Robot-assisted versus standard laparoscopic approach of total hysterectomy for deep infiltrating endometriosis and adenomyosis (ENDORAS TRIAL): study protocol for a randomised controlled trial

Endometriosis is a gynaecological condition characterised by the presence of endometrial glands and stroma outside the uterine cavity. The literature estimates that it affects 5–10% of the general female population during the reproductive period. 1 2 Deep infiltrating endometriosis (DIE), an advanced form, affects 10–15% of women of childbearing age. 3 Adenomyosis, characterised by endometrial-like lesions in the myometrium, is often associated with DIE. Managing DIE is challenging, ethically, and in public health terms. When hormonal therapy and conservative surgery fail, particularly for women without future fertility desires and suffering from chronic pelvic pain, or multiple conservative surgeries, a radical approach involving total hysterectomy with or without bilateral salpingo-oophorectomy may be the final option. 4 6 Total laparoscopic hysterectomy is considered the gold standard; however, it is associated with significant morbidity compared with hysterectomy for other benign gynaecological conditions. The risk of adverse events was approximately fourfold higher in women with endometriosis compared with other benign indications (Clavien-Dindo >2; 7.5 vs 1.9 %, p=0.01). 7 Endometriosis has been identified as an independent risk factor for most complications during laparoscopic hysterectomy, 8 particularly in cases of DIE. 9 10 Recently, robot-assisted laparoscopic surgery has been integrated into gynaecological surgery, particularly for malignant conditions. Experts advocate for robotics in treating endometriosis, citing advantages over traditional laparoscopy, such as enhanced flexibility, improved depth perception and increased wrist movements, potentially leading to improved patient outcomes. 11 13 However, the literature on robotic surgery for DIE remains limited. Some studies have demonstrated the feasibility of robot-assisted laparoscopic treatment for severe deep endometriosis. 14 15 Morelli et al suggested that robotics may offer benefits in cases of DIE with colorectal involvement, potentially reducing complications and preserving urinary and sexual functions. 16 Nezhat et al concluded that a robotic system could effectively achieve adequate debulking without conversion to laparotomy. 17 A recent meta-analysis suggested that robot-assisted surgery for endometriosis treatment is feasible and safe, although most studies were retrospective. 18 Furthermore, a large French multicentre study evaluating surgical practices and morbidity among patients who underwent robotic surgery for stage III–IV DIE over 10 years suggested that DIE might be a promising indication for robot-assisted laparoscopy, with decreased blood loss and complications, and only 5.6% of patients experienced severe postoperative complications. 19 Nonetheless, conclusive evidence remains limited owing to the absence of randomised controlled trials. To address this gap and produce conclusive scientific evidence, prospective randomised clinical trials are necessary for comparing robot-assisted total laparoscopic hysterectomy (RATLH) with standard total laparoscopic hysterectomy (TLH) in DIE patients. The purpose of the ENDORAS trial is to compare robot-assisted and laparoscopic approaches in reducing intraoperative and postoperative complications in patients undergoing total hysterectomy for DIE and adenomyosis without digestive tract involvement.

The ENDORAS trial will be conducted in accordance with the International Council on Harmonization Good Clinical Practice. All trial documents and procedures have been reviewed and approved by the Ethics Committee Ile de France II (approval ID number: 24.01408.000300). Informed consent will be obtained during the preoperative check-up by the operating gynaecologist. The results will be actively disseminated through peer-reviewed journals, conference presentations, social media, broadcast media, print media and the internet. In the event of potential future modifications to the protocol, Ethics Committee Il de France II will be notified. Due to French data protection regulations, the raw data from the study are not accessible for public use. The final trial dataset is owned by the sponsor. However, other researchers may obtain access to the comprehensive research findings. Recruitment started in December 2024 and is expected to finish in December 2026, with the aim of enrolling 224 participants. Prior to the initiation of patient enrolment, the research protocol was registered on the ClinicalTrials.gov platform ( NCT06445179 ).

ENDORAS trial is a prospective, multicentre, open-label, randomised controlled trial comparing RATLH with TLH. We perform an open-label study as RATLH scars are typically higher on the abdomen and are identifiable postoperatively. The primary outcome will be evaluated using the Clavien-Dindo classification, a widely recognised system used in surgery worldwide. The trial has been designed in accordance with Consolidated Standards of Reporting Trials 2010 Guidelines, 20 and a Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 21 figure is included ( figure 1 ). A SPIRIT Checklist file is appended ( online supplemental file 1 ). This protocol will be implemented across five centres in France, including both academic hospitals and private clinics. All have extensive experience treating endometriosis through a multidisciplinary approach. The study was supported by Ramsay Santé for Research and Education (number 2023-06-018) and monitored by EuraxiPharma (a clinical research organisation at Joué-Les-Tours). Eligible patients will be women (18 years or older) with DIE and adenomyosis without digestive tract involvement. Inclusion criteria included diagnosis of adenomyosis and DIE according to the Enzian and dPEI classifications (deep pelvic endometriosis index), failure of first-line and second-line medical treatment, and eligibility for total hysterectomy. Exclusion criteria were digestive tract involvement, adenomyosis only, contraindications to surgery and participants who are under guardianship, curatorship or deprivation of liberty. Investigators prospectively screened and consecutively enrolled eligible patients at each site. Gynaecologists coordinated recruitment, informing eligible women and referring them to research personnel for further details. They were responsible for the final determination of patients’ eligibility for surgical treatment. Before the commencement of study procedures, patients are thoroughly informed of the potential risks and benefits and are required to provide written informed consent ( online supplemental file 1 ). Pretreatment assessments include demographic information, medical and surgical history, and MRI of the uterus to assess the severity of DIE, which will be classified according to both Enzian and dPEI classifications. Questionnaires, including the Short Form Health Survey (SF-36), Endometriosis Health Profile-30 (EHP-30) and Female Sexual Function Index (FSFI), will be administered at baseline. Patients will be randomly assigned to the RATLH or TLH group in a 1:1 ratio, determined by a centralised, SAS-based randomisation schedule stratified by centre using permuted blocks of random sizes. The randomisation list was generated prior to the study’s commencement, with block sizes undisclosed to investigators, monitors or project teams. A statistician, not involved in recruitment or follow-up, will oversee the randomisation process. Surgical intervention will involve either robotic assistance or conventional laparoscopy. The experimental group will undergo RATLH using the HugoTM Robot-Assisted Surgery system (Medtronic), Da Vinci Xi or X Surgical System (Sunnyvale, California, USA), or CMR Versus (if available). The control group will undergo TLH. Both groups will be classified according to the Querleu and Morrow classification system for total hysterectomy. 22 Bilateral ureterolysis with or without bilateral concomitant salpingo-oophorectomy will be performed, along with other necessary surgical procedures. No modifications to the surgical intervention are planned. However, if required, conversion to open surgery may be considered for both groups. In the event of endometriotic nodules located in the bladder, their management will be conducted according to the surgeon’s requirements and preferences, whether through shaving or resection. These surgical interventions will be detailed in the concomitant procedures. Trial subjects will receive their planned follow-up appointments at hospital discharge by a Clinical Research Associate. To enhance adherence, a text message reminder will be sent to each participant before their appointment. The standard care protocol will be implemented for all patients, regardless of their participation in the trial. Postoperative care will adhere to the enhanced recovery after surgery protocol employed at the centre. The primary outcome will be the intraoperative and postoperative complication rates (Clavien-Dindo grade ≥2) at the 3-month postoperative follow-up. Secondary outcomes will be the following: (1) between-group difference in absolute score and change from baseline in EHP-30, SF-36 and FSFI among patients undergoing RATLH or TLH; (2) mean operative time; (3) rate of intraoperative and postoperative complications at 1, 6 and 12 months; (4) blood loss volume; (5) mean numeric rating scale pain scores; (6) total hospital stay; (7) rate of hospital readmissions within 30 days; (8) reoperation rate within 30 days after surgery; (9) number of robotic and complex laparoscopic procedures performed by the surgeons and (10) Borg CR-10 Scale and NASA-TLX (NASA-task load index) questionnaire. Follow-up visits will occur within 1 month (± 15 days), 3 months (± 15 days), 6 months (± 15 days) and 12 months (± 15 days) after the intervention. Before trial commencement, research personnel will undergo training on data collection methodologies and assessments for data entry proficiency and outcome evaluation competence. Investigators and research staff input clinical study data into an Ennov Clinical electronic data capture system hosted at EuraxiPharma. Ennov Clinical is a secure, web-based application supporting data capture for research studies. Each user is assigned a unique username and password to ensure data protection. To ensure the confidentiality of patient identities, anonymous identification codes will be generated specifically for this study. Throughout the study period and after the trial, all data management will be conducted using these ID codes. Periodic monitoring visits to the clinical sites verify protocol adherence and validate clinical data against source documentation. Verification of data in electronic case report forms involves scrutiny of source documents. Site investigators report safety outcomes to EuraxiPharma’s pharmacovigilance department (on behalf of sponsor GCS Ramsay Santé), complying with national regulations. The estimated number of participants is calculated based on an analysis comparing the superiority of RATLH versus TLH. Based on the study by Brunes et al, 1 the rate of perioperative and postoperative complications for patients with moderate to severe endometriosis is approximately 25% for standard laparoscopic hysterectomy. Assuming a 15% difference in intraoperative and postoperative complications between the two groups at 3 months postoperatively and a 10% attrition rate, a sample size of 112 patients per group is required to provide 80% power to detect this difference with a two-sided χ 2 test with a type I error of 0.05. The analysis will be performed on an intention-to-treat basis, meaning that all randomised participants will be analysed within their assigned initial groups. A per-protocol sensitivity analysis will also be conducted. The primary outcome will be analysed using a χ 2 test. Absolute and relative risk differences between the experimental and control groups will be calculated, accompanied by 95% CIs. For the secondary analysis, χ 2 or Fisher’s exact tests will be employed for qualitative variables, while Mann-Whitney tests will be used for continuous variables. All statistical tests will be two-sided, with a type I error rate of α=0.05. Analyses will be performed using SAS software release 9.6 (SAS Institute Inc.). No interim analysis is planned.

