Atezolizumab and chemotherapy for advanced or recurrent endometrial cancer (AtTEnd): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: At the time of AtTEnd trial design, standard treatment for advanced or recurrent endometrial cancer included carboplatin and paclitaxel chemotherapy. This trial assessed whether combining atezolizumab with chemotherapy might improve outcomes in this population. METHODS: AtTEnd was a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done in 89 hospitals in 11 countries across Europe, Australia, New Zealand, and Asia. Enrolled patients were aged 18 years or older, and had advanced or recurrent endometrial carcinoma or carcinosarcoma, an Eastern Cooperative Oncology Group performance status of 0-2, and received no previous systemic chemotherapy for recurrence. Patients were randomly assigned (2:1) using an interactive web response system (block size of six) to either atezolizumab 1200 mg or placebo given intravenously with chemotherapy (carboplatin at area under the curve of 5 or 6 and paclitaxel 175 mg/m2 intravenously on day 1 every 21 days) for 6-8 cycles, then continued until progression. Stratification factors were country, histological subtype, advanced or recurrent status, and mismatch repair (MMR) status. Participants and treating clinicians were masked to group allocation. The hierarchically tested co-primary endpoints were progression-free survival (in patients with MMR-deficient [dMMR] tumours, and in the overall population) and overall survival (in the overall population). Primary analyses were done in the intention-to-treat population, defined as all randomly assigned patients who gave their full consent to participation in the study and data processing. Safety was assessed in all patients included in the intention-to-treat population who received at least one dose of study treatment. Here, we report the primary progression-free survival and the interim overall survival results. This study is ongoing and is registered with ClinicalTrials.gov, NCT03603184. FINDINGS: Between Oct 3, 2018, and Jan 7, 2022, 551 patients were randomly assigned to atezolizumab (n=362) or placebo (n=189). Two patients in the atezolizumab group were excluded from all analyses due to lack of consent. Median follow-up was 28·3 months (IQR 21·2-37·6). 81 (23%) patients in the atezolizumab group and 44 (23%) patients in the placebo group had dMMR disease by central assessment. In the dMMR population, median progression-free survival was not estimable (95% CI 12·4 months-not estimable [NE]) in the atezolizumab group and 6·9 months (6·3-10·1) in the placebo group (hazard ratio [HR] 0·36, 95% CI 0·23-0·57; p=0·0005). In the overall population, median progression-free survival was 10·1 months (95% CI 9·5-12·3) in the atezolizumab group and 8·9 months (8·1-9·6) in the placebo group (HR 0·74, 95% CI 0·61-0·91; p=0·022). Median overall survival was 38·7 months (95% CI 30·6-NE) in the atezolizumab group and 30·2 months (25·0-37·2) in the placebo group (HR 0·82, 95% CI 0·63-1·07; log-rank p=0·048). The p value for the interim analysis of overall survival did not cross the stopping boundary; therefore, the trial will continue until the required number of events are recorded. The most common grade 3-4 adverse events were neutropenia (97 [27%] of 356 patients in the atezolizumab group vs 51 [28%] of 185 in the placebo group) and anaemia (49 [14%] vs 24 [13%]). Treatment-related serious adverse events occurred in 46 (13%) patients in the atezolizumab group and six (3%) patients in the placebo group. Treatment-related deaths occurred in two patients (pneumonia in one patient in each group). INTERPRETATION: Atezolizumab plus chemotherapy increased progression-free survival in patients with advanced or recurrent endometrial carcinoma, particularly in those with dMMR carcinomas, suggesting the addition of atezolizumab to standard chemotherapy as first-line treatment in this specific subgroup. FUNDING: F Hoffmann-La Roche.

Real-world first-line treatment patterns and outcomes in recurrent/advanced endometrial cancer patients in Europe.

Background: The treatment patterns and clinical outcomes in recurrent/advanced endometrial cancer in Europe are not well known. Materials & methods: Endometrial Cancer Health Outcomes-Europe-First-Line is a multicenter, retrospective chart review study conducted in the UK, Germany, Italy, France and Spain. Patients diagnosed with recurrent/advanced endometrial cancer who initiated first-line systemic therapy between 1 July 2016 and 31 March 2020 were eligible. Results: Among 242 patients, median age was 69 years and 82.2% had stage IIIB-IV disease. In first-line, most patients received platinum-based chemotherapy (78.9%); others received endocrine therapy (6.2%), taxane monotherapy (5.8%) and nonplatinum or taxane-based chemotherapy (4.1%). Median real-world progression-free survival since first-line initiation was 10.8 months and median overall survival was 20.7 months. Conclusion: Poor prognosis with platinum-based first-line chemotherapy suggests significant unmet medical need.

