Clinical trial NCT04577950: A Prospective Study Comparing Three Injection Sites to Detect Sentinel Lymph Nodes in Endometrial Cancer
Official title: A Prospective Phase 2 Study Comparing Three Injection Sites to Detect Sentinel Lymph Nodes in Endometrial Cancer: Comparison of Lymphatic Drainages and Location of the Sentinel Lymph Nodes Depending on the Injection Site of the Tracer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Endometrial Cancer
Keywords: Sentinel node
Endometrial carcinoma
Lymphatic drainage
Lead sponsor: Centre Hospitalier Universitaire Vaudois
Sponsor class: OTHER
First posted: 2020-10-08
Enrollment: 120
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: A prospective phase 2 study comparing three injection sites to detect sentinel lymph nodes in endometrial cancer.
Primary purpose: DIAGNOSTIC

Brief summary: Uterine cancer is the most common gynecologic malignancy in developed countries. Adenocarcinoma of the endometrium is the most common histologic type of uterine cancer. Endometrial cancer is the fifth most frequent cancer in women in Switzerland. The incidence rose up to 5.9% in 2015. This tumor affects mainly older women, at 63 years on average. The majority of women are diagnosed at an early stage. Seventy-five to 90% of the patients are alerted by abnormal uterine bleeding very quickly, which allows a quick management of care and a high survival rate.

Besides age, one of the main risk factor of developing an endometrial carcinoma is obesity. In fact, obese women have higher risk to have an endometrial cancer, but also at a younger age than the average and finally they have an increased risk of death due to this particular cancer. Although this cancer is linked to the co-morbidities that go with obesity like diabetes or hypertension.

The treatment of endometrial cancer in most women is surgery involving a total hysterectomy and a bilateral salpingo-oophorectomy with or without a lymph node dissection. For patients with early stage endometrial cancer, there is a disagreement regarding lymph nodes dissection, because randomized controlled trials and a meta-analysis have shown no clear evidence on overall or recurrence-free survival and a higher incidence on early and late complications in relation with pelvic lymph node dissection. A systematic lymph node dissection consists of removing all the nodes within a nodal drainage basin. This dissection proves to be very difficult in obese patient and includes a risk to damage blood vessels or nerves. Moreover, lymph node dissection is associated with a higher morbidity, longer operating time, more frequent blood loss and finally symptomatic lymphedema and seroma.

That is why, sentinel lymph node biopsy (SLNB) seems to be a good alternative to lymph node dissection. The tumor's spread is assessed in lymph nodes with a reduced morbidity. In fact, lymphadenectomy and its dangerous complications, like lymphedema, could be avoided in the vast majority of cases. Indeed, a histological analysis of these sentinel lymph-nodes (SLNs) leads to ultrastadification: cancers are graded depending on the presence and the size of metastasis in lymph nodes. Adjuvant treatments, such as radiotherapy or chemotherapy, can be suggested following these data and a better management of endometrial cancer is possible.

Detailed description: Worldwide, in 2012, 527'600 women were diagnosed with uterine cancer. It is the most common gynecologic malignancy in developed countries. In developing countries, it is the second most common, just behind cervical cancer. Adenocarcinoma of the endometrium is the most common histologic site and type of uterine cancer. Endometrial cancer is the fifth most frequent cancer in women in Switzerland. The incidence rose up to 5.9% in 2015. This tumor affects mainly older women, at 63 years on average. The majority of women are diagnosed at an early stage: confined to primary site for 67%, spread to regional organs and lymph nodes for 21% and with distant metastasis for 8%. Seventy-five to 90% of the patients are alerted by abnormal uterine bleeding very quickly, which allows a quick management of care and a high survival rate.

Besides age, one of the main risk factor of developing an endometrial carcinoma is obesity. In fact, obese women have higher risk to have an endometrial cancer, but also at a younger age than the average and finally they have an increased risk of death due to this particular cancer. Although the investigators are not sure of the reasons, it may be linked to the co-morbidities that go with obesity like diabetes or hypertension.

