Malou Gelderblom

This thesis focusses on primary prevention of epithelial ovarian cancer (EOC) in the general female population. As described in chapter 1, the identification of serous tubal intra-epithelial carcinoma (STIC) as a precursor lesion for high-grade serous carcinoma (HGSC) provided the rationale for a prevention strategy without the hormonal and long term consequences that come with oophorectomy. Once women fulfilled their childbearing, the fallopian tubes cease, as far as we know, to serve any other purpose. Therefore, removal of the fallopian tubes in women undergoing gynecological abdominal surgery for other purposes might reduce the risk of EOC, also known as opportunistic salpingectomy (OS). While worldwide the acceptance of discussing OS with patients is growing, there is a lack of a tailored implementation strategy and long-term evidence. Therefore, OS is susceptible to unnecessary variation in daily clinical practice. In part I of this thesis, we focus on studying the implementation of OS by assessing its uptake, identifying barriers and facilitators, and evaluating an implementation tool. In part II, we elaborate on the effect of OS on menopause and ovarian reserve, mentioned as a barrier for implementation of OS in part I.

PART I Implementation of opportunistic salpingectomy

First, in chapter 2, we assessed the implementation of counseling and performance of OS in women at population-risk for ovarian cancer to gain insight into OS’ clinical practice and associated characteristics. In six Dutch hospitals, a retrospective study was conducted among patients who underwent elective gynecological intra-abdominal surgery and were eligible for OS. During the study period from 2015 until 2018, there were no official recommendations concerning OS such as a national guideline or an implementation strategy. A patient was eligible for OS if she was aged at least 30 years, had completed childbearing or no child wish, and had no previous bilateral salpingectomy or salpingo-oophorectomy. Data was extracted and collected using electronic medical records. In total 3214 patient were considered eligible for OS. Overall, a minority of patients were counseled (N= 440, 13.7%) and did undergo OS (N=735, 22%). A vast majority of 96% (422 of 440) who were counseled chose to undergo OS. In 93% of these patients (394 of 422) OS was performed successfully. Counseling of OS increased from 2.9% in 2015 to 29.4% in 2018. Performance of OS increased from 6.9% in 2015 to 44.5% in 2018. The uptake of OS (both counseling and performance) differed with regard to surgical approach, indicated surgery and counseling physician. Accordingly, OS was more likely counseled and performed in patients who had laparoscopic surgery and less likely in vaginal surgery. Moreover, OS was mainly counseled and performed during hysterectomy or sterilization procedures.

Subsequently, in chapter 3, we conducted a mixed-method study to identify influencing factors on the implementation of OS from both patients’ and professionals’ perspective. In the qualitative phase, barriers and facilitators for implementation of OS were explored by interviews with patients (N=11) and physicians (N=20, gynecologists and gynecological residents). Subsequently, the importance of these factors was determined by questionnaires among patients (N=77) and physicians (N=204) in the quantitative phase. Both patients and professionals indicated the low absolute population risk of developing ovarian cancer (2.3% lifetime until 80 years), the residual cancer risk after OS, and the lack of knowledge about OS in patients as most important barriers. Physicians designated the reduced feasibility of OS in patients with adhesions and vaginal surgery as bottlenecks. Furthermore, the lack of evidence regarding long-term consequences, specifically on menopausal onset, was indicated as barrier. The risk-reducing effect on the development of ovarian cancer, the loss of function of the fallopian tubes after completed childbearing, and a positive family history for ovarian cancer were cited as the most important facilitators by both patients and physicians. Adequate information on OS was considered to be beneficial and essential for the shared-decision making. In addition, a national guideline on OS, in which safety and the risks and benefits are described would contribute to national implementation.

