Sentinel lymph node mapping and intraoperative assessment in a prospective, international, multicentre, observational trial of patients with cervical cancer: The SENTIX trial

Background: SENTIX (ENGOT-CX2/CEEGOG-CX1) is an international, multi centre, prospective observational trial evaluating sentinel lymph node (SLN) biopsy without pelvic lymph node dissection in patients with early-stage cervical cancer. We report the final preplanned analysis of the secondary end-points: SLN mapping and outcomes of intraoperative SLN pathology. Methods: Forty-seven sites (18 countries) with experience of SLN biopsy participated in SENTIX. We preregistered patients with stage IA1/lymphovascular space invasion-positive to IB2 (4 cm or smaller or 2 cm or smaller for fertility-sparing treatment) cervical cancer without suspicious lymph nodes on imaging before surgery. SLN frozen section assessment and pathological ultrastaging were mandatory. Patients were registered postoperatively if SLN were bilaterally detected in the pelvis, and frozen sections were negative. Trial registration: ClinicalTrials.gov (NCT02494063). Results: We analysed data for 395 preregistered patients. Bilateral detection was achieved in 91% (355/395), and it was unaffected by tumour size, tumour stage or body mass index, but it was lower in older patients, in patients who underwent open surgery, and in sites with fewer cases. No SLN were found outside the seven anatomical pelvic regions. Most SLN and positive SLN were localised below the common iliac artery bifurcation. Single positive SLN above the iliac bifurcation were found in 2% of cases. Frozen sections failed to detect 54% of positive lymph nodes (pN1), including 28% of cases with macrometastases and 90% with micrometastases. Interpretation: SLN biopsy can achieve high bilateral SLN detection in patients with tumours of 4 cm or smaller. At experienced centres, all SLN were found in the pelvis, and most were located below the iliac vessel bifurcation. SLN frozen section assessment is an unreliable tool for intraoperative triage because it only detects about half of N1 cases. (C) 2020 The Author(s). Published by Elsevier Ltd

Central Pathology Review in SENTIX, a Prospective Observational International Study on Sentinel Lymph Node Biopsy in Patients with Early-Stage Cervical Cancer (ENGOT-CX2)

The quality of pathological assessment is crucial for the safety of patients with cervical cancer if pelvic lymph node dissection is to be replaced by sentinel lymph node (SLN) biopsy. Central pathology review of SLN pathological ultrastaging was conducted in the prospective SENTIX/European Network of Gynaecological Oncological Trial (ENGOT)-CX2 study. All specimens from at least two patients per site were submitted for the central review. For cases with major or critical deviations, the sites were requested to submit all samples from all additional patients for second-round assessment. From the group of 300 patients, samples from 83 cases from 37 sites were reviewed in the first round. Minor, major, critical, and no deviations were identified in 28%, 19%, 14%, and 39% of cases, respectively. Samples from 26 patients were submitted for the second-round review, with only two major deviations found. In conclusion, a high rate of major or critical deviations was identified in the first round of the central pathology review (28% of samples). This reflects a substantial heterogeneity in current practice, despite trial protocol requirements. The importance of the central review conducted prospectively at the early phase of the trial is demonstrated by a substantial improvement of SLN ultrastaging quality in the second-round review

CD44 as a cancer stem cell marker and its prognostic value in patients with ovarian carcinoma

The aim of our study was to clarify whether the CD44 adhesion molecule as a cancer stem cell marker could also serve as a prognostic factor in patients with epithelial ovarian cancer (EOC). A retrospective study was performed on 87 patients with histologically verified EOC. Specimens of both primary tumour and implantation metastases were tested from 48 of them. CD44 expression was detected by immunohistochemistry. We looked for the cut-off levels of CD44 expression using the Cox regression model. We confirmed statistically significant prognostic factors for overall survival (OS) and disease-free interval (DFI) to be: stage of the disease, postoperative residual tumour and papillary serous histological type. We demonstrated a statistically significant correlation between low CD44 expression and serous papillary carcinoma histotype, tumour recurrence and chemoresistance at a value below 2%. CD44 was neither a prognostic factor of OS nor of DFI.IMPACT STATEMENT What is already known about this subject: Epithelial ovarian cancer is the second most common gynaecological cancer in developed countries. Despite great efforts devoted to ovarian cancer research during past decades, levels of patient mortality have changed very little. Cancer stem cells (CSCs) are subpopulations of cells with typical characteristics of stem cells – i.e. the ability to self-renew and differentiate in a variety of cell types. The main surface marker typical for CSCs is CD44. The aim of our study was to clarify whether the CD44 as a CSCs marker could serve as a prognostic factor in patients with epithelial ovarian cancer. Previous studies published on this topic revealed controversial results. The novelty of our study lies in looking for the cut-off using the Cox regression model. What this study adds: We demonstrated a statistically significant correlation between low CD44 expression and serous papillary carcinoma histotype, tumour recurrence and chemoresistance at a value below 2%, however, CD44 was neither a prognostic factor of overall survival nor of disease-free interval. We propose to investigate other markers including other CSCs as a prognostic factors or potential aims for targeted therapy in ovarian cancer

Lower-limb lymphedema after sentinel lymph node biopsy in cervical cancer patients

