Identifying safe diagnostic algorithms for sentinel lymph node mapping in high-risk endometrial cancer: The SENTIREC-endo study.

INTRODUCTION: It is unclear if sentinel node (SLN) mapping can replace pelvic- (PLD) and paraaortic lymphadenectomy (PALD) for high-risk endometrial cancer (EC). A diagnostically safe surgical algorithm, taking failed mapping cases into account, is not defined. We aimed to investigate the diagnostic accuracy of SLN mapping algorithms in women with exclusively high-risk EC. METHODS: We undertook a prospective national diagnostic cohort study of SLN mapping in women with high-risk EC from March 2017 to January 2023. The power calculation was based on the negative predictive value (NPV). Women underwent SLN mapping, PLD and PALD besides removal of suspicious and any FDG/PET-positive lymph nodes. Accuracy analyses were performed for five algorithms. RESULTS: 170/216 included women underwent SLN mapping, PLD and PALD and were included in accuracy analyses. 42/170 (24.7%) had nodal metastasis. The algorithm SLN and PLD in case of failed mapping, demonstrated a sensitivity of 86% (95% CI 74-100) and an NPV of 96% (95% CI 91-100). The sensitivity increased to 93% (95% CI 83-100) and the NPV to 98% (95% CI 94-100) if PLD was combined with removal of any PET-positive lymph nodes. Equivalent results were obtained if PLD and PALD were performed in non-mapping cases; sensitivity 93% (95% CI 83-100) and NPV 98% (95% CI 95-100). CONCLUSION: SLN-mapping is a safe staging procedure in women with high-risk EC if strictly adhering to a surgical algorithm including removal of any PET-positive lymph nodes independent of location and PLD or PLD and PALD in case of failed mapping.

The SENTIREC-endo study - Risks and benefits of a national adoption of sentinel node mapping in low and intermediate risk endometrial cancer.

OBJECTIVE: The SENTIREC-endo study aims to investigate risks and benefits of a national protocolled adoption of sentinel lymph node (SLN) mapping in women with early-stage low-grade endometrial cancer (EC) with low- (LR) and intermediate-risk (IR) of lymph node metastases. METHODS: We performed a national multicenter prospective study of SLN-mapping in women with LR and IR EC from March 2017-February 2022. Postoperative complications were classified according to Clavien-Dindo. Lymphedema was assessed as a change score and as incidence of swelling and heaviness evaluated by validated patient-reported outcome measures at baseline and three months postoperatively. RESULTS: 627 women were included in the analyses; 458 with LR- and 169 with IR EC. The SLN detection rate was 94.3% (591/627). The overall incidence of lymph node metastases was 9.3% (58/627); 4.4% (20/458) in the LR- and 22.5% (38/169) in the IR group. Ultrastaging identified 62% (36/58) of metastases. The incidence of postoperative complications was 8% (50/627) but only 0.3% (2/627) experienced an intraoperative complication associated with the SLN procedure. The lymphedema change score was below the threshold for clinical importance 4.5/100 CI: (2.9-6.0), and the incidence of swelling and heaviness was low; 5.2% and 5.8%, respectively. CONCLUSION: SLN mapping in women with LR and IR EC carries a very low risk of early lymphedema and peri- and postoperative complications. The national change in clinical practice contributed to a more correct treatment allocation for both risk groups and thus supports further international implementation of the SLN technique in early stage, low grade EC.

SENTIREC - The sentinel node mapping in women with cervical cancer study - Patient-reported early lymphedema and its impact on quality of life.

OBJECTIVE: To evaluate patient-reported incidence and severity of early lymphedema and its impact on quality of life (QoL) after sentinel lymph node (SLN) mapping only and after SLN and pelvic lymphadenectomy (PL) in women undergoing surgery for early-stage cervical cancer. METHODS: In a national prospective multicenter study, we included women with early-stage cervical cancer from March 2017-January 2021 to undergo radical surgery including SLN mapping. Women with tumors >20 mm underwent completion PL. The incidence and severity of early lymphedema and its influence on QoL were evaluated using validated patient-reported outcome measures before surgery and three months postoperative. We investigated changes over time using linear regression. RESULTS: Two hundred of 245 (81.6%) included women completed questionnaires at baseline and three months postoperatively. The incidence of early lymphedema was 5.6% (95% CI 2.1-11.8%) and 32.3% (95% CI 22.9-42.7%) in women who underwent SLN mapping only and SLN + PL, respectively. Lymphedema symptoms in the legs, genitals, and groins increased in both groups postoperatively but three times more in women who underwent PL. Lymphedema symptoms after SLN + PL significantly impaired physical performance (p = 0.001) and appearance (p = 0.007). Reporting lymphedema was significantly associated with impaired body image, physical-, role-, and social functioning, and a high level of fatigue. CONCLUSIONS: SLN mapping alone carries a low risk of lymphedema in women undergoing surgery for early-stage cervical cancer. In contrast, completion PL is associated with a high incidence of early lymphedema. Reporting lymphedema is associated with significant impairment of several physical, psychological, and social aspects of QoL.

