Laparoscopic surgery is effective and safe in high-risk endometrial cancer

Introduction

Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries (1), with increasing incidence and prevalence in developing countries. In economically developed cities of China, such as Beijing and Shanghai, the incidence of EC has surpassed cervical cancer and become the most common gynecologic malignancy (2). Although most EC are early-stage type I tumors with an excellent prognosis, about one fifth of the patients are diagnosed with advanced-stage or type II tumors. Type II tumors, such as uterine serous carcinoma, clear cell carcinoma and carcinosarcoma, exhibit a more aggressive behavior, with a poorer prognosis. Although these high-risk patients account for fewer than 20% of all EC cases, they collectively account for more than 50% of EC-related deaths (3).

The initial treatment of EC is comprehensive staging surgery, which consists of total hysterectomy, bilateral salpingo-oophorectomy, and retroperitoneal lymph node dissection for high-risk patients. Traditionally, the surgical approach was laparotomy through a midline incision, which is effective but associated with substantial morbidity, such as long durations of hospital stays and wound complications. In 1992, Childers et al. (4) first reported the application of laparoscopy for the treatment of EC. Since then, laparoscopy has become increasingly popular. Compared with laparotomy, laparoscopy has shown many advantages, such as less severe postoperative pain, less blood loss, less abdominal wound morbidity, shorter hospital stay and more rapid recovery (5). With the advancement of laparoscopy, some scholars have investigated the safety of laparoscopic surgery for patients with EC. The results of two well-known prospective randomized controlled trials (LAP-2 and LACE) have shown that patients receiving laparoscopic surgery have similar long-term prognosis but fewer perioperative complications than those receiving laparotomy (6,7). Due to the numerous advantages and proven safety of minimally invasive surgery, it is now established that minimally invasive surgery is the standard procedure for early-stage EC patients.

Most studies to date have mainly focused on patients with early-stage or low-risk diseases, with less specifically discussing the safety of minimally invasive surgery in advanced-stage or high-risk EC, though the latter has been questioned by the community (8). The aim of this study was to compare perioperative and survival outcomes between high-risk EC patients receiving laparoscopic surgery and laparotomy. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1578/rc).

Methods

Study subject

The data of all patients undergone primary surgical treatment for EC from January 2006 to December 2016 were retrospectively extracted from the database of Peking University People’s Hospital. We selected high-risk patients according to the following criteria: (I) stage IA, grade 3; (II) stage IA, type II tumors(non-endometrioid); (III) stage IB-III disease, regardless of histologic grade. Exclusion criteria included: patients who received neoadjuvant chemotherapy; patients with other primary synchronous malignancies; patients with incomplete medical records. Since there were no universal guidelines for the International Federation of Gynecology and Obstetrics (FIGO) 2023 staging to guide adjuvant treatment of EC, the staging of all cases was determined based on FIGO 2009 staging system (9). The cases from 2006 to 2009 were restaged according to the clinicopathological information. Histological classification and tumor grade were determined according to the classification of World Health Organization (10). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the ethics committee of Peking University People’s Hospital (No. 2022PHB097-001), and written informed consent was obtained from all patients before the study.

Therapeutic regimen

Surgical approaches were determined by surgeons based on the feasibility of the operation, comorbidities and patients’ preference (11). All included laparoscopies were early cases and were therefore performed exclusively by standard technique, with no robotic or single-port approaches used during the study period. All operations are performed by the same team of gynecological oncologists with extensive surgical experience in our center. The surgical procedures consisted of at least total hysterectomy and bilateral salpingo-oophorectomy. Lymphadenectomy was omitted for patients with potentially poor tolerance. Antibiotic prophylaxis was given half an hour before the operation. Low molecular weight heparin and lower extremity graduated compression stocking were used to prevent deep vein thrombosis 24 hours after operation. Postoperative adjuvant treatments were tailored according to relevant guidelines (12). Adjuvant chemotherapy and/or radiotherapy was recommended for patients with any recurrence risk factors. For a few of selected patients, hormonal therapy was implemented as an alternative to chemotherapy, particularly for women who are elderly or have comorbidities. A small number of patients who declined postoperative adjuvant therapy were placed under observation.

