Hysterectomy for Benign Gynaecological Conditions With or Without Tubectomy
Condition: Abdominal Hysterectomy (& Wertheim)
Study type: Interventional

Summary: 
      The purpose of this study is to determine whether a tubectomy during hysterectomy for benign
      gynaecological conditions does not result into a premature menopause.
    

Detailed description: 
      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.
    

Intervention name(s): Hysterectomy plus Tubectomy; Hysterectomy; light microscopy
Intervention type(s): Procedure; Procedure; Device
Intervention description(s): hysterectomy with tubectomy; standard hysterectomy; analysis of the incidence of dysplastic lesions (defined as: nuclear atypia, pilling of epithelial cells, multiple mitosis), if any, in the removed Fallopian tubes by light microscopy (Leica DM4000)
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: tubal carcinoma; ovarian carcinoma; tubectomy; hysterectomy; dysplastic changes; Anti Mullerian Hormone; Tubal Intraepithelial Carcinoma; Salpingectomy