The survival effect of ovary preservation in early stage endometrial cancer: a single institution retrospective analysis

Purpose We investigated the effect of ovary preserving surgery in early International Federation of Obstetrics and Gynecology (FIGO) stage endometrial cancer patients. Methods Medical records were retrospectively reviewed for 539 patients who were diagnosed with early stage endometrial cancer between Jan 2006 and Dec 2017. Patients were categorized into ovary preservation and ovary removal groups. Demographics, recurrence free survival (RFS), and five-year overall survival (OS) rate were compared, and the clinical factors affecting survival were evaluated by univariate and multivariate analysis. Results The median follow-up period was 85 months (range, 6–142 months), and the median age was 52.7 years. The mean age was higher in the ovary removal group than in the ovary preservation group (54.4 vs 40.94 years; P < 0.001). The ovary preservation group showed an earlier FIGO stage than the ovary removal group (P = 0.0264). There was a greater incidence of adjuvant chemotherapy administration in the removal group. There were no statistical differences in other baseline characteristics. When comparing the RFS and OS rates, there were no statistical differences between the preservation and removal groups. (recurrence free rate 98.5% vs 92.7%, p = 0.4360, and 5-year survival rate 98.6% vs 93.0%, p = 0.0892, respectively). Endometrioid histology (p = 0.006) and post-operative adjuvant chemotherapy (p = 0.0062) were related to OS, and adjuvant chemotherapy (p < 0.001) and radiotherapy (p = 0.005) were related to RFS. Conclusions Ovary preservation in early stage endometrial cancer is worth considering, as it does not affect survival in early stage endometrial cancer patients.

patients with endometrial cancer is as 7% [6]. However, surgical menopause caused by removing the ovaries can induce other complications, such as hot flushes, night sweats, vaginal dryness, insomnia, osteoporosis, cardiovascular problem, sexual dysfunction, and cognitive problems that can affect survival and quality of life [7][8][9][10][11]. Exogenous hormone replacement therapy may relieve these menopausal symptoms but can also induce other complications [12,13].
Meta-analysis [14] and other research [4,5,15,16] on ovarian preservation surgery in young, premenopausal early stage endometrial cancer patients has produced conflicting results. Some studies claim that it is safer to remove the ovaries, although preservation of the ovary generally does not affect patient recurrence or survival. However, in some meta-analyses and reviews, much of the patient data (34.9%) is too old records [4], therefore, there is a risk of inaccurate medical records. Further, studies included incidentally diagnosed cancer patients who were regarded as having benign disease such as leiomyoma or adenomyosis prior to surgery, and only had hysterectomy planned without salpingo-oophorectomy.
In addition, many patients receive adjuvant treatment such as radiotherapy or chemotherapy after ovarian preserving surgery, which can further damage ovarian functions. These cases do not represent true ovarian preservation or help to reduce the complications of surgical menopause.
This retrospective study compares the survival of early International Federation of Obstetrics and Gynecology (FIGO) stage endometrial cancer patients who have the ovaries preserved with those who had the ovaries removed in a real clinical setting.

Methods
Medical records of patients with endometrial cancer who were newly diagnosed by endometrial biopsy and treated at National Cancer Center in South Korea between January 2006 and December 2017 were reviewed. A total of 1578 endometrial cancer patients visited our outpatient clinics; however, 497 patients visited only once for counseling or a second opinion, and 439 patients had recurrent disease. Another 103 patients were excluded due to advanced cancer status (FIGO stage III or IV), which resulted in 539 patients who had been diagnosed and treated in our center for early (FIGO stage I or II) endometrial cancer (Fig. 1). Clinical factors including age at diagnosis, FIGO stage, FIGO grade, histology of the surgically removed tissues, surgical approach method, radicality of hysterectomy, lymph node dissection, and adjuvant chemotherapy and radiotherapy were collected.
Correlations of variables were assessed using the Fisher's exact or Student t-test. Five year overall survival (OS) rates and recurrence free survival (RFS) rates were estimated by Kaplan-Meier analysis. The log-rank test was used to compare survival curves. Cox regression analysis was performed to determine the predictive factors for prognosis with hazard ratios (HRs). P values <.05 were considered to be significant. This retrospective study was approved by the institutional review board of our institution (IRB No. NCC2019-0272).