The treatment of endometrial cancer in most women is surgery involving a total hysterectomy and a bilateral salpingo-oophorectomy with or without a lymph node dissection. For patients with early stage endometrial cancer, there is a disagreement among cancer centers regarding lymph nodes dissection, because randomized controlled trials and a meta-analysis have shown no clear evidence on overall or recurrence-free survival and a higher incidence on early and late complications in relation with pelvic lymph node dissection. A systematic lymph node dissection consists of removing all the nodes within a nodal drainage basin irrespective of size. The problem with that technique is that dissection proves to be very difficult in obese patient and includes a risk to damage blood vessels or nerves.Moreover, lymph node dissection is associated with a higher morbidity, longer operating time, more frequent blood loss and finally symptomatic lymphedema and seroma. Indeed, the risk of leg lymphedema due to a node dissection is often under-reported, with rates going from 5% to 38%.

That is why, sentinel lymph node biopsy (SLNB) seems to many authors to be a good alternative to lymph node dissection. The tumor's spread is assessed in lymph nodes with a reduced morbidity. In fact, lymphadenectomy and its dangerous complications, like lymphedema, could be avoided in the vast majority of cases. In cutaneous melanoma or in breast's cancer, this technique is already widely used throughout the world. A sentinel node is the first node involved in the movement of the tumor from the primary cancer to the lymph nodes. When tumor cells spread to lymphatic network, they arrive in the first place in that sentinel node. If it contains no metastasis, then nodes, on the lymph path below, will not be affected either.

Not only SLNB in endometrial cancer is associated with a reduction in morbidity compared to lymph node dissection, but with it, a personalized treatment can be developed. Indeed, a histological analysis of these sentinel lymph-nodes (SLNs) leads to ultrastadification: cancers are graded depending on the presence and the size of metastasis in lymph nodes. Adjuvant treatments, such as radiotherapy or chemotherapy, can be suggested following these data and a better management of endometrial cancer is possible. Now, when lymph-node status is still unknown, indication for adjuvant therapies are based on pathological features of surgical specimens of the tumor, exposing some patients to either overtreatment or undertreatment.

In fact, five-year disease free survival in stage I patients with positive SLNs is 54%, whereas survival with negative SLNs is up to 90%.Therefore, SLN is one of the most important prognostic factors in endometrial cancer.

Primary objective of SENNAN study: The study seeks primarily to compare the location of uterine SLNs depending on the injection sites of the tracers: whether in endometrium, in uterine isthmus or in the cervix.

Secondary objectives are:

1. A comparison of the sensitivity of the tracers to detect SLNs
2. A description of the incidence of adverse events
3. An evaluation of additional time required to identify SLNs with or without lymph node dissection.
4. A description of morbidity directly induced by the search of SLNs
5. A calculation of negative predictive value of the different markers and their associations
6. A correlation between the anatomical locations of the SLNs and ultrastadification of SLNs.
7. An evaluation of the data of the lymphatic drainage, depending on tumor location in the uterus.
8. An evaluation of the data of the lymphatic drainage, depending on histological grade of the tumor.
9. An analysis of cases wherein change in the treatment have been made related to results of detection of SLNs.

Procedure:

The patients will have the day before the surgery an identification of the sentinel nodes with radiocolloid (Nanocoll®). The marker at a radioactivity of 80 MBq will be injected in four points in the cervix, 0.2 ml of 20 millibecquerel each. A CTscintigraphy will be performed three or four hours after the injection. The day of the surgery, the patients will undergo a general anaesthesia and then under general anaesthesia, the first step of the surgery will be to do the injection of the other two markers :

* ICG® will be injected through hysteroscopic guidance apart of the tumoral lesions at 4 points of injections. The volume of injected ICG will be 0.5 ml at each injection at the concentration of 5 mg/ml. A total of 2 ml (10mg) of ICG will be used.
* Patent blue® will be diluted with 2 ml of physiologic serum. Then it will be injected through the cervix along the uterus isthmus at the 3 o'clock and 9 o'clock level. 2 ml will be injected on each side.