Treatment patterns & survival for recurrent/advanced endometrial cancer patients in Europe who received their first treatmentThe treatments and survival for recurrent/advanced endometrial (uterus lining) cancer patients in real-life European settings are not well known. Endometrial Cancer Health Outcomes-Europe-First-Line is a multicenter study that was conducted in the UK, Germany, Italy, France and Spain and used de-identified information from existing patient medical records. Patients diagnosed with recurrent/advanced endometrial cancer who initiated a first treatment between 1 July 2016 and 31 March 2020 were included. Among 242 included patients, the average age was 69 years and 82.2% had stage IIIB-IV disease (indicating the size and extent of their cancer). As their first treatment, most patients received platinum-based chemotherapy (78.9%), which is a type of drug that kills cancer cells. Overall, patients lived for an average of 20.7 months since their first treatment. The average length of time patients lived without their disease getting worse was 10.8 months since their first treatment. We found that patients who received platinum-based chemotherapy as their first treatment had poor survival, which suggests significant unmet medical need.

Pegylated liposomal doxorubicin combined with trabectedin as a treatment option in uterine sarcomas: a single-institution retrospective analysis.

OBJECTIVE: The use of conventional doxorubicin in combination with trabectedin leads to a considerable prolongation of progression-free survival in the treatment of uterine sarcomas but is associated with dose-limiting toxicities. Significant progression-free survival improvement was recently obtained through treatment prolongation with trabectedin single agent. We hypothesize that the therapeutic index of pegylated liposomal doxorubicin combined with trabectedin could be superior to the combination with conventional doxorubicin due to a more favorable toxicity profile. METHODS: In this retrospective cohort study, the clinical outcome was analyzed in patients with advanced or recurrent uterine sarcomas with measurable disease treated with pegylated liposomal doxorubicin 30 mg/m2 plus trabectedin 1.5 mg/m2 given every 3 weeks between January 2011 and April 2023 at the University Hospital in Innsbruck. Response evaluation was done every three cycles. Toxicity was evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria on 107 administered cycles. RESULTS: A total of 21 patients were included in the study. In 67% (n=14) of patients, pegylated liposomal doxorubicin plus trabectedin was given as first-line treatment. One patient (5%) achieved a complete response and four (19%) a partial response, resulting in an objective response rate of 24%. Four other patients (19%) had stable disease. The median duration of the response was 14 months (range 3-74). Progression was recorded in 12 patients (57%). Median progression-free survival was 6 months (95% CI 1 to 11 months), while median overall survival was 26 months (95% CI 9 to 43 months). A median of 6 (range 1-11) cycles per patient were administered. Regarding grade ≥3 toxicity, neutropenia was recorded in 29%, thrombocytopenia in 14%, and febrile neutropenia in 19% of patients. Hematologic toxicity was the most frequent reason for dose delays (n=16) and dose reductions (n=5). CONCLUSION: Our study found an overall clinical benefit for the combination of pegylated liposomal doxorubicin plus trabectedin in metastatic uterine sarcomas of 43% and appears to exhibit a favorable toxicity profile which allows prolonged administration of this regimen.

Tumoral programmed cell death 1 (PD1) expression in endometrial carcinoma is a prognostic marker for patient outcome.

OBJECTIVE: Immune checkpoint inhibitors have recently demonstrated benefit in patients with advanced and recurrent endometrial carcinoma. This retrospective study investigated immune checkpoint molecules in endometrial carcinoma as they pertain to the molecular subtypes, clinical outcomes, and predictive value. METHODS: Tumoral RNA expression of genes controlling the immune checkpoint, programmed cell death 1 (PD1, encoded by PDCD1), its ligand (PDL1, encoded by CD274), and interferon gamma (IFNG) was determined in 239 endometrial carcinoma tissues by quantitative polymerase chain reaction (qPCR) and compared with endometrial tissue from 25 controls. A total of 81 endometrial carcinoma tissues were analyzed using the ProMiSe molecular classification, and patient trajectories were analyzed for the entire cohort. Findings were validated in an independent cohort from The Cancer Genome Atlas (TCGA; n=548). RESULTS: PD1, PDL1, and IFNG expression was significantly higher in endometrial carcinoma when compared with non-malignant control tissue with a mean expression of 0.12, 0.05, and 0.05 in control tissue and 0.44, 0.31, and 0.35 in endometrial carcinoma, respectively. POLE-mutated and mismatch repair-deficient (MMRd) (immunologically hot) tumors showed the highest expression of PD1 and IFNG. Increased expression of PD1, PDL1, and IFNG was associated with improved recurrence-free (HR 0.32, p<0.001; HR 0.30, p<0.001; HR 0.47, p=0.012, respectively), disease-specific (HR 0.38, p<0.001; HR 0.29, p<0.001; HR 0.45, p=0.017, respectively), and overall survival (HR 0.56, p=0.003; HR 0.38, p<0.001; HR 0.58, p=0.006, respectively). Cox regression confirmed the prognostic significance of PD1 for recurrence-free survival (HR 0.39, p=0.009) and PDL1 for overall survival (HR 0.55, p=0.037). The prognostic value of tumoral PD1 on recurrence-free survival, disease-specific survival, and overall survival was confirmed in the TCGA cohort. CONCLUSIONS: Tumoral gene expression controlling the PD1 immune checkpoint, particularly expressed in "hot tumors", predicted recurrence-free, disease-specific, and overall survival in patients with endometrial carcinoma in two independent cohorts. Evaluation of these genes could be used to stratify patients who qualify for immune checkpoint inhibitors, which warrants prospective clinical trials.

