Objective Fertility sparing surgery for patients with early stage ovarian clear cell carcinoma is controversial. We aimed to investigate the impact of fertility sparing surgery on the oncologic outcomes of young patients with stage I ovarian clear cell carcinoma.
Methods The National Cancer Database was accessed and patients with pathological stage IA or IC ovarian clear cell carcinoma, aged <45 years, were selected. Based on site specific surgery codes, patients who underwent fertility sparing or radical surgery were identified. Overall survival was evaluated following generation of Kaplan–Meier curves, and compared with the log rank test. Multivariate Cox analysis was performed to control for possible confounders. A systematic review of literature of the Pubmed, EMBASE and Web of Science databases was also performed to summarize all reported cases.
Results A total of 57 (35.8%) and 102 (64.2%) patients underwent fertility sparing and radical surgery. There was no difference in overall survival between patients who had fertility sparing and radical surgery (p=0.92); 5 year overall survival rates were 89% and 87.9%, respectively. After controlling for the performance of lymphadenectomy and disease substage, fertility sparing surgery was not associated with worse survival (hazard ratio 0.83, 95% confidence interval 0.30 to 2.32). A systematic review of the literature identified 132 patients with stage I disease who underwent fertility sparing surgery; a total of 20 patients (15.2%) experienced a relapse at a median of 18 months from surgery.
Conclusions In a large cohort of young patients with stage I ovarian clear cell carcinoma, fertility sparing surgery was not associated with worse survival.
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A total of 57 young patients with stage I ovarian clear cell carcinoma who had fertility sparing surgery were identified in a large database.
Fertility sparing surgery did not have a negative impact on overall survival.
Based on 130 patients who had fertility sparing surgery, the cumulative relapse rate was 15.2%.
Clear cell carcinoma is a histologic subtype of epithelial ovarian cancer, accounting for approximately 5–25% of all epithelial ovarian carcinoma cases. It is characterized by a high frequency of mutations of the AT-rich interaction domain 1A gene and relative chemoresistance to platinum based chemotherapy, and most patients present with early stage disease.1 Fertility preserving surgery, usually defined as the preservation of the uterus with or without preservation of the contralateral ovary, is commonly offered to patients with epithelial low grade tumors and stage IA disease.2 Certain authors are reluctant to offer fertility preserving surgery to patients with clear cell carcinoma given the high rates of relapse and tumor chemoresistance.3 This is reflected by the paucity of evidence on the safety of fertility sparing surgery for patients with clear cell carcinoma.4–24 However, in a prior analysis of the surveillance, epidemiology, and end results database, ovarian and uterine preservation did not have a negative impact on the oncologic outcomes of premenopausal (aged <50 years) patients.25 A major limitation of the study was the absence of data on the administration of chemotherapy, while the impact of uterine and ovarian preservation was evaluated separately. Similarly, other recent retrospective studies have failed to find a detrimental effect of fertility sparing surgery compared with patients who had radical surgery.4 8
The aim of this study was to investigate the oncologic safety of fertility sparing surgery in premenopausal women with International Federation of Gynecology and Obstetrics (FIGO) stage I ovarian clear cell carcinoma using a multi-institutional, hospital based database, and to summarize the outcomes reported in the literature.
The National Cancer Database was accessed, and a cohort of patients diagnosed between January 2004 and December 2015 with a pathologically confirmed primary ovarian carcinoma and without a history of another tumor was drawn. Patients with clear cell carcinoma were identified based on International Classification of Disease-O-3 histology codes '8310–8313, 9110', as grouped by the International Agency for Research on Cancer. The National Cancer Database has been established jointly by the American Cancer Society and Commission on Cancer of the American College of Surgeons as a hospital based database capturing data of patients with newly diagnosed cancer in the USA. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytical or statistical methodology employed, or the conclusions drawn from these data. The present study was deemed exempt from the Penn institutional review board.
