Clinical trial NCT05242276: Uterine Manipulator in Endometrial Cancer Surgery: Pro MUCEI Study
Official title: A Prospective Study of the Impact of Uterine Manipulator on Oncological Outcome in Endometrial Cancer Surgery in Early-stage: Pro MUCEI Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Endometrial Cancer
Keywords: endometrial cancer
uterine manipulator
Lead sponsor: Instituto de Investigacion Sanitaria La Fe
Sponsor class: OTHER
First posted: 2022-02-16
Enrollment: 1200
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All patients older than 18 years undergoing surgery in an apparently early stage of endometrial cancer proposed by FIGO: total hysterectomy with double adnexectomy and evaluation of the lymph node status following recommendations for surgical staging by FIGO. Follow-up prospectively, gathering the necessary information already described in the previous sections.

Brief summary: The uterine manipulator is a device commonly used in minimally invasive hysterectomy surgery for endometrial cancer. However, without substantial evidence to support its use, surgeons are required to make decisions about its use based only on their personal choice and surgical experience.

A retrospective study demonstrated how uterine manipulator use in early-stage endometrial cancer (FIGO I-II) for minimally invasive surgery was associated with a worse oncologic outcome in patients with uterus-confined endometrial cancer (FIGO I-II) who underwent minimally invasive surgery.

The main objective of this study is to prospectively confirm the results obtained retrospectively, assessing the relapse rate in these patients related to the use or not of a uterine manipulator during the endometrial surgery. Secondary, the presence of risk factors that contraindicate the use of the uterine manipulator will also be evaluated.

Detailed description: The primary treatment for early-stage endometrial cancer is surgery, performing a total hysterectomy and bilateral salpingo-oophorectomy with surgical staging if it is indicated.1 The National Comprehensive Cancer Network and European Society of Gynaecological Oncology Consensus recommend minimally invasive approaches (laparoscopic/robotic) in patients with disease limited to the uterus, according to evidence reported from randomized prospective studies (GOG-LAP2 trial).2 This approach leads to lower operative morbidity and a shorter hospital stay compared to open surgery, without compromising oncologic outcomes.3 The uterine manipulator is a device commonly used in minimally invasive gynecologic hysterectomy for benign disease. It is inserted vaginally through the cervical canal into the endometrial cavity. It facilitates the uterus mobilization during the surgery, generating tension on the main supporting elements of the uterus to improve surgical field exposure and provide a landmark for the colpotomy.4

With the introduction of minimally invasive approaches in gynecological oncology treatments, this uterine device has been utilized for endometrial and cervical cancers, with controversy regarding its influence on the spread of tumoral cells and the risk of recurrence. Recently, the LACC trial showed a worse than expected oncological outcome after a laparoscopic/robotic approach in early stage cervical cancer.5 One of the hypotheses generated was that the uterine manipulator might influence this worse prognosis.6 The retrospective European Succor study found the use of a manipulator was associated with a decrease in disease-free survival in cervical cancer in the minimally invasive group.7 Therefore, there are reasonable doubts about the uterine manipulator's safety in hysterectomy performed due to cancer.

In endometrial cancer, the presence of the uterine device in a cavity lined with neoplastic tissue leads to a potential tumor-manipulator interaction. Multiple mechanisms are potentially involved in this relationship but are poorly understood, however, the concept of uterus-confined disease is important to evaluate these interactions.8 Nonetheless, we have limited evidence from retrospectives studies about the uterine manipulator in endometrial cancer surgery, in which no impact of the uterine manipulator's use on oncological outcome has been found.9-12 To date, it remains a controversial conclusion that the theoretical tumor manipulation has no clear impact on oncological prognosis in endometrial cancer.

As is already known in other gynecological tumors (such as early-stage epithelial ovarian cancer or morcellation in unexpected uterine sarcoma), when the confined disease is exposed to the peritoneal cavity, the oncological outcome worsens.29 Therefore, the concept of organ-confined disease is an essential idea to understand our results. In early-stage endometrial cancer, the myometrium acts as a containment barrier, which may be iatrogenically injured by the uterine manipulator.

The MUCEI study by Padilla et al. suggests that the use of a uterine manipulator is associated with worse oncological outcomes in patients with uterus-confined endometrial cancer (FIGO I-II) at the time of surgery; it also presented a lower recurrence-free survival and lower overall survival, regardless of the type of manipulator with no differences in the pattern of recurrence.

The study observed a worse prognosis when the uterine manipulator was used in patients with the uterine-confined disease (FIGO I-II), not present in those patients with the no-confined disease (FIGO III) at the time of surgery. These results support the concept that the uterine manipulator might act in breaking the uterine-confined disease and worsen the oncological outcomes.

The different potential interferences may explain the alteration of the myometrial barrier by the uterine device. Therefore, two hypotheses are presented to explain this relationship between the uterine manipulator and endometrial cancer.

