Cervical cancer was the fourth most common cancer in women worldwide. The estimated global yearly incidence of cervical cancer in 2018 was 570,000 cases, among which China contributing approximately one fifth (1). Guidelines indicate that radical hysterectomy is standard treatment for early-stage cervical cancer. However, disputes about the prognostic outcomes of the cervical cancer patients underwent the open radically hysterectomy (ORH) or minimally invasive surgery (MIS) laparoscopic hysterectomy had persisted nearly 25 years since the introduction of the laparoscopic approach in 1992 (2–18). Unexpectedly, a phase III randomized, open-label, non-inferiority clinical trial named the Laparoscopic Approach to Cervical Cancer identified that cervical cancer patients of Federation International of Gynecology and Obstetrics (FIGO) 2009 stage IA1 with lymphovascular invasion, IA2 and IB2 in the MIS group had almost four times the risk of recurrence and 6 times the risk of death compared with the women in the ORH group (7). Afterward, a meta-analysis, which included 15 high-quality observational studies comprising 9,499 cervical cancer patients of FIGO 2009 stage IA1-IIA2 (stage IA1 with lymphovascular invasion), concluded that patients in the ORH group had superior overall and disease-free survival than patients in the MIS group (6). Besides, the European Society of Gynecological Oncology (ESGO), the British Gynecological Cancer Society (BGCS), and two other epidemiologic studies also had the same opinion (9, 19, 20).

Based on the most recent findings, the National Comprehensive Cancer Network (NCCN) Guidelines Version 1.2021 recommended that ORH was the primary treatment for FIGO 2018 stage IA2, IB1, IB2 and IIA1 cervical cancer patients. As for operable cervical cancer patients with FIGO 2018 stage IB3, IIA2, and IIICr, laparoscopic approach is absolutely prohibited. The panel had updated the guidelines according to the revised 2018 FIGO staging system. However, trial data utilized in the guidelines were all from the previous 2009 FIGO staging system.

Accordingly, this study is conducted to compare the survival and recurrence outcomes between ORH and laparoscopic radically hysterectomy (LRH) for stage IA2-IIA2 cervical cancer patients comprising FIGO 2018 staging system. In addition, three subgroups of FIGO 2018 stage IA1, IB1, IB2 and IIA1, FIGO 2018 stage IB3 and IIA2, FIGO 2018 stage IIIC1p-IIIC2p referring to the NCCN guidelines Version 1.2021 were analyzed between the two surgical approaches. As squamous cell carcinomas account for approximately 75% to 80% of all cervical cancers (21), and stromal invasion pattern was considered to play better roles on predicting the prognosis of adenocarcinoma and adenosquamous carcinoma than FIGO stage system (22), the histology type of patients included in this study is only squamous cell carcinoma.

Since Nezhat reported the first case of LRH in 1992 (2), numerous retrospective studies and meta-analysis had proven that LRH had less bleeding, lower risk of infection, more rapid postoperative recovery, and shorter hospital stay compared with ORH (3, 5, 8). Moreover, LRH had not shown inferior 5-year overall or disease-free survival rates than ORH (5, 8, 28–33). Therefore, LRH for cervical cancer had been gradually accepted and popularized by both doctors and patients. The 2020 NCCN Guidelines still recommended treating stage IA2-IIA cervical cancer with ORH, LRH or robot-assisted LRH. However, trends had changed since the publication of the LACC trial (7). MIS was only recommended for extrafascial hysterectomy and fertility-sparing radically trachelectomy for early cervical cancer in the NCCN guidelines Version 1.2021. In addition, the FIGO Committee for Gynecologic Oncology revised the staging system of cervical cancer in 2018 (34), allowing the use of any imaging modality and/or pathological findings for allocating the stage. For the early-stage cervical cancer, the lateral extent of the lesion was not considered in stage IA, an additional cutoff at 2.0 cm was introduced in stage IB, and any patient with positive lymph nodes was upgraded to stage IIIC in the new criterion.

