Analysis of the Safety and Pregnant Outcomes of Fertility-Sparing Surgery in Ovarian Malignant Sex Cord-Stromal Tumors: A Multicenter Retrospective Study

Background: To assess the difference in survival between fertility-sparing surgery (FSS) and radical surgery (RS) and explore pregnant outcomes after FSS in stage I malignant sex cord-stromal tumors (MSCSTs). Methods: We performed a multicenter retrospective cohort study on patients who were diagnosed with stage IA or IC MSCSTs. Inverse Probability of Treatment Weighting was performed between the FSS and RS groups. The Chi-square test and Kaplan-Meier method were used to compare the categorical variables and disease-free survival (DFS). The binary logistic regression analysis and Cox proportional hazards regression analysis were used to identify high-risk factors related to DFS and pregnancy. Results: A total of 107 patients were included, of whom 54 (50.5%) women underwent FSS, and 53 (49.5%) women underwent RS. After IPTW, 208 patients were obtained, and all of the covariates were well balanced. After a median follow-up time of 50 months (range 7-156 months), there was no signicant difference of DFS between the two groups in both unweighted cohort (P=0.969) or weighted cohort (P=0.792). In the weighted cohort, stage IC (P=0.014), tumor diameter >8 cm (P=0.003), incomplete staging surgery (P=0.003) and no adjuvant chemotherapy (P <0.001) were 4 high-risk factors associated with a shorter DFS. Among 14 patients who had pregnancy desire, 11 (78.6%) women conceived successfully, and the live birth rate was 76.9%. In univariate analysis, only adjuvant chemotherapy (P=0.009) was associated with infertility. Conclusions: On the premise of complete staging surgery, FSS is safe and feasible in stage IA and IC MSCSTs with satisfactory reproductive outcomes.

patients undergoing FSS and a weight of 1 ÷ (1-PS) to the patients with RS. Then all patients were weighted by the obtained weighted value to get a weighted cohort. There is no statistical difference in the characteristics of the two groups in the weighted cohort.
Combined with the log-rank test, we compared Kaplan-Meier curves of DFS between FSS and RS groups in the before and after weighted cohorts. We used univariate Cox regression analysis to perform univariate analysis of DFS, variables with a P <0.05 were selected for subsequent multivariate Cox regression analysis to determine independent high-risk factors. The results were described as the hazard ratio (HR), 95% con dence interval (CI) and P-value. Binary logistic regression analysis was used to perform univariate analysis of pregnancy after FSS, the results were described as the odds ratio (OR), 95% CI and Pvalue.
Chi-square test, IPTW calculation, Cox regression and Kaplan-Meier analysis were all conducted with IBM SPSS statistics (version 25.0), binary logistic regression analysis were performed with R software (version 4.0.4).

Study population
One hundred and seven patients were included in this study, with 54 patients undergoing FSS and 53 with RS. The research owchart is shown in Figure. 1. The median age of patients was 26 years (range: 3-47 years) and 43 years (range: 26-49 years) in the two groups, respectively. Table 1 summarizes the characteristics of patients before and after IPTW. Patients with RS were more likely to underwent complete staging surgery (P=0.008). There were no signi cant differences in FIGO stage, histologic classi cation of the tumor, tumor diameter, surgical approach, CA-125 level and adjuvant chemotherapy between the two groups. After IPTW, all of the covariates were well balanced, and there was no statistical difference in characteristics between the two groups (P >0.05). In the weighted cohort, of the 208 patients, there were 107 patients in the FSS group and 101 patients in the RS group.

Survival outcomes
The Median follow-up time was 50 months (range: 7-156 months). As a result, there was no statistical difference of DFS between FSS and RS groups both in the unweighted cohort (P=0.969) and weighted cohort (P=0.792) ( Figure. 2). Table 2 lists the information of relapsed and dead patients. Ninety percent of relapsed patients were in stage IC, 80% did not undergo surgical staging, and 70% did not received adjuvant chemotherapy. Women were all treated with surgery after recurrence. Two women died, the 20-year old patient died of lung cancer 22 months after recurrence, the other 40-year women died after 12 months with a 2 cycles adjuvant chemotherapy.

Discussion
Based on the younger age of MSCSTs, fertility-sparing surgery is becoming increasingly important [11]. Our multicenter study suggests that FSS did not result in a shorter DFS compared with RS for stage I MSCSTs, and the pregnant outcomes are hopeful. Besides, we observed that adjuvant chemotherapy was associated with a higher risk of infertility. To our knowledge, this is the rst study to explore the in uence of single factor of FSS on the prognosis of MSCSTs.
Through propensity-score weighting, it balanced the bias of other clinical-pathological factors and individual selection differences.
Previous retrospective studies have indicated that apart from a worse cancer-speci c survival (4.3% vs 11.8%), there is no inferiority of DFS and OS in women who underwent FSS, compared those with RS [12][13][14][15]. However, there is a serious limitation that selection bias, the possibility of treatment heterogeneity and other clinicopathological features affecting oncologic outcomes were inconsistent. In our study, we used the original cohort and the weighted cohort to compare the survival difference of FSS and RS. By survival analysis and multivariate Cox regression analysis, both cohorts showed no difference in DFS between the two treatment groups. In addition, we discussed the high-risk factors of DFS in stage I MSCSTs. We got that stage IA, complete staging surgery, tumor diameter <8 cm and adjuvant chemotherapy were associated with a longer DFS. The tumor stage has proven to be the most important prognostic factor of MSCSTs, the 5-year disease-speci c survival rate of stage I MSCSTs was 98%, and the survival rate of stage II-IV was lower than 80% [7,16,17]. Complete staging surgery was also an independent predictive factor of DFS. In an analysis of 2680 OGCTs from the National Cancer Database, the incomplete surgical stage was obviously associated with an increased risk of death ( ve-year survival: 90.2% and 84.2%) [18]. Therefore, large omental biopsy, omentectomy or biopsy of the peritoneum is essential for patients with 15 to 25 years [4,5,8]. However, the prognostic signi cance of adjuvant chemotherapy in MSCSTs is controversial to now. In international guidelines, platinum-based adjuvant chemotherapy or observation is recommended for stage I MSCSTs with high-risk the comprehensive impact of chemotherapy and its regimens on fertility and survival still needs large samples to evaluate [5]. It is important to adjuvant chemotherapy indications.

Strengths and weaknesses
There are still some limitations in this study. First, this is a retrospective study, data integrity is awed, such as some patients have forgotten the speci c time of their menstrual recovery after surgery. Second, the longest follow-up time was 156 months, during which 2 deaths were monitored, the difference in OS between the two groups could not be analyzed. Besides, of the 54 patients with FSS, only 14 women tried to get pregnant during the follow-up period, and 17 patients were younger than 20 years old, so there was a limited interpretation of pregnant outcomes and survival after pregnancy.

Conclusions
We comprehensively analyzed the safety and reproductive outcomes of FSS and risk factors of recurrence in stage I MSCSTs. In conclusion, based on complete surgical staging, FSS is favorable for stage I patients with desirable pregnant outcomes.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.