The first is the macroscopic injury hypothesis. During the insertion of any uterine manipulator (with or without balloon) and its use (especially in the atrophic uterus), the manipulator´s shank may weaken the myometrium, iatrogenically leading to uterine rupture and the opening of the tumor to the peritoneal cavity and surgical field.30,31 The uterine rupture is rarely reflected in surgical reports, and it has not been considered in previous analyses. Machida et al. showed a 0.4-1% perforation rate with a balloon manipulator,32 thus, other factors could be involved.

The second hypothesis is the microscopical pathway of dissemination. The uterine device generates a significant increase in pressure inside the endometrial cavity, generating global distension according to Pascal´s principle, which is additionally increased by the maintained push needed during uterine mobilization and colpotomy.33 This increased pressure might be involved in the improved ability of tumor cells to exceed the myometrial barrier, spreading outside the uterus cavity by a passive effect through the fallopian tubes and lymphovascular space.34

Methodology Prospective and non-randomized multicenter descriptive and analytical study in which the characteristics of the patients, the details associated with the surgery, and the oncological results will be studied depending on the use or not of the uterine manipulator.

The non-randomization is due to the fact that the procedure to be evaluated is surgeon-dependent, so the criteria for the use of the uterine manipulator or not will depend on the surgeon according to the protocol of his center. In other words, inclusion in the study does not modify the surgical practice in the patient.

Inclusion criteria include women with endometrial cancer diagnosed with stage I-II in a previous pre-surgical biopsy, the surgery has been performed and there are complete data on surgery, pathological anatomy, and follow-up.

Exclusion criteria include any patient with suspected disease beyond the uterus in the preoperative assessment or confirmed during surgical exploration. Cases without pathological confirmation of endometrial cancer in the final surgical specimen, or final histology of atypical hyperplasia/endometrial intraepithelial neoplasia will not be accepted.

Patients with open surgery, conversion to laparotomy, or vaginal hysterectomy alone will also be excluded.

The surgical variables collected will be: use of uterine manipulator (the type of uterine manipulator and classification of subtypes with or without intrauterine balloon), sealing of the fallopian tubes, surgical staging, intraoperative complications, surgical time and hospital stay. Collection of postoperative complications by Clavien-Dindo Classification. The final histological data of the surgery will be collected according to the type and grade of the tumor according to the WHO classification, the invasion of the myometrium, the presence of invasion of the lymphovascular space, sentinel (+/- ultrastaging) and the number of pelvic lymph nodes. and para-aortic. The Bokhman dual classification of endometrial cancer will be used. and tumors were classified by FIGO staging. Finally, data on adjuvant treatment (vaginal brachytherapy, external beam radiation (ERBT), and chemotherapy scheme), follow-up time, relapse time, and type and pattern of relapse.

Eligibility criteria: Inclusion Criteria:

1. - Women with endometrial cancer diagnosed with stage I-II.
2. - Previous pre-surgical biopsy with a diagnosis of endometrial cancer.
3. - The surgery has been performed and there are complete data on surgery, pathological anatomy, and follow-up of at least 2 years.

Exclusion Criteria:

* Any patient with suspected disease beyond the uterus in the preoperative assessment or confirmed during surgical exploration. Cases without pathological confirmation of endometrial cancer in the final surgical specimen or final histology of atypical hyperplasia/endometrial intraepithelial neoplasia will not be accepted.

Patients with open surgery, conversion to laparotomy, or vaginal hysterectomy alone will also be excluded.

Primary outcomes:
measure: Relapse rate
timeFrame: 2 years
Secondary outcomes:
measure: Other oncological outcomes
timeFrame: 3 years
measure: Relapse pattern
timeFrame: 3 years
measure: Surgical specimen variables
timeFrame: 1 year
measure: Treatment data
timeFrame: 1 year
measure: Pathology data
timeFrame: 1 year
measure: Recurrence treatment
timeFrame: 3 years
measure: complications
timeFrame: 1 year
Other outcomes:
Locations:
city: Valencia
country: Spain
facility: Hospital universitario y politécnico La Fe
Study officials:
affiliation: Hospital Universitario La Fe
name: Pablo Padilla iserte, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Padilla-Iserte P, Lago V, Tauste C, Diaz-Feijoo B, Gil-Moreno A, Oliver R, Coronado P, Martin-Salamanca MB, Pantoja-Garrido M, Marcos-Sanmartin J, Gilabert-Estelles J, Lorenzo C, Cazorla E, Roldan-Rivas F, Rodriguez-Hernandez JR, Sanchez L, Muruzabal JC, Hervas D, Domingo S; Spanish Society of Gynecology and Obstetrics Spanish Investigational Network Gynecologic Oncology Group. Impact of uterine manipulator on oncological outcome in endometrial cancer surgery. Am J Obstet Gynecol. 2021 Jan;224(1):65.e1-65.e11. doi: 10.1016/j.ajog.2020.07.025. Epub 2020 Jul 18.