Background: to prospectively assess LLL incidence among cervical cancer patients treated by uterine surgery complemented by SLN biopsy, without PLND. Methods: a prospective study in 150 patients with stage IA1-IB2 cervical cancer treated by uterine surgery with bilateral SLN biopsy. Objective LLL assessments, based on limb volume increase (LVI) between pre- and postoperative measurements, and subjective patient-perceived swelling were conducted in six-month periods over 24-months post-surgery. Results: the cumulative incidence of LLL at 24 months was 17.3% for mild LLL (LVI 10-19%), 9.2% for moderate LLL (LVI 20-39%), while only one patient (0.7%) developed severe LLL (LVI > 40%). The median interval to LLL onset was nine months. Transient edema resolving without intervention within six months was reported in an additional 22% of patients. Subjective LLL was reported by 10.7% of patients, though only a weak and partial correlation between subjective-report and objective-LVI was found. No risk factor directly related to LLL development was identified. Conclusions: the replacement of standard PLND by bilateral SLN biopsy in the surgical treatment of cervical cancer does not eliminate the risk of mild to moderate LLL, which develops irrespective of the number of SLN removed

Sentinel lymph node mapping and intraoperative assessment in a prospective, international, multicentre, observational trial of patients with cervical cancer : the SENTIX trial

BACKGROUND: SENTIX (ENGOT-CX2/CEEGOG-CX1) is an international, multicentre, prospective observational trial evaluating sentinel lymph node (SLN) biopsy without pelvic lymph node dissection in patients with early-stage cervical cancer. We report the final preplanned analysis of the secondary end-points: SLN mapping and outcomes of intraoperative SLN pathology. METHODS: Forty-seven sites (18 countries) with experience of SLN biopsy participated in SENTIX. We preregistered patients with stage IA1/lymphovascular space invasion-positive to IB2 (4 cm or smaller or 2 cm or smaller for fertility-sparing treatment) cervical cancer without suspicious lymph nodes on imaging before surgery. SLN frozen section assessment and pathological ultra staging were mandatory. Patients were registered postoperatively if SLN were bilaterally detected in the pelvis, and frozen sections were negative. Trial registration: ClinicalTrials.gov (NCT02494063). RESULTS: We analysed data for 395 preregistered patients. Bilateral detection was achieved in 91% (355/395), and it was unaffected by tumour size, tumour stage or body mass index, but it was lower in older patients, in patients who underwent open surgery, and in sites with fewer cases. No SLN were found outside the seven anatomical pelvic regions. Most SLN and positive SLN were localised below the common iliac artery bifurcation. Single positive SLN above the iliac bifurcation were found in 2% of cases. Frozen sections failed to detect 54% of positive lymph nodes (pN1), including 28% of cases with macrometastases and 90% with micrometastases. INTERPRETATION: SLN biopsy can achieve high bilateral SLN detection in patients with tumours of 4 cm or smaller. At experienced centres, all SLN were found in the pelvis, and most were located below the iliac vessel bifurcation. SLN frozen section assessment is an unreliable tool for intraoperative triage because it only detects about half of N1 cases.The Czech Research Councilhttp://www.ejcancer.compm2021Obstetrics and Gynaecolog

Role of adjuvant therapy in intermediate-risk cervical cancer patients - Subanalyses of the SCCAN study

Objective. The "intermediate-risk" (IR) group of early-stage cervical cancer patients is characterized by nega-tive pelvic lymph nodes and a combination of tumor-related prognostic risk factors such as tumor size >= 2 cm, lymphovascular space invasion (LVSI), and deep stromal invasion. However, the role of adjuvant treatment in these patients remains controversial. We investigated whether adjuvant (chemo)radiation is associated with a survival benefit after radical surgery in patients with IR cervical cancer. Methods. We analyzed data from patients with IR cervical cancer (tumor size 2-4 cm plus LVSI OR tumor size >4 cm; N0; no parametrial invasion; clear surgical margins) who underwent primary curative-intent surgery between 2007 and 2016 and were retrospectively registered in the international multicenter Surveillance in Cervical CANcer (SCCAN) study. Results. Of 692 analyzed patients, 274 (39.6%) received no adjuvant treatment (AT-) and 418 (60.4%) re-ceived radiotherapy or chemoradiotherapy (AT+). The 5-year disease-free survival (83.2% and 80.3%; PDFS = 0.365) and overall survival (88.7% and 89.0%; POS = 0.281) were not significantly different between the AT- and AT+ groups, respectively. Adjuvant (chemo)radiotherapy was not associated with a survival benefit after adjusting for confounding factors by case-control propensity score matching or in subgroup analyses of patients with tumor size >= 4 cm and <4 cm. In univariable analysis, adjuvant (chemo)radiotherapy was not identified as a prognostic factor in any of the subgroups (full cohort: PDFS = 0.365; POS = 0.282). Conclusion. Among patients with IR early-stage cervical cancer, radical surgery alone achieved equal disease -free and overall survival rates to those achieved by combining radical surgery with adjuvant (chemo)radiotherapy. (c) 2023 Elsevier Inc. All rights reserved

Central Pathology Review in SENTIX, a Prospective Observational International Study on Sentinel Lymph Node Biopsy in Patients with Early-Stage Cervical Cancer (ENGOT-CX2)

The quality of pathological assessment is crucial for the safety of patients with cervical cancer if pelvic lymph node dissection is to be replaced by sentinel lymph node (SLN) biopsy. Central pathology review of SLN pathological ultrastaging was conducted in the prospective SENTIX/European Network of Gynaecological Oncological Trial (ENGOT)-CX2 study. All specimens from at least two patients per site were submitted for the central review. For cases with major or critical deviations, the sites were requested to submit all samples from all additional patients for second-round assessment. From the group of 300 patients, samples from 83 cases from 37 sites were reviewed in the first round. Minor, major, critical, and no deviations were identified in 28%, 19%, 14%, and 39% of cases, respectively. Samples from 26 patients were submitted for the second-round review, with only two major deviations found. In conclusion, a high rate of major or critical deviations was identified in the first round of the central pathology review (28% of samples). This reflects a substantial heterogeneity in current practice, despite trial protocol requirements. The importance of the central review conducted prospectively at the early phase of the trial is demonstrated by a substantial improvement of SLN ultrastaging quality in the second-round review.status: publishe