Hysterectomy for Benign Gynaecological Conditions With or Without Tubectomy

RATIONALE Recent studies in women at hereditary high risk to develop ovarian cancer indicate that high grade serous carcinomas arise from (ectopic and/or dysplastic) tubal epithelium. Historically, in pre-menopausal women undergoing a hysterectomy for benign indications (such as bleeding disorders, fibroids and adenomyosis) adnexa, including the Fallopian tubes, are left in situ. However, removing the tubes during a hysterectomy potentially prevents the development of serous ovarian carcinomas. Such a simple preventive procedure should avoid serious adverse effects of adnexectomy, like premature ovarian failure (POF).

STUDY DESIGN This is a randomized controlled trial in which patients undergoing a hysterectomy for benign indications will either be included into a group in which a standard hysterectomy (abdominal or laparoscopic) will be performed or into a group in which hysterectomy (abdominal or laparoscopic) will be combined with salpingectomy.The accrual is aimed to take until July 2015 and will be performed in the regular clinical setting.

STUDY POPULATION Women undergoing hysterectomy for benign conditions (fibroids, endosalpingiosis, bleeding disorders, etc) either abdominal or laparoscopic.

SAMPLE SIZE N=50/arm

TREATMENT Hysterectomy (abdominal or laparoscopic) with or without bilateral tubectomy.

METHODS

1. Study endpoint Main study endpoint: serum concentration Anti Mullerian Hormone (AMH) just before the operation and on average six months after the operation.

   Secondary study endpoint: premalignant changes within the removed Fallopian tubes from this cohort of women, defined as histological dysplastic areas detected by light microscope

2. Randomization Randomization is performed online with Alea software.
3. Study procedures One day preoperative, together with regular blood drawing, blood for AMH concentration assessment is drawn. The operation procedure will either be the regular procedure or the regular procedure plus removal of the Fallopian tubes by removing the tubes from the ovaries by dissection of the mesovarium. On an expected average of six months after the operation blood for serum AMH concentration assessment is drawn. Blood serum is stored at -80C and AMH concentration assessment is performed in one badge.
4. Withdrawal of individual subjects Subjects can leave the study at any time for any reason if they wish to do so without any consequences. After withdrawal the individual subjects will be replaced.
5. Premature termination of the study In case of serious adverse events (like postoperative haemorrhage).

SAFETY REPORTING

1. In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects and the reviewing accredited Medical Ethical Committee (METC) if anything occurs, on the basis of which it appears that the disadvantages of participation may be significantly greater than was foreseen in the research proposal. The study will be suspended pending further review by the accredited METC, except insofar as suspension would jeopardize the subjects' health. The investigator will take care that all subjects are kept informed.
2. Adverse and serious adverse events All Serious Adverse Event (SAE) s will be reported to the accredited METC that approved the protocol.

STATISTICAL ANALYSIS Data will both be described qualitatively and quantitatively. Student t-test will be applied to study differences in hormone levels between the groups.

ETHICAL CONSIDERATIONS

1. The study will be conducted according to the principles of the Declaration of Helsinki (2nd edition, 2009) and in accordance with the Medical Research Involving Human Subjects Act (WMO).
2. Patients will be recruited at the outpatient clinic when a decision is made for hysterectomy (abdominal or laparoscopic) on benign indication. They will receive oral information from their gynecologist and an information letter will be handed out (a telephone number will be stated which patients can call for extra information). On the day of preoperative admission (mostly one day preoperative) the gynecologist will answer any remaining questions and the informed consent will be signed by both the patient and the gynecologist. Patients on oral contraceptives will stop using these at least two weeks prior to the operation.
3. Literature on the effects of salpingectomy during hysterectomy for benign gynecological conditions on the ovarian reserve is very scant, but the one available study does not show any adverse effects. Furthermore, the chance of a postoperative hemorrhage is increased (estimated 1%). We believe that, in the light of the burden and risk, this study is justified since the prophylactic removal of the Fallopian tubes might diminish the risk of serous ovarian carcinomas (life time risk around 1%).

ADMINISTRATIVE ASPECTS AND PUBLICATION

1. Data will be collected from the participating hospitals by one study medical doctor. Together with the principal investigator (s)he has access to the source data which are coded by a case number. The key to the code is safeguarded in the safe from the TweeSteden hospital, Tilburg, The Netherlands. Data and human material will be kept for seven years (or fifteen with patient consent). Data security is assured by the fact that one medical doctor collects the data. The privacy of the participants is protected by the fact that the data is coded.
2. The investigator will submit a summary of the progress of the trial to the accredited METC once a year. Information will be provided on the date of inclusion of the first subject, numbers of subjects included and numbers of subjects that have completed the trial, serious adverse events / serious adverse reactions, other problems, and amendments.
3. The investigator will notify the accredited METC of the end of the study within a period of 8 weeks. The end of the study is defined as the last patient's last visit. In case the study is ended prematurely, the investigator will notify the accredited METC, including the reasons for the premature termination. Within one year after the end of the study, the investigator will submit a final study report with the results of the study, including any publications/abstracts of the study, to the accredited METC.
4. The data will be published in peer reviewed medical journals as well as presented in abstracts at medical conferences.