Results
The 539 patients included 469 in the ovarian removal group and 70 in the ovarian preservation group. The ovarian removal group was significantly older than the ovarian preservation group (P < 0.001). The FIGO stage was earlier in the ovarian preservation group (P = 0.0264). Lymph node dissection was more frequently performed in the ovarian removal group. There was no significant difference between the two groups in terms of surgical approach method, radicality of hysterectomy, or the administration of adjuvant  Table 1). The five-year OS) and RFS) graphs showed no significant differences between ovarian preservation and removal groups (OS: 98.6% vs. 93.0%, P = 0.0892, and RFS: 98.5% vs 92.7%, P = 0.436, respectively) (Fig. 2). Adjusted univariate analysis was performed for FIGO stage and patient age. Univariate analysis Previous studies have shown that preserving the ovary does not affect survival in patients with early stage endometrial cancer who are not menopausal, compared with those who have had the ovaries removed [4,5,14,15]. Previous studies are compared in Table 3. These retrospective studies were conducted in the United States, China, and Korea, conducted mainly with pre-menopausal women as patient groups. Prospective research has been difficult to perform as recruitment of early stage and premenopausal patients has been challenging. Their results showed that in the case of early stage and low FIGO grade, preservation of the ovary did not affect the prognosis of the patient. Recently, a systemic review summarized previous studies, with more than 10,000 cases, and revealed an increase in OS and no shortening of RFS. In the early stages of premenopausal women, ovarian preservation may be a viable treatment option [19]. The results are similar to ours. However, as previously noted, this research has several limitations, including a large portion of patients with benign disease, the inclusion of patients with adjuvant chemotherapy or radiotherapy after preserving the ovaries [5,16], or including patients with old records [4]. There are many reports of ovarian function deterioration after radiation or chemotherapy in premenopausal women [20][21][22][23]. These cases demonstrate that preserving the ovaries does not result in maintaining ovarian function, since adjuvant treatment can also induce menopause. Endometrial cancer in premenopausal women has been shown to be hormone related, have early stage, no myometrial invasion, and good prognosis [24]. If metastatic or synchronous malignancy has not been found in the ovary during surgery, ovarian preservation may be performed; therefore, surgical menopause of the patient is not induced, which may be more beneficial to women's health. We recommend to consider the pathology of the tumor and the necessity of maintaining fertility before surgery. Although this retrospective study has some limitations, this is the first study in which all patients had been diagnosed with endometrial cancer through preoperative endometrial biopsy, and had ovarian preservation or removal planned in advance of surgery, after confirming no other distant metastasis through computed tomography scan and lab test. Further, a relatively low ratio of patients was administered adjuvant treatment, so this study may serve as a reliable reference for early FIGO stage endometrial cancer. However, this study has limited data about the side effects of each group, especially menopausal problems that occur in the ovarian removal group. Long-term follow-up of adverse effects in postoperative patients may reveal significant differences in patients who have undergone surgical menopause. Second, although a small number of patients received adjuvant treatment after surgery, that treatment was related to survival; consequently, a more accurate group selection process is warranted for future studies.
Cancer survival and life expectancy after diagnosis are increasing, and quality of life issues are becoming more important. It is time forFurther prospective research to confirm whether it is more favorable to remove the ovaries to decrease risk of recurrence or to maintain patient quality of life through ovarian preservation.

Conclusions
Ovarian preserving surgery in early stage endometrial cancer is a beneficial option for premenopausal patients and is not related to disease recurrence or overall survival rate. More precise stratification analysis is needed to determine which additional groups may safely preserve the ovary.