INTRODUCTION:Adjuvant chemotherapy in the treatment of endometrial cancer can be difficult to tolerate for older women. This study examined age-related differences in patient preferences for chemotherapy in women with high-risk endometrial cancer. METHODS:We re-analyzed data from the cross-sectional patient preference study PRETEC-2 to determine the difference between three age groups in minimally desired survival benefit of chemotherapy. For this, patients with high-risk endometrial cancer treated with adjuvant pelvic radiotherapy with or without chemotherapy completed a treatment trade-off questionnaire. Patients also rated the importance they attributed to treatment duration and acute and late side-effects for their decision on chemotherapy, which we analyzed by age group. RESULTS:A total of 171 patients (23% <60 years, 40% 60-69 years and 37% ≥70 years) were included in the analysis. Older patients had a significantly higher median minimally desired survival benefit for preferring chemoradiotherapy (5% for <60 years, 8% for 60-69 years and 15% for patients ≥70 years; (p<0.001)), and had the largest variability in minimally desired survival benefit. For a real-life five-year survival benefit of 5%, fewer older patients preferred the addition of chemotherapy to their treatment regimen (61.5% for <60 years, 45.6% for 60-69 years and 21.9% for ≥70 years; p<0.001). Furthermore, older patients rated both treatment duration (p=0.001) and long-term tingling or numbness (p=0.005) as significantly more important than their younger counterparts. CONCLUSION:There is more heterogeneity in the desired benefit of chemotherapy among patients aged 70 years or more compared to younger patients. This underlines the importance of recognizing individual differences and the need for shared decision-making.

Universal tumor screening in endometrial carcinoma (EC) is increasingly adopted to identify individuals at risk of Lynch syndrome (LS). These cases involve mismatch repair-deficient (MMRd) EC without MLH1 promoter hypermethylation (PHM). LS is confirmed through the identification of germline MMR pathogenic variants (PV). In cases where these are not detected, emerging evidence highlights the significance of double-somatic MMR gene alterations as a sporadic cause of MMRd, alongside POLE/POLD1 exonuclease domain (EDM) PV leading to secondary MMR PV. Our understanding of the incidence of different MMRd EC origins not related to MLH1-PHM, their associations with clinicopathologic characteristics, and the prognostic implications remains limited. In a combined analysis of the PORTEC-1, -2, and -3 trials (n = 1254), 84 MMRd EC not related to MLH1-PHM were identified that successfully underwent paired tumor-normal tissue next-generation sequencing of the MMR and POLE/POLD1 genes. Among these, 37% were LS associated (LS-MMRd EC), 38% were due to double-somatic hits (DS-MMRd EC), and 25% remained unexplained. LS-MMRd EC exhibited higher rates of MSH6 (52% vs 19%) or PMS2 loss (29% vs 3%) than DS-MMRd EC, and exclusively showed MMR-deficient gland foci. DS-MMRd EC had higher rates of combined MSH2/MSH6 loss (47% vs 16%), loss of >2 MMR proteins (16% vs 3%), and somatic POLE-EDM PV (25% vs 3%) than LS-MMRd EC. Clinicopathologic characteristics, including age at tumor onset and prognosis, did not differ among the various groups. Our study validates the use of paired tumor-normal next-generation sequencing to identify definitive sporadic causes in MMRd EC unrelated to MLH1-PHM. MMR immunohistochemistry and POLE-EDM mutation status can aid in the differentiation between LS-MMRd EC and DS-MMRd EC. These findings emphasize the need for integrating tumor sequencing into LS diagnostics, along with clear interpretation guidelines, to improve clinical management. Although not impacting prognosis, confirmation of DS-MMRd EC may release patients and relatives from burdensome LS surveillance.

