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Introduction/Background* High-risk locally advanced cervical cancer has a poor prognosis, and more than half of patients recur in 2 years. External beam radiotherapy (EBRT) with concurrent chemotherapy followed by brachytherapy is the standard of care for locally advanced cervical cancer. The immunostimulatory activity of the PD-1 inhibitor pembrolizumab may be enhanced by concurrent chemoradiotherapy (CCRT). After the KEYNOTE-158 study, in which pembrolizumab showed durable antitumor activity, pembrolizumab monotherapy was approved for patients with PD-L1–positive recurrent or metastatic cervical cancer who progressed during or after chemotherapy. ENGOT-cx11/GOG 3047/KEYNOTE-A18 (NCT04221945) is a phase 3, randomized, placebo-controlled study evaluating pembrolizumab with CCRT for the treatment of high-risk, locally advanced cervical cancer. Methodology Approximately 980 patients with high-risk (International Federation of Gynecology and Obstetrics 2014 stage IB2-IIB with node-positive disease or stage III-IVA), locally advanced, histologically confirmed cervical cancer who have not received systemic therapy, immunotherapy, definitive surgery, or radiation will be randomized 1:1 to receive either 5 cycles of pembrolizumab 200 mg every 3 weeks (Q3W) + CCRT followed by 15 cycles of pembrolizumab 400 mg Q6W or 5 cycles of placebo Q3W + CCRT followed by 15 cycles of placebo Q6W. CCRT includes 5 cycles (optional 6th dose) of cisplatin 40 mg/m2 Q1W + EBRT followed by brachytherapy. Randomization is stratified by planned EBRT type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cancer stage at screening (stage IB2-IIB vs III-IVA), and planned total radiotherapy dose. Treatment will continue until the patient has received 20 cycles of pembrolizumab (5 cycles 200 mg Q3W, 15 cycles 400 mg Q6W) vs placebo (~2 years) or until disease progression, unacceptable toxicity, or withdrawal. Primary endpoints are progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 by investigator and overall survival (OS). Secondary endpoints include PFS by blinded independent central review, PFS at 2 years, OS at 3 years, complete response at 12 weeks, objective response rate, PFS and OS by PD-L1 status, quality of life, and safety. Enrolment began May 2020 and is planned for 193 sites in 30 countries. Klikněte nebo klepněte sem a zadejte text.

Introduction/Background* Lower-limb lymphedema (LLL) is a well-recognized adverse outcome of the surgical management of cervical cancer. Recently, sentinel lymph node (SLN) biopsy has emerged as an alternative procedure to systematic pelvic lymphadenectomy (PLND) aiming to decrease the risk of complications, especially LLL development. Our study represents the first prospective analysis of LLL incidence in cervical cancer patients after a uterine procedure with SLN biopsy, without systematic PLND. Methodology In a prospective international multicenter trial SENTIX, the group of 150 patients with stage IA1–IB2 cervical cancer treated by uterine surgery with bilateral SLN biopsy was prospectively evaluated using both 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. The characteristics of the patients are summarized in table 1. Result(s)* 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 (figure 1). A 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. Conclusion* Contrary to the expectations, 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. Trial registration ClinicalTrials.gov: NCT02494063 Funding This work was supported by Charles University in Prague (UNCE 204065 and PROGRES Q28/LF1) and by a grant from the Czech Health Research Council (NV19-03-00023). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Conflicts of Interest The authors declare no conflict of interest.

Molecular classification of endometrial carcinoma is becoming an important part of the diagnostic process with direct therapeutic implications. Recent international guidelines, including the joint ESGO-ESTRO-ESP recommendation, include the molecular classification into standard diagnostic algorithms. Molecular testing of endometrial carcinomas is also recommended in the latest (5th) edition of the WHO classification of Female Genital Tumors. Due to the need to implement these recommendations in practice, representatives of four professional societies of Czech Medical Association of J. E. Purkyn#283; (Czech Oncological Society, Oncogynecological Section of the Czech Gynecological and Obstetrical Society, Society of Radiation Oncology, Biology and Physics, and the Society of Czech Pathologists) organized a meeting focused on this topic. The result of this meeting is a joint recommendation for molecular testing of endometrial carcinoma in routine diagnostic practice in the Czech Republic.

Background Lower limb lymphoedema (LLL) is the most disabling adverse effect of surgical staging of pelvic lymph nodes. However, the lack of standardisation of volumetric LLL assessment hinders direct comparison between the studies and makes LLL reporting unreliable. The aim of our study is to report outcomes from a prospective trial that have implications for LLL assessment standardisation. Methods In the prospective international multicentre trial SENTIX, a group of 150 patients with stage IA1–IB2 cervical cancer treated by uterine surgery with bilateral sentinel lymph node biopsy was prospectively evaluated by objective LLL assessment, based on limb volume change (LVC) using circumferrential limb measurements and subjective patient-reported swelling. The assessments were conducted in six-month periods over 24 months post-surgery. Results Patient LVC substantially fluctuated in both positive and negative directions, which were comparable in frequency up to ±14% change. Thirty-eight patients experienced persistent LVC increase >10% classified as LLL, with nine months median time to onset. Some 34.2% of cases experienced onset later than one year after the surgery. Thirty-three patients (22%) experienced transient oedema characterised as LVC >10%, which resolved without intervention between two consequent follow-up visits. No significant correlation between LVC >10% and a patient-reported swelling was observed. Conclusions Given that we observed comparable fluctuations of the the lower-limb volumes after surgical treatment of cervical cancer in both positive and negative direction up to ±14%, the diagnostic threshold for LLL diagnosis based on LVC should be increased to >15% LVC. The distinction of transient oedema from persistent LLL requires repeated measurements. Also, as one-third of LLL cases are diagnosed >1-year post-surgery, a sufficient follow-up duration needs to be ensured. Patient-reported swelling correlated poorly with LVC and should only be used as an adjunct to objective LLL assessment. Trial registration: ClinicalTrials.gov : NCT02494063

BackgroundThe management of patients with intraoperative detection of lymph node involvement remains controversial. The most significant aspect is the decision regarding the completion of the cervical procedure, such as hysterectomy, radical hysterectomy, or a fertility sparing procedure.Primary objectiveThe primary objective of the ABandoning RAd hyst in cerviX cancer (ABRAX) trial is to determine whether the completion of the cervical procedure (ie, radical hysterectomy) improves oncological outcome in patients with intraoperatively detected lymph node involvement before they are referred for definitive chemoradiation.Study hypothesisWe hypothesize that, in patients with intraoperative lymph node involvement, completion of radical hysterectomy or other cervical procedure does not improve the oncological outcome of definitive chemoradiation.Trial designThe ABRAX trial is a multicenter, retrospective, cohort study. Patients with negative lymph nodes in clinical staging, in whom lymph node involvement is detected intraoperatively, are included. Completion or abandonment of the planned cervical procedure stratifies the cohort into two subgroups in which oncological outcome and morbidity will be compared.Major Inclusion/Exclusion criteriaPatients with early stage (pT1a–pT2b) cervical cancer, who did not have positive lymph nodes on preoperative imaging, who were scheduled for primary surgical treatment, and in whom metastatic involvement of pelvic lymph node was found during surgery either as a grossly (macroscopically) involved or on intraoperative pathology assessment will be enrolled. Patients can be included irrespective of surgical approach (minimal invasive surgery or laparotomy) and type of cervical procedure performed (hysterectomy, radical hysterectomy, or a fertility sparing procedure).Primary endpointThe primary endpoint of this retrospective study is a progression free survival in two subgroups with abandoned or completed cervical procedure followed by definitive chemoradiation in both groups.Sample sizeThe assumed sample size is 718 patients (in total for both groups).Estimated dates for completing accrual and presenting resultsEstimated end of data collection: December 2019; estimated date of presenting results: Q2/3 2020.Trial registrationClinicaltrials.gov: NCT04037124.