Real-world prevalence of microsatellite instability testing and related status in women with advanced endometrial cancer in Europe.

PURPOSE: To assess the real-world prevalence of microsatellite instability (MSI)/mismatch repair (MMR) testing and related tumor status in recurrent/advanced endometrial cancer patients in Europe. METHODS: Data were from two multi-center, retrospective patient chart review studies conducted in the United Kingdom, Germany, Italy, France and Spain: The Endometrial Cancer Health Outcomes-Europe-First-Line (ECHO-EU-1L) study and the ECHO-EU-Second-Line (ECHO-EU-2L) study. ECHO-EU-1L included recurrent/advanced endometrial cancer patients who received first-line systemic therapy between 1/JUN/2016 and 31/MAR/2020 after recurrent/advanced diagnosis. ECHO-EU-2L included patients with recurrent/advanced endometrial cancer who progressed between 1/JUN/2016 and 30/JUN/2019 following prior first-line systemic therapy. Data collected included patient demographics, MSI/MMR tumor testing and results, and clinical/treatment characteristics. RESULTS: ECHO-EU-1L included 242 first-line patients and ECHO-EU-2L included 475 s-line patients. For all patients, median age at recurrent/advanced diagnosis was 69 years, roughly half had endometrioid carcinoma histology and over 75% had Stage IIIB-IV disease at initial diagnosis. The prevalence of MSI/MMR testing in the first-line and second-line cohorts was similar (36.4 and 34.9%, respectively). Among those tested, a majority had non-MSI-high/MMR proficient tumors (80.7 and 74.7% among first- and second-line patients, respectively). About 15% had MSI-high/MMR deficient tumors in both cohorts, and a few patients had discordant results (3.4 and 10.8% among first- and second-line patients, respectively). CONCLUSION: Prior to the approvals of biomarker-directed therapies for recurrent/advanced endometrial cancer patients in Europe, there were low MSI/MMR testing rates for these patients of just over one-third. Given the availability of biomarker-directed therapies, increased MSI/MMR testing may help inform treatment decisions for recurrent/advanced endometrial cancer patients in Europe.

An angiogenic tumor phenotype predicts poor prognosis in ovarian cancer.

OBJECTIVE: Epithelial ovarian cancer (OC) is the deadliest gynecological malignancy worldwide. Blocking angiogenesis with bevacizumab, an antibody targeting vascular endothelial growth factor (VEGF), shows efficacy in different lines of OC therapy. This study investigates the clinical impact of tumoral expression of angiogenesis-related genes and their association with bevacizumab response in OC in retrospective analysis of three independent cohorts. METHODS: mRNA expression of seven angiogenic genes (VEGF, VEGFR2, PDGFA, PDGFB, PDGFRA, PDGFRB, KIT) was quantified in an inception OC cohort (n = 195) and a transcriptional tumor angiogenesis score from 0 to 3 was established and linked to progression-free survival (PFS) and overall survival (OS). This score was corroborated in an independent publicly available cohort from The Cancer Genome Atlas (TCGA, n = 582) and prediction of therapeutic efficacy of bevacizumab by the angiogenesis score was analyzed in the Gene Expression Omnibus (GEO) dataset GSE140082 (n = 380) from the ICON7-trial. RESULTS: The tumor angiogenesis score prognosticated PFS and OS in patients with OC from the inception cohort (p < 0.001, respectively). Tumoral PDGFA expression (PFS: HR 2.46, p = 0.005; OS: HR 2.26, p = 0.011) and a high tumoral transcriptional angiogenesis score (PFS: HR 1.41, p = 0.018) were identified as independent predictors of clinical outcome. The transcriptional angiogenesis score exhibited a significant though smaller effect size on PFS in the TCGA cohort. However, in the ICON7-trial, the angiogenesis score was not associated with benefit of bevacizumab treatment. CONCLUSIONS: Our study indicates that tumoral expression of angiogenic genes is unfavorable in OC. The established score could be used to identify patients who respond to targeted angiogenic therapies, a concept that warrants prospective controlled clinical trials.

