ATOPE study protocol: a randomised controlled trial comparing cystectomy and plasma vapourisation in endometriomas under 6 cm, with an observational arm for sclerotherapy in larger cysts

Endometrioma is a common manifestation of endometriosis, affecting up to 44% of patients diagnosed with the condition. 1 It is associated with pelvic pain, decreased ovarian reserve and impaired fertility. 2 The therapeutic strategy in women of reproductive age must therefore balance lesion eradication and fertility preservation. Laparoscopic cystectomy is currently considered the gold standard for the surgical treatment of endometrioma. It is effective in relieving symptoms and reducing recurrence. 3 However, it is associated with the removal of healthy ovarian tissue, with the extent of this loss being generally proportional to the volume of the endometrioma. 4 This damage may lead to a significant reduction in ovarian reserve, often reflected by a postoperative decline in anti-Müllerian hormone (AMH) levels. 5 To reduce the impact on ovarian reserve, fertility-preserving alternatives such as plasma energy vapourisation and CO₂ or argon laser ablation 6 7 have been proposed over the past decade. These techniques aim to destroy the inner cyst wall while minimising thermal and mechanical damage to surrounding ovarian tissue. Plasma energy vapourisation, in particular, is characterised by low thermal diffusion and a limited depth of necrosis. 8 Despite growing interest in plasma energy, available clinical data remain limited and mostly retrospective. In a small retrospective study of 30 women, 8 cystectomy led to a significantly lower postoperative antral follicle count (AFC) compared with plasma energy vapourisation (mean AFC: 2.9±2.4 vs 5.5±3.9; p=0.03), even after adjustment for age, parity and cyst size. A larger multicentric prospective case–control study 9 comparing postoperative pregnancy outcomes between cystectomy and plasma energy showed comparable results: pregnancy probabilities at 24 and 36 months were 69.3% and 78.3% after cystectomy, and 61.3% and 84.4% after plasma vapourisation, respectively. The surgical technique had no statistically significant effect on pregnancy probability. More recently, Puscasiu et al conducted a retrospective three-arm study comparing cystectomy, plasma ablation and simple drainage. 10 The overall postoperative pregnancy rate was 60.3%, with a significantly higher 12-month pregnancy rate in the plasma (32%) and cystectomy (27%) groups compared with drainage (16%) (p=0.015). The rate of spontaneous conception was also higher in the plasma (43%) and cystectomy (58%) groups than in the drainage group (27%). Ablative techniques such as laser or plasma vapourisation are generally restricted to smaller endometriomas (<6 cm), due to both technical and clinical limitations. From a mechanical standpoint, complete ablation of large cysts becomes challenging, with an increased risk of incomplete treatment. Moreover, a prospective study by Candiani et al demonstrated that endometriomas larger than 5 cm treated with CO₂ laser ablation had a two-fold higher risk of recurrence compared with smaller cysts. 7 In women with larger cysts, sclerotherapy has emerged as a promising alternative. Three retrospective observational studies have reported encouraging results, with only a moderate reduction in AMH levels of 1.1 ng/mL at 6 months 11 and a pregnancy rate of 57% after a 24-month follow-up. 12 However, these findings remain unconfirmed by prospective data. Thus, this monocentric randomised controlled trial (RCT) comparing fertility outcomes following cystectomy and plasma energy vapourisation for endometriomas <6 cm aims to provide high-quality evidence to allow better counsel for women wishing to conceive. Concomitantly, the prospective observational arm assessing sclerotherapy in larger endometriomas will generate robust hypotheses to inform future randomised trial design.