This study was conducted to compare the survival outcomes of the ORH and LRH comprising the new FIGO stage system. First, we identified that LRH was associated with worse 5-year overall (83.7% vs 88.4%) and progression-free (81.2% vs 88.6%) survival outcomes compared with ORH in FIGO 2009 stage IA2-IIA2 cervical cancer patients. It is consistent with the modern opinion about LRH. Second, patients of FIGO 2018 stage IA2-IIA2 in the ORH group also have superior 5-year OS (91.1% vs 85.8%) and 5-year PFS (88.6% vs 83.3%) rates than the LRH group. Third, in the subgroup analysis for patients of FIGO 2018 stage IA2, IB1-IB2, and IIA1, the LRH group showed non-inferior 5-year OS (93.5% vs 91.6%) and 5-year PFS (90.5% vs 90.6%) comparing to the ORH group. Fourth, in the subgroup of FIGO 2018 stage IB3 and IIA2, patients underwent LRH had obviously poor 5-year OS (53.4% vs 89.4%) and 5-year PFS (52.2% vs 82.2%) compared with patients underwent ORH. Patients in the LRH group almost had three times risk of death and 2 times risk of recurrence than the ORH group. Last, in the subgroup of FIGO 2018 stage IIIC1p-IIIC2p, though patients undergoing LRH suffered from obviously poor 5-year OS (72.2% vs 78.6%) and 5-year PFS (69.6% vs 77%) than patients undergoing ORH, which was not statistically significant.

In general, the survival outcomes in our study were in accordance with several population-based and high-volume institutional retrospective studies, confirming the opinion of LACC trial, which concluded that MIS increased recurrence and death for early cervical cancer patients, as the Table 2 in the research of Yang et al. has shown (35). At the same time, multivariate Cox analysis was also conducted to discover the prognostic factors associated with the recurrence and survival outcomes of cervical cancer with FIGO 2018 stage IA2-IIA2. Surgical approach, tumor size, LVSI, and parametrial invasion were found to be independent prognostic factors. The finding was essentially in agreement with the pathologic risk factors of cervical cancer. Besides, patients in the LRH group were proven to have almost two times of death and recurrence than the ORH group, which further supported the conclusion of the LACC Trial (7).

Overall, results of our study supported the indications of ORH for early-stage cervical cancer patients based on the FIGO 2018 staging system, which was in compliance with the NCCN guidelines Version 1.2021. However, in patients of FIGO 2018 stage IA2, IB1-IB2, and IIA1, LRH showed non-inferiority compared with ORH even after IPTW adjustment. This finding reminded us that the advantages of laparoscopic surgery in radical hysterectomy of cervical cancer could not be completely denied. Patients in this subgroup all had no “high-risk” prognostic factors, presenting negative nodes, negative margins, and negative parametria. According to the “intermediate-risk” Sedlis Criteria: 1) greater than 1/3 stromal invasion; 2) LVSI; or 3) cervical tumor diameters more than 4 cm (36, 37), several patients showed deep stromal invasion and positive LVSI. So LRH might be applicable for some specific cervical cancer patients. In the LACC trial, it emphasized that the results cannot be generalized to patients with “low-risk” cervical cancer (tumor size < 2 cm; no lymphovascular invasion; depth of invasion < 10 mm; and no lymph-node involvement) (7). Many previous studies also identified that LRH was non-inferior to ORH for early cervical cancer (5, 8, 28–33), especially in patients with conization before surgery and no visible tumor on the final pathology (38). In view of the currently negative point to LRH, we supposed that LRH might be applicable for early-stage cervical cancer patients without high and intermediate risk factors, including negative nodes, negative margins, negative parametria, less than 1/3 stromal invasion, negative LVSI, and tumor size less than 4 cm. And the data from our center also supposed this standpoint. Furthermore, as some studies have shown that patients with tumor size <2 cm have better prognosis, the tumor size could be set as < 2 cm as selection criterion more carefully. On this basis, patients should receive conization before LRH during clinical work (18, 39–43). Besides, histology should also be taken into consideration (22, 44, 45). Patients of FIGO stage IIIC1-IIIC2 in the LRH group have obviously worse PFS and OS than the ORH group, but which was not statistically significant. The reasons may be as follows: first, number of patients in the subgroup was limited, especially in the LRH group; second, though lymph node metastasis is an important factor associated with the prognosis of cervical cancer patients, stratifying the clinical stage according to the lymph node status individually is still controversial (46). If the local extent of the disease between the groups was not comparable, outcomes of the surgery might also be affected. However, individualized chemoradiotherapy is recommended for the FIGO 2018 IIIC1p-IIIC2p in the NCCN guidelines Version 1.2021. So the rationality of the clinical staging is better worth discussing than the operation way.

