retrospective analysis, women receiving laparoscopic hysterectomy combined with adjuvant radiotherapy or open surgery for early-stage cervical cancer had lower 3-year LRFS rates than patients who received laparoscopic hysterectomy alone. In subgroup analysis, patients with stage IB cervical cancer who underwent laparoscopic hysterectomy bene ted from adjuvant radiotherapy on LRFS and OS. The results revealed that post-operative radiotherapy can decrease the local recurrence rate of the women with early-stage cervical cancer and improve the survival of women with stage IB disease after laparoscopy hysterectomy.
Laparoscopic hysterectomy has the advantages of a decrease in operative blood loss, a shorter hospital stay, and a lower rate of postoperative complications than open radical hysterectomy in previous studies (3)(4)(5). And the recurrence and survival rates do not differ signi cantly between the two approaches (6, 7). Therefore, National Comprehensive Cancer Network (National Comprehensive Cancer Net work, NCCN) guidelines recommend that minimally invasive surgery is an acceptable approach to radical hysterectomy in patients with early-stage cervical cancer (8,9). However, the main limitations was a paucity of adequately powered, prospective, randomized trials. Postoperative adjuvant treatment was indicated depending on surgical ndings and disease stage. For patients with early stage cervical cancer who have high-risk disease ( positive pelvic nodes, positive surgical margin, and/or positive parametrium) after radical hysterectomy, postoperative pelvic external beam radiotherapy with concurrent platinumcontaining chemotherapy (category 1) with (or without) vaginal brachytherapy is recommended (10)(11)(12) In 1980s, Gynecologic Oncology Group (GOG) study of clinical and pathologic predictors of surgically treated stage carcinoma of the cervix con rmed that LTD, DSI, and LVSI could increase the probability of cancer recurrence at 3 years from 2-31% (19). The result indicated a statistically signi cant (47%) reduction in risk of recurrence (relative risk = 0.53, P = 0.008, one-tail) among the pelvic radiotherapy group. The recurrence-free rates were 88% for adjuvant radiotherapy versus 79% for the no-adjuvanttreatment group at 2 years (20).The updated analysis showed that adjuvant pelvic radiotherapy increased progression free survival; a clear trend towards improved overall survival was noted (HR = 0.70, 90%CI = 0.45 to 1.05, p = 0.074) after a long-term follow-up (12 years) (21). These results proposed the establishment of Sedlis criteria. However, laparoscopic hysterectomy for cervical cancer has not been fully carried out at that time, whether this standard is applicable to patients undergoing laparoscopic hysterectomy requires a further investigation. In a comparative study initiated by Eun-Ju Lee et al. (22),disease-free survival were compared between patients underwent laparoscopic radical hysterectomy (LRH) and radical abdominal hysterectomy(RAH). With a median follow-up time of 78 months for the LRH group and 75 months for the RAH group. There was no signi cant difference in the 5-year diseasefree survival rates between the groups (90.5% and 93.3% for LRH and RAH, respectively, p = 0.918). However, only 24 patients were enrolled and two people relapsed, the size was too small to make a meaningful statistical analysis of the failure modes of local or distant recurrences. In the trial of H. The rate of disease-free survival at 4.5 years was 86.0% with minimally invasive surgery and 96.5% with open surgery, a difference of -10.6 percentage points ( 95% con dence interval [CI], − 16.4 to − 4.7). Minimally invasive radical hysterectomy was associated with lower PFS and OS rates. However, part of enrolled patients were found to have the diseases of parametrial involvement (6.5% in the minimally invasive surgery group and 3.9% in the open-surgery group), or lymph-node involvement (12.4% in the minimally invasive surgery group and 13.1% in the open-surgery group) in postoperative histopathological assessment. And the scholars noted that this study cannot be generalized to women with "low-risk" factors (tumor size less than 2 cm; no lymphovascular invasion; depth of invasion less than 10 mm; and negative lymph-node ), because it was not powered to evaluate the oncologic outcomes of the two surgical approaches in that context. Similarity, another study was conducted by Melamed et al.
