The (Cost-)Effectiveness of Surgical Excision of Colorectal Endometriosis Compared to ART Treatment Trajectory (TOSCA)

To goal of this study is to determine whether laparoscopic resection of colorectal endometriosis results in an increased cumulative live birth rate (CLBR) both spontaneous and after ART (including in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), and better patient reported outcome measures (PROMs) compared to an IVF/ICSI treatment trajectory.

Study Overview

• Status: Recruiting
• Conditions: Endometriosis, Rectum; Subfertility, Female; Endometriosis of Colon
• Intervention / Treatment: Procedure: Laparoscopic excision of endometriosis, including colorectal endometriosis; Procedure: In vitro fertilisation or intracytoplasmic sperm injection

Detailed Description

Endometriosis is characterized by extra-uterine endometrium like tissue and affects 10-15% of the women in their reproductive years and in 5-12% of these women colorectal endometriosis is present. The quality of life is lowered due to severe pain symptoms (dysmenorrhea, dyschezia, dysuria, chronic pelvic pain) and subfertility.The management of colorectal endometriosis-related subfertility is challenging. While the impact of colorectal endometriosis per se remains inconclusive as other intraperitoneal endometriosis lesions are frequently present, fertility is most likely affected by multiple mechanisms including inflammatory alterations in peritoneal fluid, alterations in estrogen and progesterone hormone levels, lowered endometrium receptivity, associated adenomyosis, a lower ovarian reserve (in case endometriomas are present) and adhesion formation that disrupts adnexal anatomy and function. Usually, surgery is preferred in case of dominant pain complaints, while IVF/ICSI is started when the wish to conceive is dominant. Recent evidence suggests a CLBR of 44.9% in patients with rectosigmoid endometriosis treated by surgery compared to 55.9% after 4 cycles of IVF/ICSI treatment without surgery. In the Netherlands, the number of reimbursed IV/ICSI attempts in limited to three. In addition, a combined strategy may result in even higher cumulative live birth rates. However, the place and optimal timing of surgery in patients with colorectal endometriosis and a desire to have children is unknown.

To provide robust evidence that can be extrapolated to the Dutch healthcare system, this study aims to determine whether surgical excision of colorectal endometriosis results in increased CLBR both spontaneous and after IVF/ICSI, and better PROMs compared to an IVF/ICSI treatment trajectory.

• Study Type: Observational
• Enrollment (Estimated): 339

Contacts and Locations

• Study Contact: Name: Mathijs D. Blikkendaal, MD,PhD; Phone Number: 088 979 44 89; Email: M.Blikkendaal@rdgg.nl
• Study Contact Backup: Name: Rozemarijn de Koning, MD; Email: r.de_koning@lumc.nl

Study Locations

• Netherlands
  • Den Haag, Netherlands
    • Recruiting
    • Haaglanden Medical Center
    • Contact: Moniek van der Zanden
  • Eindhoven, Netherlands
    • Recruiting
    • Catharina Ziekenhuis
    • Contact: Dana Huppelschoten
  • Enschede, Netherlands
    • Recruiting
    • Medical spectrum Twente
    • Contact: Marieke Verberg
  • Groningen, Netherlands
    • Recruiting
    • University Medical Center Groningen
    • Contact: Astrid Cantineau
  • Leiden, Netherlands
    • Recruiting
    • Leiden University Medical Center
    • Contact: Dries Twijnstra
  • Maastricht, Netherlands
    • Recruiting
    • Maastricht University Medical Center
    • Contact: Jacques Maas
  • Nijmegen, Netherlands
    • Recruiting
    • Radboud University Medical Center
    • Contact: Annemiek Nap
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus Medical Centre
    • Contact: Yvonne Louwers
  • Utrecht, Netherlands
    • Recruiting
    • Utrecht Medical Center
    • Contact: Simone Broer
  • Voorburg, Netherlands
    • Recruiting
    • Nederlandse Endometriose Kliniek (Reinier de Graaf Gasthuis)
    • Contact: Tobias Limperg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 42 years (Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Subfertile women between 21 and 40 years with colorectal endometriosis facing the choice (at the start of their treatment trajectory or after one or two unsuccessful IVF/ICSI cycles) between IVF/ICSI or laparoscopic excision of (colorectal) endometriosis to increase the chance to conceive (naturally)

