Gynecological Endocrinology ISSN: 0951-3590 (Print) 1473-0766 (Online) Journal homepage: http://www.tandfonline.com/loi/igye20 Fertility sparing surgery in epithelial ovarian cancer in Italy: perceptions, practice, and main issues Alice Bergamini, Micaela Petrone, Emanuela Rabaiotti, Francesca Pella, Raffaella Cioffi, Elena Giulia Rossi, Valentina Di Mattei, Massimo Candiani & Giorgia Mangili To cite this article: Alice Bergamini, Micaela Petrone, Emanuela Rabaiotti, Francesca Pella, Raffaella Cioffi, Elena Giulia Rossi, Valentina Di Mattei, Massimo Candiani & Giorgia Mangili (2017): Fertility sparing surgery in epithelial ovarian cancer in Italy: perceptions, practice, and main issues, Gynecological Endocrinology, DOI: 10.1080/09513590.2017.1393508 To link to this article: http://dx.doi.org/10.1080/09513590.2017.1393508 Published online: 26 Oct 2017. Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=igye20 Download by: [Chalmers University of Technology] Date: 29 October 2017, At: 01:18 GYNECOLOGICAL ENDOCRINOLOGY, 2017 https://doi.org/10.1080/09513590.2017.1393508 ORIGINAL ARTICLE Fertility sparing surgery in epithelial ovarian cancer in Italy: perceptions, practice, and main issues Alice Bergaminia, Micaela Petronea, Emanuela Rabaiottia, Francesca Pellaa, Raffaella Cioffia, Elena Giulia Rossia, Valentina Di Matteib,c, Massimo Candiania and Giorgia Mangilia Downloaded by [Chalmers University of Technology] at 01:18 29 October 2017 a Department of Obstetrics and Gynecology, IRCCS San Raffaele Hospital, Milan, Italy; bFaculty of Psychology, Vita-Salute San Raffaele University, Milan, Italy; cClinical and Health Psychology Unit, Department of Clinical Neurosciences, IRCCS San Raffaele Hospital, Milan, Italy ABSTRACT ARTICLE HISTORY About 2.7% of patients epithelial ovarian cancers (EOC) are younger than 40 and present with stage I disease. For this subset of women, the issue of fertility sparing surgery (FSS) has become critical. The aim of this survey was to investigate the management of EOC patients desiring to preserve fertility in Italy. A questionnaire consisting of 30 items was developed to evaluate: patient-selection criteria, rate of FSS, patient’s counseling- and pregnancy-timing, fertility preservation, obstetrics, and oncologic outcomes. One expert clinician for each of 50 major gynecologic oncology centers was invited to participate. Data were entered into a database and statistically analyzed. 74% of questionnaires were complete. The proportion of EOC patients treated with FSS was <10%, 10%–20% and >20% in 70.3%, 24.3% and 5.4% of cases, respectively. Age, fertility preservation desire, histotype, and stage were considered relevant to select patients for a conservative treatment for 64.8%, 72.9%, and 78.3% of responders, respectively. Only 17 centers (45.9%) resulted to have an assisted reproductive technique service and Obstetrics Department. Our survey highlights discrepancies among oncologists in the management of patients with early EOC undergoing FSS. More efforts should be made to define and broadcast the best management before and after surgery. Received 14 May 2017 Accepted 13 October 2017 Published online 25 October 2017 Introduction Among all epithelial ovarian cancers (EOC), 3%–14% are diagnosed in fertile women. More than a half of these tumors are detected at an early stage and delaying childbearing has become nowadays increasingly more common, thus growing attention has been focused in the last decades on conservative treatment for EOC. In this particular setting, higher concerns and controversies exists as compared to the other gynecological malignancies, being EOC the most lethal. According to the available guidelines, fertility sparing surgery (FSS) approach is currently indicated in EOC at stage I A grade1–2 [1,2]. For high-risk patients (clear cell histology, stage IAG3) the indication to conservative surgery is still debated [1–8]. Data from literature support the evidence that FSS does not hamper the oncological outcome: recurrence rate depends on grading and stage of disease while type of surgery does not impact survival [4–8]. In the interesting study of Fruscio et al., including 240 patients treated with FSS, after a median follow-up of 9 years, 27 patients