From FIGO-2009 to FIGO-2018 in women with early-stage cervical cancer; Does the revised staging reflect risk groups?

OBJECTIVES: We aimed to evaluate if the revised staging according to FIGO-2018 in early-stage cervical cancer correctly predicts the risk for nodal metastases. METHODS: We reallocated 245 women with early-stage cervical cancer from FIGO-2009 to FIGO-2018 stages using data from a national, prospective cohort study on sentinel lymph node (SLN) mapping. We used univariate and multivariate binary regression models to investigate the association between FIGO-2018 stages, tumor characteristics, and nodal metastases. RESULTS: Stage migration occurred in 54.7% (134/245) (95% CI 48.2-61.0), due to tumor size or depth of invasion (71.6%, 96/134) and nodal metastases (28.4%, 38/134). Imaging preoperatively upstaged 7.3% (18/245); seven had nodal metastatic disease on final pathology. Upstaging occurred in 49.8% (122/245) (95% CI 43.4-56.2%) and downstaging to FIGO-2018 IA stages in 4.9% (12/245) (95% CI 2.6-8.4). The tumor size ranged from 3.0-19.0 mm in women with FIGO-2018 IA tumor characteristics, and none of the 14 women had nodal metastases. In multivariate analysis, risk factors significantly associated with nodal metastases were FIGO-2018 ≥ IB2 (RR 5.01, 95% CI 2.30-10.93, p < 0.001), proportionate depth of invasion >2/3 (RR 1.88, 95% CI 1.05-3.35, p = 0.033), and lymphovascular space invasion (RR 5.56, 95% CI 2.92-10.62, p < 0.001). CONCLUSIONS: The FIGO-2018 revised staging system causes stage migration for a large proportion of women with early-stage cervical cancer. Women who were downstaged to FIGO-2018 IA stages did not have nodal metastatic disease. The attention on depth of invasion rather than horizontal dimension seems to correctly reflect the risk of nodal metastases.

Sentinel lymph node mapping in early-stage cervical cancer - A national prospective multicenter study (SENTIREC trial).

OBJECTIVES: Sentinel lymph node (SLN) mapping may replace staging radical pelvic lymphadenectomy in women with early-stage cervical cancer. In a national multicenter setting, we evaluated SLN mapping in women with early-stage cervical cancer and investigated the accuracy of SLN mapping and FDG-PET/CT in tumors >20 mm. METHODS: We prospectively included women with early-stage cervical cancer from March 2017-January 2021 to undergo SLN mapping. Women with tumors >20 mm underwent completion pelvic lymphadenectomy and removal of FDG-PET/CT positive nodes. We determined SLN detection rates, incidence of nodal disease, sensitivity and negative predictive value (NPV) of SLN mapping, and the sensitivity, specificity, NPV, and positive predictive value (PPV) of FDG-PET/CT. RESULTS: We included 245 women, and 38 (15.5%) had nodal metastasis. The SLN detection rate was 96.3% (236/245), with 82.0% (201/245) bilateral detection. In a stratified analysis of 103 women with tumors >20 mm, 27 (26.2%) had nodal metastases. The sensitivity of SLN mapping adhering to the algorithm was 96.3% (95% CI 81.0-99.9%) and the NPV 98.7% (95% CI 93.0-100%). For FDG-PET/CT imaging the sensitivity was 14.8% (95% CI 4.2-33.7%), the specificity 85.5% (95% CI 75.6-92.5%), the NPV 73.9% (95% CI 63.4-82.7%), and the PPV 26.7% (95% CI 7.8-55.1%). CONCLUSIONS: SLN mapping seems to be an adequate staging procedure in early-stage cervical cancer tumors ≤20 mm. In tumors >20 mm, SLN mapping is highly sensitive but demands full adherence to the SLN algorithm. We recommend completion pelvic lymphadenectomy in tumors >20 mm until the oncological safety is established. FDG-PET/CT for nodal staging of women with early-stage cervical cancer seems limited.

Sentinel lymph node mapping for endometrial and cervical cancer in Denmark.