Several causes were proposed to explain the high risk of recurrence and poor survival in patients undergoing LRH, including the establishment of pneumoperitoneum through CO₂ insufflation, application of uterine manipulators and the method of colpotomy. The continuously perfusing and flowing CO₂ in the abdominopelvic cavity could lead to spread of the detached tumor cells (47–49). The compression effects of the uterine manipulator on the upper vagina might increase the risk of tumor cell detachment, especially bringing about the distant dissemination and metastasis of intra-luminal tumors in patients with positive LVSI (50, 51). The way of colpotomy was also considered to increase likely exposure of the tumor to the abdominal cavity at the end of the surgery (52, 53). These three reasons might also explain the results of our research. Besides, several studies identified that the most effective way to reduce the recurrence rate during the LRH is to avoid tumor dissemination, especially during the vaginal colpotomy (54–57). Kanao et al. have identified that the no-look no-touch technique may be useful to reduce recurrence risks through preventing intraoperative tumor spillage during LRH for early cervical cancer patients. The technique incorporates four specific measures: 1) creation of a vaginal cuff, 2) avoidance of a uterine manipulator, 3) minimal handling of the uterine cervix, and 4) bagging of the specimen (57).

Overall, the leading strength of this study was that it compared the efficacy of the ORH and LRH for the early cervical cancer patients comprising the new FIGO staging criterion. Then the study adopted the IPTW analysis to balance the prognostic risk factors between the two groups, even for the subgroup analysis. However, there are still several limitations of our study. In essence, this is a retrospectively single-center analysis. Moreover, variation of the surgeon’s operative experience on the rates of OS and PFS was not explored. Besides, since the robotic surgery was not adopted in our institution, we did not include patients accepting robotic radically hysterectomy. A recent meta-analysis conducted by Shazly et al. identified that laparoscopy and robotic RH are equivalent in terms of perioperative outcomes (5, 58). Furthermore, Gallotta et al. discovered that robotic RH and LRH had comparable perioperative, postoperative and survival outcomes for early cervical cancer patients through a large case matched control study. Therefore, robotic RH might also not play better roles than ORH for early stage cervical cancer. But to better identify the role of robotic RH, an ongoing prospective, international, multi-institutional, open-label randomized controlled Robot-assisted Approach to Cervical Cancer (RACC) trial is performed (15). It is worth mentioning that manipulator is prohibited, and patients with tumor size more than 4 cm were excluded in that study. So the research results were very worth expecting. Of course, none of these concerns alter the results of our primary outcome of interest.

In conclusion, this study confirms the superiority of open surgery on overall and progression free survival for early cervical cancer patients, no matter under FIGO 2009 or FIGO 2018 staging system. However, in subset of FIGO 2018 IA2, IB1-IB2, and IIA1, laparoscopic surgery showed non-inferiority, especially in patients with no prognostic risks. Considering the advantages and popularity of the minimally invasive surgery, laparoscopic radically hysterectomy should not be completely prohibited in early cervical cancer patients. In brief, ORH was recommended for early stage cervical cancer patients under 2018 FIGO staging system. But LRH might be suitable for early-stage cervical cancer patients without high and intermediate risk factors, including negative nodes, negative margins, negative parametria, less than 1/3 stromal invasion, negative LVSI and tumor size less than 2 cm.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

QY and FB designed and edited this study. YX and WZ enrolled and followed up the patients. WCZ analyzed the data and wrote the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by the National Natural Science Foundation of China (No. 81872125). This work was also supported by grants from 345 Talent Project of Shengjing hospital of China medical university (No. M0695).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.