Laparoscopic advanced Imaging Techniques in Endometriosis therapy: the LITE study. A pilot trial.

Endometriosis is a benign, chronic, estrogen-dependent gynaecological disorder.
It is defined as the presence of endometrial glands and stroma outside the
uterine cavity, which induces a chronic, inflammatory reaction. It*s an
established cause of infertility and causes dysmenorrhea, dyspareunia and
pelvic pain. The prevalence in the general population is not known and
difficult to determine because of the variety in symptoms. Estimates range from
2 to 10% of women in reproductive age, and up to 50% in subfertile women and
symptomatic patients. Despite it*s proven efficacy, recurrence after surgery
remains a major challenge and a crucial issue in the long-term management of
endometriosis. Evers et al. argue that 10% of patients redeveloped signs and
symptoms of endometriosis after a 1-year follow-up period, 25% after 3 years,
and 45% after 5 years. Guo et al calculated that the disease relapse rate is
>20% at 2 years and 40 to 50% at 5 years. Even in young women <=21 years of age,
the 5-year recurrence rate was as high as 56%, irrespectively of site and stage
of endometriosis. The need for hospital admission for endometriosis within four
years after surgery for additional surgical treatment is 27% and reoperation
occurs in more than 50% of the patients with endometriosis, where about 27%
needs three or more surgeries. As repeated surgery is associated with an
increase in health care costs, morbidity and damage to ovarian reserve, the
need for radical resection during primary surgery is underlined.

During laparoscopy, peritoneal endometriosis micro lesions can be hard to
distinguish from normal tissue and not all endometriosis lesions are
macroscopically identified, resulting in incomplete relief of pain after
surgery. Macroscopic identification of endometriosis lesions is currently poor,
with histological examination having a positive predictive value of 66% for
suspected lesions in laparoscopy. Because of the polymorphic appearance of
endometriosis lesions, they can be mistaken easily for other structures such as
adhesions and (post)inflammatory and changes. The American Society for
Reproductive Medicine classification distinguishes among red, white, and black
superficial implant types. In particular, the appearance of red and white
superficial implant types can vary widely. In the literature, red and white
endometriosis lesions frequently are subsumed as *nonpigmented* as opposed to
black *pigmented* lesions. Previous reports have shown that nonpigmented areas
of endometriosis represent the active form of the disease.

To improve the detection of peritoneal lesions of endometriosis by laparoscopy
and accomplice a more complete resection. We will conduct this trial to
investigate which advanced imaging technique, narrow-band imaging (NBI),
three-dimensional laparoscopy (3D) or near-infrared imaging with fluorescent
Indocyanin Green (ICG) is the most accurate to visualize endometriosis lesions
and which technique shows more endometriosis lesions.

Secondarily we will also investigate operating time, blood loss, usability,
direct costs and safety of the different modalities.

To determine which advanced image enhanced modality is the most feasible for
the detection of endometriosis lesions, with respect to the specificity and
sensitivity of the investigated modalities. To determine which imaging modality
reveals more endometriosis lesions compared to white light laparoscopy.

-3D: Drie-dimensionele imaging
-NBI: Narrow-band imaging
-NIR-ICG: Near-infrared imaging with Indocyanin Green

Prospective, phase-1 pilot (feasibility) trial.
We include 20 patients (see study population). In each of these patietns we
will, after introduction of the laparoscope and two assisting trocars, inspect
the pelvis with the following modalities: conventional white-light laparoscopy,
3D, NBI and NIR-ICG. Each region of the pelvis is inspected with every modality
in a systematically rotating different order. Images of suspected endometriosis
lesions are taken for each modality. After all lesions are photographed for
each modality, biopsies are taken of suspected endometriosis lesions. Biopsies
of healthy tissue will also be taken for negative control. After the procedure
the images are compared to the pathology results of the biopsies, thus
determining the sensitivity and specificity for each modality. Biopsies of
apparent endometriosis lesions is standard care for endometriosis therapy by
protocol.

The best imaging modality with best detection of endometriosis (higher
sensitivity when compared to white light laparoscopy, with comparable
specificity) will be investigated in a phase-3 randomised trial.

Participation in this study adds three extra proceedings:
1) the use of different imaging modalities may increase operating time and time
under narcosis.
2) possible adverse reaction to ICG, possible decrease in kidney and liver
function.
3) extra biopsies of unhealthy and healthy tissue will be taken.

Frequency/damage
The chance for damage as a result of this study is estimated at low risk. This
is because we have anticipated for the potential risks by excluding the
patients with kidney and/or liver function insufficiency and because patients
are intraoperatively monitored by the anaesthesiologist for possible adverse
effects.

Known risk
1) Extra operating time results in extra time under narcosis.
- The damage caused by this is negligible for our study population (young
relatively healthy females, ASA < 3)

2) In 1 out of every 10.000 patients and anaphylactic or urticarial reaction
can occur as a result of intravenous ICG injection.
- The damage caused by this adverse event is moderate and reversible.
- If an anaphylactic reaction occurs, the anaesthesiologist can anticipate by
following a checklist in the SPC.
- Patients with an Iodine allergy (who are more susciptable for anaphylactic
reaction) are excluded.

3) Bleeding can occur as a result of biopsies.
- The damage caused by this advert event is light and reversible.
- Any bleedings can be coagulated by the operating physician.
- No biopsies will be taken from regions with increased risk of bleeding or
perforation of the organ (e.g. intestines and ovaries)

No additional physical, psychological or social burdening is caused by this
study for the study subjects.