(2), focusing on the long-term survival of patients with minimally invasive surgery and open surgery. The results showed that the 4-year annual mortality rate was 9.1% in patients undergoing minimally invasive surgery and 5.3% in patients undergoing laparotomy (HR = 1.65, 95% CI: 1.22 to 2.22). The relative survival rate decreased by 0.8% annually during the four years since the start of minimally invasive surgery in 2006, though the tumors were relatively small, and the stage were earlier in patients undergoing minimally invasive surgery. Both trials lack of further exploration of subgroups with different stages or different risk factors, and noted that the value of adjuvant radiotherapy after laparoscopic radical hysterectomy in patients with "low-risk" cervical cancer remained unknown.
To explore the value of adjuvant radiotherapy, we conducted this study to compared the survival outcomes of three groups. In order to better rule out the impact of risk factors on the results, we used FIGO 2018 to re-stage and excluded patients with high-risk factors or intermediate-risk factors that met the Sedlis criteria. In our analysis, we were surprised to nd that even for "low-risk" patients with early cervical cancer, the recurrence rate after laparoscopic hysterectomy was still higher than that of patients undergoing open surgery, and postoperative radiotherapy could decrease the recurrence rate of patients who had underwent laparoscopic hysterectomy. This results also con rms from the side that laparoscopic hysterectomy is negatively related to survival outcomes, the conclusion of LACC that minimally invasive radical hysterectomy was associated with lower rates of disease-free survival and overall survival than open abdominal radical hysterectomy may be still applicable to "low-risk" patients with early stage cervical cancer.
In terms of 3-year DMFS rates, laparoscopic hysterectomy combined with radiotherapy group did not show advantages over the others. The patients received laparoscopic hysterectomy alone were not inferior to the open surgery. The results were similar to some previous studies (22,24,25). Postoperative radiotherapy did not reduce the rate of distant metastasis, which may be related to the biological characteristics of the tumor. Williams et al. (26) found that lymphatic vessel density was an important indicator of the prognosis of stage I cervical cancer and a low podo-planin immunoreactivity was associated with lymphatic invasion and lymph node metastasis of cervical cancer. (27). Krishnan J et al. (28) found that VEGF-C and VEGF-D were involved in mediating the direction of tumor cell migration. In subgroup analysis, patients with stage IB cervical cancer had a higher rate of local control and overall survival after postoperative radiotherapy, which revealed that patients with IB stage may be the part of population who bene ted from postoperative radiotherapy after laparoscopic hysterectomy. However, no bene ts existed in patients with stage IA and IIA1 disease. The possible reasons may be: There was only one patient with stage IIA1 in Group C, and the sample size was too small to assess the overall survival bene t. The follow-up time of some patients was not long enough to show the differences on OS or DMFS. The 3-year overall survival is already too high to show a between-group difference in subgroup of stage IA disease.
There were several limitations in our study. Firstly, robot-assisted radical hysterectomy was not carried out in our institution, it can not be inferred that this conclusion is applicable to early-stage cervical cancer patients assisted by robot. Secondly, the sample size needs to be further expanded for further exploration and analysis. Furthermore, the study is a retrospective study and patients may still have bias in the choice of treatment due to some reasons that could not be traced.
In conclusion, there is a risk of local failure in laparoscopic hysterectomy for early stage cervical cancer. Adjuvant radiotherapy can reduce the risk of recurrence and improve local control for women with early cervical cancer and bring survival bene ts for patients with stage IB disease after minimally invasive hysterectomy.

Declarations
Ethics approval and consent to participate Ethics approval and consent to participate This study was approved by our Institutional Review Board.
Consent for publication Not applicable.
Con ict of interest: all Authors have nothing to disclose.
Funding information: Self-raised funds of Health and Family Planning Commission of Guangxi Zhuang Autonomous Region (Grant/Award Number: Z20181010).
Availability of data and materials All data generated and analyzed during this study are included in this published article.

Figure 1
Local recurrence-free survival LRFS) strati ed by three groups.  Overall survival (OS) strati ed by three groups.

Figure 4
Local recurrence-free survival LRFS) strati ed by three groups for patients with stage IB1-IB3 disease.

Figure 5
OS strati ed by three groups for patients with stage IB1-IB3 disease.