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Sentinel lymph node mapping versus sentinel lymph node mapping with systematic lymphadenectomy in endometrial cancer: an open-label, non-inferiority, randomized trial (ALICE trial)
  1. Glauco Baiocchi1,
  2. Carlos Eduardo Mattos Cunha Andrade2,
  3. Reitan Ribeiro3,
  4. Renato Moretti-Marques4,
  5. Audrey Tieko Tsunoda3,5,
  6. Vanessa Alvarenga-Bezerra4,
  7. Andre Lopes6,
  8. Ronaldo Lúcio Rangel Costa6,
  9. Lillian Yuri Kumagai1,
  10. Levon Badiglian-Filho1,
  11. Carlos Chaves Faloppa1,
  12. Henrique Mantoan1,
  13. Louise De Brot7,
  14. Ricardo Dos Reis2 and
  15. Bruna Tirapelli Goncalves1
  1. 1 Gynecologic Oncology, AC Camargo Cancer Center, São Paulo, Brazil
  2. 2 Gynecology Oncology, Barretos Cancer Hospital, Barretos, Brazil
  3. 3 Gynecologic Oncology, Erasto Gaertner Hospital, Curitiba, Brazil
  4. 4 Gynecologic Oncology, Hospital Israelita Albert Einstein, São Paulo, Brazil
  5. 5 PPGTS, Universidade Positivo, Curitiba, Brazil
  6. 6 Gynecology, São Camilo Oncologia, São Paulo, Brazil
  7. 7 Pathology, AC Camargo Cancer Center, São Paulo, Brazil
  1. Correspondence to Dr Glauco Baiocchi, Gynecologic Oncology, AC Camargo Cancer Center, São Paulo 01509-010, Brazil; glauco.baiocchi{at}


Background Growing evidence suggest that sentinel lymph node (SLN) biopsy in endometrial cancer accurately detects lymph node metastasis. However, prospective randomized trials addressing the oncological outcomes of SLN biopsy in endometrial cancer without lymphadenectomy are lacking.

Primary Objectives The present study aims to confirm that SLN biopsy without systematic node dissection does not negatively impact oncological outcomes.

Study Hypothesis We hypothesized that there is no survival benefit in adding systematic lymphadenectomy to sentinel node mapping for endometrial cancer staging. Additionally, we aim to evaluate morbidity and impact in quality of life (QoL) after forgoing systematic lymphadenectomy.

Trial Design This is a collaborative, multicenter, open-label, non-inferiority, randomized trial. After total hysterectomy, bilateral salpingo-oophorectomy and SLN biopsy, patients will be randomized (1:1) into: (a) no further lymph node dissection or (b) systematic pelvic and para-aortic lymphadenectomy.

Major Inclusion and Exclusion Criteria Inclusion criteria are patients with high-grade histologies (endometrioid G3, serous, clear cell, and carcinosarcoma), endometrioid G1 or G2 with imaging concerning for myometrial invasion of ≥50% or cervical invasion, clinically suitable to undergo systematic lymphadenectomy.

Primary Endpoint(s) The primary objective is to compare 3-year disease-free survival and the secondary objectives are 5-year overall survival, morbidity, incidence of lower limb lymphedema, and QoL after SLN mapping ± systematic lymphadenectomy in high-intermediate and high-risk endometrial cancer.

Sample size 178 participants will be randomized in this study with an estimated date for completing accrual of December 2024 and presenting results in 2027.

Trial Registration Number NCT03366051.

  • endometrial neoplasms
  • sentinel lymph node
  • postoperative complications
  • quality of life (pro)/palliative care

Data availability statement

Data are available upon request.

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Sentinel lymph node (SLN) mapping has emerged as an alternative and acceptable surgical strategy for endometrial cancer staging. Compared with systematic lymphadenectomy, SLN mapping can provide a two-fold higher rate of positive lymph node diagnosis.1 Additionally, this surgical approach may avoid the morbidity associated with systematic lymphadenectomy, such as neurovascular injury, lymphedema, and lymphocyst formation.

Despite the current literature evidence in favor of SLN mapping, only five prospective studies have addressed the performance of SLN mapping in endometrial cancer staging by performing SLN biopsy followed by complete lymphadenectomy.2–6 Three of these studies included mostly or only high-risk tumors.4–6 Soliman et al4 reported a series (n=101) of only high-grade or deep invasive endometrial cancers for which patients underwent SLN mapping, followed by completion pelvic and para-aortic lymph node dissection to the renal vessels. Positive nodes were found in 23% of patients and in 40% of node-positive cases the SLN was the only positive node. An 89% detection rate was reported, suggesting that SLN mapping accurately identifies node metastases, with a negative predictive value of 98%. Second, the Swedish SHREC study5 included 257 women with high-risk features (endometrioid G3, non-endometrioid, or deep myometrial invasion) and found 21% of positive pelvic lymph nodes, a bilateral mapping of 95%, and sensitivity and negative predictive value of 98% and 99.5%, respectively. Finally, the Canadian SENTOR study6 included 156 cases (126 high-grade histologies) and reported an overall detection rate of 97% and 78% bilaterally, 17% of lymph node metastasis, sensitivity of 96% and negative predictive value of 99%.

