ORIGINAL ARTICLE: FERTILITY PRESERVATION

Safety of ovarian conservation and fertility preservation in advanced borderline ovarian tumors Limor Helpman, M.D.,a,c Mario E. Beiner, M.D.,a,c Sarit Aviel-Ronen, M.D.,b Tamar Perri, M.D.,a,c Liat Hogen, M.D.,a Ariella Jakobson-Setton, M.D.,a Gilad Ben-Baruch, M.D.,a,c and Jacob Korach, M.D.a,c a Department of Gynecologic Oncology and b Institute of Pathology, Sheba Medical Center, Tel Hashomer; and c the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Objective: To assess the impact of a fertility-sparing approach on disease recurrence in women with advanced borderline ovarian tumors. Design: Historic cohort study. Setting: A tertiary referral center for gynecological oncology patients and a university teaching hospital. Patient(s): Consecutive patients with advanced borderline ovarian tumors defined as stage IC and above, treated at a single institution during a span of 30 years. Intervention(s): Data on surgical approach (e.g., fertility sparing, ovarian conserving) as well as histopathology, disease stage, CA-125 level, and use of chemotherapy were collected from the medical records, and their impact on disease recurrence was assessed. Main Outcome Measure(s): Recurrence-free interval. Its association with the type of surgery and with other clinical and pathological features was assessed using the Kaplan Meier and Cox proportional hazards methods. Result(s): Fifty-nine patients with advanced disease were identified. Median follow-up was 55.3 months. Mean age at diagnosis was 35 years. Most of the tumors (51, 84.4%) had serous histology. Twenty-seven patients (45.8%) developed recurrences and 6 (10%) died of their disease. Mean time to recurrence was 30.6 months. Of 44 women %40 years, 33 (75%) had a fertility-sparing procedure. Fertility preservation was not associated with disease recurrence. A total of 34 pregnancies and 26 live births were documented among 21 patients attempting conception. Conclusion(s): Borderline ovarian tumors carry a favorable prognosis, even at an advanced stage. Fertility preservation was not found to be associated with an increased risk of relapse Use your smartphone in young patients with advanced disease, and may be reasonably considered. (Fertil SterilÒ to scan this QR code 2015;104:138–44. Ó2015 by American Society for Reproductive Medicine.) and connect to the Key Words: Borderline ovarian tumor, fertility preservation, ovarian conservation Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/helpmanl-fertility-preservation-advanced-borderline-tumors/

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orderline ovarian tumors (BOT) account for 10%–20% of all epithelial ovarian cancer (1, 2), and are typically indolent neoplasms (2–5). A minority of patients present at an advanced stage, and even those who do may expect extended survival (4–7). Disease extent at diagnosis, as well as histologic subtype and other

characteristics have been shown to be important prognostic factors (8, 9). Median age at diagnosis is 40– 55 years in different reports (1, 5, 10, 11). Because BOT are often diagnosed in women of childbearing age, fertility is an important consideration in planning treatment. Traditionally, fertility-sparing surgery had only been

Received January 20, 2015; revised March 17, 2015; accepted March 31, 2015; published online May 5, 2015. L.H. has nothing to disclose. M.E.B. has nothing to disclose. S.A.-R. has nothing to disclose. T.P. has nothing to disclose. L.H. has nothing to disclose. A.J.-S. has nothing to disclose. G.B.-B. has nothing to disclose. J.K. has nothing to disclose. Reprint requests: Limor Helpman, M.D., Gyneologic Oncology Service, Meir Medical Center, 59 Tcernichovsky Street, Kfar Saba 4428164, Israel (E-mail: [email protected]). Fertility and Sterility® Vol. 104, No. 1, July 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2015.03.038 138

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offered to patients with tumors limited to the ovary (12). However, more recent reports suggest that fertility preservation may be safely offered to appropriately selected patients with advanced disease (7, 13). Because most published series are heterogeneous with a preponderance of cases with early stage disease, data on the safety of ovarian conservation in advanced borderline tumors are lacking. The primary objective of this study was to establish the safety of fertility preservation and specifically, ovarian conservation in young women with advanced BOT. A secondary objective was to investigate the impact of previously described VOL. 104 NO. 1 / JULY 2015

Fertility and Sterility® prognostic features on disease outcome in this cohort of advanced tumors.

MATERIALS AND METHODS Study Population Consecutive patients with advanced BOT treated at our institution between 1981 and 2011 were identified from a prospectively maintained database. Advanced disease was defined as tumors not confined to the ovaries at diagnosis (i.e., stage IC and above).