Based on chapter 2 and 3, we concluded that a tailored implementation strategy is recommended to reduce unnecessary variation in daily clinical practice of OS. Uniform counseling material and a guideline about OS could serve as implementation tools for both patients and physicians. Therefore, in chapter 4, a patient decision aid (PtDA) was developed on OS. The PtDA was developed following a systematic development process based on the International Patient Decision Aid Standards (IPDAS) in collaboration with a patient panel with representatives of two patient associations, an expert panel of two gynecologists, a gynecological resident, a medical ethicist and an expert in the field of development and implementation of PtDAs. The online PtDA was based on current literature, guidelines and decisional needs. Following revisions by patients (N=10) and gynecologists (N=10), the PtDA consisted of two separate paths: one for salpingectomy in addition to abdominal surgery, and one for salpingectomy as a sterilization method. The PtDA contained information chapters, a knowledge quiz, consideration statements, and a detailing patient’s preference and considerations. Both paths provided information about the function of the salpinges and ovaries, the risk reduction of ovarian cancer by OS, and its possible risks and benefits. In addition, the path concerning sterilization provided information on the other method of sterilization, tubal ligation. Subsequently, the implementation of OS in daily clinical practice was evaluated using the PtDA and its influence on the decision process (chapter 5). In this multicenter (16 hospitals) observational prospective study, patients who were eligible for OS were invited to use the PtDA while they considered whether or not to undergo OS. A total of 325 patients participated in a digital questionnaire six to eight weeks post-surgery for evaluation of the PtDA, decision process and decision. According to the questionnaire, a vast majority of 274 patients received the PtDA and 97% of them (N=266) used it. They considered the PtDA a good usable aid and strongly recommended the use of the PtDA in the decision making process regarding OS. PtDA-users experienced minimal decisional conflict and a high level of shared decision-making. Regarding the decision whether or not to undergo OS, 95% of the PtDA-users chose for OS. Their main considerations for choosing to undergo OS were the risk reducing effect of ovarian cancer and the lack of known functionality of the fallopian tubes after childbearing. Patients who chose not to undergo OS mainly expressed their unwillingness to accept the risk of going into menopause slightly earlier. Furthermore, the PtDA met the requirements of 52 out of 56 applicable items from the International Patient Decision Aid Standards criteria.

PART II Effect of opportunistic salpingectomy on menopause

As OS may be associated with earlier onset of menopause, we provided a systematic review and meta-analyses on the effect of OS on both age at menopause and ovarian reserve compared to no OS in chapter 6. All randomized controlled trials, cohort and cross-sectional studies that investigated this effect were considered for inclusion. Ovarian reserve was determined by change in pre- and postoperative values of Anti-Mullerian Hormone (AMH), Antral Follicle Count (AFC), Estradiol (E2), Follicle Stimulating Hormone (FSH) and/or Luteinizing Hormone (LH). Until now, no studies were published investigating the effect of OS on age of menopause. Fifteen studies were included in the meta-analysis on ovarian reserve. The majority of these studies contained women who underwent hysterectomy for benign indication. Most studies held a three-month follow-up and only one study a nine-month follow-up. Our analyses did not show a significant short-term impact on ovarian reserve by OS. However, further research is necessary to validate these findings. As a result, a long-term follow-up study has been designed and detailed in chapter 7. This chapter describes the study called STOPOVCAyoung (NCT04757922) to evaluate the long-term effects of OS on the onset of menopause in women who underwent sterilization through bilateral salpingectomy. In this study we examine whether OS compared to no OS may result in an earlier onset of menopause, using a multicenter observational non-inferiority design. The age at menopause of women who underwent sterilization by salpingectomy will be compared with a control group who underwent sterilization by tubal ligation or no surgery at all. Eventually it will be determined whether there is more than one-year decrease in mean age of onset of menopause in women who underwent salpingectomy. Participants aged between 35 and 45 years will be asked to fill out an annual questionnaire on onset of menopause until they reach menopause, with a maximum follow-up of 15 years. Secondary outcomes that will be evaluated are decision regret and the extent of climacteric symptoms. Because of the long-term follow-up results of this study will be expected at the end of the year 2039.

In chapter 8, the main findings of this thesis are presented, discussed in view of other research and provided by implications in light of clinical practice, policy and future research. We conclude that, while there is an annual increase in the uptake of OS, substantial variations in clinical practice are observed in counseling and performing OS. Various implementation tools and a long-term follow-up study are developed as part of a tailored implementation strategy.