In summary, current evidence suggest that SLN biopsy in endometrial cancer accurately detects lymph node metastasis even for high-risk tumors and has a sensitivity and negative predictive value comparable to those observed in other primary tumors where the method is considered the standard of care such as vulvar cancer, melanoma, and breast cancer. However, prospective trials addressing the oncological outcomes in endometrial cancer are lacking. We hypothesized that there is no survival benefit in adding systematic lymphadenectomy to sentinel node mapping for endometrial cancer staging. The present multicentric, prospective, randomized, controlled, non-inferiority trial will compare SLN mapping to SLN mapping with systematic lymphadenectomy in high-intermediate and high-risk endometrial cancer and aims to add sufficient data for a paradigm shift in endometrial cancer staging.


Trial Design

This is a collaborative, multicenter, open-label, non-inferiority, randomized trial. The recruitment started in December 2017 and already includes 95 patients. Surgery will be performed preferably by a minimally invasive approach (laparoscopy, robotically-assisted laparoscopy). The surgical procedure will be performed by experienced surgeons in gynecologic oncology and sentinel node mapping and includes total hysterectomy, bilateral salpingo-oophorectomy, and lymph node staging per the study protocol.

The SLN mapping protocol will follow the National Comprehensive Cancer Network (NCCN) algorithm and more recently the consensus in competency assessment tool.7 Blue dye or indocyanine green (1.25 mg/mL) will be injected only in the cervix at the 3 and 9 o'clock positions with 1 mL superficial and 1 mL deep, for a total of 4 mL.

The surgery starts with confirmation of disease restricted to the uterus, identification, and retrieval of the SLNs. After that, a total hysterectomy and salpingo-oophrectomy is performed and the uterus sent to frozen section.

Uterine frozen section is performed to evaluate depth of myometrial invasion and cervical invasion for all cases. The randomization will be performed after frozen section and confirmation of the inclusion criteria into two arms (1:1): SLN only or SLN and completion of systematic pelvic and para-aortic lymphadenectomy up to the renal vessels (Figure 1). The retrieved SLNs will not receive frozen section, except if grossly suspicious of involvement. In cases of intra-operative positive SLNs, the patient will be excluded from the study. All SLNs will receive ultrastaging and immunohistochemistry if negative by hematoxylin and eosin. Post-operative complications up to 30 days will be classified by Clavien–Dindo score and quality of life (QoL) by the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CX24 questionnaires at baseline and follow-up at 1, 6, and 12 months after surgery.

Figure 1

Trial schema. BSO, bilateral salpingo-oophorectomy; ICG, indocyanine green; MRI, magnetic resonance imaging; QoL, quality of life; SLN, sentinel lymph node.

The adjuvant treatment will be standardized between institutions and includes chemotherapy for non-endometrioid histologies and for extrauterine involvement. Each center will enter patient data into the specific project in REDCap (Research Eletronic Data captures) maintained by AC Camargo Cancer Center. Five Brazilian institutions are participating: AC Camargo Cancer Center, Barretos Cancer Hospital, Erasto Gaertner Hospital, Brazilian Institute for Cancer Control, and Hospital Israelita Albert Einstein.


Inclusion and exclusion criteria are shown in Table 1.

Table 1

Inclusion and exclusion criteria of ALICE trial


The primary objective is 3-year disease-free survival. The secondary objectives are 5-year overall survival, morbidity related to surgical procedures and early and late surgical complications, incidence of lower limb lymphedema, and QoL related to surgical procedures.

Sample Size

For the sample size calculation, we utilized a 3-year disease-free survival of 88.5%, with the result based on a series of patients with the same inclusion criteria previously treated at our institution. For a significance level (α) of 5%, a power (1-β) of 80%, and a non-inferiority limit of 10%, the hypothesis is “if there is a difference in favor of the experimental arm of 2%, then 162 patients are needed to be 80% sure that the upper limit of the 95% CI excludes the difference in favor of the standard arm by more than 10%”. Considering a 10% loss to follow-up, the final sample size is 178 cases.

Randomization and Blinding

Randomization will be performed in the operating room with online software (Sealed Envelope; London, UK) after frozen section. Patients will be randomized after total hysterectomy and SLN mapping into two groups: SLN biopsy only or SLN biopsy followed by complete systematic lymphadenectomy (1:1).

Statistical Analysis

The SLN detection rate will be considered as the percentage of patients evaluated where the sentinel node was found. The presence of a negative sentinel node will be considered a false-negative when another non-SLN has metastatic disease in the same hemipelvis.