Abstract Re-irradiation is a common treatment option for recurrent high-grade glioma (HGG), though the optimal dose-fractionation regimen remains unclear. This report presents single-center data from an ongoing multicenter, retrospective study in the Netherlands. We included adult HGG patients treated with re-irradiation. Dose-fractionation regimens were categorized in 3 groups: conventionally fractionated radiotherapy (CFRT, <3Gy/fraction), hypofractionated radiotherapy (HFRT, 3-5 Gy/fraction) and stereotactic radiotherapy (SRT, ≥5Gy/fraction). We compared baseline characteristics, overall survival, and toxicity including incidence of radionecrosis between groups to identify the optimal dose-fractionation regimen. Of 112 patients, 33 underwent CFRT, 60 HFRT and 19 SRT. 21 patients had a good prognostic Niyazi score, 70 intermediate and 6 poor, with more poor scores in the SRT group. SRT patients had smaller median GTVs compared to HFRT and CFRT (1.9, 20.5, 32.8 respectively, p=0.003). Radiation groups also differed in primary histology (less grade 4 in CFRT, p=0.009), but not in age and KPS. Overall survival (OS) was worse for HFRT (median OS 9 months (95%-CI 6.5-11.5)) compared to CFRT (12 months (8.9-15.2, p=0.039)) and SRT (12 months (9.2-14.8, p = 0.012)), but did not differ between CFRT and SRT (p=0.437). In Cox regression, Karnofsky performance score <80 (hazard ratio (HR): 1.874, p=0.006) and large GTV (HR: 1.011, p=0.003) were independently associated with poor survival, while the fractionation schedule was not. Multivariable logistic regression on toxicity analysis indicated an increased risk of radionecrosis in the CFRT and HFRT groups compared to the SRT group (OR 5.861, p=0.011), even after adjusting for GTV and age. In conclusion, re-irradiation schemes in HGG are univariably, but not independently, associated with overall survival; this relationship seems to be confounded by differences in GTV and possibly by KPS. Radionecrosis was more common in HFRT and CFRT than in SRT. Extension and/or validation of findings will be performed in a multicenter cohort.

BACKGROUND:Patients with advanced endometrial cancer have a poor prognosis, and treatment options are limited. The investigator-initiated, multicenter, phase II DOMEC trial (NCT03951415) is the first trial to report data on efficacy and safety of combined treatment with PD-L1 and PARP inhibition for advanced endometrial cancer.PATIENTS AND METHODS:Patients with metastatic or recurrent endometrial cancer were enrolled. Patients received durvalumab 1500 mg intravenously q4w and olaparib 300 mg 2dd until disease progression, unacceptable toxicity, or patient withdrawal. Patients with at least 4 weeks of treatment were evaluable for analysis. The primary endpoint was progression-free survival at 6 months. Evidence for efficacy was defined as progression-free survival at 6 months in ≥50% of patients. Secondary endpoints included safety, objective response and overall survival.RESULTS:From July 2019, through November 2020, 55 patients were enrolled. At data cut-off (September 2021), 4 of the 50 evaluable patients were still on treatment. Seventeen patients (34%) were progression-free at 6 months. Objective response rate was 16% (95% CI, 8.3 to 28.5) with 1 complete and 7 partial responses. With a median follow-up of 17.6 months, median progression-free survival was 3.4 months (95% CI, 2.8 to 6.2) and median overall survival was 8.0 months (95% CI, 7.5 to 14.3). Grade 3 treatment-related adverse events occurred in 8 patients (16%), predominantly anemia. There were no grade 4 or 5 treatment-related adverse events.CONCLUSION:The combination of durvalumab and olaparib was well tolerated, but did not meet the prespecified 50% 6-month progression-free survival in this heterogeneous patient population with advanced endometrial cancer.

PURPOSE:Radiation therapy techniques have developed from 3-dimensional conformal radiation therapy (3DCRT) to intensity modulated radiation therapy (IMRT), with better sparing of the surrounding normal tissues. The current analysis aimed to investigate whether IMRT, compared to 3DCRT, resulted in fewer adverse events (AEs) and patient-reported symptoms in the randomized PORTEC-3 trial for high-risk endometrial cancer.METHODS AND MATERIALS:Data on AEs and patient-reported quality of life (QoL) of the PORTEC-3 trial were available for analysis. Physician-reported AEs were graded using Common Terminology Criteria for Adverse Events v3.0. QoL was assessed by the European Organisation for Research and Treatment of Cancer QLQC30, CX24, and OV28 questionnaires. Data were compared between 3DCRT and IMRT. A P value of ≤ .01 was considered statistically significant due to the risk of multiple testing. For QoL, combined scores 1 to 2 ("not at all" and "a little") versus 3 to 4 ("quite a bit" and "very much") were compared between the techniques.RESULTS:Of 658 evaluable patients, 559 received 3DCRT and 99 IMRT. Median follow-up was 74.6 months. During treatment no significant differences were observed, with a trend for more grade ≥3 AEs, mostly hematologic and gastrointestinal, after 3DCRT (37.7% vs 26.3%, P = .03). During follow-up, 15.4% (vs 4%) had grade ≥2 diarrhea, and 26.1% (vs 13.1%) had grade ≥2 hematologic AEs after 3DCRT (vs IMRT) (both P < .01). Among 574 (87%) patients evaluable for QoL, 494 received 3DCRT and 80 IMRT. During treatment, 37.5% (vs 28.6%) reported diarrhea after 3DCRT (vs IMRT) (P = .125); 22.1% (versus 10.0%) bowel urgency (P = 0039), and 18.2% and 8.6% abdominal cramps (P = .058). Other QoL scores showed no differences.CONCLUSIONS:IMRT resulted in fewer grade ≥3 AEs during treatment and significantly lower rates of grade ≥2 diarrhea and hematologic AEs during follow-up. Trends toward fewer patient-reported bowel urgency and abdominal cramps were observed after IMRT compared to 3DCRT.