had relapsed (11%). Of these, 11(5%) had died of disease for a distant recurrence. Interestingly, in multivariate analysis only grade 3 was found to affect prognosis. It is possible to speculate that overall prognosis is unaffected by preservation of the contralateral ovary, rather could it be related to the more aggressive biology of the tumor . If this is true, recurrence could not be prevented neither in conservative nor in radical surgery. Several studies have focused on the role of FSS in EOC to better select patients who can benefit from this therapeutic strategy. CONTACT Alice Bergamini [email protected] ß 2017 Informa UK Limited, trading as Taylor & Francis Group KEYWORDS Ovarian cancer; fertility; pregnancy; conservative surgery However, there is still no consensus on the best management and recommended timing of pregnancy after completion of treatment . The aim of this survey was firstly to investigate the management of these patients in Italy by sending a properly developed questionnaire to the major gynecologic oncology experts. Secondly, based on the results of our survey, evidences from literature have been evaluated, critically reviewing all the potential related issues. Materials and methods A questionnaire evaluating the approach to FSS in EOC was properly developed by two experts in surgical and medical oncology and one psycho-oncologist. The questionnaire consisted of 30 questions covering the following items: responder’s professional characteristics, rate of FSS performed, patientsselection criteria, adjuvant therapy, patients counseling, pregnancy-timing related issues, fertility preservation, obstetric, and oncologic outcomes. Item response options included yes/no, multiple choice, comment boxes. Answer choices were categorized in order to facilitate the completion of questionnaire forms. 50 major gynecologic oncology centers in north, central and southern Italy have been considered eligible for the survey, including University Medical Hospital and Clinical Centers. One expert clinician for each center was invited to participate by completing the questionnaire. Department of Obstetrics and Gynecology, IRCCS San Raffaele Hospital, Via Olgettina 60, Milan, Italy 2 A. BERGAMINI ET AL. Data obtained from the filled questionnaires were entered into a database using Microsoft Access and analyzed. Statistical analyzes were performed using SPSS version 17.0(SPSS Inc., Chicago, IL, United States). Results At the end of the survey, 37 completed questionnaires were collected (74% of the target population). Respondents’ characteristics are summarized in Table 1 and answers to main questions are reported in Table 2. Table 1. Responders characteristics. N ¼37 (%) Downloaded by [Chalmers University of Technology] at 01:18 29 October 2017 Characteristic Age Mean ± SD (range) Sex M F Clinical activity Surgeon Medical Oncologist Both Years of experience Mean Center Clinical center University Medical Hospital Scientific Research Institute 50.03 ± 8.51 26 (70.2) 11 (29.7) 22 (59.4) 11 (29.7) 4 (10.8) 18.43 ± 8.02 16 (43.3) 12 (32.4) 9 (24.3) Discussion Results from the current survey can be interpreted as a cross section of the national perception regarding the optimal management for FSS in EOC, from selection of patients to optimal timing to conceive. Each of these issues will be herein discussed considering the available evidence from literature and international consensus guidelines. Criteria for selecting patients to a conservative approach have been widely discussed. In the largest retrospective series available  including 1189 patients with early EOC,432 of whom treated conservatively, stage IC and grade 3 were the only independent predictors of survival. Another important retrospective study by Fruscio et al.  confirmed that G3 was the only independent predictor for survival and was associated with a significant higher rate of distant recurrence. Interestingly, among patients treated conservatively, only one patient had a pelvic recurrence and was treated with salvage surgery, while 83% had a distant recurrence and died of disease. From these data, it seems that distant recurrences would not have been affected by conservative surgery, being rather related to the aggressive biology of