Observed indicators

Clinical parameters analyzed included age, menopausal status, history of parity, diabetes, hypertension, body mass index (BMI), previous history of abdominal surgery, surgical procedure, status of peritoneal cytology, histological subtype, grade, depth of myometrial invasion, lymphovascular space invasion (LVSI) status, adjuvant therapy, etc. Molecular features including immunobiological expression of estrogen receptor (ER), progestin receptor (PR), p53 and Ki67 were also collected. Wild-type p53 is defined as scattered nuclear positivity by immunohistochemistry (IHC), reflecting its low and transient expression in normal cells, while mutant p53 is defined as diffuse strong positive staining or complete loss of expression by IHC. However, TP53 gene sequencing, POLE mutation status and mismatch repair (MMR) protein expression could not be obtained due to limitations of EC management at the time

Perioperative complications were also analyzed. Intraoperative complications were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Postoperative complications were assessed as grade 2 or higher adverse events using the Clavien-Dindo classification (13). Perioperative complication-related parameters included operation time(the time from the beginning of the incision to the completion of the surgical incision suture), estimated blood loss (calculated according to the blood volume in the vacuum cleaner at the end of the operation), transfusion, urinary retention, bladder injury, nerve injury, great vessel injury, febrile morbidity, incision hernia, ileus, deep vein thrombosis, lymphocele, lymphatic ascites, reoperation due to hemorrhage, wound separation, length of hospital stay (the duration from the operation date to the discharge date).

Follow-up

Patients were followed up by outpatient or telephone after surgery. Telephone follow-up was mainly used for patients undergoing re-examination at local hospitals. Follow-up included patient symptoms, serum tumor markers, ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), recurrence and death. During the telephone follow-up, patients with any abnormalities found were referred to our center for further examination and recurrences were diagnosed accordingly. Survival outcomes included overall survival (OS): the duration between the date of surgery and the date of death or the last follow-up; and disease-free survival (DFS): the duration between the date of surgery and the date of first recurrence or last follow-up.

Statistical analysis

Descriptive statistics were used to describe patient characteristics. Continuous variables were expressed as mean ± standard deviation or median (range). The distribution of demographic and clinical characteristics was compared between the laparotomy and laparoscopic groups using Student’s t-test or Chi-squared test, as appropriate. For survival analysis, the Kaplan-Meier method was used to construct survival curves, with statistical comparisons performed by log-rank test. To identify potential prognostic indicators, univariate Cox regressions were performed. Subsequently, surgical approach and factors with P<0.05 in univariate analyses were included in multivariate Cox regression. The multivariate Cox proportional hazards model was developed using stepwise regression (variables included: factors with P<0.05 in univariate Cox regressions; method: backward: Wald; entry criteria for variables: P<0.05). Statistical analysis was performed using SPSS statistical software package (version 24.0). Plots were generated using R (version 4.3.2) (14). All statistical analyses were two-tailed, and P<0.05 was considered as statistically significant.

Results

Baseline characteristics

A total of 267 high-risk EC patients who underwent surgery in Peking University People’s Hospital between January 2006 and December 2016 were retrospectively reviewed. One hundred and seventy-one (64.0%) patients underwent laparotomy, and 96 (36.0%) patients underwent laparoscopy. The baseline demographics were summarized in Table 1. The mean age was not significantly different between laparotomy and laparoscopic groups (58.9±9.9 vs. 57.6±8.0, P=0.24). BMI, parity, menopausal status, history of abdominal surgery, diabetes, hypertension, and rates of obesity were also similar between the two groups (P>0.05).

Clinicopathologic characteristics

Clinicopathologic characteristics of the two groups of patients were detailed in Table 2. There were no significant differences between the two groups in the distribution of FIGO stages, histological types, grades, ER/PR expression, p53 status, Ki67 positive rate and rates of LVSI and positive peritoneal cytology. About 90% of patients received retroperitoneal lymph node biopsy or resection. The proportion of patients in the laparotomy group who received pelvic and para-aortic lymph node resection was higher than that in the laparoscopic group (80.1% vs. 59.4%, P<0.001). The number of lymph nodes resected was higher in the laparotomy group compared with the laparoscopic group (31.8±12.4 vs. 25.7±11.0, P<0.001). About 80% of patients received adjuvant therapy, and the proportion of patients in the laparotomy group who did not receive any type of adjuvant therapy was higher than that in the laparoscopy group (24.0% vs. 12.5%, P=0.006).