Then the patients will have a laparoscopic surgical approach with identification of the sentinel nodes in the pelvic and lower abdomen areas. After identification of all the sentinel nodes : blue and / or radioactive and / or fluorescent nodes, the patients will have a total hysterectomy with bilateral oophorectomy and salpingectomy. The surgical technique for this procedure is the same as the one usually performed for this kind of lesions.

The major benefit of looking for SLNs in endometrial cancer is that lymphadenectomy can be avoided for patients who have already comorbidities. Indeed, endometrial cancer is found in aged women and obese women are also more affected. Lymphadenectomy is a heavy procedure with a risk of lymphedema. That is why the technique of SLNs offers a good alternative with lesser surgical risks.

Eligibility criteria: Inclusion Criteria:

* Informed Consent as documented by signature
* Early endometrial cancers (of International Federation of Gynecology and Obstetrics stage IA-IB), whatever histological grade and type
* Primary surgical treatment with hysterectomy
* No metastasis, no other cancers, no recurrency of cancers
* No signs of lymph nodes metastasis on the preoperative workup (MRI +/- positron emission computed tomography)
* No contraindication to laparoscopic procedures.
* Women of \> 18 years

Exclusion Criteria:

* Known severe allergies (antecedents of Quincke oedema, anaphylactic shock,...) and a history of allergy to iodides
* Contraindications to the injected products because of known hypersensitivity or allergy to ICG of blue dye
* Antecedent of pelvic lymph nodes surgery
* Previous lymphadenectomy or surgery that could change the uterine lymphatic drainage (conisation or myomectomy)
* Other diagnosed cancer during treatment or care
* Stage II and above (tumor invading cervix stroma) including those after a neo-adjuvant treatment
* Suspicion of lymph nodes metastasis at preoperative workup
* Medical or uterine conservative treatment
* Patient, who does not understand, speak or write in French
* Drugs that can interfere with ICG : anti convulsants - bisulphite compounds - haloperidol - heroin - pethidine \[meperidine\] - methamizole - methadone - morphine - nitrofurantoin - opium alkaloids - phenobarbitone- phenylbutazone - cyclopropane - probenecid - rifamycin - sodium bisulphite (mostly combined with heparin)
* Radioactive iodine uptake performed less than one week following the use of ICG.
* Hypersensitivity to Nanocoll, to any of the excipients (Stannous chloride, dihydrate Glucose, anhydrous Poloxamer 238 Sodium phosphate, dibasic, anhydrous Sodium phytate, anhydrous) or to any of the components of the labelled radiopharmaceutical.
* A history of hypersensitivity to products containing human albumin
* Hypersensitivity to dyes made of triphenylmethane
* Lymphostasis

Primary outcomes:
measure: Lymphatic route of endometrial cancer dissemination
timeFrame: 1 month
Secondary outcomes:
measure: Sensibility/sensitivity of the tracers
timeFrame: 1 month
measure: Adverse events
timeFrame: 1 month
measure: Additional time required to identify SLNs
timeFrame: 1 month
measure: Morbidity directly induced by the search of SLNs
timeFrame: 1 month
measure: Negative predictive value of the different markers
timeFrame: 1 month
measure: Correlation between the per-operative anatomical locations of the SLNs and ultrastadification of SLNs.
timeFrame: 1 month
measure: Comparison between the results of lymphatic drainage and location of the tumor.
timeFrame: 1 month
measure: Comparison between the results of lymphatic drainage and grade of the tumor.
timeFrame: 1 month
measure: Cases with change in treatment in relation with SLNs detection and histology.
timeFrame: 1 month
Other outcomes:
Locations:
city: Lausanne
country: Switzerland
facility: CHUV department of gynecology
Study officials:
affiliation: Centre Hospitalier Universitaire Vaudois
name: Patrice Mathevet, MD - PhD
role: PRINCIPAL_INVESTIGATOR
References: