Large Loop Excision of the Transformation Zone During Follicular vs. Luteal Phase of the Menstrual Cycle (LLETZ-MC)

Sponsor

Ruhr University of Bochum (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05391243

Collaborator

(none)

152

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

Cervical cancer is one of the most common cancers in women and one of the leading causes of death in women worldwide. Pre-cancerous lesions (dysplasias) are detected by the preventive smear test at the gynecologist and can thus contribute to a 100% chance of cure if they are clarified by a colposcopic examination as part of the dysplasia consultation and dysplastic lesions are then surgically removed if necessary (conization).

There are few data in the literature on the influence of the menstrual cycle on the bleeding pattern during and after conization. Hormonal variations during the menstrual cycle affect both the extent of blood flow to reproductive organs and hemostasis. In the follicular phase, there is a decrease in local blood flow in the uterus and pelvic organs and an increase in coagulability. Conversely, in the luteal phase there is an increase in local blood supply and a decrease in coagulability. Therefore, it seems reasonable to perform conization in the follicular phase to possibly reduce the extent and incidence of bleeding and bleeding complications. This assumption is supported by clinical observations. For example, there is evidence from other specialties that selection of the timing of surgery, taking into account the menstrual phase, may influence the risk of bleeding. Another factor of interest in menstruation-based surgical planning is psychological vulnerability, which may also vary with the menstrual cycle. Until now, consideration of the menstrual cycle in surgical planning for conization has not been standard practice and there is no recommendation in this regard in the current S3 guideline of the German Society of Gynecology and Obstetrics.

Therefore, this study now aims to answer the question under prospective randomized conditions whether LLETZ conization performed during the follicular phase results in lower blood loss and higher patient satisfaction and lower anxiety scores compared to LLETZ conization performed during the luteal phase.

Condition or Disease	Intervention/Treatment	Phase
Cervical Dysplasia	Procedure: LLETZ	N/A

Detailed Description

HPV and dysplasia of the uterine cervix

Human papillomaviruses (HPV) are the most common sexually transmitted pathogens worldwide. The prevalence in both male and female populations is high. Epidemiological estimates suggest that 85-91% of sexually active adults acquire at least one genital HPV infection by the age of 50, with approximately 95% of HPV infections being spontaneously eliminated within 2 years in terms of HPV immunological clearance. HPV preferentially infects the epithelial cells of the anogenital area and, through incorporation of HPV DNA into the host genome of the basal cells of the squamous epithelium of the cervix and subsequent expression of viral components, causes dysplastic changes in the cervical epithelium that, if left untreated, can develop into invasive carcinoma of the cervix (cervical carcinoma). Cervical carcinoma is the fourth most common cancer as well as the fourth leading cause of cancer-related death in women worldwide, responsible for 6.6% (570,000) of all new cancer cases and 7.5% (311,000) of cancer-related deaths in women in 2018. The precursor of squamous cell carcinoma of the uterine cervix (approximately 80% of all cervical cancers) is cervical intraepithelial neoplasia (CIN), which has three grades of expression (CIN1, CIN 2, and CIN 3). Compared with invasive cervical carcinoma, the incidence of precancerous lesions of the cervix uteri is much higher. It is estimated that approximately 100,000 women in Germany develop high-grade dysplasia (CIN2/CIN3) each year.

Therapy of cervical dysplasia

Dysplasia of the cervix is typically detected during the gynecological screening examination at the gynecologist. Smears are taken from the ectocervix and endocervix and cytologically evaluated for dysplastic cells and smear quality after Papanicolaou staining. For further clarification of dysplastic changes, presentation to a specialized dysplasia consultation is recommended in the case of abnormalities with suspected presence of cervical dysplasia. Histological confirmation of abnormal areas is performed during colposcopic examination. The histopathological processing of the tissue samples and the colposcopic image of the spread of the changes in the cervix then allow individualized therapy planning.

Conization as the standard of surgical treatment

If precancerous lesions with the potential to develop into an invasive cervical tumor are detected, conization (= surgical removal of a cone of tissue from the cervix) is the method of choice for removing the diseased tissue. The worldwide standard surgical procedure for conization is LLETZ conization (="Large Loop Excision of the Transformation Zone"). In addition to the risk of local persistence of precancerous lesions if cervical dysplasia is incompletely removed, LLETZ also increases the risk of preterm delivery in subsequent pregnancy. This risk increases with increasing volume of removed tissue. To reduce or avoid the aforementioned complications, conization should be performed under colposcopic vision and as little healthy cervical tissue as possible should be removed.

