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

April 25, 2024 updated by: Clemens Tempfer, Ruhr University of Bochum

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

  1. 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.

  2. 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 Type

Interventional

Enrollment (Estimated)

216

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Germany
    • NRW
      • Herne, NRW, Germany, 44625
        • Recruiting
        • Marien Hospital Herne
        • Contact:
          • Clemens B Tempfer, MD, MBA

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

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

Exclusion Criteria:

  • Pregnant patients
  • Patients with insufficient knowledge of the German language
  • Treatments already performed on the cervix uteri, in particular conization
  • Blood coagulation disorders
  • Taking blood thinning substances
  • Iodine allergy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of R1 resections
Time Frame: 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.
Specimen from surgery (result expected 1-2 days after surgery)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of complications
Time Frame: During surgery up to 14 days post surgery
The occurring intra- and postoperative complications in a period within 14 days after surgery
During surgery up to 14 days post surgery
Cone mass
Time Frame: During surgery, immediately after the excision
The weight of the cone specimen (measured in grams in the unfixed state)
During surgery, immediately after the excision
Procedure duration
Time Frame: At surgery
Duration of the procedure (from start until complete hemostasis is achieved)
At surgery
Surgeon's rating of handling
Time Frame: 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)
Immediately after surgery
Surgeon's satisfaction
Time Frame: 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)
Immediately after surgery
Time to complete hemostasis
Time Frame: During surgery
The time from start of electro-coagulation until complete hemostasis (seconds)
During surgery
Blood loss
Time Frame: At surgery
The intraoperative blood loss (measured as the difference between preoperative and 3-5 hours postoperative Hb levels).
At surgery

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ruhr University of Bochum

Investigators

  • Principal Investigator: Clemens B Tempfer, MD, MBA, Ruhr-Universität Bochum / Marien Hospital Herne

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 17, 2022

Primary Completion (Estimated)

July 1, 2024

Study Completion (Estimated)

October 1, 2024

Study Registration Dates

First Submitted

November 11, 2021

First Submitted That Met QC Criteria

November 22, 2021

First Posted (Actual)

November 24, 2021

Study Record Updates

Last Update Posted (Actual)

April 26, 2024

Last Update Submitted That Met QC Criteria

April 25, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • LLETZ-IOLI-1

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Data will be shared upon reasonable request made to the corresponding author. This includes individual participant data underlying the results presented here, after deidentification, as well as data dictionaries and the the study protocol. Data is available after publication, without a specific end date. Requesting investigators must show that their proposed use of the data has been approved by an independent review committee identified for this purpose.

IPD Sharing Time Frame

After publication of the study results, no time limit.

IPD Sharing Access Criteria

Reasonable request, approval of the intended study by an independent review committee identified for this purpose.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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