Hereditary tumor syndromes with a possible manifestation in the female internal genital tract represent a heterogeneous group of diseases. The two most common entities are the hereditary breast and ovarian cancer syndrome, and the Lynch syndrome. The less common syndromes include the rhabdoid tumor predisposition syndrome, Cowden syndrome, tuberous sclerosis complex, DICER1 syndrome, nevoid basal cell carcinoma syndrome, Peutz-Jeghers syndrome, von Hippel-Lindau disease, and hereditary leiomyomatosis and renal cell cancer syndrome. The goal of this manuscript is to provide a comprehensive overview of those hereditary tumor syndromes which can manifest in the area of the female genital system, with an emphasis on their summary, the characteristics of the tumors which can develop in association with these syndromes, and the approach to the processing of prophylactically removed tissues and organs. The issue of Lynch syndrome screening is also discussed.

The European Society of Gynaecological Oncology (ESGO), the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG), the International Ovarian Tumour Analysis (IOTA) group, and the European Society for Gynaecological Endoscopy (ESGE) jointly developed clinically relevant and evidence-based statements on the pre-operative diagnosis of ovarian tumors, including imaging techniques, biomarkers, and prediction models. ESGO/ISUOG/IOTA/ESGE nominated a multidisciplinary international group, including expert practising clinicians and researchers who have demonstrated leadership and expertise in the pre-operative diagnosis of ovarian tumors and management of patients with ovarian cancer (19 experts across Europe). A patient representative was also included in the group. To ensure that the statements were evidence-based, the current literature was reviewed and critically appraised. Preliminary statements were drafted based on the review of the relevant literature. During a conference call, the whole group discussed each preliminary statement and a first round of voting was carried out. Statements were removed when a consensus among group members was not obtained. The voters had the opportunity to provide comments/suggestions with their votes. The statements were then revised accordingly. Another round of voting was carried out according to the same rules to allow the whole group to evaluate the revised version of the statements. The group achieved consensus on 18 statements. This Consensus Statement presents these ESGO/ISUOG/IOTA/ESGE statements on the pre-operative diagnosis of ovarian tumors and the assessment of carcinomatosis, together with a summary of the evidence supporting each statement. ispartof: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER vol:31 issue:7 pages:961-982 ispartof: location:England status: published

There are multiple classifications in imaging and surgery of endometriosis and in this article, we offer a review of the main evaluation systems. The International Deep Endometriosis Analysis group consensus is the leading document for ultrasound assessment, while magnetic resonance imaging is guided by the European Society for Urogenital Radiology recommendations on technical protocol. In surgery, the revised American Society for Reproductive Medicine classification is the oldest system, ideally combined with newer classifications, such as Enzian or Endometriosis Fertility Index. Recently, The World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project introduced detailed proforma for clinical and intraoperative findings. There is still no universal consensus, so the initial emphasis should be on the uniform reporting of the disease extent until research clarifies more the correlations between extent, symptoms and progression in order to develop a reliable staging system.Impact Statement

Objective DCVAC/OvCa is an active cellular immunotherapy designed to stimulate an immune response against ovarian cancer. We explored the safety and efficacy of DCVAC/OvCa plus carboplatin and gemcitabine in platinum-sensitive ovarian cancer. Methods In this open-label, parallel-group, phase 2 trial ( ClinicalTrials.gov number NCT02107950 ), patients with platinum-sensitive ovarian cancer relapsing after first-line chemotherapy were randomized to DCVAC/OvCa and chemotherapy or chemotherapy alone. DCVAC/OvCa was administered every 3–6 weeks (10 doses). Endpoints included safety, progression-free survival (PFS; primary efficacy endpoint) and overall survival (OS; secondary efficacy endpoint). Results Between November 2013 and May 2015, 71 patients were randomized to chemotherapy in combination with DCVAC/OvCa or to chemotherapy alone. Treatment-emergent adverse events related to DCVAC/OvCa, leukapheresis and chemotherapy occurred in six (16.2%), two (5.4%), and 35 (94.6%) patients in the DCVAC/OvCa group. Chemotherapy-related events occurred in all patients in the chemotherapy group. Seven patients in the DCVAC/OvCa group were excluded from primary efficacy analyses due to failure to receive ≥1 dose of DCVAC/OvCa. PFS was not improved (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.42–1.28, P = 0.274, data maturity 78.1%). Median OS was significantly prolonged (by 13.4 months) in the DCVAC/OvCa group (HR 0.38, 95% CI 0.20–0.74, P = 0.003; data maturity 56.3%). A signal for enhanced surrogate antigen-specific T-cell activity was seen with DCVAC/OvCa. Conclusions DCVAC/OvCa combined with chemotherapy had a favorable safety profile in patients with platinum-sensitive ovarian cancer. DCVAC/OvCa did not improve PFS, but the exploratory analyses revealed OS prolongation and enhanced surrogate antigen-specific T-cell activity.

IntroductionSentinel lymph node dissection is widely used in the staging of endometrial cancer. Variation in surgical techniques potentially impacts diagnostic accuracy and oncologic outcomes, and poses barriers to the comparison of outcomes across institutions or clinical trial sites. Standardization of surgical technique and surgical quality assessment tools are critical to the conduct of clinical trials. By identifying mandatory and prohibited steps of sentinel lymph node (SLN) dissection in endometrial cancer, the purpose of this study was to develop and validate a competency assessment tool for use in surgical quality assurance.MethodsA Delphi methodology was applied, included 35 expert gynecological oncology surgeons from 16 countries. Interviews identified key steps and tasks which were rated mandatory, optional, or prohibited using questionnaires. Using the surgical steps for which consensus was achieved, a competency assessment tool was developed and subjected to assessments of validity and reliability.ResultsSeventy percent consensus agreement standardized the specific mandatory, optional, and prohibited steps of SLN dissection for endometrial cancer and informed the development of a competency assessment tool. Consensus agreement identified 21 mandatory and three prohibited steps to complete a SLN dissection. The competency assessment tool was used to rate surgical quality in three preselected videos, demonstrating clear separation in the rating of the skill level displayed with mean skills summary scores differing significantly between the three videos (F score=89.4; PConclusionSpecific mandatory and prohibited steps of SLN dissection in endometrial cancer have been identified and validated based on consensus among a large number of international experts. A competency assessment tool is now available and can be used for surgeon selection in clinical trials and for ongoing, prospective quality assurance in routine clinical care.

Summary Background Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue factor-directed antibody–drug conjugate, in this patient population. Methods This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396. Findings 102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1–13·0). The confirmed objective response rate was 24% (95% CI 16–33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 [38%] of 101 patients), epistaxis (30 [30%]), nausea (27 [27%]), conjunctivitis (26 [26%]), fatigue (26 [26%]), and dry eye (23 [23%]). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three [3%] patients), fatigue (two [2%]), ulcerative keratitis (two [2%]), and peripheral neuropathies (two [2%] each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two [2%] patients) and pyrexia (two [2%]). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes. Interpretation Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer. Funding Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups.

BackgroundPlatinum-resistant ovarian cancer patients have a poor prognosis and few treatment options are available. Preclinical and clinical data demonstrated that the combination of poly-ADP ribose polymerase inhibitors with immune checkpoint inhibitors could have a synergistic antitumor activity in this setting of patients.Primary ObjectiveThe primary objective is to assess the efficacy of niraparib plus dostarlimab compared with chemotherapy in recurrent ovarian cancer patients not suitable for platinum treatment.Study HypothesisThis trial will assess the hypothesis that niraparib plus dostarlimab therapy is effective to increase overall survival, progression-free survival, and time to first subsequent therapy respect to chemotherapy alone, with an acceptable toxicity profile.Trial DesignThis is a phase III, multicenter trial, where recurrent ovarian cancer patients not eligible for platinum re-treatment will be randomized 1:1 to receive niraparib plus dostarlimab vs physician’s choice chemotherapy until disease progression, intolerable toxicity, or withdrawal of patient consent. The study will be performed according to European Network for Gynaecological Oncological Trial groups (ENGOT) model B and patients will be recruited from 40 sites across MITO, CEEGOG, GINECO, HeCOG, MANGO, and NOGGO groups.Major Inclusion/Exclusion criteriaEligible patients must have recurrent epithelial ovarian cancer not eligible for platinum retreatment. Patients who received previous treatment with poly-ADP ribose polymerase inhibitors and/or immune checkpoint inhibitors will be eligible. No more than two prior lines of treatment are allowed.Primary EndpointThe primary endpoint is overall survival defined as the time from the randomization to the date of death by any cause.Sample Size427 patients will be randomized.Estimated Dates for Completing Accrual and Presenting ResultsJune 2024Trial Registration NumberNCT04679064.