AGO-OVAR 28/ENGOT-ov57. Niraparib alone versus niraparib in combination with bevacizumab in patients with carboplatin-taxane-based chemotherapy in advanced ovarian cancer: a multicenter randomized phase III trial.

BACKGROUND: Phase III trial data have shown a significant benefit by the addition of a maintenance treatment with niraparib, irrespective of BRCA or HRD status, in patients with advanced high-grade ovarian cancers; and, a significant benefit of the combination of olaparib and bevacizumab compared with bevacizumab monotherapy in HRD positive patients. However, it is unclear whether a PARP inhibitor monotherapy is sufficient, or if the addition of bevacizumab is needed. PRIMARY OBJECTIVES: This trial will investigate if the treatment strategy of carboplatin/paclitaxel/bevacizumab/niraparib is superior to the treatment of carboplatin/paclitaxel/niraparib in an all-comer population. STUDY HYPOTHESIS: Adding bevacizumab to chemotherapy followed by niraparib maintenance improves progression-free survival in patients with newly diagnosed advanced ovarian cancer. TRIAL DESIGN: AGO-OVAR 28/ENGOT-ov57 is an international, multicenter, randomized, prospective phase III trial within the the European Network for Gynecological Oncological Trial (ENGOT), led by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) study group. All patients should have completed the first cycle of chemotherapy (carboplatin and paclitaxel) as part of the Study Run-In-Period. Prior to day 1 of cycle 2, patients with a valid central tumor BRCA (tBRCA) test result were randomized in a 1:1 ratio into either: Arm 1, to receive five additional cycles of carboplatin and paclitaxel q21d, followed by niraparib for up to 3 years; or Arm 2, to receive five 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. MAJOR INCLUSION/EXCLUSION CRITERIA: The trial population is composed of adult patients with newly diagnosed, advanced high-grade epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer FIGO III/IV (except FIGO IIIA2 without nodal involvement). Patients who are scheduled for neoadjuvant chemotherapy and interval debulking surgery are also eligible for the trial. PRIMARY ENDPOINT: The primary endpoint is progression-free survival. SAMPLE SIZE: The study plans to recruit 970 patients (485 patients in each arm). ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The Last-Patient-In is expected to be enrolled in September 2024, with presentation of the primary endpoint in 2028. TRIAL REGISTRATION: NCT05009082; EudraCT Number: 2021-001271-16.

Treatment strategies in patients with gynecological sarcoma: Results of the prospective intergroup real-world registry for gynecological sarcoma in Germany (REGSA-NOGGO RU1).

OBJECTIVE: Gynecological sarcomas account for 3% of all gynecological malignancies and are associated with a poor prognosis. Due to the rarity and heterogeneity of gynecological sarcomas there is still no consensus on optimal therapeutic strategies. This study's objective was to describe the treatment strategies used in patients with gynecological sarcomas in the primary course of disease. METHODS: The German prospective registry for gynecological sarcoma (REGSA) is the largest registry for gynecological sarcomas in Germany, Austria and Switzerland. Primary inclusion criteria for REGSA are histological diagnosis of sarcoma of the female genital tract, sarcoma of the breast or uterine smooth muscle tumors of uncertain malignant potential (STUMP). We evaluated data of the REGSA registry on therapeutic strategies used for primary treatment from August 2015 to February 2021. RESULTS: A total of 723 patients from 120 centers were included. Data on therapeutic strategies for primary treatment were available in 605 cases. Overall, 580 (95.9%) patients underwent primary surgery, 472 (81.4%) of whom underwent only hysterectomy. Morcellation was reported in 11.4% (n=54) of all hysterectomies. A total of 42.8% (n=202) had no further surgical interventions, whereas an additional salpingo-ophorectomy was performed in 54% (n=255) of patients. An additional lymphadenectomy was performed in 12.7% (n=60), an omentectomy in 9.5% (n=45) and intestinal resection in 6.1% (n=29) of all patients. Among 448 patients with available information, 21.4% (n=96) received chemo- or targeted therapies, more commonly as single-agent treatment than as drug combinations. Information about anti-hormonal treatment was available for 423 patients, among which 42 (9.9%) received anti-hormonal treatment, 23 (54.8%) of whom with low-grade endometrial stroma sarcomas. For radiotherapy, data of 437 patients were available, among which 29 (6.6%) patients underwent radiotherapy. CONCLUSION: Our study showed that treatment of patients with gynecologic sarcomas is heterogeneous. Further trials are needed along with more information on treatment modalities, therapy response and patient-reported outcomes to implement new treatment strategies.

Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup.

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.

Real-life data on treatment and outcomes in advanced ovarian cancer: An observational, multinational cohort study (RESPONSE trial).

BACKGROUND: This study aimed to describe the treatment strategies and outcomes for women with newly diagnosed advanced high-grade serous or endometrioid ovarian cancer (OC). METHODS: This observational study collected real-world medical record data from eight Western countries on the diagnostic workup, clinical outcomes, and treatment of adult women with newly diagnosed advanced (Stage III-IV) high-grade serous or endometrioid OC. Patients were selected backward in time from April 1, 2018 (the index date), with a target of 120 patients set per country, followed for ≥20 months. RESULTS: Of the 1119 women included, 66.9% had Stage III disease, 11.7% had a deleterious BRCA mutation, and 26.6% received bevacizumab; 40.8% and 39.3% underwent primary debulking surgery (PDS) and interval debulking surgery (IDS), respectively. Of the patients who underwent PDS, 55.5% had no visible residual disease (VRD); 63.9% of the IDS patients had no VRD. According to physician-assessed responses (at the first assessment after diagnosis and treatment), 53.2% of the total population had a complete response and 25.7% had a partial response to first-line chemotherapy after surgery. After ≥20 months of follow-up, 32.9% of the patients were disease-free, 46.4% had progressive disease, and 20.6% had died. Bevacizumab use had a significant positive effect on overall survival (hazard ratio [HR], 0.62; 95% CI, 0.42-0.91; p = .01). A deleterious BRCA status had a significant positive effect on progression-free survival (HR, 0.60; 95% CI, 0.41-0.84; p < .01). CONCLUSIONS: Women with advanced high-grade serous or endometrioid OC have a poor prognosis. Bevacizumab use and a deleterious BRCA status were found to improve survival in this real-world population. LAY SUMMARY: Patients with advanced (Stage III or IV) ovarian cancer (OC) have a poor prognosis. The standard treatment options of surgery and chemotherapy extend life beyond diagnosis for 5 years or more in only approximately 45% of patients. This study was aimed at describing the standard of care in eight Western countries and estimating how many patients who are diagnosed with high-grade serous or endometrioid OC could potentially be eligible for first-line poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) maintenance therapy. The results highlight the poor prognosis for these patients and suggest that a significant proportion (79%) would potentially be eligible for first-line PARPi maintenance treatment.

A Randomized Trial of Lymphadenectomy in Patients with Advanced Ovarian Neoplasms.

BACKGROUND: Systematic pelvic and paraaortic lymphadenectomy has been widely used in the surgical treatment of patients with advanced ovarian cancer, although supporting evidence from randomized clinical trials has been limited. METHODS: We intraoperatively randomly assigned patients with newly diagnosed advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIB through IV) who had undergone macroscopically complete resection and had normal lymph nodes both before and during surgery to either undergo or not undergo lymphadenectomy. All centers had to qualify with regard to surgical skills before participation in the trial. The primary end point was overall survival. RESULTS: A total of 647 patients underwent randomization from December 2008 through January 2012, were assigned to undergo lymphadenectomy (323 patients) or not undergo lymphadenectomy (324), and were included in the analysis. Among patients who underwent lymphadenectomy, the median number of removed nodes was 57 (35 pelvic and 22 paraaortic nodes). The median overall survival was 69.2 months in the no-lymphadenectomy group and 65.5 months in the lymphadenectomy group (hazard ratio for death in the lymphadenectomy group, 1.06; 95% confidence interval [CI], 0.83 to 1.34; P = 0.65), and median progression-free survival was 25.5 months in both groups (hazard ratio for progression or death in the lymphadenectomy group, 1.11; 95% CI, 0.92 to 1.34; P = 0.29). Serious postoperative complications occurred more frequently in the lymphadenectomy group (e.g., incidence of repeat laparotomy, 12.4% vs. 6.5% [P = 0.01]; mortality within 60 days after surgery, 3.1% vs. 0.9% [P = 0.049]). CONCLUSIONS: Systematic pelvic and paraaortic lymphadenectomy in patients with advanced ovarian cancer who had undergone intraabdominal macroscopically complete resection and had normal lymph nodes both before and during surgery was not associated with longer overall or progression-free survival than no lymphadenectomy and was associated with a higher incidence of postoperative complications. (Funded by Deutsche Forschungsgemeinschaft and the Austrian Science Fund; LION ClinicalTrials.gov number, NCT00712218.).

