LncRNA FIRRE regulated endometrial cancer radiotherapy sensitivity via the miR-199b-5p/SIRT1/BECN1 axis-mediated autophagy.

BACKGROUND: Endometrial cancer (EC) poses a serious threat to women's health. Radiotherapy has been widely used for EC treatment. However, the mechanism of FIRRE in EC development and radioresistance remains unknown. METHODS: MTT and colony formation assays determined cell proliferation. The degree of autophagy was tested by the measurement of autophagy-related genes and immunofluorescence staining of LC3. Molecular interactions were demonstrated via luciferase reporter assay, RIP, and Co-IP. The FIRRE role's was analyzed by in vivo xenograft tumor model. RESULTS: FIRRE and SIRT1 were upregulated in EC tumor tissues, whereas miR-199b-5p was reduced. FIRRE knockdown increased EC cell radiotherapy sensitivity by sponging miR-199b-5p and inhibiting autophagy. SIRT1 was targeted and negatively regulated by miR-199b-5p. SIRT1 could otherwise deacetylate BECN1 protein and participate in FIRRE-mediated autophagy. Silencing FIRRE increased sensitivity of EC radiotherapy in vivo. CONCLUSION: FIRRE reduced EC cell radiotherapy sensitivity by stimulating autophagy via miR-199b-5p/SIRT1/BECN1 axis.

Lunchbox trial: A randomized phase III trial of cisplatin and irradiation followed by carboplatin and paclitaxel versus sandwich therapy of carboplatin and paclitaxel followed by irradiation then carboplatin and paclitaxel for advanced endometrial carcinoma.

BACKGROUND: The objective was to compare sequencing strategies for treatment of advanced endometrial carcinoma. METHODS: Patients were eligible if they had FIGO 2009 Stage III or IVA endometrial carcinoma or Stage I or II serous or clear cell endometrial carcinoma and positive cytology. Patients were randomized to: Cisplatin 50 mg/m2 IV Days 1 and 29 plus radiation followed by Carboplatin AUC 5 or 6 plus Paclitaxel 175 mg/m2 q 21 days for 4 cycles (chemoRT then chemo) vs. Carboplatin AUC 6 plus Paclitaxel 175 mg/m2 q 21 days for 3 cycles followed by radiation followed by Carboplatin AUC 5 or 6 plus Paclitaxel 175 mg/m2 q 21 days for 3 cycles (sandwich therapy). Futility analysis was planned. The primary objective was to determine if chemoRT then chemo improves recurrence-free survival (RFS) compared to sandwich therapy. RESULTS: Of the 48 patients enrolled at 8 sites, 42 patients were eligible for futility analysis, and the trial was closed early. The median follow-up was 30.9 months. The 3-year RFS was 85.7% (95% confidence interval [CI], 62 to 95) in the chemoRT then chemo arm and 73.4% (95% CI, 43 to 89) in the sandwich therapy group (p = 0.58). The 3-year overall survival (OS) was 88.4% (95% CI, 61 to 97) in the chemoRT then chemo arm and 80.9% (95% CI, 51 to 93) in the sandwich therapy group (p = 0.55). CONCLUSION: There was no observed significant difference between chemoRT then chemo compared to sandwich therapy in terms of RFS, OS, or adverse events, although the trial was underpowered and closed early due to low accrual.

Prevalence of trauma history and symptoms in patients who have received vaginal brachytherapy as part of their endometrial cancer treatment.

OBJECTIVE: Vaginal brachytherapy (VBT) is an essential component of curative intent treatment for many patients with endometrial cancer. The prevalence of trauma history in this population is unknown and important to understand considering VBT requires patients to have an instrument vaginally inserted while in the vulnerable lithotomy position. We aim to identify patients treated with intracavitary VBT and collect survey data to assess trauma endpoints. METHODS: We retrospectively identified patients with endometrial cancer who underwent intracavitary VBT at our institution between 01/2017 and 08/2022. Patients were mailed and/or electronically mailed a survey that included demographics, psychosocial background, and validated trauma surveys to be filled out as they relate to their trauma experiences prior to VBT and again considering any trauma symptomatology related to VBT. Electronic medical record review was performed. Descriptive statistics as well as multivariate analysis were performed. RESULTS: 206 patients met inclusion criteria, 66 (32.1%) of whom returned the survey and were included for analysis. Thirty-two percent of patients self-reported a personal history of any prior mental health diagnosis. Eighty-eight percent of patients screened positive for a history of trauma exposure, 23% endorsed symptoms of PTSD related to their VBT experience, and 5% screened positive for a likely PTSD diagnosis from VBT. CONCLUSION: A majority of included patients had a history of trauma exposure prior to VBT. In a subset of patients, VBT re-induced trauma and was considered to be an independent traumatic event. This study highlights the importance of practicing trauma informed care, particularly in this patient population.