Influence of the menstrual cycle on the bleeding pattern during and after conization

Hormonal variations during the menstrual cycle influence both the extent of blood flow to reproductive organs and hemostasis. Concentrations of fibrinogen, von Willebrand factor antigen, and von Willebrand factor activity show significant menstrual cycle variations with maximum values during the luteal phase. In this sense, during the first cycle phase, the follicular phase, there is a decrease in local blood flow in the uterus and pelvic organs and an increase in coagulability. In contrast, in the second cycle phase, the luteal phase, there is a subsequent increase in local blood supply and a decrease in coagulability. Therefore, it seems reasonable to perform conization in the follicular phase to possibly reduce the extent and incidence of bleeding and bleeding complications. This assumption is supported by clinical observations. For example, there is evidence from other specialties that selecting the timing of surgery, taking into account the menstrual phase, may influence the risk of bleeding. In two non-controlled, retrospective studies of patients undergoing mammary reduction surgery and rhinoplasty, the magnitude of intraoperative and postoperative blood loss was lower during the follicular phase than during the luteal phase. In addition, a small randomized trial of 73 patients undergoing cervical uterine surgery (loop electrosurgical excision procedure [LEEP]) found a demonstrable advantage in terms of intraoperative and postoperative blood loss when LEEP was performed during the follicular phase. Another factor of interest in menstruation-oriented surgical planning is psychological vulnerability, which also varies with the menstrual cycle. This factor, which is important for the extent of psychological stress and processing of surgery, also seems to be relevant in the context of conization. Thus, Paraskevaidis et al. were able to show in a randomized study that women who underwent LLETZ conization in the luteal phase had significantly higher anxiety scores and evaluated the surgery more negatively than women who underwent surgery during the follicular phase. This aspect also supports the usefulness of performing conization during the follicular phase. So far, consideration of the menstrual cycle in surgical planning of conization is not standard and there is no recommendation in this regard in the current S3 guideline of the German Society of Gynecology and Obstetrics (DGGG). To date, the selection of the appropriate time for surgery depends only on the patient's time preference and the availability of the surgical site.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

152 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Prospective randomized trial with 2 groups (follicular phase, luteal phase)Prospective randomized trial with 2 groups (follicular phase, luteal phase)

Masking:

Single (Care Provider)

Masking Description:

Surgeons will not be provided information about the menstrual cycle

Primary Purpose:

Treatment

Official Title:

Performance of Large Loop Excision of the Transformation Zone (LLETZ) in Women With Cervical Dysplasia in the Follicular Phase Versus the Luteal Phase of the Menstrual Cycle: a Prospective Randomized Trial

Anticipated Study Start Date :

Sep 1, 2022

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Mar 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Other: Follicular phase LLETZ performed during the follicular phase of the menstrual cycle	Procedure: LLETZ Large loop excision of the transformation zone Other Names: LEEP conization
Other: Luteal phase LLETZ performed during the luteal phase of the menstrual cycle	Procedure: LLETZ Large loop excision of the transformation zone Other Names: LEEP conization

Arm

Intervention/Treatment

Other: Follicular phase

LLETZ performed during the follicular phase of the menstrual cycle

Procedure: LLETZ

Large loop excision of the transformation zone

Other Names:

LEEP

conization

Other: Luteal phase

LLETZ performed during the luteal phase of the menstrual cycle

Procedure: LLETZ

Large loop excision of the transformation zone

Other Names:

LEEP

conization

Outcome Measures

Primary Outcome Measures

Intraoperative blood loss (weight) [During surgery]
The intraoperative blood loss, measured by the net-weight (in grams) of the surgical swabs used for hemostasis

Secondary Outcome Measures

Intraoperative blood loss (Hb) [Day of surgery]
The intraoperative blood loss, assessed through the difference between the Hb values measured preoperatively and 2 hours postoperatively, respectively.
Intraoperative blood loss (subjective) [Immediately after surgery]
The extent of intraoperative blood loss estimated by the surgeon (blinded to menstrual cycle phase) using a subjective categorization (mild, moderate, severe).
Postoperative bleeding (subjective) [Interview 14 days after surgery]
The extent of postoperative bleeding during the first 24 hours after surgery (assessed by the patient using an 11-item Numerical Rating Scale; 0 [minimal bleeding] - 10 [strong bleeding]).
Postoperative bleeding (days) [Interview 14 days after surgery]
The number of postoperative days where bleeding occurred
Patient's anxiety [On the day of surgery, before surgery]
The patient's anxiety level due to surgery as measured by the Spielberger State-Trait Anxiety Inventory (STAI, situational anxiety STAI-S, trait anxiety, STAI-T). Score range 20 to 80 points for each of the two parts of the test (a higher score means higher levels of anxiety).
Rate of complications [During surgery up to 14 days post surgery]
The occurring intra- and postoperative complications in a period within 14 days after surgery
Cone mass [During surgery, immediately after the excision]
The weight of the cone specimen (measured in grams in the unfixed state)
Procedure duration [At surgery]
Duration of the procedure (from start until complete hemostasis is achieved)
Patient satisfaction [At discharge and 14 days after surgery]
Overall patient satisfaction (11-item numerical rating scale).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Written consent
Regular menstrual cycle, defined as an interval between 21 and 35 days and a bleeding duration between 3 and 10 days during the last 3 months
Colposcopy performed preoperatively
Histologically (by previously performed colposcopy) confirmed dysplasia (CIN 1, CIN 2 or CIN 3)
Suspicion of low-grade or high-grade squamous intraepithelial lesion based on Papanicolaou smear with inconclusive colposcopy and need for surgical workup to exclude lesions
Age >18 years