2022-RA-809-ESGO Figure 1 Kaplan-Meier survival curves for recurrence-free survival for patients with LS-associated EC (germline mutation in MMR gene) and other non-LS-associated MMRd EC. All Cases with MMRd phenotype without MLH1 promoter hypermethylation are included in this analysis, including cases with a concurrent POLE mutation (POLEmut-MMRd EC). P value reflect 2-sided log-rank test. Abbreviations: EC, endometrial cancer; LS, Lynch syndrome; MMR, mismatch repair; MMRd, mismatch repair-deficient; Conclusion Identification of an underlying cause for unmethylated MMRd is feasible in the majority of EC cases applying matched tumor-normal tissue NGS. A significant proportion was confirmed to be LS-associated or sporadic MMRd, while only a small subset remained unresolved. Although this distinction did not carry prognostic relevance, identification of definitive sporadic causes may release patients and relatives from burdensome LS-surveillance. 2022-RA-815-ESGO ENDOMETRIAL CANCER INCIDENCE IN PATIENTS WITH ATYPICAL ENDOMETRIAL HYPERPLASIA ACCORDING TO MODE OF MANAGEMENT Anas Barakat, Aemn Ismail, Supratik Chattopadhyay, Quentin Davies. Gynaecology Oncology Department, University Hospitals of Leicester NHS Trust, LEICESTER, UK; Leicester Cancer Research Centre, University of Leicester, Leicester, UK 10.1136/ijgc-2022-ESGO.245 Introduction/Background It is well established that around one-third of patients with atypical Endometrial hyperplasia (AEH) develop endometrial cancer (EC). The aim of the study is to determine the incidence of EC in AEH patients in UHL and to explore the reasons why AEH patients opted for conservative management. Abstracts A112 Int J Gynecol Cancer 2022;32(Suppl 2):A1–A504 on D ecem er 2, 2022 by gest. P rocted by coright. http/ijgc.bm jcom / nt J G ynecol C acer: frst pulished as 10.11ijgc-2022-E S G O .44 on 20 O cber 222. D ow nladed fom

PurposeThe survival results of the PORTEC-3 trial showed a significant improvement in both overall and failure-free survival with chemoradiation therapy versus pelvic radiation therapy alone. The present analysis was performed to compare long-term adverse events (AE) and health-related quality of life (HRQOL).Methods and MaterialsIn the study, 660 women with high-risk endometrial cancer were randomly assigned to receive chemoradiation therapy (2 concurrent cycles of cisplatin followed by 4 cycles of carboplatin/paclitaxel) or radiation therapy alone. Toxicity was graded using Common Terminology Criteria for Adverse Events, version 3.0. HRQOL was measured using EORTC QLQ-C30 and CX24/OV28 subscales and compared with normative data. An as-treated analysis was performed.ResultsMedian follow-up was 74.6 months; 574 (87%) patients were evaluable for HRQOL. At 5 years, grade ≥2 AE were scored for 78 (38%) patients who had received chemoradiation therapy versus 46 (24%) who had received radiation therapy alone (P = .008). Grade 3 AE did not differ significantly between the groups (8% vs 5%, P = .18) at 5 years, and only one new late grade 4 toxicity had been reported. At 3 and 5 years, sensory neuropathy toxicity grade ≥2 persisted after chemoradiation therapy in 6% (vs 0% after radiation therapy, P < .001) and more patients reported significant tingling or numbness at HRQOL (27% vs 8%, P < .001 at 3 years; 24% vs 9%, P = .002 at 5 years). Up to 3 years, more patients who had chemoradiation therapy reported limb weakness (21% vs 5%, P < .001) and lower physical (79 vs 87, P < .001) and role functioning (78 vs 88, P < .001) scores. Both treatment groups reported similar long-term global health/quality of life scores, which were better than those of the normative population.ConclusionsThis study shows a long-lasting, clinically relevant, negative impact of chemoradiation therapy on toxicity and HRQOL, most importantly persistent peripheral sensory neuropathy. Physical and role functioning impairments were seen until 3 years. These long-term data are essential for patient information and shared decision-making regarding adjuvant chemotherapy for high-risk endometrial cancer.