Perioperative complications

Perioperative complications were summarized in Table 3. The mean operative time of laparoscopic group was shorter than that of laparotomy group (183.0±60.3 vs. 202.3±67.0 mins, P=0.02). Blood transfusion and febrile morbidity were the two most common complications. Laparoscopy was associated with less blood loss (210.2±255.5 vs. 484.9±328.2 mL, P<0.001) and lower transfusion rate (10.4% vs. 31.6%, P<0.001) than laparotomy, while there was no significant difference in febrile morbidity between the two groups (14.6% vs. 11.5%, P=0.47). In terms of urinary system complications, there was no ureter and bladder injury in the laparoscopic group, but one case of bladder injury occurred in the laparotomy. There were three cases of urine retention, one case in the laparoscopic group and two cases in the laparotomy group, and all recovered spontaneously after retaining the catheter. There was no intraoperative bowel injury recorded, though one patient in the laparotomy group had the intestine incisional hernia which required intestinal resection. Thirteen patients developed ileus in laparotomy group compared two in laparoscopy, with no statistically significant difference. In the laparoscopic group, there were two cases of great vessel injury, two cases of nerve injury, two cases of deep venous thrombosis, one case of postoperative hemorrhage requiring a second operation, six cases of lymphatic ascites and lymphocele. In the laparotomy group, there were nine cases of great vessel injury, eight cases of deep venous thrombosis, one cases of postoperative hemorrhage requiring a second operation, and 14 cases of lymphatic ascites and lymphocele. Eight cases of wound separation occurred in laparotomy group, which, comparing with three cases in laparoscopy group, showed no statistically significant difference. The duration of hospital stay was similar between two groups (14.5±8.3 days in laparotomy group vs. 12.8±10.3 days in laparoscopy group, P=0.15).

Oncological outcomes

The median follow-up time was 54.5 months (interquartile range, 29.4–71.6 months). During the follow-up period, a total of 29 cases experienced recurrence. The 5-year DFS of the laparoscopy group and laparotomy group was 88.8% and 84.6%, respectively. By log-rank test, the difference between the two groups was not statistically significant (P=0.33). The Kaplan-Meier survival curve for DFS was shown in Figure 1A. Subsequently, the survival influence of multiple clinicopathological characteristics was analyzed. In univariate analyses, FIGO stage, histology, grade, ER/PR status, p53 status, LVSI and peritoneal cytology were associated with DFS in varying degrees (Table 4). The prognostic effect of surgical approach was further verified. We included the surgical method and other prognostic factors into a multivariate Cox regression model. Only FIGO stage and grade were independent risk factors of recurrence, p53 status (P=0.09) and peritoneal cytology (P=0.09) lacked statistical significance, and the surgical approach (P=0.24) was not associated with DFS (Table 4).

Figure 1 Kaplan-Meier curves of high-risk endometrial cancer patients with different surgical approaches. (A) Disease-free survival; (B) overall survival.

A total of 20 patients died during the follow-up period. The 5-year OS of the laparoscopy and laparotomy group was 95.6% and 90.2%, respectively. By log-rank test, the difference was not statistically significant (P=0.58). The Kaplan-Meier survival curve for OS was shown in Figure 1B. Then the survival influence of multiple factors was analyzed. Univariate Cox regressions showed FIGO stage, grade, ER/PR status, p53 status, LVSI, peritoneal cytology as factors significantly associated with patients’ OS (Table 5). We included these adverse prognostic factors and surgical approach into a multivariate Cox regression model. Only FIGO stage (P=0.004) and grade (P=0.007) were independent risk factors of death, and the surgical approach was still not significantly associated with patient’s OS (Table 5).

Discussion

Laparoscopic surgery has advantages over laparotomy, and the application of laparoscopy in gynecology has been becoming more and more extensive. The Gynecological Oncology Group (GOG) LAP2 study and the LACE study are two well-known prospective randomized controlled studies on the safety of laparoscopic surgery in EC. The results of both studies showed no statistically significant differences in DFS and OS between the laparoscopic and laparotomy groups (7,15). Based on these evidences, laparoscopic surgery was recommended by the National Comprehensive Cancer Network (NCCN) guidelines as the standard procedure for low-grade endometrioid EC.