Maintenance Therapy with Aromatase Inhibitor in epithelial Ovarian Cancer (MATAO): study protocol of a randomized double-blinded placebo-controlled multi-center phase III Trial.

BACKGROUND: A high percentage of epithelial ovarian cancers (EOC) express the estrogen receptor (ER), which is an ideal target for endocrine therapy. Letrozole is a proven, potent aromatase inhibitor, extensively tested and used in the treatment of ER positive breast cancer. In addition, it seems a potent drug for patients with heavily pre-treated OC as demonstrated in several distinctive settings. However, it has never been evaluated prospectively in a maintenance setting for ovarian cancer after standard of care. The here proposed trial aims to define a population of EOC patients, who would benefit from the effectiveness of the generic agent letrozole, with little expected toxicity and thus beneficial impact on overall quality of life (QoL). METHODS: In this international multicenter randomized, placebo-controlled phase III trial at clinical centers in Switzerland, Germany and Austria, we plan to include 540 patients with primary, newly diagnosed FIGO Stage II to IV and histologically confirmed low- or high-grade serous or endometrioid epithelial ovarian/fallopian tube/peritoneal cancer. Patients are randomized in a 1:1 ratio into two groups: receiving blinded study treatment (letrozole or placebo tablets). When assuming a HR of 0.7, a median PFS of 18 months in the control arm and a median PFS of 25.7 months in the treatment arm, a two-sided alpha level of 5%, 3.5 years recruitment and 1.5 years observation time, we expect 330 events to have occurred within these 5 years in the total cohort yielding a power of 90%. Follow-up data for the whole cohort will be collected for up to 10 years and for the low-grade cancer for up to 12 years. DISCUSSION: The here proposed randomized phase III trial aims to identify patients with EOC in the maintenance setting, who benefit from the effectiveness of the letrozole, by proving its efficacy whilst maintaining a high standard of QoL due to the limited toxicity expected in comparison to the current alternative drugs on the market for this treatment phase. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov under the identifier NCT04111978 . Registered 02 October 2019.

Dubious effects of methadone as an "anticancer" drug on ovarian cancer cell-lines and patient-derived tumor-spheroids.

BACKGROUND: The opioid agonist D,L-methadone exerts analgesic effects via the mu opioid receptor, encoded by OPRM1 and therefore plays a role in chronic pain management. In preclinical tumor-models D,L-methadone shows apoptotic and chemo-sensitizing effects and was therefore hyped as an off-label "anticancer" drug without substantiation from clinical trials. Its effects in ovarian cancer (OC) are completely unexplored. METHODS: We analyzed OPRM1-mRNA expression in six cisplatin-sensitive, two cisplatin-resistant OC cell-lines, 170 OC tissue samples and 12 non-neoplastic control tissues. Pro-angiogenetic, cytotoxic and apoptotic effects of D,L-methadone were evaluated in OC cell-lines and four patient-derived tumor-spheroid models. RESULTS: OPRM1 was transcriptionally expressed in 69% of OC-tissues and in three of eight OC cell-lines. D,L-methadone exposure significantly reduced cell-viability in five OC cell-lines irrespective of OPRM1 expression. D,L-methadone, applied alone or combined with cisplatin, showed no significant effects on apoptosis or VEGF secretion in cell-lines. Notably, in two of the four spheroid models, treatment with D,L-methadone significantly enhanced cell growth (by up to 121%), especially after long-term exposure. This is consistent with the observed attenuation of the inhibitory effects of cisplatin in three spheroid models when adding D,L-methadone. The effect of methadone treatment on VEGF secretion in tumor-spheroids was inconclusive. CONCLUSIONS: Our study demonstrates that certain OC samples express OPRM1, which, however, is not a prerequisite for D,L-methadone function. As such, D,L-methadone may exert also detrimental effects by stimulating the growth of certain OC-cells and abrogating cisplatin's therapeutic effect.

EPIK-O/ENGOT-OV61: alpelisib plus olaparib vs cytotoxic chemotherapy in high-grade serous ovarian cancer (phase III study).