The ATOPE trial will be conducted in full compliance with the Declaration of Helsinki, the guidelines of GCP as defined by the International Council for Harmonisation, and all applicable French and European regulatory requirements, including the GDPR and the French Public Health Code. Ethical approval for the trial has been obtained from the Comité de Protection des Personnes (CPP): CPP Ile de France II ([email protected]), reference 25.01105.000405-MS01. The study is classified as a “research involving minimal risk and constraints” (RIPH2), as it compares standard surgical procedures that are routinely performed at the IFEM Endo centre. A key ethical consideration of the trial is that all surgical techniques under investigation, cystectomy, plasma vapourisation and sclerotherapy—are part of the usual care provided to patients with endometriomas and a desire for pregnancy. Participants are thoroughly informed about each option and are required to accept the possibility of being allocated to any of the procedures before inclusion. The final choice of intervention is determined through randomisation (for endometriomas ≤6 cm) or clinical criteria (for endometriomas >6 cm, allocated to sclerotherapy). All participants will provide written informed consent after receiving oral and written information from the investigator ( online supplemental file 1 ). The informed consent process includes explanations of the study objectives, procedures, risks, potential benefits and data protection measures. Patients are given adequate time for reflection prior to consent. Data will be pseudonymised and handled in compliance with MR-001 standards (CNIL registration number 2237821). Data confidentiality and patient privacy will be strictly maintained throughout the study. The results of the trial will be reported in accordance with the CONSORT guidelines. The trial will be submitted for publication in an open-access, peer-reviewed journal. Authorship will follow the recommendations of the ICMJE. The full protocol and trial results will also be disseminated through the national clinical trials registry and presented at national and international congresses in the fields of gynaecology and reproductive medicine. Exploratory analyses or secondary outcomes may be published in separate open-access journals depending on their scope. Patients or members of the public were not involved in the design, conduct, reporting or dissemination plans of this research. However, the research team plans to engage patient representatives from the EndoFrance association during the dissemination phase, notably for communication of results to the broader endometriosis community and for the preparation of patient-friendly educational materials.

The Ablative Technique Options for Preserving fertility in Endometrioma (ATOPE) study is a single-centre, prospective interventional trial including a two-arm RCT and an observational cohort. The protocol complies with 13 13 Consolidated Standards of Reporting Trials (CONSORT) guidelines. 14 The RCT compares cystectomy with plasma vapourisation for ovarian endometriomas measuring 2–6 cm. In parallel, the study includes a separate, non-randomised exploratory observational cohort evaluating laparoscopic sclerotherapy for larger endometriomas (>6 cm). This observational cohort does not contribute to the primary hypothesis or to the sample size calculation, but follows the same standardised data collection procedures to allow descriptive comparison. Study participants will be recruited at the ‘Institut Franco-Européen de prise en charge multidisciplinaire de l’endométriose’ (IFEM ENDO), Clinique Tivoli-Ducos in Bordeaux, France. Surgical procedures will be carried out in Clinique Tivoli-Ducos and assisted reproductive procedures will be carried out at various public and private fertility clinics, with no primary fertility clinic site. Participant recruitment will begin in October 2025 and is expected to continue until December 2032. Inclusion criteria: Female patient aged between 18 and 43 years (inclusive). Patient with diagnosed endometriosis (confirmed by histology or imaging), symptomatic and requiring surgery for deep infiltrating endometriosis (DIE), with associated endometrioma (pelvic pain and/or infertility and/or risk of organ damage). Pelvic MRI or ultrasound performed within the past year, identifying at least one endometrioma larger than 20 mm in diameter. Patient with a desire to conceive (probable or confirmed) after surgery. Patient informed and having signed the consent form. Patient covered by a national health insurance system. Exclusion criteria: Intraoperative finding that the cyst is not an endometrioma. Patient under guardianship or curatorship, or unable to provide informed consent. Patient with insufficient understanding of the French language. Patient under legal protection (sauvegarde de justice). Patient who is pregnant or breastfeeding. Recruitment of eligible participants will take place at the first consultation after referral for DIE and eligibility for surgery. Endometrioma and DIE are confirmed by transvaginal ultrasound and/or a pelvic MRI scan. In routine practice, women with imaging or tumour markers suspicious for malignancy are systematically referred to an oncologic pathway and are not considered for inclusion. If the woman is a candidate for complete DIE surgery and has pregnancy intention, she will be asked if she agrees to participate in the study. Detailed information on the study will be provided during the consultation by the gynaecologist. In addition, written participant information and a consent form will be given to the woman. The surgical procedure will start with a complete exploration of the pelvis and confirmation of the presence and size of endometrioma. If the size of the cyst is confirmed to be lower than 6 cm, a randomisation will be performed in the operating room: plasma vapourisation or cystectomy. The plasma vapourisation procedure has been described in the literature. 