The European Society of Gynaecological Oncology (ESGO), the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG), the International Ovarian Tumour Analysis (IOTA) group and the European Society for Gynaecological Endoscopy (ESGE) jointly developed clinically relevant and evidence-based statements on the preoperative diagnosis of ovarian tumors, including imaging techniques, biomarkers and prediction models. ESGO/ISUOG/IOTA/ESGE nominated a multidisciplinary international group, including expert practising clinicians and researchers who have demonstrated leadership and expertise in the preoperative diagnosis of ovarian tumors and management of patients with ovarian cancer (19 experts across Europe). A patient representative was also included in the group. To ensure that the statements were evidence-based, the current literature was reviewed and critically appraised. Preliminary statements were drafted based on the review of the relevant literature. During a conference call, the whole group discussed each preliminary statement and a first round of voting was carried out. Statements were removed when consensus among group members was not obtained. The voters had the opportunity to provide comments/suggestions with their votes. The statements were then revised accordingly. Another round of voting was carried out according to the same rules to allow the whole group to evaluate the revised version of the statements. The group achieved consensus on 18 statements. This Consensus Statement presents these ESGO/ISUOG/IOTA/ESGE statements on the preoperative diagnosis of ovarian tumors and the assessment of carcinomatosis, together with a summary of the evidence supporting each statement.

TPS5603 Background: Despite the use of platinum-taxane doublets ± bev in eligible patients (pts), overall survival (OS) outcomes for pts with r/mCC remain poor. With the US approval of pembro + chemotherapy ± bev in the 1L setting for r/mCC with ≥1% of programmed death ligand 1–positive cells in the tumor, an unmet need remains for pts who do not meet this threshold and for pts who progress or are intolerant to standard treatment (tx). TV is a tissue factor–directed antibody–drug conjugate that has been granted accelerated approval in the United States for the tx of adults with r/mCC with disease progression on or after chemotherapy. To develop more effective treatments, we investigated TV in combination with agents with known activity in cervical cancer. We conducted a 2-part, multicohort phase 1b/2 trial, ENGOT-cx8/GOG-3024/innovaTV 205 (NCT03786081), to evaluate TV in combination with bev, pembro, or carbo. The phase 1b dose-escalation phase of innovaTV 205 established the recommended phase 2 dose (RP2D) and the feasibility of these doublet combinations (Monk et al, IGCS 2021). Moreover, we recently reported encouraging antitumor activity from the dose-expansion cohort of TV + carbo (1L; confirmed objective response rate [ORR], 55%; median duration of response [DOR], 8.3 mo) and TV + pembro (second-line; confirmed ORR, 38%; median DOR, 13.8 mo) (Vergote et al, ESMO 2021). The current report describes the design of a new, ongoing dose expansion cohort in the innovaTV 205 study to evaluate the combinations of TV, pembro, and carbo ± bev. Methods: A new cohort has been added to the innovaTV 205 study, comprising adult pts with recurrent or stage IVB squamous, adenosquamous, or adenocarcinoma of the cervix with no prior systemic therapy and an Eastern Cooperative Oncology Group score of 0 or 1. Pts will be treated with the RP2D of TV (2.0 mg/kg) + carbo (AUC 5 mg/mL), pembro (200 mg), and bev (15 mg/kg) every 3 weeks or with TV + carbo (AUC 5 mg/mL) and pembro (200 mg). To assess the regimen’s initial tolerability, there will be a dose-limiting toxicity evaluation period that will consist of completion of 1 tx cycle of 21 days for 6 pts enrolled to receive the quadruplet combination. The primary endpoint of this dose expansion phase is confirmed ORR per RECIST v1.1; secondary endpoints include DOR, time to response, progression-free survival, OS, and safety. Enrollment is ongoing in the United States and Europe, with additional sites planned globally. Clinical trial information: NCT03786081.

TPS5612 Background: Standard of care chemotherapy in patients (pts) with advanced ovarian cancer (AOC) is the combination of carboplatin and paclitaxel. Data from the PRIMA trial has shown a significant benefit in pts by the addition of a maintenance treatment (MT) with niraparib irrespective of BRCA or HRD-status in high-grade ovarian cancers (OC). The PAOLA-1 trial evaluated MT in pts with AOC with the combination of olaparib and bevacizumab and has also shown a significant benefit compared to bevacizumab monotherapy. However, it is unclear if a PARP-inhibitor (PARPi) MT monotherapy is sufficient or if the addition of bevacizumab is needed. Therefore, we investigate, if the treatment strategy of carboplatin / paclitaxel / bevacizumab / PARPi is superior to the treatment of carboplatin / paclitaxel / PARPi in an all-comer population. Methods: AGO-OVAR 28/ ENGOT-ov57 (NCT05009082; EudraCT Number: 2021-001271-16) is an Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Study Group led, international, multicenter, randomized, prospective phase III trial within the ENGOT trial network. The trial population is composed of adult pts with newly diagnosed, advanced high-grade epithelial OC, primary peritoneal cancer or fallopian tube cancer FIGO III/IV (except FIGO IIIA2 without nodal involvement). All pts should have completed the first cycle of chemotherapy (carboplatin and paclitaxel) as part of Study Run-In-Period. Prior to day1 of cycle2, pts with a valid central tumor BRCA ( tBRCA) test result will be randomized 1:1 into either Arm1 and will receive 5 additional cycles of carboplatin and paclitaxel, q21d followed by niraparib for up to 3 years; or into Arm2 where pts will receive 5 additional cycles of carboplatin and paclitaxel plus bevacizumab, q21d followed by bevacizumab, q21d (for up to 1 year) and niraparib for up to 3 years. Patients who are scheduled for neoadjuvant chemotherapy and interval debulking surgery are also allowed to be included in the trial. The primary objective is progression free survival (PFS). Secondary objectives include but are not limited to: PFS according to tBRCA-status, overall survival, PFS2, safety and tolerability, and quality of life. The trial will start in Q1/2022 with First Patient First Visit expected in Q2/2022. It is planned to recruit 970 patients. Clinical trial information: NCT05009082.

TPS5623 Background: Carboplatin-paclitaxel chemotherapy (with trastuzumab for HER2+ uterine serous carcinoma) is the standard of care first-line systemic treatment for recurrent or metastatic endometrial carcinoma (EC), which has a 5-year relative survival rate of only 17%. Worse survival outcomes have been shown for the mismatch repair deficient (dMMR) subtype of EC. Pembrolizumab (pembro), an anti-PD-1 antibody, showed compelling antitumor activity in previously treated, advanced MSI-H/dMMR EC in the phase 2 KEYNOTE-158 study (ORR, 48%; median duration of response [DOR], not reached; O’Malley JCO 2022). KEYNOTE-C93/GOG-3064/ENGOT-en15 (NCT05173987) is a phase 3, randomized, open-label study evaluating first-line pembro versus carboplatin-paclitaxel chemotherapy in patients with dMMR advanced or recurrent EC. Methods: Patients aged ≥18 years with histologically confirmed stage III/IV recurrent EC including carcinosarcoma (mixed Mullerian tumor), radiographically evaluable disease (measurable or nonmeasurable per RECIST v1.1), no prior systemic therapy (prior radiation with or without radiosensitizing chemotherapy > 2 weeks before first dose or prior hormonal therapy ≥1 week before randomization is permitted), and an ECOG PS ≤1 are eligible. Patients must have central confirmation of dMMR status. Approximately 350 patients will be randomized 1:1 to receive pembro 400 mg IV Q6W for 18 cycles (̃2 years) or carboplatin AUC 5 or 6 mg/mL/min IV Q3W and paclitaxel 175 mg/m2 IV Q3W for 6 cycles (with option for > 6 cycles). Trastuzumab is permitted for patients in the chemotherapy arm with HER2+ serous EC. Randomization is stratified by disease status (newly diagnosed advanced EC vs recurrent EC) and histology (endometrioid vs nonendometrioid). Treatment will continue for the specified number of cycles or until PD or unacceptable toxicity. Patients in the chemotherapy arm have the option to receive pembro following confirmed PD by blinded independent central review (BICR). Tumor imaging will be performed Q9W from randomization to week 54 and Q12W thereafter. AEs will be assessed from randomization to 30 days (90 days for serious AEs) after treatment discontinuation and graded per NCI CTCAE version 5.0. Dual primary endpoints are PFS per RECIST v1.1 by BICR and OS. Secondary endpoints are ORR, disease control rate, and DOR per RECIST v1.1 by BICR; PFS per RECIST v1.1 by investigator review; PFS2 (ie, time from randomization to PD per investigator assessment or death from any cause after start of subsequent anticancer therapy); safety; and patient-reported outcomes. PFS and OS will be estimated by the Kaplan-Meier method, with treatment differences assessed by the stratified log-rank test and HRs with 95% CIs determined using a Cox proportional hazard model. Enrollment is ongoing. Clinical trial information: NCT05173987.

