Objective Investigate the overall survival of patients with stage IC2/IC3 epithelial ovarian carcinoma undergoing fertility-sparing surgery.
Methods Patients aged <45 years diagnosed between January 2004 and December 2015 with epithelial ovarian carcinoma, who underwent surgical staging and had tumor involving the ovarian surface (IC2), malignant ascites or positive cytology (IC3), were identified in the National Cancer Database. The fertility-sparing surgery group included patients who had preservation of the uterus and the contralateral ovary while the radical surgery group included patients who had hysterectomy with bilateral salpingo-oophorectomy. Overall survival was evaluated following generation of Kaplan–Meier curves while a Cox model was constructed to control for tumor grade and performance of lymphadenectomy. A systematic review of the literature was performed and cumulative relapse rate among patients with IC2/IC3 disease who underwent fertility-sparing surgery was calculated.
Results A total of 235 cases were identified; 105 (44.7%) patients underwent fertility-sparing surgery. There was no difference in overall survival between the fertility-sparing and radical surgery groups (p=0.37; 5- year overall survival rates 90.2% and 85%, respectively). After controlling for tumor grade and performance of lymphadenectomy, fertility-sparing surgery was not associated with worse overall survival (HR 1.22, 95% CI 0.56, 2.62). A systematic review identified 151 patients with stage IC2/IC3 disease who underwent fertility-sparing surgery. Cumulative relapse rate was 19.3% (n=29) while 12 (6.7%) deaths were reported. Median time to recurrence was 19 (range 1–128.5) months. Tumor recurrence involved the ovary exclusively in 42% (11/26) of patients, while 15% (4/26) had a lymph node, 35% (9/26) a pelvic/abdominal, and 8% (2/26) a distant tumor relapse.
Conclusions In a large cohort of patients with stage IC2/IC3 epithelial ovarian carcinoma, fertility-sparing surgery was not associated with worse overall survival. However, based on a literature review, relapse rate is approximately 20%.
- ovarian cancer
Data availability statement
Data may be obtained from a third party and are not publicly available. Data obtained from the American College of Surgeons.
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Data on the oncologic safety of fertility-sparing surgery for stage IC2/IC3 epithelial ovarian carcinoma are scarce.
Fertility-sparing surgery is not associated with worse overall survival.
Relapse rate based on 151 patients is approximately 20%.
Epithelial ovarian carcinoma is the most common histologic subtype of ovarian cancer. Most patients are postmenopausal and present with advanced stage disease (stage III-IV). However, almost 10% of all patients with epithelial ovarian carcinoma are younger than 40 years old and may have not completed their childbearing.1 Given the advancement of imaging modalities and the fact that women delay childbearing, the number of nulliparous patients diagnosed with early-stage ovarian cancer is expected to increase.2 During the past two decades the concept of fertility-sparing surgery, usually defined as the preservation of the uterus with or without preservation of the contralateral ovary, was introduced in the management of early-stage epithelial tumors. Fertility-sparing surgery is commonly offered to patients with epithelial low-grade tumors and stage IA disease.3 Since patients with stage IC have a higher relapse rate, certain surgeons are reluctant to offer fertility-preserving surgery, especially to those with grade 2 or grade 3 tumors.4 Based on the new staging schema, stage IC is further subdivided in stage IC1 (intra-operative tumor spillage), IC2 (tumor on ovarian surface), and stage IC3 (positive peritoneal washings or ascites). Patients with stage IC2 or IC3 have a higher relapse rate compared with those with IC1 or stage IA.5 This higher relapse rate is taken into consideration and according to the combined European guidelines, fertility-sparing surgery can be safely offered for patients with low grade and stage IA and IC1 tumors.6 Evidence on the oncologic safety of fertility-sparing surgery in this high-risk subgroup (IC2/IC3) is scarce and derives from small retrospective studies.7–19 Given the paucity of evidence, the aim of our study was to investigate the survival of pre-menopausal patients with stage IC2 or IC3 epithelial ovarian cancer who underwent fertility-sparing surgery using a large hospital-based database. In addition, we performed a systematic review of the literature summarizing the outcomes of fertility-sparing surgery in this patient population.