disease. Both Fruscio and Ditto et al. conclude that type of surgical approach does not influence survival, thus patients with high risk early EOC should be offered conservative surgery with complete surgical staging [4,7]. Nevertheless, available guidelines are not always concordant, in particular concerning high risk early stage EOC (stage IC or IA,B G3), which is still considered by many Authors questionable [3,9]. The most recent NCCN 2017 guidelines Table 2. Results from survey questions evaluating practice in FSS for EOC. Question/answer option Criteria included to evaluate feasibility of fertility sparing surgery Age Fertility preservation desire Histotype, stage FSS/all surgical interventions for EOC (%) <10 10–20 >20 Is Psycho-oncology evaluation performed? Yes No Is fertility assessment perfumed before FSS? Yes No Does fertility assessment affect choice of surgical approach? Yes No Is fertility assessment performed during follow-up? Yes No ART contraindicated after FSS No Yes Minimum interval suggested before attempting pregnancy (months) Median (range) Responders Not defined Patients attempting a pregnancy after FSS (%) Mean (±SD) Is an ART service available within the center performing FSS? Yes No Is there an Obstetrics Department within the center performing FSS? Yes No Is completion of surgery suggested after treatment completion? Yes No Unknown N (%) 24 (64.8) 27 (72.9) 29 (78.3) 26 (70.3) 9 (24.3) 2 (5.4) 18 (48.6) 19 (51.4) 25(67.6) 12(32.4) 22 (88%) 3 (12%) 26 (70.3) 11 (29.7) 29 (78) 8 (22) 12 (6–12) 17 10 39.33 ± 5.21 17 (45.9) 20 (54.1) 16 (43.2) 21 (56.8) 26 (70.3) 9 (24.3) 2 (5.4%) Downloaded by [Chalmers University of Technology] at 01:18 29 October 2017 GYNECOLOGICAL ENDOCRINOLOGY suggest as primary treatment for all grades IA or IC EOC unilateral salpingo-oophorectomy along with comprehensive staging for all patients who desires to preserve fertility . In the most recent ESMO and ESGO guidelines, a conservative approach is limited to G1–2 IA and IC EOC with unilateral involvement, in case of mucinous, serous, endometrioid, or mixed histotype . Still there is no unanimous consensus concerning patients’ selection neither in our survey nor in literature; in some cases FSS in EOC is even considered an experimental approach. This highlights the ongoing efforts in updating clinical guidelines as well as the necessity of further studies to better assess this issue. In our survey, a median of 39% of patients undergoing FSS eventually attempts to get pregnant. This results are in line with other studies available on this topic, with an overall rate ranging between 16% and 50% . Several reasons could explain the discrepancy between patient selection and pregnancy-attempt outcome: first of all, the perception of the disease and their increased consciousness in risk of recurrence, which could change during the treatment plan. As reported by a recent literature review, cancer is known to influence survivors’ motivation to childbearing, raising concerns on conceiving, on the potential negative effects of both cancer and treatments on a future child, as well as partner-related fears . It is clear how, in this setting, an adequate and multidisciplinary counseling should be mandatory. This should be structured considering all the potential confounding aspects including, apart from the gynecological and oncological evaluation, a psychooncological, obstetric, and reproductive one. As reported in Table 2, less than half of the centers examined offer a proper psychooncological counseling to their patients. Counseling is a major field of psychological science with knowledge and experience for dealing with a variety of issues and has much to offer to medical settings. Specifically, FSS psychological counseling is a communication process aimed at helping individuals in properly considering the different risks and opportunities associated with this surgical option. The individual must be able to make informed choices particularly regarding future risks. Psychological counseling should closely examine and take into consideration the type of disease, the age of the patient, the presence or not of a partner, the presence of children, and the psychological conditions of the patient (i.e. psychopathological