Patients aged ≤45 years with pathological stage IA or IC disease, who had at least 1 month of follow-up, were identified. Performance of hysterectomy and bilateral salpingo-oophorectomy were assessed from site specific surgery codes. In the present study, fertility sparing surgery was defined as preservation of the uterus and one ovary, while radical surgery was defined as hysterectomy with bilateral salpingo-oophorectomy. Performance of lymph node sampling/dissection was evaluated from the pathology report. The presence of medical comorbidities was evaluated using the Charlson–Deyo Comorbidity Index score and was categorized into absent (score 0) and present (score ≥1).
Categorical and continuous variables were compared between patients who did and did not undergo hysterectomy with the χ2 and Mann–Whitney U tests, respectively. In the National Cancer Database, overall survival is defined as the number of months elapsed from tumor diagnosis to the date of death or last follow-up. Kaplan–Meier curves were generated to determine 5 year overall survival rates while univariate analysis was performed with the log rank test. A Cox multivariate model was constructed to evaluate the impact of hysterectomy on overall survival after controlling for a priori selected variables known to be associated with overall survival. Statistical analysis was performed with the Statistical Package for the Social Sciences V.24 statistical package (International Business Machines Corporation Corporation, Armonk, New York, USA), and the alpha level of statistical significance was set at 0.05.
In addition, a review of the literature on the outcome of fertility sparing surgery for patients with ovarian clear cell carcinoma was also performed. The Pubmed/Medline, Excerpta Medica, and Web of Science databases were searched from January 1 1990 to April 10, 2020, using the keywords: 'ovary' and 'cancer' and 'fertility' and ('preserving' or 'sparing'), while references of included articles were also hand searched. Studies in English language that reported at least one patient with stage I clear cell carcinoma and provided data on tumor relapse were eligible for inclusion. In the case of overlapping populations, the most recent/updated study was selected for inclusion.
A total of 159 patients who met the inclusion criteria were identified. Median patient age was 41 years (range 22–45), while the majority of patients were white (n=128, 80.5%), with private insurance (n=126, 79.2%), and without comorbidities (n=148, 93.1%). Most patients had stage IA disease (n=98, 61.6%), underwent lymphadenectomy (n=108, 67.9%), and received chemotherapy (n=110, 69.2%). A total of 57 (35.8%) and 102 (64.2%) patients underwent fertility sparing and radical surgery, respectively. Patients who underwent fertility sparing surgery were younger (median age 36 vs 42 years, p<0.001) and less likely to undergo lymphadenectomy (52.6% vs 76.5%, p=0.002) compared with those who had radical surgery. However, the rate of chemotherapy administration was comparable between the fertility sparing and radical surgery groups (63.2% vs 72.5%, p=0.22). Similarly, the rate of fertility sparing surgery was comparable between patients with stage IA (33.7%) and stage IC (39.3%) disease (p=0.47). Table 1 summarizes the clinicopathological characteristics of patients with stage I ovarian clear cell carcinoma who underwent fertility sparing and radical surgery.
Median follow-up of the present cohort was 73.4 months (range 1.28–162.7). There was no difference in overall survival between patients who had fertility sparing (n=57) and radical (n=102) surgery (p=0.92); 5 year overall survival rates were 89% and 87.9%, respectively (Figure 1). After controlling for the performance of lymphadenectomy and disease substage, fertility sparing surgery was not associated with worse survival (hazard ratio 0.83, 95% confidence interval 0.30 to 2.32). Following stratification by disease substage for patients with stage IA disease, there was no difference in overall survival between patients who had fertility sparing (n=33) and radical surgery (n=65) (p=0.68); 5 year overall survival rates were 89% and 90.9%, respectively (online supplementary Figure 1). Similarly, for patients with stage IC disease, there was no difference in overall survival between those who had fertility sparing (n=24) or radical surgery (n=37) (p=0.61); 5 year overall survival rates were 89.5% and 82.5%, respectively (online supplementary Figure 2).
Our review of the literature identified a total of 19 eligible studies reporting on 132 patients with stage I ovarian clear cell carcinoma who underwent fertility sparing surgery. Online supplementary Figure 3 depicts the study selection flowchart. Table 2 summarizes the country of origin, publication date, and stage distribution of each study. Data on the outcomes of 21 patients who had fertility sparing surgery and were registered at the Tokai Ovarian Tumor Study Group database were extracted from four separate reports.4 22–24 Substage was available for 92 patients, 40 patients had stage IA, and 52 patients had stage IC disease. A total of 20 relapses were reported with a calculated recurrence rate of 15.2%. Table 3 summarizes the characteristics and outcomes of patients who underwent fertility sparing surgery and experienced a tumor relapse. Based on the available data, the rate of relapse for patients with stage IA and IC disease was 12.5% (5/40) and 23.1% (12/52) (p=0.28), respectively. Among patients with stage IC disease, the relapse rate for those with stage IC1 disease was 21.4% (6/28) compared with 38.5% (5/13) for those with stage IC2/3. Median time to recurrence was 18 months (n=19, range 6–55) while the majority of patients who experienced a tumor relapse had received adjuvant chemotherapy (82.4%, 15/18). Information on the location of the tumor recurrence was available for 18 patients; only 2 (11.1%) patients had a relapse that involved solely the residual ovary while 4 (22.2%) relapses involved exclusively the pelvic or para-aortic lymph nodes. At the end of follow-up, six deaths were observed, while six patients were alive with disease.
In the largest cohort of young premenopausal patients with FIGO stage IA or IC ovarian clear cell carcinoma reported, fertility sparing surgery was not associated with a worse overall survival even after controlling for major confounders. A systematic review of the literature was also performed and underlined the paucity of evidence on the oncologic safety of fertility sparing surgery for patients with ovarian clear cell carcinoma since only 132 patients were identified. However, the overall relapse rate was acceptable (15.15%) in accordance with our results. Unfortunately, the majority of evidence on the safety of fertility sparing surgery for patients with ovarian clear cell carcinoma derives from small retrospective studies that do not include a comparison group of patients who had radical surgery. In a prior analysis of a population based database that included 96 and 71 premenopausal patients with stage IA or IC clear cell, diagnosed between 1988 and 2013, uterine or ovarian preservation did not have a detrimental effect on overall or cancer specific survival after controlling for confounders, even for patients with stage IC disease.25 Similarly, Park et al compared the outcomes of 22 adequately staged patients who had fertility sparing surgery with 25 patients who had radical surgery and did not find any difference in overall (91% vs 88%, p=0.48) or progression free (77% vs 84%, p=0.85) survival while anatomical location of recurrence did not differ.8 Recently, Yoshihara et al4 performed a propensity score analysis and matched 21 patients who had fertility sparing surgery to 82 patients who had radical surgery; 10 year progression free (68.8% vs 72.1%) and overall (79.8% vs 70.1%) survival rates were comparable between the two groups.4 In this study, only substage IC2/IC3 was associated with a higher risk of relapse.4
Stage IC disease, especially IC2/3, was associated with higher relapse rates.26–28 Kajiyama et al investigated the oncologic outcomes and prognostic indicators in reproductive age patients with ovarian clear cell carcinoma. For those with stage I disease, preoperative capsule rupture or positive ascites (IC2/3) was associated with higher relapse rates and worse overall survival.26 27 As such, several authors are hesitant to recommend fertility sparing surgery for patients with stage IC disease. Currently, the National Comprehensive Cancer Network treatment guideline suggests that fertility sparing surgery can be performed in all patients with stage IA and stage IC epithelial ovarian cancer, including clear cell carcinoma, but the Gynecologic Cancer InterGroup consensus review does not recommend fertility sparing surgery for stage IC, clear cell carcinoma.3 29 A key question is not whether these patients have lower progression or overall survival but whether fertility sparing surgery has an independent negative impact on oncologic outcomes. In our study, we did not find a detrimental effect on overall survival for patients with stage IC disease who underwent fertility sparing surgery, although the small number of patients precluded us from drawing firm conclusions. In our systematic review based on limited available data, patients with stage IC disease had almost double the relapse rate compared with those with stage IA disease (23.1% vs 12.5%) although this difference was not statistically significant. However, this rate seems to be comparable with patients who undergo radical surgery. Discrimination between stage IC1 and IC2/3 may be important since in a large cohort of patients with stage I ovarian clear cell carcinoma the relapse rate for patients with IC1 (n=107) and IC2/3 (n=67) disease were 9.3% and 35.8%, respectively.30 Potentially, fertility sparing surgery can be offered to adequately staged patients with stage IC1 disease and a strong desire for future fertility following extensive counseling regarding the high risk of relapse and close follow-up.