However, there were limited data on high-risk ECs. According to our literature review, there were only a few retrospective studies on laparoscopic treatment of patients with grade 3 endometrioid or type II EC, and only one study on the application of laparoscopy in patients with advanced-stage EC. These studies were all from developed countries, and there was no study on perioperative complications in high-risk ECs from developing countries. Therefore, we conducted the first study from a developing country, evaluating both patients with high-risk histologic subtypes and patients with advanced stages. We also compared the perioperative complications between high-risk EC patients receiving laparotomy and laparoscopy. This study revealed that laparoscopy was as effective and safe as laparotomy for the treatment of high-risk EC. The laparoscopic surgery group had comparable DFS and OS, yet fewer complications than the laparotomy group, with shorter operation time, less blood loss and lower transfusion rate.

Our study showed that laparoscopy was associated with less blood loss (210.2±255.5 vs. 484.9±328.2 mL, P<0.001) and a lower transfusion rate (10.4% vs. 31.6%, P<0.001) than the laparotomy approach, which were consistent with a previous meta-analysis of three RCTs, showing that laparoscopic surgery significantly reduced blood loss by an average of 106.82 ml compared with laparotomy (5).

The operation time varied greatly in different studies. The median operative time for laparoscopy in LACE study and LAP2 study was 130 minutes and 204 minutes, respectively (7,15). But the results of both studies showed that the operation time of the laparoscopic group was longer than that of the laparotomy group. However, our results showed that the average operation time in the laparoscopic group was shorter (183 minutes) than that in the laparotomy group (202 minutes). The discordance might be due to the following reasons. First, it was related to the scope of the surgery. The operation time of LAP2 study was longer than that of LACE study, which might be partly due to the larger extent of surgical resections in cases included in the LAP2 study. The number of lymph nodes removed in LAP2 study was 24, while that in LACE study was 11. Similarly, in our study, the rate of para-aortic lymph node resection in the laparoscopic group was lower than that in the laparotomy group (59.4% vs. 80.1%, P<0.001), and the number of lymph nodes removed was fewer than that in the laparotomy group (25.7±11.0 vs. 31.8±12.4, P<0.001). Second, the operative time was closely related to the experience and learning curve of the surgeons. With the improvement of surgical techniques, laparoscopic operation time tends to become shorter.

The length of hospital stay was similar between two groups (14.5±8.3 days in laparotomy group vs. 12.8±10.3 days in laparoscopy group, P=0.15). The results of this study were similar to a study from South Korea, which reported the average hospital stay of laparoscopic surgery was 16.4 days (16). However, it was much longer than that reported in most other previous studies. In the LAP2 study, the median duration of hospital stay for laparoscopic surgery group was only 2 days. In the LACE study, 62.1% of patients were hospitalized for less than 2 days. The longer duration of hospital stay in Chinese cohort was mainly affected by social and economic factors, including patients’ willingness to stay in hospital until complete recovery (removal of drainage tube, urinary catheter or suture), and less concern about medical expenses due to high insurance coverage.