Description

Inclusion Criteria:

• Colorectal endometriosis defined as endometriosis involving the (colo)rectum:

  #Enzian classification score C1,C2,C3 (C=rectum) or FI (F=far locations, I=sigmoid colon) detected with ultrasound or MRI;

• Women in a heterosexual or in a same-sex relationship;

• The patient has an active wish to conceive and experiences at least one of the following criteria:

  • At least one year of non-conception (either spontaneous of after intra uterine inseminations)
  • Inability to have timed intercourse because of pain (dyspareunia and/or chronic pelvic pain)
  • Severe complaints (expectant management is not acceptable (anymore)

• The patients has an indication for IVF/ICSI according to Dutch guidelines (Werkgroep netwerkrichtlijn, december 2010);

  • failed intra uterine insemination
  • male factor subfertility (oligoasthenoteratozoospermia defined as VCM <1 million)
  • bilateral tubal pathology (e.g. bilateral hydrosalpinx, bilateral tubal occlusion)
  • age > 38 years and (unexplained) subfertility
  • severe endometriosis in case of subfertility
• The patient is faces the choice between IVF/ICSI or laparoscopic (colorectal) endometriosis or is on the waiting list for a respective treatment at T=0 (at the beginning of the treatment trajectory), T=1 (after one unsuccessful IVF/ICSI cycle) or T=2 (after 2 unsuccessful IVF/ICSI cycles)

Exclusion Criteria:

• Patients with deep endometriosis without colorectal involvement;
• Patients who conceive spontaneously prior to intervention;
• Patients requiring surgery on short notice and therefore unable to opt for IVF/ICSI (e.g. in case of unilateral or bilateral hydronephrosis, severe bowel stenosis and suspicion of an impending ileus);
• Patients with a contra-indication for IVF/ICSI (e.g. diminished ovarian reserve (premature ovarian failure) (AMH (when available) <p10 adjusted for age), untreated congenital uterine abnormalities, maltreated/untreated systemic or malignant disease or severe risk factors for oocyte aspiration);
• Patients diagnosed with other diseases causing infertility (e.g. recurrent miscarriages, antiphospholipid syndrome);
• Not able to read and understand Dutch or English.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Colorectal endometriosis patients; Subfertile women between 21 and 40 years with colorectal endometriosis facing the choice between IVF/ICSI or laparoscopic resection of (colorectal) endometriosis.

Procedure: Laparoscopic excision of endometriosis, including colorectal endometriosis; Laparoscopic resection of deep endometriosis, including colorectal endometriosis, in a (candidate) level 2 centre of expertise. Complete resection can exist of either 'shaving' of the nodule from the bowel (leaving the lumen closed), discoid excision or segmental resection, depending on the nodule size and extent of disease.; Procedure: In vitro fertilisation or intracytoplasmic sperm injection; IVF/ICSI treatment trajectory (maximum of 3 cycles), according to the local protocol. Preferably preceded by 3 months downregulation with either Gonadotrophin-releasing hormone (GnRH) analogue or oral contraceptive pill. One IVF/ICSI cycle is defined as the transfer of all the embryos created after one follicle puncture until pregnancy confirmation or failure of the last embryo transfer.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative live birth rate	Live birth is defined as the complete expulsion or extraction from a women of a product of fertilization, after 20 weeks of gestational age; which, after such separation, breathes or shows any other evidence of life, such as heart beat, umbilical cord pulsation or definite movement of voluntary muscles, irrespective of whether the umbilical cord has been cut of the placenta is attached. A birth weight of 350 grams or more can be used if gestational age is unknown	At the end of the study period (live birth or after 3 IVF/ICSI attempts and/or surgery in the follow-up period (40 months) )