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 without a history of another tumor was selected. Patients with epithelial ovarian carcinoma were identified based on International Classification of Disease (ICD-O-3) histology codes 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 United States. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytical or statistical methodology employed nor 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 I disease who had at least 1 month of follow-up were identified. Based on the extent of disease variable, patients with malignant ascites or positive washings (stage IC3) and those with ovarian surface involvement (stage IC2) were selected for further analysis. Unfortunately, in the National Cancer Database pre-operative (classified IC2) and intra-operative (classified as IC1) capsule rupture are not discriminated thus we opted to exclude patients marked as “capsule rupture”. 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 co-morbidities was evaluated using the Charlson–Deyo Comorbidity Index score and was categorized into absent (score 0) and present (score >1). Methodology has been previously described in the authors’ prior paper examining fertility-sparing surgery in ovarian clear cell carcinoma.20
Categorical and continuous variables were compared between patients who did and did not undergo fertility-sparing surgery with the chi-square and Mann–Whitney U tests, respectively. Kaplan–Meier curves were generated to determine 5-year overall survival rates while univariate analysis was performed with the log-rank test. Survival was also evaluated following stratification by tumor grade. A Cox multivariate model was constructed to evaluate the impact of fertility-sparing surgery on overall survival after controlling for performance of lymphadenectomy (used as a surrogate of adequate staging) and tumor grade. Statistical analysis was performed with the Statistical Package for the Social Sciences v.24 statistical package (IBM 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 stage IC2 or IC3 epithelial ovarian carcinoma was also performed. The Pubmed/Medline, Excerpta Medica and Web of Science database was searched from January 1, 1990 to August 30, 2020 using the keywords “ovary” and “cancer” and “fertility” and (“preserving” or “sparing”), while references of included articles and prior reviews were also hand-searched. Studies in the English language that reported at least one patient with stage IC2 or IC3 epithelial ovarian carcinoma and provided data on tumor relapse were eligible for inclusion. In cases of overlapping patient populations, we opted to include the most updated study with the largest patient population.
A total of 235 patients who met the inclusion criteria were identified. Median patient age was 39 (range 15–45) years, while the majority were White and did not have co-morbidities (91.5%). A total of 121 patients (51.5%) had stage IC3 disease while 114 patients (48.5%) had stage IC2 disease. The most common histologic subtype was serous (86 patients, 36.6%), followed by endometrioid (67 patients, 28.5%), mucinous (53 patients, 22.6%), and clear cell (29 patients, 12.3%). Grade was equally distributed: grade 1 (66 patients, 28.1%), grade 2 (55 patients, 23.4%), grade 3 (52 patients, 22.1%), and unknown (62 patients, 26.4%). Chemotherapy was administered to 135 patients (57.4%), while lymph node sampling/dissection was performed for 135 patients (57.4%).
A total of 105 (44.7%) and 130 (55.3%) patients had fertility-sparing and radical surgery, respectively. Rate of fertility-sparing surgery was comparable between stage IC2 (47.4%) and stage IC3 (42.1%) patients (p=0.65). Rate of fertility-sparing surgery was higher for patients with mucinous tumors (77.4%) compared with those with serous (34.9%), endometrioid (34.3%), and clear cell (37.9%) tumors (p<0.001). However, overall rate of fertility-sparing surgery was comparable for patients with grade 1 (50%), grade 2 (45.5%), and grade 3 (36.5%) tumors (p=0.34). Patients who had fertility-sparing surgery were younger (median age 33 vs 41 years, p<0.001), and less likely to receive lymphadenectomy (40% vs 72.3%, p<0.001) and chemotherapy (42.9% vs 69.2%, p<0.001). There were no differences between the two groups in terms of race (p=0.07), presence of co-morbidities (p=0.17), and type of insurance (p=0.26). Table 1 depicts the clinicopathological characteristics of patients who had fertility-sparing or radical surgery.
Median follow-up of the cohort was 71.6 (95% CI 61.0, 82.2) months. There was no difference in overall survival between the fertility-sparing and radical surgery groups (p=0.37; 5-year overall survival rates 90.2% and 85%, respectively) (Figure 1). Following stratification by tumor grade there was no difference in overall survival between the fertility-sparing and radical surgery groups for patients with grade 1 (p=0.62; 5-year overall survival rates 94.4% and 88.1%), grade 2 (p=0.55; 5-year overall survival rates 90.9% and 78.6%), and grade 3 tumors (p=0.63; 5-year overall survival rates 80.5% and 69.6%). After controlling for tumor grade and performance of lymphadenectomy, fertility-sparing surgery was not associated with worse overall survival (HR 1.22, 95% CI 0.56, 2.62).
A systematic review of the literature identified 151 patients with epithelial ovarian carcinoma and stage IC2 or IC3 disease who underwent fertility-sparing surgery (Table 2). Cumulative relapse rate was 19.3% (n=29) while 12 (6.7%) deaths were reported. Based on data from 27 patients, median time to recurrence was 19 (range 1–128.5) months, while five (18.5%) relapses occurred within 6 months from surgery (Table 3). Among patients who experienced a relapse, the majority (18/29, 62%) had grade 1 or 2 tumors, while 85% (23/27) had received adjuvant chemotherapy, and the majority 80% (16/20) did not undergo lymphadenectomy. Based on the available data, relapse rate was 23% (14/61) and 14.8% (9/61) for patients with stage IC3 and IC2 disease, respectively. Regarding the location of tumor relapse, recurrence involved the ovary exclusively in 42% (11/26) of patients while 15% (4/26) had a lymph node recurrence, 35% (9/26) a pelvic/abdominal relapse, and 8% (2/26) a distant tumor relapse. All but one patient (91%, 10/11) who experienced an ovarian-only relapse had grade 1 or 2 tumors compared with 53% (8/15) of those who had a non-ovarian relapse (p=0.08). Median time to relapse was comparable between low-grade (n=14, grade 1) and high-grade (n=13, grade 2/3/clear cell) tumors (median 17.65 vs 20.3 months, p=0.91). Similarly, time to relapse was comparable between stage IC2 (n=10, median 17 months) and stage IC3 (n=17, median 20.3 months) (p=0.90).
Summary of Main Results
In the largest cohort of young pre-menopausal patients with International Federation of Gynecology and Obstetrics (FIGO) stage IC2 or IC3 ovarian epithelial 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 demonstrated a relapse rate of 19.3% with a median time to recurrence of 19 months.
Results in the Context of Published Literature
Patients with stage IC2 and IC3 epithelial ovarian carcinoma have a higher relapse rate compared to those with stage IA or IC1 disease. However, given the lack of evidence on the safety of fertility-sparing surgery in this subgroup there is a discrepancy in treatment recommendations. Currently the National Comprehensive Cancer Network guidelines suggests that fertility-sparing surgery can be offered to all adequately counseled patients with stage IA and IC epithelial ovarian cancer.21 Conversely, according to the combined European Society of Medical Oncology and European Society for Gynecologic Oncology guidelines, fertility-sparing surgery is acceptable for patients with stage IA/IC1 low-grade serous, endometrioid, or expansile mucinous ovarian carcinoma.6 However, for patients with other stage I substages or pathologic histologic subtypes an individualized decision and planning should be made following extensive counseling of the patients.6
While patients with stage IC2/IC3 disease who undergo fertility-sparing surgery have a higher relapse rate compared with those with stage IA or IC1 disease, a key question is whether fertility-sparing surgery has an independent negative impact on their oncologic outcomes. In our cohort, fertility-sparing surgery does not appear to alter the prognosis of patients with stage IC2/IC3 disease. Unfortunately, given the rarity of this clinical scenario, most retrospective studies investigating the safety of fertility-sparing surgery do not include a comparison group or do not perform a subanalysis exclusively to patients with stage IC2/IC3 disease given the small number of patients. In a large retrospective study, Fruscio et al identified 240 patients (47 of them had stage IC2/IC3) with epithelial ovarian carcinoma who underwent fertility-sparing surgery in two tertiary centers and a relative long follow-up (9 years). Interestingly, by multivariable analysis, tumor grade (grade 3 vs grade 1 or 2) but not substage (IC/II vs IA/IB) was associated with worse recurrence-free survival.14 Conversely, in another multicenter retrospective study, that included 94 patients (51 with stage IC disease) both substage IC2/IC3 (HR 5.44, 95% CI 1.56, 19.0) and tumor grade 3 (HR 5.59, 95% CI 1.29, 24.3) were associated with worse recurrence-free survival.7 Satoh et al performed a multicenter retrospective study and identified 85 patients with stage IC disease.16 Authors concluded that fertility-sparing surgery can be offered only to those with favorable histology (grade 1 or 2 non-clear cell tumors) since this subgroup had a 5-year relapse free survival of 92.1% and outcomes did not differ based on substage (IC1: 92.9%, IC2: 91.7%, IC3: 90%).16