5507 Background: TV monotherapy has received US accelerated approval for previously treated r/mCC with disease progression on or after chemotherapy based on clinically meaningful tumor response rate and duration of response (DOR) reported from the GOG-3023/ENGOT-cx6/innovaTV 204 study (Coleman et al., Lancet Onc. 2021). Recently, the recommended phase 2 dose (RP2D) and feasibility of TV + pembro, TV + carboplatin (carbo), and TV + bevacizumab in r/mCC were reported from the dose-escalation phase (Monk et al, IGCS 2021); interim safety and efficacy data from 2 dose-expansion cohorts, 1L TV + carbo and second-line/third-line (2L/3L) TV + pembro (Vergote et al, ESMO 2021) from the ENGOT-cx8/GOG-3024/innovaTV 205 (NCT03786081) study, were also reported. Here we report interim safety and efficacy results from a third dose-expansion cohort evaluating 1L TV + pembro in patients with r/mCC. Methods: Patients with r/mCC who had not received prior systemic therapy (excluding chemoradiation) for r/mCC were treated with the RP2D of TV 2.0 mg/kg + pembro 200 mg intravenously every 3 weeks. The primary endpoint was investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1; secondary endpoints included DOR, progression-free survival (PFS), overall survival (OS), and safety. Results: 33 pts were treated with 1L TV + pembro (median 6 cycles). At data cutoff (July 1, 2021), median duration of exposure to TV + pembro was 5.1 mo (range 1-17) and median follow-up was 12.2 mo (range 1-17). Confirmed ORR among 32 evaluable patients was 41% (95% CI 24-59), with 3 (9%) complete responses and 10 (31%) partial responses. Median time to response was 1.4 mo (range 1.2-2.8); median DOR was not reached, with response ongoing in 7/13 patients. Median PFS was 5.3 mo (95% CI 4.0-12.2); median OS was not reached. The most common treatment-emergent AEs (TEAEs) were alopecia (61%), diarrhea (55%), epistaxis (49%), conjunctivitis (46%), and nausea (46%). Grade ≥3 TEAEs occurred in 67% of patients, the most common being anemia (12%); asthenia (9%); hypokalemia (9%); and increased alanine aminotransferase, decreased white blood cell count, dyspnea, and acute kidney injury (6% each). Three grade 5 TEAEs were reported of which one, disseminated intravascular coagulation, was considered treatment-related. Prespecified AEs of interest (grade 1-2/grade ≥3) with TV included ocular (58%/9%), peripheral neuropathy (45%/3%), and bleeding (61%/6%). Updated results with longer follow-up for this cohort and the 1L TV + carbo and 2L/3L TV + pembro cohorts will be provided at the meeting. Conclusions: TV + pembro demonstrated encouraging, durable antitumor activity with a manageable and acceptable safety profile as a 1L regimen for patients with r/mCC. This trial is ongoing and final analyses will be reported in the future. Clinical trial information: NCT03786081.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.

We thank Isabelle Thomassin-Nagarra et al for their interest in the ESGO/ISUOG/IOTA/ESGE consensus statement on the pre-operative diagnosis of ovarian tumors. This statement is based on a careful review of the relevant literature and available evidence as well as on structured discussions between

IntroductionComprehensive updated information on cervical cancer surgical treatment in Europe is scarce.ObjectiveTo evaluate baseline characteristics of women with early cervical cancer and to analyze the outcomes of the ESGO quality indicators after radical hysterectomy in the SUCCOR database.MethodsThe SUCCOR database consisted of 1272 patients who underwent radical hysterectomy for stage IB1 cervical cancer (FIGO 2009) between January 2013 and December 2014. After exclusion criteria, the final sample included 1156 patients. This study first described the clinical, surgical, pathological, and follow-up variables of this population and then analyzed the outcomes (disease-free survival and overall survival) after radical hysterectomy. Surgical-related ESGO quality indicators were assessed and the accomplishment of the stated recommendations was verified.ResultsThe mean age of the patients was 47.1 years (SD 10.8), with a mean body mass index of 25.4 kg/m2 (SD 4.9). A total of 423 (36.6%) patients had a previous cone biopsy. Tumor size (clinical examination) ConclusionsIn this European cohort, the rate of adjuvant therapy after radical hysterectomy is higher than for most similar patients reported in the literature. The majority of centers were already following the European recommendations even 5 years prior to the ESGO quality indicator implementations.

BACKGROUND: Up to 26% of patients with early-stage cervical cancer experience relapse after primary surgery. However, little is known about which factors influence prognosis following disease recurrence. Therefore, our aims were to determine post-recurrence disease-specific survival (PR-DSS) and to identify respective prognostic factors for PR-DSS.METHODS: Data from 528 patients with early-stage cervical cancer who relapsed after primary surgery performed between 2007 and 2016 were obtained from the SCANN study (Surveillance in Cervical CANcer). Factors related to the primary disease and recurrence were combined in a multivariable Cox proportional hazards model to predict PR-DSS.RESULTS: The 5-year PR-DSS was 39.1% (95% confidence interval [CI] 22.7%-44.5%), median disease-free interval between primary surgery and recurrence (DFI1) was 1.5 years, and median survival after recurrence was 2.5 years. Six significant variables were identified in the multivariable analysis and were used to construct the prognostic model. Two were related to primary treatment (largest tumour size and lymphovascular space invasion) and four to recurrence (DFI1, age at recurrence, presence of symptoms, and recurrence type). The C-statistic after 10-fold cross-validation of prognostic model reached 0.701 (95% CI 0.675-0.727). Three risk-groups with significantly differing prognoses were identified, with 5-year PR-DSS rates of 81.8%, 44.6%, and 12.7%.CONCLUSIONS: We developed the robust model of PR-DSS to stratify patients with relapsed cervical cancer according to risk profiles using six routinely recorded prognostic markers. The model can be utilised in clinical practice to aid decision-making on the strategy of recurrence management, and to better inform the patients.