Background: Standard screening of endometrial cancer (EC) for Lynch syndrome (LS) is gaining traction; however, the prognostic impact of an underlying hereditary etiology is unknown. We established the prevalence, prognosis, and subsequent primary cancer incidence of patients with LS-associated EC in relation to sporadic mismatch repair deficient (MMRd)-EC in the large combined Post Operative Radiation Therapy in Endometrial Carcinoma-1, -2, and -3 trial cohort. Methods: After MMR-immunohistochemistry, MLH1-promoter methylation testing, and next-generation sequencing, tumors were classified into 3 groups according to the molecular cause of their MMRd-EC. Kaplan-Meier method, log-rank test, and Cox model were used for survival analysis. Competing risk analysis was used to estimate the subsequent cancer probability. All statistical tests were 2-sided. Results: Among the 1336 ECs, 410 (30.7%) were MMRd. A total of 380 (92.7%) were fully triaged: 275 (72.4%) were MLH1-hypermethylated MMRd-ECs; 36 (9.5%) LS MMRd-ECs, and 69 (18.2%) MMRd-ECs due to other causes. Limiting screening of EC patients to 60 years or younger or to 70 years or younger would have resulted in missing 18 (50.0%) and 6 (16.7%) LS diagnoses, respectively. Five-year recurrence-free survival was 91.7% (95% confidence interval [CI] = 83.1% to 100%; hazard ratio = 0.45, 95% CI = 0.16 to 1.24, P =.12) for LS, 95.5% (95% CI = 90.7% to 100%; hazard ratio = 0.17, 95% CI = 0.05 to 0.55, P =.003) for "other" vs 78.6% (95% CI = 73.8% to 83.7%) for MLH1-hypermethylated MMRd-EC. The probability of subsequent LS-associated cancer at 10 years was 11.6% (95% CI = 0.0% to 24.7%), 1.5% (95% CI = 0.0% to 4.3%), and 7.0% (95% CI = 3.0% to 10.9%) within the LS, "other," and MLH1-hypermethylated MMRd-EC groups, respectively. Conclusions: The LS prevalence in the Post Operative Radiation Therapy in Endometrial Carcinoma trial population was 2.8% and among MMRd-ECs was 9.5%. Patients with LS-associated ECs showed a trend towards better recurrence-free survival and higher risk for second cancers compared with patients with MLH1-hypermethylated MMRd-EC.

The prognosis of recurrent or metastatic endometrial cancer is poor, with five-year survival of only 10-20 %. First-line therapy consists of either platinum-based chemotherapy or hormonal therapy. No standard subsequent-line therapy has been identified. In recent years, significant progress has been made in the knowledge on underlying molecular biology of endometrial cancer and potential targets for therapy have been identified. Targeted therapies as poly (ADP-ribose) polymerase (PARP) inhibitors and immunotherapy as PD-1/PD-L1 checkpoint inhibitors have the potential to be effective against specific subtypes of endometrial cancer. Preclinical studies have shown that combining these agents may result in a synergistic effect. In this review, we focus on the molecular basis of checkpoint inhibition and targeted therapy as PARP inhibition in endometrial cancer and summarize available clinical data, and ongoing and planned clinical trials that investigate these agents as mono- or combination therapies in endometrial cancer and where relevant, other gynecological cancers.

PURPOSE OR OBJECTIVE:Re-irradiation is a generally accepted method for salvage treatment in patients with recurrent glioma. However, no standard radiation regimen has been defined. This study aims to compare the efficacy and safety of different treatment regimens and to independently externally validate a recently published reirradiation risk score. MATERIAL AND METHODS:We retrospectively analyzed a cohort of patients with recurrent malignant glioma treated with salvage conventionally fractionated (CFRT), hypofractionated (HFRT) or stereotactic radiotherapy (SRT) between 2007 and 2017 at the University Medical Centers in Utrecht and Groningen. RESULTS:Of the 121 patients included, 60 patients (50%) underwent CFRT, 22 (18%) HFRT and 39 (32%) SRT. The primary tumor was grade II-III in 52 patients and grade IV in 69 patients with median Overall Survival (mOS) since first surgery of 113 [Interquartile range: 53.2-137] and 39.7 [24.6-64.9] months respectively (p < 0.01). Overall, mOS from the first day of re-irradiation was 9.7 months [6.5-14.6]. No significant difference in mOS was found between the treatment groups. In multivariate analysis, the Karnofsky performance scale ≥70% (p < 0.01), re-irradiation for first recurrence (p = 0.02), longer time interval between RT start dates (p < 0.01) and smaller planning target volume (p < 0.05) were significant favorable prognostic factors. The reirradiation risk score was validated. CONCLUSION:In our series, mOS after reirradiation was sufficient to justify use of this modality. Until a reliable treatment decision tool is developed based on larger retrospective research, the decision for re-irradiation schedule should remain personalized and based on a multidisciplinary evaluation of each patient.