Clinical trial NCT03366051: Sentinel Node Mapping in High Risk Endometrial Cancer
Official title: Sentinel Node Mapping Versus Sentinel Node Mapping With Systematic Lymphadenectomy in High Risk Endometrial Cancer: a Open Label, Non-inferiority, Randomized Trial.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Endometrial Cancer
Lymph Node Metastases
Keywords: Endometrial Cancer
Sentinel Lymph Node
Lymphadenectomy
Lead sponsor: AC Camargo Cancer Center
Sponsor class: OTHER
First posted: 2017-12-08
Enrollment: 178
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized Controlled Non-Inferiority Trial
Primary purpose: TREATMENT

Brief summary: This study will evaluate the role of systematic lymphadenectomy after sentinel node (SLN) mapping in high risk endometrial cancer (high grade histologies or deep myometrial invasion). The participants will be randomized in a non-inferiority controlled trial in 2 groups: SLN mapping or SLN mapping followed by systematic lymphadenectomy.

Detailed description: Although most patients with endometrial cancer present with early-stage disease, the standard treatment still includes systematic lymph node dissection for staging. Recently, SLN mapping has emerged as an acceptable surgical strategy when deciding between complete lymphadenectomy and no node dissection. This approach can help avoid the morbidity that is associated with a complete lymphadenectomy, such as neurovascular injury, lymphocyst formation, and lymphedema. A recent meta-analysis that included 55 studies and 4915 patients reported an overall SLN detection rate of 81% versus 50% for bilateral SLNs. Moreover, the use of indocyanine green increased the bilateral SLN detection rate compared with blue dye (74.6% vs. 50.5%). Yet, the studies noted an overall sensitivity of 96% and false negative rates of less than 5% when analyzed per hemipelvis. Since 2014, the National Comprehensive Cancer Network (NCCN) guidelines have recommended SLN mapping as an alternative option for node staging in endometrial cancer. However, most studies on SLN mapping have included patients who are at low risk for lymph node involvement and thus might underestimate the false negative rate. Recently, Soliman et al. reported a series of only high-grade and deep invasive endometrial cancers for which patients underwent SLN mapping, followed by pelvic and para-aortic lymph node dissection. An 89% detection rate was reported, suggesting that SLN mapping accurately identifies node metastases, with an negative predictive value (NPV) of 98% and an false negative predictive value (FNPV) of 2% when analyzed by hemipelvises. Positive nodes were found in 22.8% of patients (43% of isolated tumor cells and micrometastases), and in 40% of cases, the SLN was the only positive node. Data from the investigators corroborate these findings-26.7% of high-risk cases had positive nodes (50% of isolated tumor cells and micrometastases), and when analyzed by hemipelvis, the NPV was 97.9% and the FNPV was 2.1%. In 14 (70%) patients, the SLN was the only positive node. Moreover, there are few publications that have compared the results of the addition of SLN mapping to lymphadenectomy alone. Raimond et al. compared 156 patients that had SLN mapping with 95 who had pelvic node dissection. In their study, SLN mapping and imuno-histochemistry (IHC) were performed in low- and intermediate-risk patients, and the former detected metastatic node 3 times more often than complete pelvic lymphadenectomy alone (16.2% vs. 5.1%, p=0.03). They had no false negatives, and the IHC findings modified the adjuvant therapy in half of all cases. Holloway et al. compared a series of 661 patients who had undergone pelvic and para-aortic lymphadenectomy with 119 who were subjected to SLN mapping plus node dissection, including 68 high-intermediate- and high-risk patients in the SLN mapping group (GOG99 stratification). Despite the similarity in demographics and pathological risk factors, the SLN group had more LN metastases that were detected (30.3% vs. 16.3%; p\<0.001) and received more adjuvant therapy (28.6% vs. 16.3%; p=0.003). The SLN was the only positive node in 18 (50%) of mapped cases, and the false negative rate was 2.8%.The investigators recently published a series on high risk endometrial cancer and also recorded a higher pelvic node metastasis rate for the SLN mapping group (26.7% vs. 14.3%, p=0.02) but no significant difference in para-aortic node metastases (13.5% vs. 5.6%, p=0.12). Notably, if considered only patients in whom SLNs were mapped, 31.3% had pelvic positive nodes. Despite the differences in uterine risk factors between groups, 10.6% (8/75) of patients in the SLN group had node metastasis that was diagnosed only after IHC. Excluding these patients, the SLN group would have had a node positivity rate of 17.3%, similar to the N-SLN group (17.4%), reinforcing the impact of IHC in the detection of node metastases. Moreover, the SLN group received more adjuvant chemotherapy (33.5% vs. 48%). The overall detection rate for SLNs was 85.3%, and bilateral SLNs were observed in 60%. The investigators noted an overall sensitivity of 90%, a negative predictive value of 95.7%, and a false negative predictive value of 4.3%. Recently, Touhami et al. showed that the risk of non-SLN metastasis is 61% when the SLN metastasis size is ≥2mm, and 5% for SLN metastasis of \<2mm. However, one of the remaining uncertainties is the role of systematic lymphadenectomy after a positive SLN. In other words, is there any benefit in favor of systematic lymphadenectomy in a patient that already undergo adjuvant chemotherapy? The investigators hypothesized that there is no disease free survival benefit in adding systematic lymphadenectomy to only sentinel node mapping and proposed a prospective randomized controlled non-inferiority trial comparing SLN mapping to SLN mapping with systematic lymphadenectomy in high risk endometrial cancer.