Objectives: The Phase III SOLO2 trial (NCT01874353) showed the significant benefit of maintenance olaparib for patients (pts) with platinum-sensitive relapsed ovarian cancer (PSROC) and a BRCA mutation (BRCAm), compared with placebo (median progression-free survival [PFS] 19.1 vs 5.5 months [m], respectively); however, no pts had a confirmed somatic (s) BRCAm and data prospectively evaluating efficacy of olaparib in this pt group were limited. ORZORA (NCT02476968), an open-label, single-arm, multicenter trial, was conducted to assess efficacy and safety of maintenance olaparib in PSROC pts with a BRCAm (s or germline [g]) who were in response to their most recent platinum-based chemotherapy after ≥2 lines of treatment. Methods: Pts underwent prospective central screening for tumor BRCAm status (myChoice CDx, Myriad Genetic Laboratories, Inc.), then s or g BRCAm status was determined by central g testing (BRACAnalysis CDx, Myriad Genetic Laboratories, Inc.). Pts received maintenance olaparib (400 mg bid; capsules) until disease progression. Co-primary endpoints were investigator-assessed PFS (RECIST v1.1) in BRCAm and s cohorts, conducted at 60% maturity. Secondary endpoints included time to second progression or death (PFS2), health-related quality of life (HRQoL; FACT-O trial outcome index) and tolerability. An additional exploratory cohort comprised pts with predefined homologous recombination repair gene mutations (HRRm) excluding BRCAm (FoundationOne CDx, Foundation Medicine, Inc.). Results: A total of 181 pts were enrolled in ORZORA (BRCAm n=145 [s n=55; g n=87; n=3 s vs g status unknown]; HRRm n=33; unassigned n=3). Pt characteristics were similar between s and g cohorts: ≥3 prior lines of chemotherapy (38% vs 48%, respectively); partial response to prior platinum (45% vs 49%); tumor BRCA1-mutated (65% vs 64%). At the data cut-off (April 17, 2020), median follow-up for PFS was 22.3 months. Median PFS was similar in the BRCAm, s and g cohorts, and exploratory HRRm cohort (Figure). Median PFS2 for BRCAm pts was 30.9 m (95% confidence interval [CI] 24.7–40.0; s 24.7 [21.8–36.1]; g 32.5 [25.3–not calculable]). HRQoL was comparable in BRCAm and s cohorts (best overall change from baseline: improved 22 vs 21%; no change 69 vs 68%; worsened 11 vs 12%, respectively). Most common adverse events (AE; n=177 treated pts) were nausea (54% pts), fatigue (43%), anemia (42%) and vomiting (28%). A total of 25% and 35% pts experienced serious and grade ≥3 (anemia 16% pts) AEs, respectively. 5% had an AE leading to treatment discontinuation. A total of 2 new primary malignancies, two acute myeloid leukemia and no myelodysplastic syndrome cases occurred. Download : Download high-res image (102KB) Download : Download full-size image Conclusions: PFS in pts with PSROC who received maintenance olaparib was similar irrespective of s or g BRCAm status. Activity of maintenance olaparib was also shown in pts with a non-BRCA HRRm. PFS, HRQoL and tolerability were consistent with previous olaparib studies in this population. Results highlight that PSROC pts beyond those with a gBRCAm can benefit from maintenance olaparib.

In centers with access to high-end ultrasound machines and expert sonologists, ultrasound is used to detect metastases in regional lymph nodes from melanoma, breast cancer and vulvar cancer. There is, as yet, no international consensus on ultrasound assessment of lymph nodes in any disease or medical condition. The lack of standardized ultrasound nomenclature to describe lymph nodes makes it difficult to compare results from different ultrasound studies and to find reliable ultrasound features for distinguishing non-infiltrated lymph nodes from lymph nodes infiltrated by cancer or lymphoma cells. The Vulvar International Tumor Analysis (VITA) collaborative group consists of gynecologists, gynecologic oncologists and radiologists with expertise in gynecologic cancer, particularly in the ultrasound staging and treatment of vulvar cancer. The work herein is a consensus opinion on terms, definitions and measurements which may be used to describe inguinal lymph nodes on grayscale and color/power Doppler ultrasound. The proposed nomenclature need not be limited to the description of inguinal lymph nodes as part of vulvar cancer staging; it can be used to describe peripheral lymph nodes in general, as well as non-peripheral (i.e. parietal or visceral) lymph nodes if these can be visualized clearly. The association between the ultrasound features described here and histopathological diagnosis has not yet been established. VITA terms and definitions lay the foundations for prospective studies aiming to identify ultrasound features typical of metastases and other pathology in lymph nodes and studies to elucidate the role of ultrasound in staging of vulvar and other malignancies. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Background The composition of the microbiome plays an important role in human health and disease. Whether there is a direct association between the cervicovaginal microbiome and the host’s epigenome is largely unexplored. Results Here we analyzed a total of 448 cervicovaginal smear samples and studied both the DNA methylome of the host and the microbiome using the Illumina EPIC array and next-generation sequencing, respectively. We found that those CpGs that are hypo-methylated in samples with non-lactobacilli (O-type) dominating communities are strongly associated with gastrointestinal differentiation and that a signature consisting of 819 CpGs was able to discriminate lactobacilli-dominating (L-type) from O-type samples with an area under the receiver operator characteristic curve (AUC) of 0.84 (95% CI = 0.77–0.90) in an independent validation set. The performance found in samples with more than 50% epithelial cells was further improved (AUC 0.87) and in women younger than 50 years of age was even higher (AUC 0.91). In a subset of 96 women, the buccal but not the blood cell DNA showed the same trend as the cervicovaginal samples in discriminating women with L- from O-type cervicovaginal communities. Conclusions These findings strongly support the view that the epithelial epigenome plays an essential role in hosting specific microbial communities.

Background High-risk locally advanced cervical cancer (CC) has a poor prognosis, and >50% of patients recur in 2 years. Concurrent chemoradiotherapy (CRT) may enhance the immunostimulatory activity of the PD-1 inhibitor pembrolizumab. After KEYNOTE-158, in which pembrolizumab demonstrated durable antitumor activity, pembrolizumab monotherapy was approved for patients with PD-L1–positive recurrent or metastatic CC who progressed during or after chemotherapy. ENGOT-cx11/KEYNOTE-A18 (NCT04221945) is a phase 3, randomized, placebo-controlled study evaluating pembrolizumab with concurrent CRT in locally advanced CC. Trial design Approximately 980 patients with high-risk, locally advanced, histologically confirmed CC who have not received systemic therapy, immunotherapy, definitive surgery, or radiation will be randomized 1:1 to receive 5 cycles of pembrolizumab 200 mg Q3W + CRT (5 cycles [with optional 6th cycle] of cisplatin 40 mg/m2 Q1W + external beam radiotherapy [EBRT] followed by brachytherapy) followed by 15 cycles of pembrolizumab 400 mg Q6W or 5 cycles of placebo Q3W + CRT followed by 15 cycles of placebo Q6W. Randomization is stratified by planned EBRT type, cancer stage at screening, and planned total radiotherapy dose. Treatment will continue until patient receives ≤20 cycles of pembrolizumab (5 cycles 200 mg Q3W, 15 cycles 400 mg Q6W) vs placebo (~2 years) or until disease progression, unacceptable toxicity, or withdrawal. Primary endpoints are PFS per RECIST v1.1 by blinded independent central review and OS. Secondary endpoints include PFS at 2 years, OS at 3 years, complete response at 12 weeks, ORR, PFS and OS in PD-L1–positive patients, and safety. Enrollment is ongoing.

Background Tumor Treating Fields (TTFields) are a non-invasive, antimitotic cancer therapy. The Phase 2 INNOVATE study demonstrated safety of TTFields/weekly paclitaxel in 31 PROC (platinum-resistant ovarian cancer) patients (Vergote Gyn Onc 2018); efficacy: median PFS 8.9 months, 25% partial response,71% clinical benefit and 61% 1-year survival rate. This phase 3 ENGOT-ov50/GOG-329/INNOVATE-3 study [NCT03940196] investigates TTFields plus weekly paclitaxel in PROC patients. Study Design Patients (N=540) will have PROC (RECIST V1.1) within 6 months of last platinum therapy with maximum of 2–5 prior lines of systemic therapy, ECOG 0–1 and no peripheral neuropathy >grade1. Patients with primary refractory disease will be excluded. Patients will be randomized 1:1 to weekly paclitaxel alone or weekly paclitaxel (starting of dose 80 mg/m2 weekly for 8 weeks, and then on Days 1, 8, and 15 for subsequent 28-day cycle ) plus TTFields (200 kHz for 18 hours/day and continued if no progression in the abdominal or pelvic regions (‘in-field region’) per RECIST V1.1. Clinical follow-up will be performed q4w, with radiological follow-up (CT or MRI scans of the abdomen and chest) q8w. The primary endpoint is overall survival. Secondary endpoints: PFS, objective response rate, AEs, and quality of life (EORTC QLQ-C30 with QLQ-OV28). Sample size (n=540) will detect an increase in median OS from 12 to 16 months (HR 0.75). Data Monitoring Committee (DMC) meeting (March 2020) concluded that data to-date showed no safety issues and recommended trial continuation.

