Minimally Invasive Versus Open Surgery for Radical Hysterectomy Followed By Adjuvant Radiotherapy in Intermediate- or High-Risk Early-Stage Cancer of The Cervix: A Retrospective Study

Background Postoperative radiotherapy (RT) or chemoradiotherapy (CRT) improves outcomes of cervical cancer patients with risk factors. Minimally invasive surgery (MIS) has an inferior survival than open radical hysterectomy (ORH), however, the impact of MIS on postoperative RT remains uncertain. The study compared the impacts of MIS versus ORH on delivering of adjuvant RT or CRT for intermediate- or high-risk early-stage cervical cancer. Data on stage IB1-IIA2 patients who underwent radical hysterectomy and postoperative RT/CRT in our institution, from 2014 to 2017, were retrospectively collected. Patients with high or intermediate-risk factors who met the Sedlis criteria received postoperative pelvic external beam radiotherapy (50Gy/25f) with platinum-based chemotherapy (0–6 cycles) according to guidelines. Disease-free survival (DFS) and overall survival (OS) were compared in the two surgical groups. and twenty-nine and The median time interval from to and was shorter in the MIS group. Three-year DFS and OS were similar in both groups. Further sub-analysis indicated that the DFS and OS in intermediate/high-risk groups had no signicant difference. Cox-multivariate analyses found that tumor size > 4 cm and time interval from were adverse independent DFS.

Introduction Surgery or radiotherapy (RT), with or without chemotherapy (CT) [1], is the recommended treatment for early-stage cervical cancer. Most patients opt for surgical management. Surgical options for cervical cancer include minimally invasive surgery (MIS) or open radical hysterectomy (ORH). These surgical methods have comparable 5-year overall survival (OS) and disease-free survival (DFS) rates [2][3][4], and the

Patients
This study included patients diagnosed with stage IB1-IIA2 cervical cancer according to the 2009 FIGO staging system [12]. All patients underwent a type III RH [13] with pelvic lymph node dissection, and patients with high or intermediate-risk factors that met the Sedlis criteria had received postoperative external beam radiotherapy (EBRT), with or without CT in our hospital, from 2014 to 2017 (Fig. 1).
Patients were excluded from the study if they had previously received RT, had missing clinical or pathological data or had relapsed before receiving RT. Patients were divided into two groups based on the surgical approach: the open radical hysterectomy (ORH) and minimally invasive surgery (MIS) groups.

Treatment regimen
Following RH, patients with intermediate or high-risk factors should receive postoperative adjuvant therapy, as recommended by the NCCN guidelines [10]. Intermediate-risk factors include lympho vascular involvement (LVSI), stromal invasion, and tumor size [14], and high-risk factors include lymph nodepositive, parametrial involvement, and margin status [7]. We implemented adjuvant RT and 4-6 cycles of platinum-based CT when one or more high-risk characteristics were present. Patients with multiple intermediate-risk factors that met the Sedis criteria received adjuvant RT and 2-4 cycles of platinum-based CT [10]. All patients received EBRT following surgery utilizing pelvic intensity-modulated radiotherapy (IMRT) or three-dimensional conformal radiation therapy (3D-CRT) with computed tomography-based treatment planning. The clinical target volume was determined using the criteria of the Radiation Therapy Oncology Group [15]. EBRT was delivered at a dose of 2 Gy/d on ve days per week (total dose 50 Gy). Brachytherapy was given to patients with positive vaginal margins or vaginal invasion close to the surgical margin (0.5 cm).

Data collection and follow-up
Patient data were retrospectively collected by reviewing the medical record system of our hospital. The following data were obtained: baseline demographics, histologic type, FIGO stage, tumor size, surgical approach, pelvic lymph nodes involvement, and other risk factors identi ed by pathological examination.
We also collected data regarding adjuvant treatments such as CT, RT, or brachytherapy, the initiation of CT or RT, and the number of CT cycles.
Follow-up information was obtained through outpatient clinic appointments and a telephone questionnaire. The primary outcome was DFS, de ned as the period from surgery to the detection of recurrence or cervical cancer-related death. The secondary outcome was OS, de ned as the period from initial surgery to cervical cancer-related death.

