Background Systematic para-aortic and bilateral pelvic lymphadenectomy is included in the standard comprehensive surgical staging in presumed early epithelial ovarian cancer. No prospective randomized evidence suggests it has potential therapeutic value, and related morbidity is not negligible.
Primary Objective(s) To assess sensitivity, safety, and feasibility of the sentinel lymph node technique in identifying the presence of lymph node metastases in patients with early stage epithelial ovarian cancer.
Study Hypothesis Sentinel lymph node detection with indocyanine green can accurately predict nodal status in a cohort of women with early stage epithelial ovarian cancer.
Trial Design The SELLY trial is a prospective phase II interventional multicenter study.
Major Inclusion/Exclusion Criteria Inclusion criteria: Eastern Cooperative Oncology Group 0–1, apparent International Federation of Gynecology and Obstetrics (FIGO) stage I-II, histologically proven epithelial ovarian cancer.
Exclusion criteria: evidence of carcinomatosis, mucinous only at definitive histology.
Endpoint(s) Primary endpoint is sensitivity (true positive rate). Secondary endpoints include safety (complications rate of the procedure) and feasibility.
Sample Size Assuming a sensitivity of 98.5% in predicting positive sentinel lymph nodes at histology, a pathological lymph node prevalence of 14.2%, a precision of estimate (ie, the maximum marginal error) d=5%, and a type I error α=0.05, a sample size of 160 patients is needed to test the general hypothesis (ie, to answer whether sentinel lymph nodes identified with indocyanine green can accurately predict nodal status at histology of patients with apparently early epithelial ovarian cancer). Assuming a drop-out rate of 10%, a total of 176 patients will be enrolled in the study.
Estimated Dates for Completing Accrual and Presenting Results The accrual should be completed by December 2020 and results should be presented by March 2021.
Trial Registration The trial is registered at clinicaltrials.gov (NCT03563781).
- early ovarian cancer
- indocyanine green (ICG)
- minimally-invasive surgery
- sentinel node
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- early ovarian cancer
- indocyanine green (ICG)
- minimally-invasive surgery
- sentinel node
The incidence of lymph node metastases in apparent early stage epithelial ovarian cancer is estimated to be around 14–15%;1 2 approximately 35% of patients have only pelvic positive nodes, 37% have only para-aortic positive nodes, and the remaining 28% have both pelvic and para-aortic involvement.2
The performance of a complete pelvic and para-aortic lymphadenectomy is recommended as part of surgical staging for this disease,3 4 and data on nodal status appear relevant to guide decisions on adjuvant therapy.2 However, the prognostic importance of the information provided by full nodal dissection must be balanced against the morbidity related to such a radical surgical procedure.5–9
Lymphatic mapping for the assessment of sentinel lymph nodes (SLNs) is a widely accepted part of the surgical treatment of breast and cutaneous melanoma and has been successfully implemented in several gynecological malignancies.10–12
So far, only five case series and three case reports have investigated the role of SLN biopsy in early stage epithelial ovarian cancer.13 The SEntineL LYmph Node in early-stage ovarian cancer (SELLY) trial is a prospective study designed to test whether SLN detection can accurately predict nodal status in a cohort of women with the cancer.
The SELLY trial is a prospective, multicenter study designed to assess the safety, feasibility, and accuracy of SLN in measuring the presence/absence of lymph node metastases in patients with early stage epithelial ovarian cancer. All patients will undergo SLN mapping followed by complete pelvic (overlying and antero-lateral to the common iliac vessel, overlying and medial to the external iliac vessel, overlying and medial to the hypogastric vessels, and from the obturator fossa at a minimum anterior to the obturator nerve) and para-aortic (up to the level of the renal vessels) dissection according to the National Comprehensive Cancer Network guidelines. Two mL of a 1.25 mg/mL of indocyanine green solution (Novadaq Technologies, Mississauga, Ontario, Canada)—will be injected into both the perivascular connective tissue of the infundibulo-pelvic ligament and the utero-ovarian ligament (if the uterus is in situ) of the affected site (independently from the presence/absence of the ovary/ovaries) through a 200 mm long, 20 gauge spinal needle. In cases of minimally invasive surgery the needle will be inserted transcutaneously under optic guide.
Patients will be accrued at eight hospitals in Italy. The study scheme is illustrated in figure 1.