symptoms). Along with psychological and oncological issues, fertilityrelated ones should be discussed from the beginning. An interesting study by Peate et al. reports how, in breast cancer patients, a low level of fertility-related knowledge was associated with higher decisional difficulties regarding their fertility options . One of the possible problems of these patients is premature ovarian failure (POF), as adjuvant chemotherapy may affect the ovarian reserve. The gonadotoxic risk is related to the type of chemotherapeutic agent, administration schedule, age, and previous ovarian reserve . Chemotherapeutic agents used in EOC, such carboplatin and paclitaxel, are considered less gonadotoxic as compared to other cytostatics; however, an accurate evaluation is mandatory before starting FSS. Despite this, in our survey, such evaluation is performed in only 67.6% of the centers before starting FSS and in 70.3% during follow-up. There is no consensus on the optimal evaluation of ovarian reserve in these patients. Several methods have been investigated, including ultrasonographic features (antral follicle count, AFC, and ovarian volume), hormonal tests (AMH, FSH, E2), as well as clinical characteristics, like menses regularity. AMH, in particular, is considered by several Authors as the most reliable marker even in patients undergoing gonadotoxic treatments. A value of 1.2 ng/mL prior to the beginning of chemotherapy has been set as a cutoff to 3 select those breast cancer patients with higher possibilities on assisted reproductive technique (ART) at the end of treatment . In our survey, most centers rely on AMH evaluation, transvaginal ultrasound and hormonal assessment. Another controversial issues emerging from our survey is related to the role of ART for these patients. In 22% of our responders, EOC is a supposed contraindication for subsequent ART. Literature evaluating these issue is limited by the heterogeneity of histological subtypes and, in some cases, by the inclusion of borderline tumors. In the few series including only EOC, the conception rate of patients after FSS has been reported to be higher than 60% in women with childbearing desire [3,15], no relevant fertility impairment has been detected and only a minority of patients required ART. Experience on conservative surgery in EOC is surely lower as compared to borderline ovarian tumors, where the role of ART after FSS has been widely evaluated. Further studies are recommended in order to clarify the feasibility, role, and timing of ART in this population. Even if sufficient evidence is lacking, completion of surgery after childbearing should be recommended in order to prevent recurrence. The cases of late recurrences after conservative treatment described in literature support this indication . Strict follow-up of patients is mandatory. A 3-month schedule including clinical and ultrasound evaluation seems us reasonable with major imaging evaluation every 6 months. Moreover, patients should be tested for BRCA 1–2 genes mutations, the detection of which might modify the follow-up program. The final aim of FSS is pregnancy. The optimal time to conceive is still highly debated, as shown in the results of our survey, with a suggested minimum interval of 6 months to a maximum of 36 months from the end of chemotherapy, and a lack of indication given by 27% of the responders. No conclusive data in literature neither guidelines are available. ESMO guidelines recommend at least a 6 months interval after completion of treatment, to reduce the possible teratogenic effect of chemotherapy . In the absence of a clear evidence from studies designed for this specific subset of patients, each case should be managed separately and thoroughly discussed. As suggested in other settings , the peak of relapse should be taken into consideration before planning conception, in order to avoid disease recurrence during pregnancy. Conception should be therefore suggested after the estimated peak of recurrence, assessed according to low and high-risk disease. Considering the largest series available in literature [3–5,17], for low-risk disease (IAG1-G2) relapse is a rare event and usually involves the contralateral ovary, allowing clinicians to successfully