Ten-Year Results of Postoperative Adjuvant Treatment In Women With Stage I Endometrial Cancer

Background: It remains controversial whether postoperative adjuvant treatment is benecial for the survival of patients after surgery for early-stage endometrial cancer. To evaluate whether postoperative adjuvant treatment is benecial for the survival of patients after surgery for early-stage endometrial cancer. We analyzed the outcomes of patients treated with radiotherapy, chemotherapy, or progestagen combined with other adjuvant treatments. Methods: We retrospectively examined disease-free survival (DFS), overall survival (OS) and high risk factors that affected the survival status of all patients who received different postoperative adjuvant therapies. Results: The total relapse and mortality rates were 5.57% and 1.68%, respectively. During follow-up period, fourteen patients (7.29%) developed isolated local recurrence, and 2 patients died (1.04%) of recurrence. The 5-year DFS and OS rates in all patients were 95.83% and 93.75%, respectively. No signicant differences were observed in the 5-year DFS, 5-year OS, OS, or DFS among the four groups of patients with FIGO stage I endometrial cancer. The differences in the log-rank test results of the estimates of the 5-year DFS, 5-year OS, DFS and OS of patients with different disease stages and different ages were all signicant, but no differences were observed in these parameters between patients with varying degrees of differentiation. Histologic grade, CA125 level, ER and PR status and whether adjuvant therapies had no signicant effect on the DFS and OS of all patients according to univariate and multivariate regression analyses, but age stratication did reveal signicant differences in DFS and OS in the univariate and multivariate analyses. Conclusion: This retrospective study showed that adjuvant treatments after surgery were not signicantly associated with in early-stage


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risk and low-intermediate risk factors do not need adjuvant treatment, as they would not derive a bene t.
Moreover, the optimal adjuvant treatment is still controversial for patients with intermediate risk and highintermediate risk factors. Although pelvic external-beam radiotherapy (EBRT) reduced the local recurrence rate after 15 years of follow-up, EBRT treatment of endometrial cancer is associated with lasting intestinal and urinary symptoms and role-physical functioning. Therefore, these data suggested that postoperative radiotherapy be avoided in patients with low-and intermediate-risk endometrial cancer [7].
Another randomized phase III trial randomly recruited 385 women to receive either pelvic radiation therapy or chemotherapy consisting of cisplatin/doxorubicin/cyclophosphamide. No signi cant differences were observed in the progression-free survival (PFS) or OS between two groups [8]. These ndings supported the idea that the use of adjuvant radiotherapy does not improve disease-speci c survival (DSS) or OS in women with stage I or IIA endometrial cancer.
In recent years, many doctors reconsider the use of chemotherapy in HIR stage I endometrial cancer patients despite the insu ciency of randomized data to support this. Chemotherapy may be an appropriate therapeutic option that can improve the outcomes of patients with risk factors (possibly improving PFS). Current NCCN guidelines recommend adjuvant chemotherapy for groups with a poor prognosis. The results of a Cochrane Collaboration meta-analysis suggested a small numerical bene t in PFS and OS after patients received platinum-based chemotherapy for endometrial cancer [9]. Of course, many scholars have expressed different viewpoints. According to a systematic review, adjuvant chemoradiotherapy had no advantage over radiotherapy alone for overall survival and failure-free survival in high-risk patients with FIGO stages I-II endometrial cancer [10]. Chemotherapy as an adjuvant treatment results in a bene t in terms of 5-year PFS, but not for OS, in early-stage EC with HIR factors [11].
Therefore, whether early-stage high-risk patients can bene t from adjuvant chemotherapy is worthy of further exploration.
The value of progestogenic agents in advanced endometrial carcinoma has been well demonstrated, while their role as adjuvant therapies in early-stage endometrial cancer is somewhat contentious. Some studies have shown that adjuvant progestagen therapy can reduce the recurrence and improve survival rate in patients with early endometrial cancer. In the 1970s and 1980s, several small studies suggested a survival bene t from progestagen in patients with endometrial cancer [12]. However, in observational studies, progestogens have been demonstrated to have a limited role in preventing recurrence compared with control treatments [13]. Four trials showed that the risk of death at ve years between patients who received adjuvant progestagen therapy and those who received no further treatment was not signi cantly different. Importantly, in one study of patients with low-risk endometrial cancer, no difference was found in the risk of death in patients who did and did not receive progestogens, and an increased risk of death was observed in patients who were treated with progestogens compared with those who did not receive adjuvant progestagen treatment [14]. Since then, researchers have paid little attention to adjuvant endocrine therapy for early-stage endometrial cancer. Therefore, the primary theme of this study was to retrospectively evaluate the oncologic outcomes and survival statuses associated with various postoperative adjuvant therapies and to assess the risk factors that affect the status of women with stage I endometrial cancer.