Eligibility criteria: Inclusion Criteria:

* High grade histologies (endometrioid grade 3, serous, clear cell and carcinosarcoma)
* Endometrioid grades 1 or 2 with myometrial invasion of ≥50%
* Endometrioid grades 1 or 2 with cervical invasion
* Clinically suitable to receive systematic lymphadenectomy
* Consent statement

Exclusion Criteria:

* Previous hysterectomy in other institution
* Presence of extra-uterine disease (peritoneal, visceral or suspicious lymph node metastasis)
* Previous pelvic node dissection

Primary outcomes:
measure: Recurrence
timeFrame: 3 years
Secondary outcomes:
measure: Survival
timeFrame: 5 years
measure: Early morbidity
timeFrame: <30 days after surgery
measure: Late morbidity
timeFrame: >30 days after surgery
measure: Lymphedema
timeFrame: Evaluation before surgery and after 6 and 12 months of follow-up
measure: Quality of Life Questionary (QLQ)
timeFrame: Evaluation before surgery and after 1 and 6 months of follow-up
Other outcomes:
Locations:
city: Curitiba
country: Brazil
facility: Hospital Erasto Gaertner
state: Parana
city: Barretos
country: Brazil
facility: Hospital do Cancer de Barretos
state: Sao Paulo
city: Sao Paulo
country: Brazil
facility: AC Camargo Cancer Center
state: SP
city: São Paulo
country: Brazil
facility: Albert Einstein Hospital
state: SP
city: São Paulo
country: Brazil
facility: Sao Camilo Oncologia
state: SP
Study officials:
affiliation: Department of Gynecologic Oncology - AC Camargo Cancer Center
name: Glauco Baiocchi, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Baiocchi G, Mantoan H, Kumagai LY, Goncalves BT, Badiglian-Filho L, de Oliveira Menezes AN, Faloppa CC, De Brot L, da Costa AABA. The Impact of Sentinel Node-Mapping in Staging High-Risk Endometrial Cancer. Ann Surg Oncol. 2017 Dec;24(13):3981-3987. doi: 10.1245/s10434-017-6132-8. Epub 2017 Oct 20.
citation: Holloway RW, Abu-Rustum NR, Backes FJ, Boggess JF, Gotlieb WH, Jeffrey Lowery W, Rossi EC, Tanner EJ, Wolsky RJ. Sentinel lymph node mapping and staging in endometrial cancer: A Society of Gynecologic Oncology literature review with consensus recommendations. Gynecol Oncol. 2017 Aug;146(2):405-415. doi: 10.1016/j.ygyno.2017.05.027. Epub 2017 May 28.
citation: Holloway RW, Gupta S, Stavitzski NM, Zhu X, Takimoto EL, Gubbi A, Bigsby GE, Brudie LA, Kendrick JE, Ahmad S. Sentinel lymph node mapping with staging lymphadenectomy for patients with endometrial cancer increases the detection of metastasis. Gynecol Oncol. 2016 May;141(2):206-210. doi: 10.1016/j.ygyno.2016.02.018. Epub 2016 Mar 2.
citation: Soliman PT, Westin SN, Dioun S, Sun CC, Euscher E, Munsell MF, Fleming ND, Levenback C, Frumovitz M, Ramirez PT, Lu KH. A prospective validation study of sentinel lymph node mapping for high-risk endometrial cancer. Gynecol Oncol. 2017 Aug;146(2):234-239. doi: 10.1016/j.ygyno.2017.05.016. Epub 2017 May 18.
citation: Rossi EC, Kowalski LD, Scalici J, Cantrell L, Schuler K, Hanna RK, Method M, Ade M, Ivanova A, Boggess JF. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. Lancet Oncol. 2017 Mar;18(3):384-392. doi: 10.1016/S1470-2045(17)30068-2. Epub 2017 Feb 1.
citation: Bodurtha Smith AJ, Fader AN, Tanner EJ. Sentinel lymph node assessment in endometrial cancer: a systematic review and meta-analysis. Am J Obstet Gynecol. 2017 May;216(5):459-476.e10. doi: 10.1016/j.ajog.2016.11.1033. Epub 2016 Nov 18.
citation: Abu-Rustum NR. Sentinel lymph node mapping for endometrial cancer: a modern approach to surgical staging. J Natl Compr Canc Netw. 2014 Feb;12(2):288-97. doi: 10.6004/jnccn.2014.0026.
citation: Raimond E, Ballester M, Hudry D, Bendifallah S, Darai E, Graesslin O, Coutant C. Impact of sentinel lymph node biopsy on the therapeutic management of early-stage endometrial cancer: Results of a retrospective multicenter study. Gynecol Oncol. 2014 Jun;133(3):506-11. doi: 10.1016/j.ygyno.2014.03.019. Epub 2014 Mar 15.
citation: Baiocchi G, Andrade CEMC, Ribeiro R, Moretti-Marques R, Tsunoda AT, Alvarenga-Bezerra V, Lopes A, Costa RLR, Kumagai LY, Badiglian-Filho L, Faloppa CC, Mantoan H, De Brot L, Dos Reis R, Goncalves BT. Sentinel lymph node mapping versus sentinel lymph node mapping with systematic lymphadenectomy in endometrial cancer: an open-label, non-inferiority, randomized trial (ALICE trial). Int J Gynecol Cancer. 2022 May 3;32(5):676-679. doi: 10.1136/ijgc-2022-003378.