Interestingly, according to the results of the systematic review, five patients experienced a tumor relapse within 6 months from surgery and based on data from four cases all of these had an extra-ovarian relapse. While details on the staging procedures performed were not available, one could argue that occult disease stage IIIC1 disease may had been present. In addition, among patients who experienced a relapse, the majority did not undergo lymph node sampling/dissection, even patients with high-grade tumors (8/9, 90%). For 3 patients (all with high-grade tumors), lymph nodes were the exclusive site of recurrence. Differences in the thoroughness of staging procedures performed may also account for the discrepancy in relapse rate observed among the four studies that reported at least 10 patients (10% to 33%).7 14 16 17 These findings underline the paramount importance of adequate staging, that includes washings, total omentectomy, and multiple peritoneal biopsies, and lymph node dissection for patients with high-grade tumors when offering fertility-sparing surgery. Identification of patients with stage IIIC1 disease has not only prognostic value but can alter adjuvant and maintenance treatment recommendations.
In addition, since ovarian stimulation is not recommended for patients with a history of an epithelial ovarian carcinoma, timely referral to a fertility specialist to evaluate the patient’s ovarian reserve and the likelihood of a future spontaneous pregnancy is of paramount importance. This information can be used when counseling patients who have a high relapse risk. It should also be mentioned that recent data suggest that pregnancy outcomes (pre-term delivery and miscarriage rate) are comparable to the general population and should not discourage patients from pursuing fertility preservation.2
Strengths and Weaknesses
A major strength of our study is the large number of patients identified and the performance of a systematic literature review to further validate our results. However, several limitations of the present study should be noted. First, given the absence of central pathology review possible tumor histology and stage misclassifications cannot be excluded. In addition, as previously discussed, we could not extract data from the National Cancer Database on patients with pre-operative capsule rupture. Moreover, while all patients underwent staging surgery, the quality and extent of staging procedures performed could not be verified. Specific details regarding the composition of the chemotherapy regimen administered, and presence of germline or somatic mutations, were not available. Lastly, the National Cancer Database does not collect data on tumor relapse or cause of death, precluding us from analyzing differences in progression-free survival, cancer-specific survival, as well as location of tumor relapse.
Implications for Practice and Future Research
In a large cohort of young pre-menopausal patients with FIGO stage IC2 or IC3 epithelial ovarian carcinoma, performance of fertility-sparing surgery did not have a negative impact on overall survival. As such fertility-sparing surgery could be considered for carefully selected patients with stage IC2/IC3 disease following extensive counseling, especially for patients with low-grade tumors. However, based on the results from the database analysis and a systematic review of the literature, there are limited data to support fertility-sparing surgery for patients with high-grade tumors and stage IC2/IC3 disease. Unfortunately, most studies did not report the distribution of tumor grade and histology among patients with stage IC2/IC3 disease thus we could not calculate the tumor relapse rate based on tumor grade. We propose an international collaboration with the creation of an international registry capturing detailed data on patients with high-risk characteristics receiving fertility-sparing surgery.
Fertility-sparing surgery is not associated with worse overall survival for patients with stage IC2/IC3 disease compared with radical surgery. However, one in five patients will experience a tumor relapse at a median of 19 months. Fertility-sparing surgery should be considered for carefully counseled patients following adequate staging.
Data availability statement
Data may be obtained from a third party and are not publicly available. Data obtained from the American College of Surgeons.
Patient consent for publication
Contributors DN: conception, data collection, statistical analysis, critical analysis, drafting/final editing, guarantor. QDH: data collection, critical analysis, drafting/final editing. AFH, EMK, SK, LC, RLG: critical analysis, drafting/final editing. NL: supervision, critical analysis, 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.
Provenance and peer review Not commissioned; externally peer reviewed.