8 15 Plasma energy was selected as the comparator because it is the standard ablative technology used at our institution, supported by long-standing expertise and multiple peer-reviewed publications. 9 15 The surgeon proceeds to a large fenestration of the endometrioma and eversion of the inner wall to apply plasma energy (group 1). Cystectomy by divergent traction will be performed in the other arm (group 2). Minimal use of bipolar energy will be applied for coagulation. In cases of endometrioma larger than 6 cm, a 10 min ethanol sclerotherapy will be performed (group 3). Endometrioma sclerotherapy is a standardised technique in our centre. Details on our 10-step procedure 16 and cohort postoperative outcomes have been previously reported. 11 12 After the endometrioma procedure, a complete removal of all other visible endometriosis lesions will be performed. All surgeries will be conducted by specialised gynaecologists (HR, AC, BM, TD and P-HG) in collaboration with specialised colorectal or urological surgeons. As part of our standard operative protocol, tubal patency will systematically be assessed using methylene-blue chromotubation. In case of abnormalities such as fimbrial adhesions or distal tubal stenosis, a conservative tubal repair (fimbrioplasty or salpingoplasty) will be undertaken whenever feasible. A diagnostic hysteroscopy will also be performed at the start of the procedure if required, with operative intervention when needed (eg, polypectomy, adhesiolysis). All operative details regarding time, postoperative complications and the extent of resections will be recorded. All tissue removed will be sent for pathological examination. We calculated the sample size specifically for the group of patients with endometriomas <6 cm. Power analysis assumes a 50% pregnancy rate in the cystectomy group versus 65% in the vapourisation group. With a type I error rate of 5.0%, a type II error rate of 20.0% (corresponding to a power of 80.0%), a one-sided test, and an anticipated loss to follow-up rate of 20.0%, 166 patients are required in both Group 1 and Group 2. The total duration of the study is expected to be 108 months. Patient recruitment will take place over a period of 84 months. Each patient will participate in the study for 24 months following inclusion. Of the annual 1000 surgeries performed for endometriosis at IFEM Endo, we estimate that 50 patients will meet inclusion criteria and be enrolled in the trial. This recruitment capacity supports the feasibility of enrolling the required number of participants over the planned inclusion period. Randomisation (1:1) will be performed through the electronic case report form (eCRF) website Dotter.science, in the operating room after confirmation of the size of the biggest endometrioma. No stratification is planned. No blinding is possible for interventions. At IFEM ENDO, all patients are included in our prospective cohort hosted on the NOENDO (National Observatory for Endometriosis) platform. Data collection is planned in four blocks. The following data will be recorded in the eCRF, with a note specifying that these are routinely collected in our IFEM Endo cohort, hosted on the NOENDO platform: Age, weight, height. Medical history (start and end date, condition), systemic autoimmune diseases are systematically recorded as part of the medical history. Surgical history (date, endometriosis-related surgery – if yes, number of procedures –, abdominal surgery, caesarean section, other surgeries). Concomitant treatments at the time of surgery: combined oral contraceptives, progestins, GnRH analogues, intrauterine device. Amenorrhoea – if present, duration in months. Infertility (yes/no); if yes, duration and methods used: ovulation induction, intrauterine insemination, in vitro techniques, oocyte/sperm donation. Semen analysis results will be documented when available. Gravidity: 0, 1–2 or ≥3. For prior pregnancies: mode of conception (spontaneous or assisted reproduction) and pregnancy outcome (caesarean section, vaginal delivery or pregnancy loss). Parity: 0, 1–2 >3. Smoking status (yes/no). Clinical symptoms: dysmenorrhoea, dyspareunia, pelvic pain, menorrhagia, urinary symptoms, pelvic heaviness or other. Pain score on a numeric rating scale (0 to 10). Biberoglu and Behrman pain score. Surgical approach: robotic, laparoscopic or laparotomy. Ovarian surgery performed on the index endometrioma: cystectomy or plasma energy vapourisation (for endometriomas 2–6 