Survival Outcomes
The last follow-up time was April 2021. The average follow-up duration was 67.5 months (interquartile range: 52-78 months). The data were censored at the time of last follow-up or cancer-related death.
Patients in the MIS group who underwent postoperative RT or CRT had a slightly lower 3-year DFS and OS than those in the ORH group (85.2% vs 89.7%, P = 0.274; 89.9% vs 98.5%, P = 0.499, respectively) ( Fig.  2A,2B). Subgroup survival analyses in the intermediate-risk and high-risk groups revealed no signi cant differences in DFS and OS between the two surgical approaches (Fig. 2C-2F). Univariate and multivariate analysis for DFS is shown in The recurrence and mortality rates were summarized in Table 4; there was no difference in the recurrence rate or pattern between the two groups (P = 0.463 and P = 0.709, respectively). Until the last follow-up, ve (7.3%) patients in the ORH group and six (9.8%) patients in the MIS group had died of cervical cancer (P = 0.614).

Discussion
Adjuvant RT or CRT is typically delivered after RH for early-stage cervical cancer patients with certain risk factors. One study from Levine Cancer Institute (one of the LACC trial centers) indicated that adjuvant therapy might be an important confounder for the survival outcomes of MIS and open surgery [11]. MIS is associated with a shorter recovery time and a lower risk of postoperative complications than ORH [5], and the TI from surgery to adjuvant may differ. We hypothesized that the initiation of postoperative RT or CRT might impact survival outcomes among the treatment-related variables. The results of the present study have con rmed the hypothesis.
We found that the DFS and OS had no signi cant difference in both groups, despite the TI from surgery to postoperative CT or RT being shorter in the MIS group. Tumor size > 4 cm and TI from surgery to RT beyond seven weeks were revealed to be independent predictive variables for DFS after being adjusted for important prognostic parameters.
The study results showed that the DFS and OS were similar between the MIS and ORH groups, which were different from the outcomes of the LACC trial. The following factors might explain the different results. Firstly, the surgical-related factors that may result in poor survival, such as utilizing uterine manipulator, the effect of insu ation gas (CO2), and the degree of resection, can be improved by postoperative RT or CRT [5,6,8,16]. Furthermore, the TI from surgery to postoperative CT and RT were shorter in the MIS group, resulting in a shorter overall treatment time, which was a critical factor for pelvic control and survival in cervical cancer [17].
Most patients in the study received pelvic IMRT, which could reduce the toxicity of postoperative RT with a non-inferior survival outcome [18,19]. The update of GOG 92 [9], a randomized trial of postoperative RT versus no further therapy in stage IB cervical cancer after RH, revealed that the 3-year PFS and OS was around 86% and 88% for patients with intermediate-risk factors. In high-risk patients, the three-year PFS and OS were around 84% and 88% [7]. Similarly, our research indicated that the 3-year DFS rates and OS rates in ORH and MIS groups were 89.7% vs. 85.2% and 98.5% vs. 89.9%, respectively. Meanwhile, IMRT helps decrease GI and GU toxicity, with a greater incidence of grade 3 or higher acute HT complications [20].
Tumor size is generally accepted as an independent prognostic factor [21,22]. However, the optimal time to start postoperative RT in individuals with risk factors has not been well de ned. The role of postoperative adjuvant therapy is to control the residual subclinical disease. Some animal studies revealed that surgery might stimulate angiogenesis by releasing circulating growth factors and accelerating the growth of minimal residual disease [23,24]. The delay in postoperative adjuvant therapy could allow more time for a tumor cell to proliferate, and the early initiation of postoperative adjuvant treatment might improve oncological outcomes. In the present study, the median time for patients to receive postoperative adjuvant CT and RT were seven days vs. eight days, and 28 days vs. 35 days in MIS and ORH groups, respectively. We delivered adjuvant therapy in such a short TI and got a favorable survival outcome. It showed that patients received postoperative adjuvant treatment timely is very important to ensure the treatment outcome.
We found that the median TI from surgery to RT beyond seven weeks had an independent signi cant adverse effect on survival. The median TI from surgery to RT was within seven weeks; despite some differences in both groups, the slight disparity has little impact on DFS. Consistent with our results, Hanprasertpong J. et al. [25] found that delaying adjuvant therapy in patients with early-stage squamous cell cervical cancer beyond four weeks after surgery resulted in a lower RFS. And Jhawar. et al. [26] concluded that postoperative therapy should be administered within eight weeks after surgery whenever possible. Although the de nite initiate time of postoperative adjuvant therapy is not clear in cervical cancer, it is recommended for postoperative RT to be delivered as early as possible.
This study has some limitations worth noting. It is a retrospective study performed at a single institution, and the retrospective study design has inherent biases and limitations. A multicenter study with larger sample size and longer follow-up duration is needed to verify these results.
In conclusion, for the early-stage (IB1-IIA2) cervical cancer patients with intermediate or high-risk factors who received postoperative RT or CRT, no matter they received ORH or MIS as their primary treatment, the DFS and OS had no signi cant difference, despite TI from surgery to postoperative adjuvant therapy being shorter in the MIS group than ORH.