rescue these patients. Relapses have been reported even several years after diagnosis, but the recurrence rate decrease in most series after 2 years. Pregnancy with careful ultrasound surveillance during pregnancy could therefore be considered after this time span [7,8,15]. For high-risk disease, recurrence rate is as high as 24% in the largest series available in literature . In this group, distant recurrence is frequent, and these patients are difficulty rescued with chemotherapy or surgery. The peak of recurrence decrease between three to four years, according to the different series reported in literature. Careful evaluation of the risk profile should be observed before suggesting conceiving. This choice could be obviously criticized as delaying pregnancy could further reduce the ovarian reserve, potentially harming the childbearing potential. Our survey highlights discrepancies among oncologists in the management of patients with early EOC undergoing FSS, from counseling to selection of patients and follows up. More efforts should be made in order to define the best management for this 4 A. BERGAMINI ET AL. subset of patients and to give light on the abovementioned debated issues, expected to become increasingly more common giving the growing trend toward both FSS in EOC and late childbearing. Disclosure statement The authors report no conflicts of interest. 7. 8. 9. 10. 11. References 1. Downloaded by [Chalmers University of Technology] at 01:18 29 October 2017 2. 3. 4. 5. 6. Ledermann JA, Raja FA, Fotopoulou C, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24:24–32. National Comprehensive Cancer Network. Ovarian Cancer (Version 1.2017). 2017. Available from: https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf Zapardiel I, Diestro MD, Aletti G. Conservative treatment of early stage ovarian cancer: oncological and fertility outcomes. Eur J Surg Oncol 2014;40:387–93. Fruscio R, Corso S, Ceppi L, et al. Conservative management of earlystage epithelial ovarian cancer: results of a large retrospective series. Ann Oncol 2013;24:138–44. Ditto A, Martinelli F, Bogani G, et al. Long-term safety of fertility sparing surgery in early stage ovarian cancer: comparison to standard radical surgical procedures. Gynecol Oncol 2015;138:78–82. Park JY, Suh DS, Kim JH, et al. Outcomes of fertility-sparing surgery among young women with FIGO stage I clear cell carcinoma of the ovary. Int J Gynaecol Obstet 2016;134:49–52. 12. 13. 14. 15. 16. 17. Ditto A, Bogani G, Martinelli F, et al. Fertility-sparing surgery in highrisk ovarian cancer. J Gynecol Oncol 2015;26:350–1. Ghezzi F, Cromi A, Fanfani F, et al. Laparoscopic fertility-sparing surgery for early ovarian epithelial cancer: a multi-institutional experience. Gynecol Oncol 2016;141:461–5. Utrilla-Layna J, Zapardiel I. Are we ready for conservative treatment in ovarian cancer? J Gynecol Oncol 2015;26:75–6. Wright JD, Shah M, Mathew L, et al. Fertility preservation in young women with epithelial ovarian cancer. Cancer 2009; 115:4118–26. Tomao F, Peccatori F, Del Pup L, et al. Special issues in fertility preservation for gynecologic malignancies. Crit Rev Oncol Hematol 2016;97:206–19. Peate M, Meiser B, Friedlander M, et al. It's now or never: fertilityrelated knowledge, decision-making preferences, and treatment intentions in young women with breast cancer–an Australian fertility decision aid collaborative group study. JCO 2011;29:1670–7. Schmidt R, Richter D, Sender A, et al. Motivations for having children after cancer-a systematic review of the literature. Eur J Cancer Care (Engl) 2016;25:6–17. Kim HA, Seong MK, Kim JH, et al. Prognostic value of AntiM€ ullerian hormone and Inhibin B in patients with premenopausal hormone receptor-positive breast cancer. Anticancer Res 2016; 36:1051–7. Fotopoulou C, Braicu I, Sehouli J. Fertility-sparing surgery in early epithelial ovarian cancer: a viable option? Obstet Gynecol Int 2012;2012:238061. Weibull CE, Eloranta S, Smedby KE, et al. Pregnancy and the risk of relapse in Patients Diagnosed With Hodgkin Lymphoma. J Clin Oncol 2016;34:337–44. Satoh T, Hatae M, Watanabe Y. Outcomes of fertility-sparing surgery for stage I epithelial ovarian cancer: a proposal for patient selection. JCO 2010;28:1727–32.