Patients with platinum-resistant or -refractory high-grade serous ovarian cancer (HGSOC) have a poor prognosis, and their management represents a substantial unmet medical need. Preclinical data and results from a phase Ib trial demonstrated the efficacy and tolerability of the combination of the α-specific phosphatidylinositol-3-kinase (PI3K) inhibitor alpelisib plus the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib in platinum-resistant, non-BRCA-mutated ovarian cancer. Here, we describe the study design and rationale for the phase III, multicenter, open-label, randomized, active-controlled EPIK-O/ENGOT-OV61 trial investigating alpelisib in combination with olaparib compared with standard-of-care chemotherapy in patients with platinum-resistant or -refractory HGSOC with no germline BRCA mutation. Progression-free survival (blinded independent review committee) is the primary end point. Overall survival is a key secondary end point. Clinical Trial Registration:: NCT04729387 (ClinicalTrials.gov).

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001.

BACKGROUND: Pembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with advanced endometrial cancer (KEYNOTE-146/Study 111) after ≤2 previous lines of therapy. In a randomized phase 3 trial of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer (KEYNOTE-775/Study 309), after 1‒2 previous lines of therapy (including neoadjuvant/adjuvant), this combination improved objective response rates, progression-free survival, and overall survival compared with chemotherapy. PRIMARY OBJECTIVE: To compare the efficacy and safety of first-line pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV or recurrent endometrial cancer, with measurable or radiographically apparent disease. STUDY HYPOTHESIS: Pembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression-free survival and overall survival in patients with mismatch repair-proficient tumors and all patients (all-comers). TRIAL DESIGN: Phase 3, randomized (1:1), open-label, active-controlled trial. Patients will receive pembrolizumab intravenously every 3 weeks plus lenvatinib orally daily or paclitaxel plus carboplatin intravenously every 3 weeks, stratified by mismatch repair status (proficient vs deficient). Patients with mismatch repair-proficient tumors will be further stratified by Eastern Cooperative Oncology Group performance status (0/1), measurable disease (yes/no), and prior chemotherapy and/or chemoradiation (yes/no). MAJOR INCLUSION/EXCLUSION CRITERIA: Adults with stage III/IV/recurrent histologically confirmed endometrial cancer that is measurable or radiographically apparent per blinded independent central review. Patients may have received previous chemotherapy only as neoadjuvant/adjuvant therapy and/or concurrently with radiation. Patients with carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, or other high grade sarcomas, or endometrial stromal sarcomas were excluded. PRIMARY ENDPOINTS: Progression-free and overall survival (dual primary endpoints). SAMPLE SIZE: About 875 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Enrollment is expected to take approximately 24 months, with presentation of results in 2022. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03884101.

Efficacy of an optimal ovarian cancer screening: a best-case scenario study based on real-world data.

PURPOSE: To date, ovarian cancer screening in asymptomatic women has not shown a mortality benefit. The aim of this simulation study was to outline the impact of different histological subtypes on a potential stage-shift, achieved by screening. METHODS: Real-world data were derived in the period of 2000-2017 from the Klinischen Tumorregister Austria. We estimated five-year overall survival (OS) of patients with ovarian cancer regarding different histological subtypes and FIGO stages. A theoretical model was generated predicting the trend of OS mediated by an eventual down-shifting of ovarian cancer from FIGO stage III/IV to FIGO stage I/II by screening, considering the influence of different histological subtypes. RESULTS: 3458 ovarian cancer patients were subdivided according to histological subtypes and FIGO classification. Major difference in distribution of histological types was found between FIGO stage I/II and III/IV. A theoretical down-shift of tumors from high to low FIGO stages based on our registry calculations showed that the five-year OS would increase from 50% to nearly 80% by perfect screening. CONCLUSION: In our simulation study, we showed that down-shifting ovarian cancers by successful screening might increase OS by 30 percentage point. Our results underscore the importance to recognize ovarian cancer as a heterogenous disease with distinct epidemiologic, molecular and clinical features. The individual characteristic of each histotype is of utmost impact on the definition of screening aims and may influence early detection and stage-shift. Efficacy of screening is mainly dependent on detection of high-risk cancer types and not the slow growing low-grade types.

The impact of COVID-19 pandemic on the rate of newly diagnosed gynecological and breast cancers: a tertiary center perspective.