INTRODUCTION: This was a surgical pilot study to systematically introduce the technique of sentinel lymph node (SLN) mapping in women with early-stage stage cervical cancer (CC) and endometrial cancer (EC) in Denmark. The study aimed to facilitate structured surgical training to ensure surgeon proficiency in SLN mapping. The study precedes two national prospective studies on the oncological safety and correct patient selection for SLN mapping in CC and EC. METHODS: The study was conducted at four gynaecological cancer centres at Odense and Aarhus University Hospital, Rigshospitalet and Herlev Hospital, between September 2016 and August 2019. All centres went through a protocolled introduction to the surgical technique, pelvic lymphatic drainage, pathological ultra-staging and data entry. A criterion of a total (uni- and bilateral) SLN detection of > 80%, based on 30 SLN mappings was set. RESULTS: The four centres performed 140 (range: 30-46) procedures. The total SLN detection rate was 91.3% with bilateral SLN detection in 68.8% and unilateral SLN detection in 22.5% of cases. The cumulated total SLN detection rate at three centres was above the pre-set 80% criterion from the beginning of inclusion, whereas one centre reached the criterion after 20 procedures. CONCLUSIONS: In this study, all centres demonstrated international-level SLN detection rates within 30 procedures. Hence, all centres met the study criterion regarding surgeon proficiency and were eligible for the national studies. FUNDING: Eva and Henry Frænkels Fond, Frimodt-Heineke Fonden, Kong Christian X Fond. TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency (R. no.15/52037). The SENTIREC studies including this pilot study are registered with clinicaltrials.gov (NCT02825355 and NCT02820506).

Risk for borderline ovarian tumours after exposure to fertility drugs: results of a population-based cohort study.

STUDY QUESTION: Do fertility drugs increase the risk for borderline ovarian tumours, overall and according to histological subtype? SUMMARY ANSWER: The use of any fertility drug did not increase the overall risk for borderline ovarian tumours, but an increased risk for serous borderline ovarian tumours was observed after the use of progesterone. WHAT IS KNOWN ALREADY: Many epidemiological studies have addressed the connection between fertility drugs use and risk for ovarian cancer; most have found no strong association. Fewer studies have assessed the association between use of fertility drugs and risk for borderline ovarian tumours, and the results are inconsistent. STUDY DESIGN, SIZE, DURATION: A retrospective case-cohort study was designed with data from a cohort of 96 545 Danish women with fertility problems referred to all Danish fertility clinics in the period 1963-2006. All women were followed for first occurrence of a borderline ovarian tumour from the initial date of infertility evaluation until a date of migration, date of death or 31 December 2006, whichever occurred first. The median length of follow-up was 11.3 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Included in the analyses were 142 women with borderline ovarian tumours (cases) and 1328 randomly selected sub-cohort members identified in the cohort during the follow-up through 2006. Cases were identified by linkage to the Danish Cancer Register and the Danish Register of Pathology by use of personal identification numbers. To obtain information on use of fertility drugs, hospital files and medical records of infertility-associated visits to all Danish fertility clinics were collected and supplemented with information from the Danish IVF register. We used case-cohort techniques to calculate rate ratios (RRs) and corresponding 95% confidence intervals (CIs) for borderline ovarian tumours, overall and according to histological subtype, associated with the use of any fertility drug or five specific groups of fertility drugs: clomiphene citrate, gonadotrophins (human menopausal gonadotrophins and follicle-stimulating hormone), gonadotrophin-releasing hormone analogues, human chorionic gonadotrophins and progesterone. MAIN RESULTS AND THE ROLE OF CHANCE: Analyses within the cohort showed that the overall risk for borderline ovarian tumours was not associated with the use of any fertility drug (RR 1.00; 95% CI 0.67-1.51) or of gonadotrophins (RR 1.32; 95% CI 0.81-2.14), clomiphene citrate (RR 0.96; 95% CI 0.64-1.44), human chorionic gonadotrophins (RR 0.91; 95% CI 0.61-1.36) or gonadotrophin-releasing hormone analogues (RR 1.10; 95% CI 0.66-1.81). Furthermore, no associations were observed between the risk for borderline ovarian tumours and these groups of fertility drugs according to the number of cycles of use, length of follow-up or parity. In contrast, use of progesterone increased the risk for borderline ovarian tumours, particularly serous tumours, for which statistically significantly increased risks were observed with any use of progesterone (RR 1.82; 95% CI 1.03-3.24), among women treated with ≥4 cycles of progesterone (RR 2.63; 95% CI 1.04-6.64) and for all women followed up for ≥4 years after their first treatment with progesterone. LIMITATIONS, REASONS FOR CAUTION: Although we tried to minimize the effects of the underlying infertility, the severity of infertility might have affected our risk estimates, as women with more severe fertility problems may receive more treatment. The results from the subgroup analyses, e.g. the findings of an elevated risk for borderline ovarian tumours associated with increased time since first use of progesterone and with increased number of treatment cycles, should be interpreted with caution as these analyses are based on a limited number of women with borderline ovarian tumours. WIDER IMPLICATIONS OF THE FINDINGS: Although this study, which is the largest to date, provides reassuring evidence that there is no strong link between the use of fertility drugs and risk for borderline ovarian tumours, the novel observation of an increased risk for serous tumours after use of progesterone should be investigated in large epidemiological studies. The results of the present study provide valuable knowledge for clinicians and other health care personnel involved in the diagnosis and treatment of fertility problems. STUDY FUNDING/COMPETING INTERESTS: No conflict of interest was reported. S.M.B. was supported by a research scholarship from the Danish Cancer Society.