cm), or sclerotherapy (for endometriomas >6 cm). Details specific to vapourisation: complete treatment (yes/no), wall coagulation (yes/no). Details specific to cystectomy: wall coagulation (yes/no) to control bleeding, number of hemostatic sutures. Details specific to sclerotherapy: unilateral or bilateral, alcohol volume injected, exposure time, ring-shaped excision of puncture orifice (yes/no), alcohol washing, endometrioma fenestration at the end of the procedure. Technique feasibility: yes/no, and reason for failure if applicable. Associated ovarian procedures on a second endometrioma (if present): sclerotherapy, cystectomy or vapourisation. Associated pelvic procedures (if applicable): unilateral or bilateral uterosacral ligament resection, ureterolysis, parametrial excision, colorectal shaving, disc or segmental resection, colpectomy, other digestive resections (small bowel, appendix, wedge or ileocecal resection), resection around sacral roots; rASRM score and stage, #ENZIAN and EFI. Intraoperative complications: ureteral, bladder or bowel injury; intraoperative bleeding requiring transfusion; conversion to laparotomy or laparoscopic failure. Preoperative AMH level (ng/mL) and date of test (within 12 months prior to surgery). Postoperative Visit (Month one to Month three). Date of the visit. Postoperative complications: haematoma, fever, urinary tract infection, bladder dysfunction (need for self-catheterisation and duration), pelvic abscess, urogenital or enterogenital fistula, patient-reported dizziness, vaginal suture dehiscence, digestive suture dehiscence, hemoperitoneum due to ovarian bleeding, others; classified using the Clavien-Dindo system (Grade I to V). Hospital readmission within 30 days postdischarge: reason (complication, reoperation), dates of readmission and discharge. Visual Analogue Scale for pain (0 to 10). A remote consultation with the surgeon will be conducted 24 months after surgery. The following data will be collected: Date of the visit. Pregnancy status: occurrence (yes/no) and number of pregnancies. For each pregnancy: Mode of conception: spontaneous or medically assisted reproduction (stimulation, insemination, IVF, ICSI, oocyte donation), with number of procedures. Date of pregnancy onset. Date of ultrasound confirming an ongoing intrauterine pregnancy. Multiple pregnancy (yes/no). End of pregnancy: date and outcome (vaginal delivery, caesarean section, pregnancy loss, late miscarriage >14 weeks of gestation), or ongoing pregnancy. Clinical symptoms: dysmenorrhoea, dyspareunia, pelvic pain, menorrhagia, urinary symptoms, pelvic heaviness or other. Pain assessment: Biberoglu and Behrman score, and numeric pain rating scale (0 to 10). Postoperative imaging: performed (yes/no), type (MRI, ultrasound and other), date, presence of endometrioma (number, laterality and size) and associated endometriotic lesions. Postoperative AMH test (if performed): date and value (ng/mL). Any surgical procedure performed during the follow-up period, regardless of indication (eg, endometriosis recurrence, intrauterine procedures or other gynaecologic surgery) and technique used in case of endometrioma management (plasma energy, sclerotherapy, laser, cystectomy, fenestration, oophorectomy or other [ figure 1 ]). Study data will be collected using a dedicated eCRF created for each participant. The eCRF will be implemented within the secure platform Dotter.science, in accordance with Good Clinical Practice (GCP) and regulatory requirements. All information required by the protocol will be entered into the eCRF to ensure compliance with the study design and facilitate statistical analyses. The eCRF will also enable identification of any major protocol deviations. Each participant will be assigned a unique identification number automatically generated by Dotter.science, followed by the first letter of the patient’s first and last names. This pseudonymised identifier will be the only one appearing in the eCRF and will allow data to be linked back to the patient when required. A correspondence table linking these IDs to personal identifying information will be securely maintained by the principal investigator at the study site, in a locked and access-restricted location. No clinical data will be stored in this correspondence table. Study data will be entered by designated research team members (investigator, clinical research associate or study nurse), as defined in the site’s delegation log. All source data (eg, imaging reports, lab results) will be coded in accordance with the assigned study ID before inclusion in the eCRF. All data will be pseudonymised prior to any statistical analysis or dissemination. No direct identifying information (eg, full names, addresses) will appear in the research dataset. Data will be handled in full compliance with the General Data Protection Regulation (GDPR) and the French Data Protection Act. The study complies with the CNIL’s “Méthodologie de Référence MR-001” under registration number 2237821 for Clinique Tivoli Ducos. The data controller is Dr Adrien Crestani (IFEM Endo, Clinique Tivoli-Ducos). Access to study data will be limited to authorised study personnel, including the research team, clinical staff, the study statistician