This study also showed that there was no significant difference in survival outcomes between patients receiving laparoscopic surgery and laparotomy. Multivariate Cox regression showed that only FIGO stage and grade were independent risk factors of OS and DFS. Our findings support previously published studies on the application of minimally invasive surgery in high-risk EC (17-23). In 2012, Fader et al. (17), for the first time, retrospectively analyzed the application of laparoscopy in high-risk ECs, including 383 cases of G3 and type II cases. The study showed that there were no difference in 3-year OS and DFS between the laparoscopic and laparotomy groups after controlling for stage, thus indicating high-risk histopathological types was not a contraindication of laparoscopy (17). In 2015, Gao et al. (18) selected 81 pairs of high-risk EC patients through propensity score matching analysis. The 5- and 10-year survival rates for patients undergoing laparotomy were 89.2% and 75.8%, respectively, while those for patients undergoing laparoscopic surgery were 85.3% and 85.3%, respectively. There was no significant difference in survival rates between the two groups (18). In 2016, Koskas et al. (19) assessed 228 patients with stage I-III endometrioid carcinoma whose histological subtypes were grade 3 endometrioid and type II tumors. By matching patients based on age, stage, histology, and lymphadenectomy, laparoscopic surgery and laparotomy showed no significant difference in DFS and OS, although the proportion of patients undergoing para-aortic lymphadenectomy and the extent of lymphadenectomy were lower in the former (19). In the post-hoc analysis of the LAP2 trial, Fader et al. (20) further assessed the survival outcomes of the patients with type II tumors. Recurrence rates, recurrence patterns, PFS and OS were comparable between the laparoscopy and laparotomy groups (20). In 2017, Monterossi et al. (23) enrolled 283 type II endometrial carcinoma patients with clinical stage I–II, and they also found no significant difference in the survival outcome between the two groups (23). In 2019, Vardar et al. (22) evaluated 801 patients with EC and divided the patients into low, medium, and high-risk groups according to the ESMO-ESGO-ESTRO consensus report. In low-risk and medium-risk patients, the OS of the laparoscopic group was similar to the laparotomy group, but in the high-risk group, the OS was higher in the former (22). In 2020, Tanaka et al. (21) analyzed 229 patients with high-risk EC confined to the uterus, and found that there was no significant difference in oncological outcomes between the two groups. However, among the 176 patients with advanced stages, the laparoscopic group had a higher PFS and OS than the laparotomy group. The authors reasoned that the superior prognosis of patients undergoing laparoscopic surgery might be due to relatively earlier stages, while patients undergoing laparotomy were more frequently in advanced stages on diagnosis (21).

Appropriate adjuvant therapy can improve the prognosis of patients with EC (24), but traditional adjuvant therapy is mainly determined by stage and histological type, lacks accuracy, and often causes under-treatment/over-treatment. With advancements in cancer genomics, molecular testing of EC is gradually being incorporated in risk assessment and adjuvant therapy (25,26), but molecular feature-guided surgical approaches have been studied sparingly. Our team previously analyzed TCGA data and found, for the first time, that in EC patients, with POLE mutations, MSI-H, homologous recombination repair pathway mutations, or MUC16 mutations, the prognosis after laparoscopic or laparotomy surgery was similar. However, in patients with TP53 mutations or CNL with CTNNB1 mutations, the prognosis after laparoscopic surgery was significantly worse than that of laparotomy (8). This suggests that molecular characteristics can guide the selection of EC surgery methods. It is speculated that the reason is due to the stronger anti-tumor immune response in EC patients with high mutation load, which can balance the risk of intra-abdominal tumor dissemination caused by minimally invasive surgery; while in patients with TP53 or CTNNB1 mutations, in which cases the tumors are more invasive, the risk of recurrence after minimally invasive surgery is significantly increased. For the first time, the selection of surgical methods based on molecular characteristics has been proposed, opening up new ideas for future research, but further validation is needed (8).

To the best of our knowledge, this is the first study to investigate the perioperative and survival outcomes between laparoscopic surgery and laparotomy in patients with high-risk EC in developing countries, and we preliminarily demonstrated that laparoscopy was safe in the treatment of high-risk ECs. However, there are several limitations in the current study. First, due to the retrospective nature of the study, uncertain potential confounding factors could affect the accuracy of the results. In our study, surgical approach was associated with disease severity, comorbidities and tumor characteristics, rather than randomization, and proper subgroup analyses were absent due to a relatively small number of outcome events. Such systematic deficiencies in retrospective studies could not be fundamentally compensated by multivariate analysis. Second, the cohort size was small, so stratified analysis of patients based on different high-risk factors was not possible. Besides, according to previous reports, the prognosis of recurrent EC is significantly related to the recurrence pattern (27). A larger sample size study to determine whether laparoscopic surgery has the same recurrence pattern as open surgery is expected in the future. Collectively, more prospective, randomized controlled trials in developing countries are still required to further verify our conclusions.

Conclusions

In conclusion, laparoscopy appears to be effective and safe in the management of high-risk EC patients, showing fewer complications and comparable oncological outcomes to laparotomy. More prospective randomized controlled trials would be needed to confirm our conclusions.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1578/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1578/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1578/prf

Funding: This work was supported by the Capital’s Funds for Health Improvement and Research (No. CFH-2022-1-4081), Research and Development Fund of Peking University People’s Hospital (No. RDJP2023-11), and the National Natural Science Foundation of China (No. 82203646).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1578/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the ethics committee of Peking University People’s Hospital (No. 2022PHB097-001), and written informed consent was obtained from all patients before the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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