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Endometriosis specific symptoms	Endometriosis Health Profile-30 (EHP-30). The overall EHP-30 score ranges from 0 to 100, with a high score indicating poorer health-related quality of life.	At baseline (T=0: when informed consent is granted), 12, 24 and 36 months and in case of surgery, before surgery.
Quality of life in general	EuroQql five-dimensional 5 levels (EQ-5D-5L) and EuroQql Visual Analog Scale (EQ-VAS). According to the Dutch scoring algorithm, the EQ-5D-5L score index value ranges from -0.446 (55555 worst health state) to 1 (11111, best health state). Overall health will be represented by the EQ-VAS, ranging from 0 to 100, with higher scores indicating better health.	At baseline (T=0: when informed consent is granted), 6, 12, 18, 24, 30, 36 and 40 months and in case of surgery, before surgery.
Bowel specific symptoms	Lower Anterior Resection Syndrome score (LARS score). The total LARS score ranges from 0, indicating no LARS to 42 points, indicating major LARS.	At baseline (T=0: when informed consent is granted), 12, 24 and 36 months and in case of surgery, before surgery.
Pain scores	NRS score for dysmenorrhea, dysuria, dyschezia, dyspareunia and chronic pelvic pain. The NRS scale ranges from 0 (no pain) to 10 (worst pain imaginable).	At baseline (T=0: when informed consent is granted), 12, 24 and 36 months and in case of surgery, before surgery.
Productivity costs	Productivity costs questionnaire: institute for Medical Technology Assessment (iMTA) Productivity Cost Questionnaire (iPCQ). Productivity costs will be measured by calculating absence from paid work (absenteeism), reduced productivity at paid work (presenteeism), and productivity loss in unpaid work. Hours of productivity loss will be translated by a standard cost price of productivity per hour.	At baseline (T=6, 12, 18, 24, 30, 36 and 40 months and in case of surgery, before surgery.
Medical costs per group	Costs surgery, costs IVF/ICSI treatment, costs extra hospital admissions / emergency room visits / visits outpatient care	At the end of the study period (live birth or after 3 IVF/ICSI attempts and/or surgery in the follow-up period (40 months) )
Complications	Intraoperative and postoperative complications, IVF/ICSI associated complications, pregnancy complications	At the end of the study period (live birth or after 3 IVF/ICSI attempts and/or surgery in the follow-up period (40 months) )

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Radboud University Medical Center; University Medical Center Groningen; Maastricht University Medical Center; UMC Utrecht; Catharina Ziekenhuis Eindhoven; Reinier de Graaf Groep; Haaglanden Medical Centre
• Investigators: Study Chair: Andries RH Twijnstra, MD, PhD, Leiden University Medical Center; Study Chair: Astrid EP Cantineau, MD, PhD, University Medical Center Groningen; Study Chair: Jacques Maas, MD, PhD, Maastricht University Medical Center; Study Chair: Annemiek Nap, MD, PhD, Radboud University Medical Center; Study Chair: Dana Huppelschoten, Catharina Ziekenhuis; Study Chair: Simone Broer, UMC Utrecht; Principal Investigator: Mathijs D. Blikkendaal, MD, PhD, Nederlandse Endometriose Kliniek (NEK), Reinier de Graaf Gasthuis; Study Chair: Tobias Limperg, Nederlandse Endometriose Kliniek (NEK), Reinier de Graaf Gasthuis; Study Chair: Yvonne Louwers, Erasmus Medical Center; Study Chair: Marieke Verberg, Medisch Spectrum Twente

Publications and helpful links

General Publications

• F Barra, C Scala, S Bogliolo, N Di Donato, M Ceccaroni, S Ferrero, O-309 Surgery versus IVF/ICSI in infertile women with rectosigmoid endometriosis: the FERTILITY-RECTOSIGMOID study, Human Reproduction, Volume 37, Issue Supplement_1, July 2022

Study record dates

Study Major Dates

• Study Start (Actual): February 17, 2023
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: December 9, 2022
• First Submitted That Met QC Criteria: December 22, 2022
• First Posted (Actual): January 10, 2023

Study Record Updates

• Last Update Posted (Estimated): November 21, 2024
• Last Update Submitted That Met QC Criteria: November 19, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Surgery; Quality of life; Cost-effectiveness; In vitro fertilisation; Live birth rate; Colorectal endometriosis; Subfertility
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Diseases, Female; Infertility; Infertility, Female; Endometriosis
• Other Study ID Numbers: N22.085

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No