and the data manager. On completion of the study, pseudonymised data may be shared in accordance with International Committee of Medical Journal Editors (ICMJE) data-sharing recommendations, subject to approval by the funding body and the appropriate data protection authorities. Data sharing will require a valid research proposal, and external parties must agree to cover any associated transfer or management costs. All analyses will be conducted according to the intention-to-treat principle. If statistically significant differences are observed between groups following randomisation, adjusted analyses will be performed. Continuous variables with a normal distribution will be presented as means with SD and compared using Student’s t-test or analysis of variance (ANOVA). Non-normally distributed continuous variables will be presented as medians with interquartile ranges (Q1–Q3) and compared using the Kruskal–Wallis test. Categorical variables will be presented as proportions and compared using the χ 2 test or Fisher’s exact test, as appropriate. Time to pregnancy will be estimated using Kaplan–Meier survival curves. For the primary endpoint, the cumulative pregnancy rate at 24 months will be calculated with a 95% CI. The effects of different covariates on pregnancy onset over time will be assessed using Cox proportional hazards models, with corresponding 95% CIs. Exploratory adjusted models will include clinically relevant factors such as age, body mass index, smoking status, endometriosis severity (rASRM, #ENZIAN, associated surgical procedures, …) EFI, prior medically assisted reproduction, when available , any documented male factor infertility derived from semen analysis results. No interim analysis is planned. A two-sided p value <0.05 will be considered statistically significant. All statistical analyses will be performed using STATA (College Station, TX, USA, v.19.0) and R (RStudio Team, 2020. RStudio: Integrated Development for R . RStudio, PBC, Boston, MA. URL: http://www.rstudio.com ).

This study protocol describes a pragmatic RCT comparing cystectomy and plasma vapourisation for ovarian endometriomas in women undergoing surgery for endometriosis, with a parallel observational cohort evaluating sclerotherapy for larger cysts. The assumed 15% absolute difference in cumulative pregnancy rate at 24 months was selected as a clinically meaningful and plausible effect size, based on the existing literature and our previously published data. Although this assumption may appear ambitious, it remains within the range of effect sizes reported across heterogeneous studies and reflects a difference that would be relevant for clinical decision-making. We acknowledge that this population is characterised by substantial heterogeneity in fertility-related clinical contexts, including postoperative fertility pathways, male factor infertility, tubal status and associated endometriosis procedures. While no clear biological rationale suggests that surgical technique should directly determine subsequent fertility strategies, randomisation is expected to balance known and unknown confounders between groups. Blinding was not feasible due to the nature of the surgical interventions, as cystectomy carries a specific risk of early postoperative ovarian bleeding requiring tailored immediate postoperative monitoring for patient safety. This may influence counselling or patient expectations and thus affect fertility management trajectories. For this reason, fertility treatments and relevant reproductive covariates will be systematically documented and considered in exploratory analyses, and any differences will be interpreted cautiously. Overall, this protocol aims to combine methodological rigour with real-world clinical practice to generate evidence applicable to women undergoing surgery for endometriosis-associated endometriomas.

To compare pregnancy rates within 24 months following surgical treatment of ovarian endometrioma. The primary outcome of the study is the pregnancy rate observed 24 months after treatment of the endometrioma. Pregnancy will be defined by either a β-hCG level >1000 IU or the presence of an ongoing intrauterine pregnancy confirmed by ultrasound after 5 weeks’ gestational age. To compare live birth rates (LBRs), spontaneous pregnancy rates, assisted reproductive technology (ART) pregnancy rates and rate of ongoing pregnancies beyond 12 weeks’ gestational age within 24 months following surgical treatment of ovarian endometrioma. To compare recurrence rate. To measure and compare complication rate. To evaluate postoperative pain scores using the Biberoglu and Behrman scale (>4 considered clinically significant). LBR within 24 months following treatment; Rate of spontaneous pregnancies. Rate of pregnancies achieved through ART. Rate of ongoing pregnancies beyond 12 weeks’ gestational age Recurrence: Symptoms: pain score >4 on the Biberoglu and Behrman scale. Imaging: ultrasound or MRI showing an endometrioma >2 cm on the treated or contralateral ovary (if imaging has been performed and shared by the patient). Intraoperative complications: bleeding, operative time. Postoperative complications according to the Clavien-Dindo classification. Postoperative pain scores.