OBJECTIVE: Voiding dysfunctions represent a leading morbidity after radical hysterectomy performed in patients with early-stage cervical cancer. The aim of this study was to perform ad hoc analysis of factors influencing voiding recovery in SENTIX (SENTinel lymph node biopsy in cervIX cancer) trial. METHODS: The SENTIX trial (47 sites, 18 countries) is a prospective study on sentinel lymph node biopsy without pelvic lymphadenectomy in patients with early-stage cervical cancer. Overall, the data of 300 patients were analysed. Voiding recovery was defined as the number of days from surgery to bladder catheter/epicystostomy removal or to post-voiding urine residuum ≤50 mL. RESULTS: The median voiding recovery time was three days (5th-95th percentile: 0-21): 235 (78.3%) patients recovered in 30 days. In the multivariate analysis, only previous pregnancy (p = 0.033) and type of parametrectomy (p < 0.001) significantly influenced voiding recovery >7 days post-surgery. Type-B parametrectomy was associated with a higher risk of delayed voiding recovery than type-C1 (OR = 4.69; p = 0.023 vs. OR = 3.62; p = 0.052, respectively), followed by type-C2 (OR = 5.84; p = 0.011). Both previous pregnancy and type C2 parametrectomy independently prolonged time to voiding recovery by two days. CONCLUSIONS: Time to voiding recovery is significantly related to previous pregnancy and type of parametrectomy but it is not influenced by surgical approach (open vs minimally invasive), age, or BMI. Type B parametrectomy, without direct visualisation of nerves, was associated with longer recovery than nerve-sparing type C1. Importantly, voiding dysfunctions after radical surgery are temporary, and the majority of the patients recover in less than 30 days, including patients after C2 parametrectomy.

Purpose. We aimed to compare the learning curves of an ultrasound trainee (obstetrics and gynecology resident) and a radiology trainee when assessing pelvic endometriosis. Methods. Consecutive patients with suspected endometriosis were prospectively enrolled in a tertiary center. They underwent an ultrasound and magnetic resonance imaging preoperatively, which was reported according to the International Deep Endometriosis Analysis (IDEA) group consensus. Trainees reported on deep endometriosis (DE), endometriomas, frozen pelvis, and adenomyosis. Using the Kappa agreement, their findings were compared against laparoscopy/histology and expert findings. The learning curve was considered positive when performance improved over time and indeterminate in all other cases. Results. Reports from thirty-five women were divided chronologically into 3 equal blocks to assess the learning curve. For ultrasound, trainee versus expert showed a positive learning curve in overall pelvic DE assessment. There was an excellent agreement for adenomyosis (Kappa=1.00, p=0.09), frozen pelvis (Kappa=0.90, p=0.01), bowel (Kappa=1.00, p=0.01), and bladder DE assessment (Kappa=1.00, p=0.01). Endometrioma and uterosacral ligament assessment showed an indeterminate curve. For radiology, trainee versus expert showed a positive curve when detecting adenomyosis (Kappa=0.42, p=0.09) and bladder DE (Kappa=1.00, p=0.01). The assessment of endometriomas, frozen pelvis, overall pelvic DE, bowel, and uterosacral ligament DE showed indeterminate curve. Agreement between trainees and laparoscopy/histology showed a positive curve for bladder (both) and frozen pelvis (ultrasound only). Conclusion. A positive learning curve can be seen in some areas of pelvic endometriosis mapping after as little as 35 cases, but a bigger caseload is required to demonstrate the curve in full. The ultrasound trainee had positive learning curves in more anatomical locations (bladder, adenomyosis, overall bowel DE, frozen pelvis) than the radiology trainee (bladder, adenomyosis), which could be down to individual factors, differences in training, or the imaging method itself.

PURPOSE Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC. METHODS This was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician’s choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ≥ 1 prior platinum-based chemotherapy but ≤ 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety. RESULTS A total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ≥ 12.0 months) versus 6.7 months (0.03 to ≥ 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ≥ 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent. CONCLUSION Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib.

ispartof: ULTRASOUND IN OBSTETRICS & GYNECOLOGY vol:55 issue:6 pages:879-885 ispartof: location:England status: published

BackgroundRadical trachelectomy is considered a viable option for fertility preservation in patients with low-risk, early-stage cervical cancer. Standard approaches include laparotomy or minimally invasive surgery when performing radical trachelectomy.Primary ObjectiveTo compare disease-free survival between patients with FIGO (2009) stage IA2 or IB1 (≤2cm) cervical cancer who underwent open versus minimally invasive (laparoscopic or robotic) radical trachelectomy.Study HypothesisWe hypothesize that minimally invasive radical trachelectomy has similar oncologic outcomes to those of the open approach.Study DesignThis is a collaborative, multi-institutional, international, retrospective study. Patients who underwent a radical trachelectomy and lymphadenectomy between January 1, 2005 and December 31, 2017 will be included. Institutional review board approval will be required. Each institution will be provided access to a study-specific REDCap (Research Electronic Data Capture) database maintained by MD Anderson Cancer Center and will be responsible for entering patient data.Inclusion CriteriaPatients with squamous, adenocarcinoma, or adenosquamous cervical cancer FIGO (2009) stages IA2 and IB1 (≤2 cm) will be included. Surgery performed by the open approach or minimally invasive approach (laparoscopy or robotics). Tumor size ≤2 cm, by physical examination, ultrasound, MRI, CT, or positron emission tomography (at least one should confirm a tumor size ≤2 cm). Centers must contribute at least 15 cases of radical trachelectomy (open, minimally invasive, or both).Exclusion CriteriaPrior neoadjuvant chemotherapy or radiotherapy to the pelvis for cervical cancer at any time, prior lymphadenectomy, or pelvic retroperitoneal surgery, pregnant patients, aborted trachelectomy (intra-operative conversion to radical hysterectomy), or vaginal approach.Primary EndpointThe primary endpoint is disease-free survival measured as the time from surgery until recurrence or death due to disease. To evaluate the primary objective, we will compare disease-free survival among patients with FIGO (2009) stage IA2 or IB1 (≤2cm) cervical cancer who underwent open versus minimally invasive radical trachelectomy.Sample SizeAn estimated 535 patients will be included; 256 open and 279 minimally invasive radical trachelectomy. Previous studies have shown that recurrence rates in the open group range from 3.8% to 7.6%. Assuming that the 4.5-year disease-free survival rate for patients who underwent open surgery is 95.0%, we have 80% power to detect a 0.44 HR using α level 0.10. This corresponds to an 89.0% disease-free survival rate at 4.5 years in the minimally invasive group.

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. ispartof: CANCERS vol:12 issue:5 ispartof: location:Switzerland status: published

OBJECTIVE To revise FIGO staging of carcinoma of the cervix uteri, allowing incorporation of imaging and/or pathological findings, and clinical assessment of tumor size and disease extent. METHODS Review of literature and consensus view of the FIGO Gynecologic Oncology Committee and related societies and organizations. RESULTS In stage I, revision of the definition of microinvasion and lesion size as follows. Stage IA: lateral extension measurement is removed; stage IB has three subgroups-stage IB1: invasive carcinomas ≥5 mm and

ObjectiveSentinel lymph node (SLN) biopsy has been increasingly used in the management of early-stage cervical cancer. It appears in guidelines as an alternative option to systematic pelvic lymphadenectomy. The evidence about safety is, however, based mostly on retrospective studies, in which SLN was combined with systematic lymphadenectomy.Materials and methodsSENTIX is a prospective multicenter trial aiming to prove that less-radical surgery with SLN is non-inferior to treatment with systematic pelvic lymphadenectomy. The primary end point is recurrence rate; the secondary end point is the prevalence of lower-leg lymphedema and symptomatic pelvic lymphocele. The reference recurrence rate was set up conservatively at 7% at 24 months after treatment. With a sample size of 300 patients treated per protocol, the trial is powered to detect a non-inferiority margin of 5% (90% power, p = 0.05) for recurrence rate, 30% reduction in the prevalence of symptomatic lymphocele or lower-leg lymphedema, with reference rates of 30% and 6% at 12 months (p = 0.025, Bonferroni correction). The patients eligible for SENTIX have stage IA1/LVSI+, IA2, IB1 (IB1), or a positive intra-operative SLN assessment. The quality of SLN pathology evaluation will be assessed by central review. Three interim safety analyses are pre-planned when 30, 60, 150 patients complete 12 months' follow-up.ConclusionsThe first patient was enrolled into the study in June 2016 and, by June 2018, 340 patients had been enrolled. The first analysis of secondary outcomes should be available in 2019 and the oncological outcome of 300 patients at the end of 2021. The trial is registered as a CEEGOG trial (CEEGOG CX-01), ENGOT trial (ENGOT-Cx 2), and at the ClinicalTrials.gov database (NCT02494063).