Patients
We retrospectively patients treated for endometrial cancer at our hospital (one of the major tertiary referral hospitals in China) from 2006 to 2016, and 654 patients diagnosed with FIGO stage I-IV endometrial cancer were identi ed. he Ethics Committee of the Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, approved the study (TJ-IRB20210737). After diagnosis, all patients underwent either laparoscopic, open total hysterectomy or bilateral salpingo-oophorectomy with or without pelvic/para-aortic lymph node dissection and pelvic washing. Two gynecologic pathologists reviewed and con rmed the pathologic specimens. All patients were diagnosed as stage I endometrial cancer according to the revised FIGO staging criteria [15]. Surgical treatment was followed by adjuvant radiotherapy (RT) alone, chemotherapy (CT) alone, hormone therapy with other adjuvant treatments, or no further adjuvant treatment.

Adjuvant therapy after surgery
The selection of adjuvant therapy was at the discretion of the attending gynecological oncologist who managed the patient. Treatment of patients was performed according to international guidelines and included vaginal brachytherapy at a total dose of 45 Gray over 5 weeks. The chemotherapy regimen used at our institution during the study period was platinum-based chemotherapy, with paclitaxel (135-175 mg/m 2 ) and carboplatin (AUC=5) given for two to four cycles every 3 weeks. Progestagen treatment was initiated 3 to 4 weeks after surgery or after other adjuvant treatments ended. The medroxyprogesterone acetate (MPA) dose was 250-500 mg administered once per day. This treatment was continued for 1 year.

Follow-up
Follow-up examinations were performed at either our institution or at hospitals local to the patients. All patients were followed-up after the completion of comprehensive treatment every 3 months for the rst 2 years, every 6 months during the next 3 years, and then yearly thereafter during the study period. The oncological status of patients at the last medical visit was also assessed and determined to be either remission, recurrence or death.
Statistical analysis SPSS 20.0 statistical software was used for the statistical analysis; the 'survival' package was utilized to apply complete survival analysis to the right-censored data, while the results were visualized with the 'survminer' package. The univariate comparison of the four groups was summarized by descriptive statistics and tested by Fisher's exact method. The count data were expressed as N (%), and the chisquare test was used to analyze differences between groups. The measurement data were expressed as x ± s, and variance analysis was used to test for differences between groups. The log-rank test was used for single-factor analysis of OS or DFS, and the Cox proportional risk model was used for multifactor analysis. The statistical signi cance threshold was p < 0.05.

Patients and tumor characteristics
In all, 339 patients were successfully followed-up, whereas 315 patients were lost to follow-up after treatment. Overall, 147 patients with advanced-stage disease (II to IV) were excluded from this study.  The baseline characteristics of all patients are summarized in Table 1. The median follow-up for all patients was 51 months (range: 18-143). No signi cant difference was found among the four groups in terms of age, histologic subtype, ER expression or CA125 level in the serum. A few patients were diagnosed with rare pathological types, such as adenocarcinoma (endocervical type), adenocarcinoma/clear cell carcinoma, clear cell carcinoma, serous papillary carcinoma, mucinous papillary adenocarcinoma of the intestinal epithelium, and papillary adenocarcinoma (villous-tubular carcinoma subtype). The proportions of these rare subtypes did not differ among the groups. In addition, we found that histologic grade, FIGO stage and PR expression differed among the four groups (p = 0.0005, p = 0.0112 and p = 0.0064). Among 192 patients, 168 (87.5%) underwent pelvic lymphadenectomy, and 11.46% (22/192) underwent pelvic and para-aortic lymphadenectomy. No difference was found in the proportion of lymphadenectomy among the four groups (p = 0.9688 and p = 0.4211).