Since the Food and Drug Administration approved robotic laparoscopic surgery (RLS) in 2005, it has expanded to 69 countries with 6730 certified surgeons worldwide. 23 RLS addresses the limitations in open and laparoscopic surgeries, enhancing surgical performance. Its integration into gynaecology represents a significant advancement in treating malignant and benign conditions. Over the last decade, RLS has gained popularity in endometriosis surgery, especially in advanced cases. There is growing interest in robot-assisted laparoscopic surgery for DIE as a safe and efficient alternative to conventional laparoscopy. RLS offers advantages, including improved ergonomics, enhanced dexterity, articulated instruments, tremor filtration and a three-dimensional optical system with superior depth perception. 24 25 Conventional laparoscopic surgery is widely considered the gold standard treatment for endometriosis, particularly for deep infiltrative lesions. Its efficacy is well established in patients requiring total hysterectomy. However, it has higher morbidity rates than hysterectomy for other benign gynaecological conditions. Uterine removal in patients with DIE often presents more difficulties than in other benign cases, even for experienced surgeons. The pelvis’ complex anatomy and conventional laparoscopy’s limitations, like restricted motion from bidimensional visualisation and reliance on an assistant for camera stability, create challenges in radical pelvic surgery, particularly in DIE cases. Robotic systems provide a versatile platform for a multidisciplinary approach, offering advantages in deep and precise dissection of the female pelvis, potentially improving long-term outcomes and reducing complications. However, to date, the literature on robotic surgery for DIE is limited. Some studies show that robot-assisted laparoscopy is a viable option for managing severe deep endometriosis. 14 17 Robotics may decrease complications and improve urinary and sexual function preservation compared with open and laparoscopic surgeries. The largest French multicentre cohort study evaluating robot-assisted laparoscopy for DIE treatment reported diminished blood loss and fewer intraoperative or postoperative complications, with only 5.6% of patients experiencing severe postoperative complications (Clavien-Dindo classification ≥Grade III). 19 Kanno et al highlighted that despite extended operative times, robot-assisted removal of deep endometriosis lesions was achieved without increased blood loss or complications while preserving pelvic autonomic nerves. 26 This preservation is crucial for minimising voiding dysfunction and enhancing quality of life. A recent review indicated that RLS learning curves are steeper than those for conventional laparoscopy in radical hysterectomy. 27 However, most studies were retrospective, with heterogeneous populations and various endometriosis types. The current literature lacks robust randomised controlled trial data to substantiate the application of robotics in DIE treatment. To address this knowledge gap, we developed a protocol for a trial assessing the safety and efficacy of RATLH in a randomised controlled setting, with follow-up extending to 12 months post surgery. Our study population is homogeneous, excluding patients with digestive involvement and isolated adenomyosis. The multicentre nature of the study, representing the French population and conducted in reference care hospitals with advanced endometriosis surgery expertise, enhances the external validity of the findings. These methodological strengths will contribute to the standardisation of surgical techniques and facilitate the broader application of the study’s outcomes. The ENDORAS trial aims to provide evidence on using robotic assistance for managing DIE with adenomyosis, excluding colorectal involvement. If it demonstrates the efficacy and safety of RATLH for DIE, gynaecological surgeons should consider employing RATLH over TLH.