Effects of vaginal dilation therapy on vaginal condition and sexual function of endometrial cancer patients treated with radiotherapy after surgery.

OBJECTIVE: This study aimed to evaluate the effect of vaginal dilation therapy on vaginal length, vaginal stenosis, vaginal elasticity, and sexual function of endometrial cancer patients treated with radiotherapy after surgery. METHODS: A total of 117 women were enrolled in this study. They received 6 months of vaginal dilation therapy. We evaluated their vaginal length, vaginal diameter, vaginal elasticity, and sexual function before radiotherapy, after radiotherapy, and after 6 months of vaginal dilation therapy. Their vaginal condition was assessed by customized vaginal dilating molds. Their sexual function was assessed by female sexual function index. The SPSS 25 software was used to analyze all the data. RESULTS: According to multivariate analysis, vaginal diameter (ß = 0.300, 95% CI [0.217-1.446], p = 0.010) and sexual intercourse frequency before diagnosis (ß = 0.424, 95% CI [0.164-0.733], p = 0.006) were significantly correlated with female sexual function after radiotherapy. Vaginal dilation therapy helped increase vaginal length, improve vaginal stenosis and sexual function (p < 0.05), though most of the figures at the end of the intervention did not fully return to those before radiotherapy. Noticeably, vaginal dilation therapy was ineffective in improving vaginal elasticity and the incidence rate of female sexual dysfunction (p > 0.05). Moreover, patients with medium or good vaginal elasticity benefited more from vaginal dilation therapy than patients with poor vaginal elasticity (p < 0.05). CONCLUSION: Vaginal dilation therapy should be carried out timely and preventatively in endometrial cancer patients treated with radiotherapy after surgery to improve their vaginal condition and sexual function.

Peritoneal mesometrial resection with lymphadenectomy following prior hysterectomy in intermediate/high-risk endometrial cancer: feasibility and safety.

OBJECTIVE: Peritoneal mesometrial resection (PMMR) plus targeted compartmental lymphadenectomy (TCL) aims at removal of the locoregional cancer field in endometrial cancer (EC). Optimal locoregional control without adjuvant radiotherapy should be achieved concomitantly sparing systematic lymphadenectomy (LNE) for most of the patients. However, intermediate/high-risk EC is often definitely diagnosed postoperatively in simple hysterectomy specimen. Our aim was to evaluate feasibility and safety of a completing PMMR + TCL in patients following prior hysterectomy. METHODS: We evaluated data from 32 patients with intermediate/high-risk EC treated with PMMR + TCL or systematic pelvic and periaortic LNE following prior hysterectomy. Perioperative data on disease characteristics and morbidity were collected and patients were contacted for follow-up to determine the recurrence and survival status. RESULTS: We report data from 32 patients with a mean follow-up of 31.7 months. The recurrence rate was 12.5% (4/32) without any isolated locoregional recurrences. Only 21.9% of patients received adjuvant radiotherapy. Rates of intra- and postoperative complications were 6.3% and 18.8%, respectively. CONCLUSION: Our data suggest that robotic PMMR can be performed following prior hysterectomy when previously unknown risk factors arise, albeit with a moderate increase in morbidity. Moreover, despite a relevant reduction of adjuvant radiotherapy, follow-up data suggest an excellent locoregional control even without adjuvant radiotherapy.

Abnormal preoperative haematological parameters in Endometrial cancer; reflecting tumour aggressiveness or reduced response to radiotherapy?