Simple frequencies of all variables will be calculated. Associations between categorical variables will be analyzed using the chi-squared test and Fisher’s test when at least one expected frequency is less than 5. Survival curves will be estimated using the Kaplan–Meier method, and the comparison between the curves will be performed using the log rank test. The follow-up time will be calculated from the date of surgery to the date of the last objective information in the data update. Disease-free survival rates will be analyzed based on date of first local or distant recurrence. Overall survival rates will be calculated according to the date of the last objective information in the data update. For all tests performed, an alpha error of up to 5% (p<0.05) will be considered. The QoL scores will be analyzed according to the European Organization for Research and Treatment of Cancer Scoring Manual. An interim analysis will be planned when at least 14 events are observed.


Despite growing evidence supporting SLN mapping in endometrial cancer in which SLN status can accurately predict the status of the regional lymphatic basin, the oncological outcomes of SLN mapping have not been evaluated in prospective studies. Furthermore, one of the main uncertainties in SLN mapping is the value of adding a complete lymph node dissection particularly when the SLN is positive. The size of the SLN metastasis has been described as a major risk factor for non-SLN metastasis. Five studies addressed this topic and the risk of non-SLN metastasis is related to the SLN metastasis size. Yet a pooled analysis suggests that when SLN metastasis has isolated tumor cells, micrometastasisn and macrometastasis, metastases in non-SLNs is found in 4%, 21%, and 45% of cases, respectively.8

However, the benefit of adding systematic lymphadenectomy in a patient that already will undergo adjuvant chemotherapy after a positive lymph node metastasis is questionable. Theoretically, adjuvant treatment with chemotherapy or radiotherapy can be administered to treat the remaining microscopic lymph node metastases. Aloisi et al9 reported a series of 207 patients with regard to patterns of the first recurrence in pelvic node-positive patients who did not undergo para-aortic lymph node dissection at primary staging. Sixty-two (30.1%) cases recurred, and 17 (8.3%) had isolated nodal recurrences, 8 (3.9%) of which were para-aortic. Micro- and macrometastases were associated with twice the recurrence rate compared with isolated tumor cells (37% vs 17%). In the multivariate analysis, non-endometrioid type was the only independent factor that maintained an association with a higher risk of recurrence. Additionally, Multinu et al10 noted that SLN mapping did not compromise survival outcomes compared with systematic lymph node staging in non-bulky positive lymph nodes, and retrospective studies have demonstrated similar survival when comparing SLN alone with systematic lymph node dissection even for serous and carcinosarcoma histologies.11 12

The published prospective studies in SLN mapping aimed to analyze the performance of SLN mapping in staging endometrial cancer rather than oncological outcomes. Along with the present study, another three other prospective ongoing clinical trials will address the survival outcomes of SLN mapping, though with diverse inclusion criteria. First, the SELECT (SEntinel Lymph node Endometrial Cancer Trial) trial13 (NCT04291612) is an international, single-arm, observational study led by Memorial Sloan Kettering Cancer Center which will include 182 women with intermediate-risk endometrioid endometrial carcinoma (stages IaG3 or IbG1 and G2) and will assess whether the 3-year prevalence of pelvic (non-vaginal) recurrence is non-inferior to historical control, estimated at 2.5%. Second, the SNEC trial14 (NCT04276532) is a Chinese, multicentric, non-inferiority, randomized trial in which 780 patients with intermediate-high risk factors (endometrioid endometrial cancer G3, myometrial invasion ≥50%, tumor size >2 cm, non-endometrioid endometrial cancer; cervical involvement) will be randomized to SLN mapping or pelvic lymphadenectomy ± para-aortic lymphadenectomy. The primary outcome is 2 years disease-free survival. Finally, the ENDO-3 trial15 (NCT04073706) is a multicentric study in Australia and New Zealand which will evaluate the role of lymph node staging with SLN biopsy, including all histologies. The study will randomize 760 patients to SLN mapping or no lymph node staging. The primary endpoint is 4.5 years disease-free survival. All the trials are going to address the surgical morbidity and QoL as secondary endpoints.

In summary, the present study (NCT03366051) aims to confirm that SLN mapping without systematic node dissection does not negatively impact oncological outcomes. Women with endometrioid (G3 ± deep myometrial invasion ± cervical invasion) or non-endometrioid and confined uterine tumors are being randomized to SLN biopsy only or to SLN with addition of a systematic lymph node dissection. We are including only patients with higher-risk factors for lymph node metastasis and believe that our data will provide valuable data to support SLN mapping as the standard of care for endometrial cancer staging without retrieval of other microscopic lymph node metastasis. Moreover, the morbidity profile and QoL will also be assessed, and we expect to find an additional benefit in reduction of early and late morbidity related to systematic lymph node dissection.

Data availability statement

Data are available upon request.

Ethics statements

Patient consent for publication

Ethics approval

This study involves human participants and was approved by IRB name: Comite de Etica em Pesquisa da Fundacao Antonio Prudente (ID approval: #2.392.088). Participants gave informed consent to participate in the study before taking part.



  • Twitter @glaucobaiocchi, @andrelopesMD

  • Contributors Study concept and design: GB, BTG. Data acquisition: GB, BTG. Manuscript preparation and editing: GB, BTG. Manuscript review: all authors. Author responsible for the overall content as the guarantor: GB.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.