Sentinel lymph node (SLN) biopsy has been increasingly used in the management of early-stages cervical cancer instead of systematic pelvic lymph node dissection (PLND). The aim of this article is to give a critical overview of key aspects related to this concept, such as a necessity for reliable detection of micrometastases (MIC) in SLN and the requirements for SLN pathologic ultrastaging, low accuracy of intraoperative detection of SLN involvement, and still a limited evidence of oncological safety of the replacement of PLND by SLN biopsy only in ≥IB1 tumours due to unknown risk of MIC in non-SLN pelvic lymph nodes in patients with negative SLN, and absence of any prospective evidence.

Background: High grade serous ovarian cancer (HGSC), the most common and aggressive type of ovarian cancer, is nearly always driven by TP53 mutations, which can be detected in uterine lavages using ultra-deep duplex sequencing. While this finding supports the development of a uterine lavage assay for early HGSC detection, age-related TP53 mutations compromise specificity. The goal of this study was to thoroughly characterize the nature of TP53 mutations identified in uterine lavage of women with and without HGSC to better understand TP53 clonal evolution during aging and to determine its association to HGSC. Methods: Uterine lavages were collected preoperatively in 54 “average-risk” women undergoing gynecological surgery for suspicious masses (34 women ultimately had HGSC, 20 were cancer free) and in 98 “high-risk” women undergoing risk-reducing salpingo-oopherectomy (17 were found to have HGSC or serous tubal intraepithelial carcinomas (STICs), 81 were cancer-free). Ultra-deep (>10,000x), ultra-accurate sequencing of TP53 was performed on uterine lavage DNA using duplex sequencing. Tumors and STICs were also duplex sequenced to determine TP53 tumor-driving mutations. The frequency of TP53 mutations and large TP53 mutant clones (those found in >2 duplex reads) was compared between women with and without HGSC. Results: The tumor-specific TP53 mutation was detected in 53% of lavages from average-risk women with HGSC and in 22% of lavages from high-risk women with HGSC/STICs. As in prior studies, TP53 biological background mutations were identified in nearly all women and their frequency was age-related. TP53 background mutations, however, were more abundant in women with prior chemotherapy, regardless of their cancer status or age. In women without prior chemotherapy and without high-risk of HGSC, having HGSC was associated with a significantly higher frequency of large TP53 mutant clones (p=0.007) and large TP53 mutant clones containing pathogenic mutations (p=0.007) or TP53 mutations commonly found in cancer (p=0.001). Interestingly, women at high risk of HGSC also carried high frequency of large and pathogenic TP53 mutant clones in lavage, even in those cases in which cancer or STICs were not identified. Conclusions: Ultra-sensitive duplex sequencing enabled detection of a patient’s HGSC or STIC driver mutations, respectively, in about half and a quarter of uterine lavages. However, of even greater interest, we observed a significant excess of large and pathogenic TP53 mutant clones in lavages of women with HGSC that were not present in the tumor. These results indicate that TP53 somatic evolution is associated with HGSC development and suggest that the measurement of TP53 mutant clones in uterine lavages harbors value as a predictor of ovarian cancer risk. Citation Format: Rosana Risques, Thomas H. Smith, Zachary K. Norgaard, Roniz Katz, Fang Yin Lo, Elizabeth K. Schmidt, Jacob E. Higgins, Martin Filipits, Intidhar Labidi-Galy, David Cibula, Lukáš Dostálek, Gabriel Jelenek, Magdalena Plch, Jiří Bouda, Alexander Mustea, Mateja Condic, Sabine Grill, Noreen Gleeson, Peter Oppelt, Gunda Pristauz-Telsnigg, Adriaan Vanderstichele, Siel Obrecht, Adam Rosenthal, Paul Speiser, Jesse Salk. TP53 field defects in uterine fluid are associated with ovarian cancer risk [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr PR005.

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR005) of the Conference Proceedings. Citation Format: Rosana Risques, Thomas H. Smith, Zachary K. Norgaard, Roniz Katz, Fang Yin Lo, Elizabeth K. Schmidt, Jacob E. Higgins, Martin Filipits, Intidhar Labidi-Galy, David Cibula, Lukáš Dostálek, Gabriel Jelenek, Magdalena Plch, Jiří Bouda, Alexander Mustea, Mateja Condic, Sabine Grill, Noreen Gleeson, Peter Oppelt, Gunda Pristauz-Telsnigg, Adriaan Vanderstichele, Siel Obrecht, Adam Rosenthal, Paul Speiser, Jesse Salk. TP53 field defects in uterine fluid are associated with ovarian cancer risk [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A008.

To evaluate morbidity and oncological outcome in a multicentre series of women with gynaecological malignancies infiltrating pelvic side wall (PSW) that received laterally extended pelvic resection (LEPR). Patients operated between 2007 and 2017 at three institutions were included. LEPR was defined as an en bloc lateral resection of a pelvic tumour involving sidewall muscle, and/or bone, and/or major nerve, and/or major vascular structure. Postsurgical complications and survivals were evaluated. Sixty-three women with gynaecological tumours involving PSW were treated with LEPR. Five women underwent primary LEPR, whereas 58 (92%) patients needed LEPR because of recurrence. Twenty-four women (38%) received previous radiation therapy before the surgery. R0 resection was achieved in 54 patients (85.7%), whereas the pathologic margins were microscopically and macroscopically positive in 8 (12.7%) patients and 1 (1.6%) patient, respectively. There was one perioperative death, whereas major postoperative complications occurred in 17 patients (27.7%). Thirty (47.5%) women experienced recurrences: 24/54 (44.4%) were in the R0 group, and 6/9 (66.6%) were in the R1 group, with a median PFS of 15 months and 7 months, respectively (p = 0.024). In total, 11 of 54 (20.3%) patients died of disease in the R0 group and 5 of 9 (55.5%) in the R1 group; a median OS was not reached and was 32 months for R0 and R1 groups, respectively (p = 0.033). Involvement of the PSW should not prevent obtaining R0 resection. Although the LEPR is associated with considerable morbidity (≈ 30%), a long-term survival seems to be achieved in those women with complete resection.

Objectives The role of adjuvant radiotherapy for lymph node-negative stage IB patients with tumor-related negative prognostic factors is not uniformly accepted. It is advocated based on the GOG 92 trial, which was initiated in 1989. The aim of the current study is to report the oncological outcome of “intermediate risk” patients treated by tailored surgery without adjuvant radiotherapy. Data from two institutions that refer these patients for adjuvant radiotherapy served as a control group. Methods Included were patients with stage IB cervical cancer treated with radical hysterectomy and pelvic lymphadenectomy, who had negative pelvic lymph nodes but a combination of negative prognostic factors adopted from the GOG 92 trial. Data were obtained from prospectively collected databases of three institutions. Radical surgery was a single-treatment modality in one of them and in the remaining two institutes it was followed by adjuvant chemoradiation. Results In 127 patients who received only radical surgery, with a median follow-up of 6.1 years, the local recurrence rate was 1.6% (2 cases), and total recurrence was 6.3% (8 cases). Disease-specific survival at 5 years was 95.7% (91.9%; 99.4%) and 91% (83.7%; 98.3%) at 10 years. The only significant factor for disease-specific survival was tumor size ≥4 cm (P = 0.032). The recurrence rate, local control or overall survival did not differ from the control group. Adjuvant radiotherapy was not a significant prognostic factor within the whole cohort. Conclusions An excellent oncological outcome, especially local control, can be achieved by both radical surgery or combined treatment in stage IB lymph node-negative cervical cancer patients with negative prognostic factors. The substantially better outcome than in the GOG 92 trial can be attributed to more accurate pre-operative and pathological staging and an improvement in surgical techniques.