Data Collection Medical records, including patient charts, operative and pathology reports, and chemotherapy records were reviewed. Data were extracted from patient records and included clinical and demographic variables at presentation: patients' age, disease stage, and CA-125 level at diagnosis. Data were generally complete on medical history, pathological and surgical data. Missing data on fertility and gestational outcome were completed by telephone interview. This was done for all patients who had fertility-preserving surgery and were alive at the time of data collection (30 patients), as recording of fertility and gestational information in the gynecological oncology follow-up record was poor. The FIGO 2009 staging system for epithelial ovarian tumors was used for determining disease stage. This study was approved by the Institutional Review Board at Chaim Sheba Medical Center in adherence with Helsinki Convention principles.

Pathology Histopathological features included tumor type (serous, mucinous, or endometrioid), ovarian surface involvement, and implant type (invasive vs. noninvasive) in patients with peritoneal disease. The histologic criteria used for the diagnosis of BOT included proliferation of the epithelial cells lining the ovarian cysts with the formation of papillary projections present in more than 10% of the lining epithelium, mild-to-moderate nuclear atypia, minimal mitotic activity, and the absence of destructive stromal invasion. A micropapillary pattern was reported when complex micropapillary structures in a filigree pattern were present in a serous borderline tumor. Intraepithelial carcinoma was diagnosed when borderline tumor showed severe nuclear atypia but no stromal invasion was identified. Microinvasion was diagnosed when a focus of stromal invasion was limited to an area of no more than 10 mm2. No pathological review of the specimens was undertaken for this series. Sheba Medical Center is a major referral center and the largest gynecological oncology practice in the country, thus the original pathology reporting was done by pathologists with significant expertise.

Surgical Information Data were also collected on the completeness of surgical staging and on surgical approach used. Many patients had initial cystectomy and were referred to our center after the diagnosis of BOT had been made. These patients may have had a second, VOL. 104 NO. 1 / JULY 2015

definitive surgical procedure after referral. The extent of surgery was determined by combining primary and completion surgery. Fertility preservation was defined as surgery sparing the uterus and some ovarian tissue to allow spontaneous conception in the future. Conservation of an involved ovary was defined as the removal of tumor from an ovary with macroscopic disease yet leaving apparently healthy ovarian tissue in situ. Surgical staging was defined as either [1] incomplete: peritoneal, including visual inspection of peritoneal surfaces, omentectomy, or omental biopsy and removal of any visible tumor; or [2] complete, including lymph node sampling. Use of adjuvant chemotherapy and follow-up data, including disease recurrence, treatment of recurrence(s), and survival were also collected.

Statistical Analyses Primary outcome was defined as the disease-free interval, calculated as the interval of time from definitive surgery to first recurrence or last follow-up. Overall survival was also investigated as a secondary outcome. Recurrence-free interval and overall survival were assessed using the Kaplan Meier method and the log-rank test. The associations of clinical, pathological, and surgical variables with the disease-free interval were assessed using the Cox proportional hazards methods. The association between disease recurrence and the following variables was evaluated: patients' age, disease stage (stage IC vs. stage II-III), CA-125 level at diagnosis; tumor histology (serous vs. mucinous) and pathological characteristics such as a micropapillary pattern, intraepithelial carcinoma, and microinvasion; implant type (invasive vs. noninvasive) and use of chemotherapy in patients with peritoneal disease (n ¼ 34); fertility preservation, and conservation of an involved ovary in women 40 years old and younger (n ¼ 44). All statistical analyses were performed on SPSS software.

RESULTS A total of 246 patients with BOT were treated in the Sheba Medical Center between 1981 and 2011; 59 of these had advanced disease at presentation and are the subject of this report. Twenty-three of the patients (39%) had stage IC disease, 8 patients (13.5%) had stage II disease, and 28 patients (47.5%) had stage III disease. Mean CA-125 level before surgery was 406 (range, 5–2,150). Staging was incomplete for 10 patients; 17 patients had peritoneal staging without lymph node sampling and 33 patients had complete surgical staging. The principal factor appearing to determine the extent of surgical staging was the date of surgery. Only three patients with complete surgical staging (including lymph node sampling) had their procedure after 2006. Microscopic nodal metastases were diagnosed in six patients (18% of those who had complete staging). Most tumors (51, 84.4%) were of serous histology, and 14 (27.5%) of these had a micropapillary pattern. Of eight mucinous tumors, three (37.5%) had features of intraepithelial carcinoma. All cases of mucinous tumors were diagnosed at stage IC. Microinvasion was reported in 11 patients (18.6%) with BOT in this study. Of 34 patients with peritoneal disease, 139