Our systematic review also yielded interesting findings. A main question is whether the retained ovary can be the source of a relapse. Interestingly, from 19 cases, 7 (36.8%) tumor relapses involved the retained ovary and only 2 were exclusively located at the ovary. Moreover, the majority of relapses (74%, 14 out of 19) occurred within 2 years from initial surgery at a median of 18 months. As such it is reasonable to discourage patients from pursuing a pregnancy within the first 2–3 years after surgery. It should be underlined that fertility sparing surgery should be offered only to adequately staged patients. In our systematic review, 3 of the 17 relapses involved exclusively the pelvic or para-aortic lymph nodes, raising the question of whether these patients had occult stage IIIA disease. This underscores the importance of systematic lymphadenectomy to assess for lymphatic tumor spread since approximately 5% of patients with apparent early stage disease will harbor lymph node metastases.25 31 Moreover, the majority (82%) of patients who experienced a relapse had received adjuvant chemotherapy. In our database analysis, there was no difference in overall survival between patients who did and did not receive chemotherapy. However, a prior large database analysis of 2325 patients with stage I ovarian clear cell carcinoma reported an association with better overall survival even among patients with stage IA disease.32 The majority of the literature on fertility sparing surgery for patients with ovarian clear cell carcinoma is derived from Asian countries. Whether the biology of the tumor or enzymatic polymorphisms accounting for different responses to chemotherapy varies based on patient race remains to be elucidated.33
Several limitations of the present study should be noted. First, given the absence of central pathology review, possible tumor misclassifications cannot be excluded. In addition, molecular data were not collected, precluding us from investigating the incidence of germline and somatic mutations in our patient population. Moreover, while all patients underwent staging surgery and were assigned FIGO stage I, we do not have specific details on the thoroughness of the staging procedures performed. Also, we could not discriminate between stage IC with preoperative and intraoperative tumor capsule rupture. Details regarding the composition of the chemotherapy regimen administered were not available. Lastly, the National Cancer Database does not collect data on tumor relapse, precluding us from analyzing differences in progression free survival, median delay of recurrence, as well as location of tumor relapse. However, as data from the systematic review suggest the majority of relapses are unfortunately not salvageable, this would have been reflected in the overall survival. Similarly, the majority of papers included in the systematic review did not provide specific data on the components of the staging performed. A future individual patient data meta-analysis of all reported cases would further clarify if relapse rate may be attributed to inadequate staging.
In a large cohort of young premenopausal patients with FIGO stage I, a negative impact on overall survival was not found. Further studies are warranted to confirm the safety of fertility sparing surgery for patients with ovarian clear cell carcinoma, especially those with stage IC disease.34 With great interest we await the results of the prospective non-randomized phase III from the Japan Clinical Oncology Group Study that enrolled adequately staged patients with stage IA ovarian clear cell carcinoma who underwent fertility sparing surgery and received adjuvant chemotherapy.33 We also propose the collaboration of cancer societies and the creation of an international registry on the performance of fertility sparing surgery in patients with high risk characteristics, such as clear cell, other high grade epithelial tumors, or substage IC2/3 disease.
Contributors DN: conception, statistical analysis, critical analysis, and drafting/final editing. LM-G, EM, EC-D, MKF, and KH: critical analysis and drafting/final editing.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The present study was deemed exempt from institutional review board (IRB) review by the Penn IRB.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data may be obtained from a third party and are not publicly available. Data acquired by the American College of Surgeons.