Objectives: Prospective studies comparing poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors with standard-of-care (SOC) chemotherapy (CT) in patients (pts) with relapsed ovarian cancer (OC) are currently limited. ARIEL4 (NCT02855944) is a phase III, randomized, open-label, international, multicenter study of the efficacy and safety of rucaparib vs SOC CT as treatment for PARP-inhibitor naive pts with relapsed high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer, who had a deleterious BRCA1/2 (BRCA) mutation and had received ≥2 prior CT regimens. Methods: Pts were randomized 2:1 to oral rucaparib 600 mg twice daily or SOC CT and stratified based on progression-free interval (≥1 to Results: A total of 233 pts were randomized to rucaparib and 116 to CT (visit cutoff Sep 30, 2020); 179 (51.3%) had platinum-resistant, 96 (27.5%) had partially platinum-sensitive, and 74 (21.2%) had fully platinum-sensitive disease. A total of 23 pts (6.6%) with BRCA reversion mutations and 1 pt without a BRCA mutation were excluded from the efficacy population. Median PFS was significantly longer with rucaparib vs CT in both the efficacy and ITT populations (Table). In an exploratory analysis of pts with BRCA reversion mutations, median PFS was shorter with rucaparib (n=13) vs CT (n=10); 2.9 vs 5.5 months, hazard ratio 2.769 (95% CI, 0.989–7.755). ORR was not significantly different between the rucaparib and CT arms in both populations (Table). Adverse events were consistent with the known safety profiles of rucaparib and CT. Download : Download high-res image (119KB) Download : Download full-size image Conclusions: Patients with BRCA-mutated advanced, relapsed OC who received rucaparib had a significant improvement in PFS vs SOC CT. No new safety signals were identified. This is the first prospective report from a randomized trial demonstrating that the presence of a BRCA reversion mutation predicts for primary resistance to rucaparib.

Objectives: Although primary results from the IMagyn050 trial showed no statistically significant improvement in progression-free survival (PFS) with atezo added to carboplatin/paclitaxel/bevacizumab (CPB) [Moore, ESMO 2020], the impact of this regimen on selected patient (pt)-reported ovarian cancer symptoms, function, and health-related quality of life (HRQoL) is unknown and the focus of this study. Methods: IMagyn050 is a double-blind randomized phase 3 trial evaluating the efficacy and safety of adding atezo/placebo to CPB followed by maintenance bevacizumab + atezo/placebo. The trial includes two cohorts: neoadjuvant chemotherapy (NACT) and primary surgery (PS). Pts complete EORTC QLQ-C30, QLQ-OV28, and FACT-G single-item GP5 at baseline (BL) and at regular intervals during treatment and follow-up. In NACT pts, prespecified responder analyses (using a ≥10-point cutoff for clinically meaningful change) assessed improvement in abdominal pain (OV28 item 31) and bloating (OV28 item 32) at week 9, comparing treatment arms by Cochran-Mantel-Haenszel (CMH) testing. Additional secondary objectives in the NACT and PS cohorts were assessments of function (physical, role, emotional, social) and HRQoL, as measured by QLQ-C30 functional and global health status/quality of life scales. Exploratory endpoints included mean change from BL in symptoms (QLQ-C30 and OV28) and treatment side-effect bother (FACT-G GP5) in both cohorts. Results: Of 1301 randomized pts, completion rates for each of the 3 questionnaires were 83-100% at BL and >85% on treatment. In NACT pts, mean BL scores were similar in the atezo vs placebo arms for abdominal pain (40.2 vs 44.8) and bloating (50.4 vs 56.3). At week 9, there was no difference between treatments in the proportion of NACT pts with ≥10-point improvement in either symptom (abdominal pain: 69/136 [51%] with atezo vs 77/142 [54%] with placebo, CMH p=0.56; bloating: 74 [54%] vs 89 [63%], CMH p=0.14). Results were consistent when restricted to NACT pts with sufficient BL symptoms to show ≥10-point improvement. There was no difference between treatments in the proportion of NACT pts with improvement in function or HRQoL at week 9. In the PS cohort, similar proportions of pts in each arm showed on-treatment improvement, stabilization, or deterioration in function and HRQoL. In both cohorts, neither arm showed meaningful changes from BL in treatment-related symptoms and similar proportions of pts in both arms reported being ‘a little bit’ or ‘somewhat’ bothered by treatment side effects while on therapy. Conclusions: Consistent with PFS results, there were no differences between arms in the proportion of NACT pts with a clinically meaningful improvement in abdominal pain and bloating after 3 cycles of bevacizumab-containing therapy. Pt-reported outcome analyses in both cohorts showed that adding atezo to CPB did not increase treatment burden for pts, thereby demonstrating the tolerability of this 4-drug regimen and providing further insight on the benefit-risk assessment of atezo.

BACKGROUND: Minimally invasive radical trachelectomy has emerged as an alternative to open radical hysterectomy for patients with early-stage cervical cancer desiring future fertility. Recent data suggest worse oncologic outcomes after minimally invasive radical hysterectomy than after open radical hysterectomy in stage I cervical cancer. OBJECTIVE: We aimed to compare 4.5-year disease-free survival after open vs minimally invasive radical trachelectomy. STUDY DESIGN: This was a collaborative, international retrospective study (International Radical Trachelectomy Assessment Study) of patients treated during 2005–2017 at 18 centers in 12 countries. Eligible patients had squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma; had a preoperative tumor size of ≤2 cm; and underwent open or minimally invasive (robotic or laparoscopic) radical trachelectomy with nodal assessment (pelvic lymphadenectomy and/or sentinel lymph node biopsy). The exclusion criteria included neoadjuvant chemotherapy or preoperative pelvic radiotherapy, previous lymphadenectomy or pelvic retroperitoneal surgery, pregnancy, stage IA1 disease with lymphovascular space invasion, aborted trachelectomy (conversion to radical hysterectomy), or vaginal approach. Surgical approach, indication, and adjuvant therapy regimen were at the discretion of the treating institution. A total of 715 patients were entered into the study database. However, 69 patients were excluded, leaving 646 in the analysis. Endpoints were the 4.5-year disease-free survival rate (primary), 4.5-year overall survival rate (secondary), and recurrence rate (secondary). Kaplan-Meier methods were used to estimate disease-free survival and overall survival. A post hoc weighted analysis was performed, comparing the recurrence rates between surgical approaches, with open surgery being considered as standard and minimally invasive surgery as experimental. RESULTS: Of 646 patients, 358 underwent open surgery, and 288 underwent minimally invasive surgery. The median (range) patient age was 32 (20–42) years for open surgery vs 31 (18–45) years for minimally invasive surgery (P=.11). Median (range) pathologic tumor size was 15 (0–31) mm for open surgery and 12 (0.8–40) mm for minimally invasive surgery (P=.33). The rates of pelvic nodal involvement were 5.3% (19 of 358 patients) for open surgery and 4.9% (14 of 288 patients) for minimally invasive surgery (P=.81). Median (range) follow-up time was 5.5 (0.20–16.70) years for open surgery and 3.1 years (0.02–11.10) years for minimally invasive surgery (P

Neuroendocrine tumors account for only 1–2% of cervical carcinomas, but they are known to have the worst prognosis of all. Given the low incidence, their management is based on retrospective series of small cohorts, and pharmacological treatment is adopted from experience with small cell lung