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

Studien-Informationen Einschlusskriterien Studien-Rationale Studien-Arme Geprüfte Regime

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NCT-Nummer:
NCT05391243

Studienbeginn:
Mai 2024

Letztes Update:
26.04.2024

Wirkstoff:
-

Indikation (Clinical Trials):
Uterine Cervical Dysplasia

Geschlecht:
Frauen

Altersgruppe:
Erwachsene (18+)

Phase:
-

Sponsor:
Ruhr University of Bochum

Collaborator:
-

Studienleiter

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

Kontakt

Clemens B. Tempfer, MD, MBA
Kontakt:
Phone: +492323499
Phone (ext.): 1801
E-Mail: clemens.tempfer@rub.de» Kontaktdaten anzeigen

Studienlocations
(1 von 1)

Gynäkologisches Krebszentrum der Ruhruniversität Bochum am Marien Hospital Herne
Hölkeskampring 40
44625 Herne
Deutschland» Google-Maps
Ansprechpartner:
Clemens B Tempfer, MD» Ansprechpartner anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

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

Exclusion Criteria:

- Pregnant patients

- Patients with insufficient knowledge of the German language

- Pre-existing oncological diseases

- Blood coagulation disorders

- Taking blood thinning substances

- Use of a hormonal intrauterine device (e.g. Mirena);

- Use of a progesterone pill or progesterone injectate;

- Use of long cycle contraceptive (no monthly bleeding).

Studien-Rationale

Primary outcome:

1. Intraoperative blood loss (weight) (Time Frame - During surgery):
The intraoperative blood loss, measured by the net-weight (in grams) of the surgical swabs used for hemostasis

Secondary outcome:

1. Intraoperative blood loss (Hb) (Time Frame - Day of surgery):
The intraoperative blood loss, assessed through the difference between the Hb values measured preoperatively and 2 hours postoperatively, respectively.

2. Intraoperative blood loss (subjective) (Time Frame - 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).

3. Postoperative bleeding (subjective) (Time Frame - 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]).

4. Postoperative bleeding (days) (Time Frame - Interview 14 days after surgery):
The number of postoperative days where bleeding occurred

5. Patient's anxiety (Time Frame - 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).

6. 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

7. Cone mass (Time Frame - During surgery, immediately after the excision):
The weight of the cone specimen (measured in grams in the unfixed state)

8. Procedure duration (Time Frame - At surgery):
Duration of the procedure (from start until complete hemostasis is achieved)

9. Patient satisfaction (Time Frame - At discharge and 14 days after surgery):
Overall patient satisfaction (11-item numerical rating scale).

Studien-Arme

Other: Follicular phase
LLETZ performed during the follicular phase of the menstrual cycle
Other: Luteal phase
LLETZ performed during the luteal phase of the menstrual cycle

Geprüfte Regime

LLETZ (LEEP / conization / ):
Large loop excision of the transformation zone

Quelle: ClinicalTrials.gov

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