Patients are eligible if they have an apparent International Federation of Gynecology and Obstetrics (FIGO) stage I-II histologically proved epithelial ovarian cancer and if they are submitted to immediate or delayed (when diagnosis of epithelial ovarian cancer is incidental) comprehensive staging surgery. Patients must have a negative pre-operative CT scan for positive nodes (defined as lymph nodes <1 cm in their larger axis). Patients will be excluded if the evidence indicates carcinomatosis or mucinous-only definitive histology (ie, mucinous histology without mixed features).
The study has been designed to estimate the sensitivity of SLN(s), identified with indocyanine green, in early stage epithelial ovarian cancer regarding each patient as a unit.
False-positive results are impossible by definition. The test is considered a true positive if at least one SLN has metastatic disease, and as a false negative if the SLNs are free of metastatic disease but non-SLNs show metastases. The test is considered a true negative if all lymph nodes are free of metastases.
Secondary endpoints include safety (complications rate of the procedure) and feasibility. Intra-operative and early post-operative complications will be documented and classified according to the Clavien-Dindo classification. The detection rate is calculated as the number of patients with at least one detected SLN divided by the total number of patients who undergo the procedure.
Translational endpoints are assessment of (i) free circulating DNA, (ii) miRNome from circulating exosome/microvesicles, and (iii) circulating levels of vascular endothelial growth factor-C and SEMA4C.
Sample size was calculated according to Karimollah Hajian-Tilaki 2014 for diagnostic studies14: assuming a sensitivity of 98.5% in predicting positive sentinel lymph nodes at histology, a pathological lymph node prevalence of 14.2%, a precision of estimate (ie, the maximum marginal error) d=5%, and a type I error α=0.05, a sample size of 160 patients is needed to test the general hypothesis (ie, to answer whether SLN(s) identified with indocyanine green can accurately predict nodal status at histology of patients with apparently early epithelial ovarian cancer). Assuming a drop-out rate of 10%, a total of 176 patients will be enrolled in the study.
Statistical analysis has been performed using Software for Statistics and Data Science (STATA/IC 13.0 for Windows, College Station, TX, StataCorp LP). For the analysis, patients will be divided in two groups according to the lymph nodal status at histology: those with positive SLN(s) at histology and those with negative SLN(s) at histology. Results will be presented as absolute frequency (percentage) for nominal variables, as mean±SD for normally distributed continuous variables or normally distributed after transformation, and as median (min-max) for continuous variables not normally distributed. A Shapiro-Wilk test will be used to assess the normality of distribution of variables. A Student t-test and Mann-Whitney test will be used for comparison between histological groups for normally distributed or normally distributed after transformation and not normally distributed variables, respectively. χ2 or Fisher’s exact test will be used as appropriate for nominal variables. Two-sided tests will be used, and the significance level is set at p<0.05.
Strengths of this trial are the inclusion of centers with an extensive experience in systematic pelvic and para-aortic lymphadenectomy and SLN technique for other gynecological tumors, by both open and minimally invasive surgery, and the adoption of surgical standardized procedures. Indocyanine green has been widely used in solid malignancies, showing an excellent safety profile without requiring any pre-operative organization.15 From a technical point of view, the ovarian pedicle represents a safe, reasonable, and easily accessible choice even in cases of a previous salpingo-opherectomy. However, the procedure is likely to be more challenging and its feasibility less effective in women undergoing delayed surgical staging, owing to the closure/disruption of lymphatic vessels during previous surgery. This could limit the adoption of the procedure, even if proved to be effective, although the number of patients undergoing surgical re-staging among patients with apparent early stage epithelial ovarian cancer is going to be reduced according to new released European Society of Gynecological Oncology–European Society for Medical Oncology guidelines (https://www.esmo.org/Guidelines/Gynaecological-Cancers/ESMO-ESGO-Consensus-Conference-Recommendations-on-Ovarian-Cancer). The high number of connections between lymphatic channels of each site may represent another challenge in finding the proper SLN with adequate dissection.
With this in mind, if proved safe, effective, and reliable, the SLN procedure has the potential to become a standard approach for staging patients with early stage epithelial ovarian cancer in referral centers. On the one hand, it can guarantee key information for prognosis and treatment provided by adequate surgical staging, on the other, it can reduce the level of morbidity related to lymph node dissection.
Contributors SU, CN did the study design, patient recruitment, data analysis and interpretation, statistical analysis, and wrote the report. AF and GS supervised the whole process. SU, CN, EV, FG, FC, AF and GS participated in patient recruitment. SU and CN contributed to collection and organization of the data. All authors approved the ﬁnal report.
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.
Patient consent for publication Obtained.
Provenance and peer review Commissioned; externally peer reviewed.