ORIGINAL ARTICLE: FERTILITY PRESERVATION

TABLE 1 Characteristics of study groups. Characteristic Age at diagnosis (y), mean Tumor histology Serous Mucinous Disease stage IC II-III Invasive implants Chemotherapy CA-125 before surgery, mean

Fertility-sparing surgery (n [ 33)

No fertility-sparing surgery (n [ 26)

28

45

28 5

23 3

17 16 1 3 183

6 20 6 10 636

Helpman. Advanced borderline tumors: sparing fertility. Fertil Steril 2015.

7 (20.5%) had invasive implants. Thirteen patient received chemotherapy: 7 with invasive implants, 1 with noninvasive implants, 3 with nodal involvement, and 2 with stage IC disease. Mean age at diagnosis was 35 years (range, 19–81 years). Of 44 women aged %40 years at diagnosis, 33 (75%) had a fertility-sparing procedure, leaving the uterus and some intact ovarian tissue in situ. Of these, 17 patients (39%) retained the involved ovary, having cystectomy only and/or resection of ovarian surface metastases. Patients undergoing fertility-sparing surgery were younger and tended to have earlier disease (P ¼ not significant [NS]). Baseline characteristics of patients undergoing fertility-sparing surgery and those whose fertility was compromised at surgery are presented in Table 1.

Disease Outcome Median follow-up was 55 months (range, 1–281 months). Twenty-seven patients (45.8%) developed recurrences and 6

(10%) died of their disease. Mean time to recurrence was 30.6 months (range, 2.6–92 months). Eleven cases recurred as metastatic disease with noninvasive (1/11) or invasive (9/11) implants. One patient was lost to follow-up after recurrence, and one other was not treated surgically, therefore the histology of her metastatic recurrence is unknown. Fifteen patients had isolated ovarian recurrences; 7 of these occurred in an ovary that had been conserved despite involvement at initial surgery. Only two metastatic recurrences occurred in patients who had ovarian conservation for disease confined to an ovary (stage IC). Both these patients had complete surgical staging at initial surgery. Metastatic recurrences similarly occurred in two patients with stage IC disease who did not have ovarian conservation at primary surgery. Most (25/27) initial recurrences were treated surgically. Half (14/27) of the patients who had an initial recurrence, including all patients who recurred with invasive implants, recurred again. At the second relapse, 7 of 14 patients were treated with chemotherapy and only 6 of 14 had surgery (1 patient succumbed to her disease before receiving treatment for a second recurrence). Kaplan Meier survival curves for the interval to first disease recurrence are presented in Figure 1. None of the variables assessed were found to be associated with an increased hazard ratio for recurrence (Table 2). Although patients whose fertility was preserved showed a tendency for earlier recurrence (27 vs. 39 months; P ¼ NS), Cox proportional hazards modeling found no association between fertility preservation, the conservation of an involved ovary and an increased hazard ratio for recurrence (Table 2), or with significantly earlier recurrence (Fig. 1). Overall survival was similar, as well, with three patients succumbing to disease in each group, although numbers are too small for definitive conclusions. Among the six patients who eventually succumbed to their disease, the time to death was between 28 and 165 months. Five of the six died of disease after a second recurrence. Half of these patients had fertility-sparing surgery

FIGURE 1

Kaplan Meier survival curves for interval to first disease recurrence. (A) Disease-free survival in patients undergoing fertility-preserving surgery (black) versus those whose fertility was compromised (gray). (B) Disease-free survival in patients in whom an involved ovary was conserved (black) versus those whose involved ovary was sacrificed (gray). Helpman. Advanced borderline tumors: sparing fertility. Fertil Steril 2015.

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Fertility and Sterility®

TABLE 2 Hazard ratios for disease recurrence. CI

P value

0.96 1.69

0.93–1.00 0.61–4.68

.06 .31

1.41

0.59–3.32

.44

Reference 0.97 1.20

0.29–3.25 0.47–3.00

.96 .7

Reference 0.78 0.65

0.35–1.71 0.19–2.26

.53 .5

0.52

0.17–1.63

.26

0.99

0.99–1.00

.22

Variable

HR

Age at diagnosis (y) Fertility preservation (in patients