The clinical factors that affect survival status
To assess the risk factors that affect the survival status of women with stage I endometrial cancer, we performed a univariate analysis of different variables. The log-rank test (time series test) was used for the univariate analysis to analyze the impact of various factors on prognosis. Histologic grade, estrogen receptor status, progesterone receptor status and CA125 level were not associated with signi cant differences in DFS and OS (log-rank, p = 0.6946, 0.9199, 0.9347 and 0.3272), but patient age was associated with prognosis (log-rank, p = 0.0045 for DFS and 0.0003 for OS) ( Table 2).   [19]. No difference was found in the survival rates between groups after a 5-year follow-up [20]. The current retrospective study revealed no statistically signi cant differences in the 5-year DFS, 5-year OS, OS, or DFS across the four groups of stage I endometrial cancer patients. Similar results were observed in two randomized trials (GOG-99 and PORTEC-1) and a retrospective study, which suggested no overall survival advantage of adjuvant radiation in patients with stage I, high-intermediate risk cancer [21][22][23]. In contrast, 50% of the 192 patients presented to our hospital for secondary surgery or further follow-up treatment after their rst surgery, which was performed at other hospitals. As the LVSI status of these patients was unknown, we could not evaluate this factor.
A review from 2010 found no evidence that endocrine therapy improved survival in endometrial cancer [24]. In a few studies, researchers reported that adjuvant endocrine therapy may provide a bene t in terms of delaying recurrence or prolonging survival of patients with early endometrial cancer [25]. However, most randomized trials of adjuvant progestagen therapy have failed to show any advantage in endometrial cancer, and data have even revealed that death due to cardiovascular disease tended to be higher in the progestagen group than in the control group [26-28]. These ndings are consistent with our results. Postoperative adjuvant chemotherapy is often recommended for high-risk stage I endometrial cancer. In our study, carboplatin plus paclitaxel was adopted as postoperative adjuvant chemotherapy in many patients with stage I disease. The data suggested that women gain little bene t from adjuvant chemotherapy, including women with high risk factors, such as deep myometrial invasion and the serous or clear cell histologic type. Indeed, many studies have demonstrated that adjuvant chemotherapy for high-risk endometrial cancer does not improve survival rates [29][30]. However, the results of randomized trials have varied, and some previous studies have suggested that adjuvant chemotherapy after surgery is bene cial for early-stage EC with HIR factors. 31 Furthermore, two retrospective studies showed that adjuvant platinum-based chemotherapy plus vaginal brachytherapy (VBT) achieved excellent results in high-risk early-stage endometrial cancer [32][33]. However, we were unable to con rm this result because this retrospective study contained no such cases.
According to our retrospective observations, the differences in DFS and OS were signi cant between stage IA and stage IB. That is, even in early endometrial cancer, the FIGO stage still affects the DFS and OS of endometrial cancer patients. Moreover, it was found that age (< 60 years and ≥ 60 years) was another factor that in uences the prognosis of patients with early-stage endometrial cancer. Notably, according to both the univariate and multivariate analyses, ER status, PR status, CA125 level, histologic grade and the type of adjuvant therapy did not affect PFS or OS in FIGO stage I endometrial cancer patients in our study, but age was associated with differences in OS and PFS. Many physicians have veri ed that the cancer antigen 125 (CA125) level, age older than 60 years, and depth of myometrial invasion > 50% were signi cant factors for overall survival in a retrospective study [34]. Age > 60 years (or > 50 years) and degree of differentiation may be high-intermediate risk factors according to a systematic review of guidelines in the US [35]. Among all the factors analyzed in our study, age was the only indicator that independently affected OS and DFS in stage I endometrial cancer. Due to incomplete data on lymph node metastasis in this study, it was not possible to analyze this factor and its impact on survival status.
The goal of adjuvant therapy in endometrial cancer is to reduce the risk of disease recurrence, and whether postoperative adjuvant therapy should be used for early endometrial cancer is controversial. Our results agree with the above ndings and suggest that postoperative adjuvant treatments are not associated with better OS or DFS in patients with either FIGO stage IA or stage IB endometrial cancer. All the above evidence seems to support the conclusion that women do not gain a survival advantage from postoperative adjuvant therapy after operation for stage I endometrial cancer regardless of the disease stage (IA and IB). Nevertheless, our study still has some shortcomings. It is limited by its retrospective nature, the heterogeneity of the data and the reliance on clinical endometrial cancer data not originally collected for research purposes. Also, it was limited by single-center experience and the potential selection bias, which may limit its external validity. And our results may not represent the ndings of other hospitals.
Therefore, it is necessary to further discuss the bene ts and disadvantages of adjuvant endocrine therapy, chemotherapy and radiotherapy as well as major risk factors for early endometrial cancer. In the future, it will be possible to achieve the goal of personalized treatment for individual patients. Availability of data and materials The data used and analysed during the study will be made available upon reasonable request made through the corresponding author.

Competing interests
All authors declare that there are no con icts of interests.

Funding
This work was supported by National Natural Science Foundation of China (81572563).

Authors' contributions
Conceived the experiment: RL. Analysed the data: RL and PF. Wrote the rst draft of the manuscript: RL and PF. Assisted with the data analysis: SW and PF. Agree with the manuscript results and conclusions: PF, TZ, PC, SW and RL. All authors reviewed the manuscript.

Figure 1
Retrospective study ow diagram