LLETZ-IOLI: Large Loop Excision of the Transformation Zone (LLETZ) With vs Without IntraOperative Application of Lugol's Iodine

Sponsor

Ruhr University of Bochum (Other)

Overall Status

Recruiting

CT.gov ID

NCT05132114

Collaborator

(none)

216

Enrollment

Location

Arms

24.5

Anticipated Duration (Months)

8.8

Patients Per Site Per Month

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 gynecologist's preventive smear test 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, if necessary, surgically removed. Conization (= surgical removal of a cone of tissue from the cervix) is the method of choice for removing the diseased tissue. LLETZ conization (Large Loop Excision of the Transformation Zone) is the worldwide standard surgical procedure for conization. There is risk of local persistence of the precancerous lesion if the cervical dysplasia is not completely removed. To minimize this, the iodine test can be used. Here, a 5% iodine solution (so-called Lugol's solution) is dabbed onto the cervix uteri, resulting in an intense and characteristic brown staining of the healthy cervical epithelium. Sites without staining are termed iodine negative and may contain dysplastic cells. The strength of iodine testing lies in its high specificity, i.e., the reliable ability to exclude false-positive results. The purpose of intraoperative iodine staining is to select the resection line with a high degree of certainty in healthy (i.e., iodine-positive) tissue in order to reduce the rate of cervical dysplasia that is not completely removed (so-called non-in-sano resection, or R1 resection). Systematic survey data from the dysplasia units certified in Germany on the question of the use of intraoperative iodine testing in Germany are lacking, as is the literature as a whole. For example, the current S3 guideline of the German Society of Gynecology and Obstetrics on the diagnosis and treatment of cervical dysplasia (as of March 2020) names intraoperative iodine testing only as a possible option for performing LLETZ.

In this prospective, randomized study, the investigators aim to answer the question whether LLETZ performed with the help of an iodine test with selection of the resection line in the iodine-positive area leads to a lower rate of R1 resections compared to the standard LLETZ without iodine test.

Condition or Disease	Intervention/Treatment	Phase
Cervical Dysplasia	Diagnostic Test: Lugol's iodine test	N/A

Detailed Description

Background 1.1. HPV and dysplasias of the cervix uteri 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) annually.

1.2. 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. Worldwide standard as surgical procedure for conization is LLETZ-conization (Large Loop Excision of the Transformation Zone). In addition to the risk of local persistence of the precancerous lesion if the cervical dysplasia is incompletely removed, LLETZ also increases the risk of preterm birth in a 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. One method of LLETZ that is as tissue-conserving as possible is the intraoperative use of the so-called 'iodine test'.

1.3. The iodine test For the identification of healthy squamous epithelium of the cervix uteri, the so-called Schiller's iodine test can be used, which has been part of the clinical routine in the context of colposcopy of cervical dysplasias for decades. In the iodine test, a 5% iodine solution (so-called Lugol's solution) is dabbed onto the cervix uteri, resulting in an intense and characteristic brown staining of the healthy cervical epithelium. Sites without staining are termed iodine negative and may contain dysplastic cells. The strength of iodine testing lies in its high specificity, i.e., the reliable ability to exclude false-positive results. Not all iodine-negative areas contain CIN, but iodine-positive areas are almost certainly healthy. In some centers, because of these characteristics of the iodine sample, it is used during LLETZ to define the resection line of LLETZ. The aim of this approach is to select the resection line with a high degree of certainty in healthy (i.e., iodine-positive) tissue in order to reduce the rate of cervical dysplasia that is not completely removed (so-called 'non-in-sano resection' or 'R1 resection'). Systematic survey data from the dysplasia units certified in Germany on the question of the use of intraoperative iodine testing in Germany are lacking. The current S3 guideline of the German Society of Gynecology and Obstetrics on the diagnosis and therapy of cervical dysplasia (as of March 2020) also refers to intraoperative iodine testing as a possible option for performing LLETZ. However, exact figures from controlled studies on the usefulness of iodine test-guided LLETZ are lacking in the literature (PubMed search on 10/15/2021; search terms: cervical dysplasia, colposcopy, Lugol's test, iodine test, Lugol's staining; LLETZ; LEEP; conization). At our certified dysplasia center, it is the decision of the respective surgeon whether an additional intraoperative iodine test is performed or not.

Aim of the study The aim of this study is to answer the question under prospective randomized conditions whether LLETZ performed with the aid of iodine assay with selection of the resection line in the iodine-positive region leads to a lower rate of R1 resections compared with standard LLETZ without iodine assay.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

216 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Prospective randomized trial with 2 groups (use vs not use of Lugol's iodine during LLETZ)Prospective randomized trial with 2 groups (use vs not use of Lugol's iodine during LLETZ)

Masking:

Single (Participant)

Masking Description:

Participants are not aware of their treatment allocation in order not to influence patient reported outcomes

Primary Purpose:

Treatment

Official Title:

Large Loop Excision of the Transformation Zone (LLETZ) With Versus Without Intraoperative Application of Lugol's Iodine in Women With Cervical Dysplasia: a Prospective Randomized Trial

Actual Study Start Date :

Jan 17, 2022

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Feb 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Control Group LLETZ (without intraoperative Lugol's iodine)
Experimental: Iodine group LLETZ after the intraoperative application of Lugol's iodine	Diagnostic Test: Lugol's iodine test Intraoperative application of Lugol's iodine (i.e. staining of the cervix with Lugol's iodine solution)

Arm

Intervention/Treatment

No Intervention: Control Group

LLETZ (without intraoperative Lugol's iodine)

Experimental: Iodine group

LLETZ after the intraoperative application of Lugol's iodine

Diagnostic Test: Lugol's iodine test

Intraoperative application of Lugol's iodine (i.e. staining of the cervix with Lugol's iodine solution)

Outcome Measures

Primary Outcome Measures

Rate of R1 resections [Specimen from surgery (result expected 1-2 days after surgery)]
The primary outcome parameter is the rate of R1 resections, defined as the presence of a CIN I, CIN II, or CIN III at the ectocervical and/or endocervical resection margin, as indicated in the histopathologic report.

Secondary Outcome Measures

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)
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
Surgeon's rating of handling [Immediately after surgery]
The assessment of the surgeon's handling of the surgical technique (LLETZ with/without intraoperative iodine assay) (11-item numerical rating scale [NRS]; 0 = very cumbersome, 10 = very easy)
Surgeon's satisfaction [Immediately after surgery]
The surgeon's satisfaction with the course of the operation in general (11-item NRS; 0 = no satisfied at all, 10 = very satisfied)
Time to complete hemostasis [During surgery]
The time from start of electro-coagulation until complete hemostasis (seconds)
Blood loss [At surgery]
The intraoperative blood loss (measured as the difference between preoperative and 3-5 hours postoperative Hb levels).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Written consent
Colposcopy performed preoperatively
Histologically (by previously performed colposcopy) confirmed dysplasia (CIN 1, CIN 2 or CIN 3)
Age >18 years