PURPOSE: The aim of the present study was to assess the impact of postponed screening examinations and lockdown measures on gynecological and breast cancer diagnoses throughout the year 2020 in a gynecological oncological center in Austria. METHODS: Data of 889 patients with either newly diagnosed gynecological or breast cancer between January 2019 and December 2020 were collected. Clinical parameters including symptoms, performance status, comorbidities and referral status were compared in patients, who were newly diagnosed with cancer in the period of the first lockdown from March 2020 to April 2020 and the second lockdown from November 2020 to December 2020 and compared to the same period in 2019. RESULTS: Our results showed a strong decline in newly diagnosed cancers during the lockdown periods: -45% in gynecological cancer and -52% in breast cancer compared to the same period in 2019. Compared to the analogue period of 2019, breast cancer patients reported significantly more tumor-associated symptoms (55% vs. 31%, p = 0.013) during and in between (48% vs. 32%, p = 0.022) the lockdowns. During the lockdown, periods in the group of breast cancer patients' tumor stage varied significantly compared to 2019 (T2-T4; p = 0.047). CONCLUSION: Both lockdowns led to a strong decrease in newly diagnosed gynecological and breast cancers. Treatment delays in potentially curable disease could lead to inferior clinical outcomes, with the risk of missing the optimal treatment window. As the COVID-19 pandemic will be a challenge for some time to come, new strategies in patient care are needed to optimize cancer screening and management during the pandemic.

European Society of Gynaecological Oncology quality indicators for the surgical treatment of endometrial carcinoma.

BACKGROUND: Quality of surgical care as a crucial component of a comprehensive multi-disciplinary management improves outcomes in patients with endometrial carcinoma, notably helping to avoid suboptimal surgical treatment. Quality indicators (QIs) enable healthcare professionals to measure their clinical management with regard to ideal standards of care. OBJECTIVE: In order to complete its set of QIs for the surgical management of gynecological cancers, the European Society of Gynaecological Oncology (ESGO) initiated the development of QIs for the surgical treatment of endometrial carcinoma. METHODS: QIs were based on scientific evidence and/or expert consensus. The development process included a systematic literature search for the identification of potential QIs and documentation of the scientific evidence, two consensus meetings of a group of international experts, an internal validation process, and external review by a large international panel of clinicians and patient representatives. QIs were defined using a structured format comprising metrics specifications, and targets. A scoring system was then developed to ensure applicability and feasibility of a future ESGO accreditation process based on these QIs for endometrial carcinoma surgery and support any institutional or governmental quality assurance programs. RESULTS: Twenty-nine structural, process and outcome indicators were defined. QIs 1-5 are general indicators related to center case load, training, experience of the surgeon, structured multi-disciplinarity of the team and active participation in clinical research. QIs 6 and 7 are related to the adequate pre-operative investigations. QIs 8-22 are related to peri-operative standards of care. QI 23 is related to molecular markers for endometrial carcinoma diagnosis and as determinants for treatment decisions. QI 24 addresses the compliance of management of patients after primary surgical treatment with the standards of care. QIs 25-29 highlight the need for a systematic assessment of surgical morbidity and oncologic outcome as well as standardized and comprehensive documentation of surgical and pathological elements. Each QI was associated with a score. An assessment form including a scoring system was built as basis for ESGO accreditation of centers for endometrial cancer surgery.

ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multi-disciplinary 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 and 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.

TNFα signalling predicts poor prognosis of patients with endometrial cancer.

Endometrial cancer (EC) is the most common gynaecologic tumour in the Western world. Previous studies have implicated an imbalance of oestrogens and progestogens in the development of most ECs, while the role of low-grade tissue inflammation remains largely unexplored. We investigated the impact of tumour necrosis factor alpha (TNFα), a central mediator of inflammation and spermatogenesis-associated protein 2 (SPATA2), a regulator of TNF receptor signalling, on clinical outcomes in EC. We evaluated TNFA and SPATA2 transcript levels in 239 EC patients and 25 non-malignant control tissues. Findings were validated in a cohort of 332 EC patients from The Cancer Genome Atlas (TCGA). Expression of TNFA and SPATA2 was increased in EC when compared with control tissues (P < 0.001). TNFA expression correlated with SPATA2 expression in non-malignant (P = 0.003, rS = 0.568) and EC tissue (P = 0.005, rS = 0.179). High TNFA and SPATA2 expression were associated with poor recurrence-free survival (RFS; P = 0.049 and P = 0.018) and disease-specific (P = 0.034 and P = 0.002) survival. Increased SPATA2 expression was also associated with decreased overall survival (OS; P = 0.013). In multivariate analysis, both TNFA and SPATA2 were predictors of clinical outcome. The impact of SPATA2 on RFS and OS could be validated in the TCGA cohort. Our study demonstrates that ECs exhibit a TNF signature which predicts clinical outcome. These findings indicate that TNF signalling modulates the course of EC, which could be therapeutically utilized in the future.