BACKGROUND: In endometrial cancer (EC), preoperative anaemia, thrombocytosis and leucocytosis appear to be associated with worse prognosis. It remains unclear whether these parameters solely reflect tumour aggressiveness, or also impact response to adjuvant treatment. Therefore, our primary aim is to evaluate the prognostic relevance of anaemia, thrombocytosis and leucocytosis on survival in EC. Secondary, to explore their predictive relevance in response to radiotherapy in EC. METHODS: A retrospective multicentre cohort study was performed within 10 hospitals. Preoperative haematological parameters were defined as: Anaemia - haemoglobin <7.45 mmol/L (<12 g/Dl), thrombocytosis - platelets >400 × 109 platelets/L, leucocytosis - leukocytes >10 × 109/L. The relationship of haematological parameters with clinicopathological characteristics, ESGO/ESTRO/ESP risk groups and survival were evaluated. Furthermore, the predictive value of haematological parameters was determined on the overall response to adjuvant radiotherapy and for the ESGO/ESTRO/ESP intermediate-risk group solely receiving radiotherapy. RESULTS: A total of 894 patients were included with a median follow-up of 4.5 years. Anaemia was present in 103 (11.5%), thrombocytosis in 79 (8.8%) and leucocytosis in 114 (12.7%) patients. The presence of anaemia or thrombocytosis was significantly associated with ESGO/ESTRO/ESP high-risk (respectively, P = 0.002 and P = 0.041). In the entire cohort, anaemia remained independently associated with decreased disease-specific survival (HR 2.31, 95% CI (1.19-4.50), P = 0.013) after adjusting for age, the abnormal haematological parameters and ESGO/ESTRO/ESP risk groups. In patients that were treated with adjuvant radiotherapy (n = 239), anaemia was associated with significant reduced 5-year disease-specific and recurrence-free survival (P = 0.005 and P = 0.025, respectively). In ESGO/ESTRO/ESP intermediate risk patients that received solely vaginal brachytherapy (n = 74), anaemia was associated with reduced disease-specific survival (P = 0.041). CONCLUSIONS: Current data demonstrate the importance of preoperative anaemia as independent prognostic factor in patients with EC. Moreover, anaemia seems to be associated with reduced response to radiotherapy. Prospective validation in a larger study cohort is needed to verify anaemia as predictive biomarker for radiotherapy.What is already known on this subject? In endometrial cancer, preoperative abnormal haematological parameters like, anaemia, thrombocytosis and leucocytosis appears to be associated with FIGO advanced-stage and unfavourable outcome.What do the results of this study add? It remains unclear whether anaemia, thrombocytosis or leucocytosis solely reflecting worse prognosis by advanced tumour stage, or also impact response to adjuvant treatment. Current data demonstrate that anaemia is independent associated with decreased disease-specific survival and anaemia seems related with reduced response to radiotherapy and in specific to vaginal brachytherapy in ESGO/ESTRO/ESP intermediate risk patients.What are the implications of these findings for clinical practice and/or further research? Specific applied adjuvant treatment is needed if patients with anaemia have a reduced response to radiotherapy in EC. Prospective validation in a larger study cohort is required to verify anaemia as predictive biomarker for radiotherapy and to further evaluate the prognostic/predictive impact of anaemia in addition to the molecular subgroups.

In this study we focused on three specific blood values before surgery to predict survival outcomes in endometrial cancer patients: low haemoglobin (anaemia), high platelet count (thrombocytosis) and high white blood cell count (leucocytosis). We studied 894 patients with endometrial cancer over about 4.5 years, in which 11.5% had anaemia, 8.8% thrombocytosis and 12.7% leucocytosis. Anaemia was linked to a lower chance of surviving endometrial cancer, even after we considering patients' age, thrombocytosis, leucocytosis and the endometrial cancer risk classification groups. In patients who received radiotherapy after surgery (293 patients), anaemia was linked to a lower change of surviving and cancer coming back within 5 years. In patients within the intermediate endometrial cancer risk classification group who only received specific radiotherapy (74 patients), anaemia was even linked with lower chance of survival. In conclusion, anaemia is an important factor in predicting endometrial cancer outcomes, and it might also make radiotherapy less effective for some patients.

Adjuvant radiation therapy and health-related quality of life among older women with early-stage endometrial cancer: an analysis using the SEER-MHOS linkage.

PURPOSE: Radiation therapy (RT) has been associated with decreased health-related quality of life (HRQOL) in clinical trials of early-stage endometrial cancer (EC), but few studies have examined the association in real-world settings. We assessed HRQOL associated with adjuvant RT for older women with early-stage EC within a large U.S. population-based registry resource. METHODS: The Surveillance Epidemiology and End Results and the Medicare Health Outcomes Survey linkage (1998-2017) was used to identify women with early-stage EC aged ≥ 65 years at survey who received surgery and were diagnosed ≥ 1-year prior (n = 1,140). HRQOL was evaluated with the 36-item Short-Form Health Survey (SF-36) until 2006 and the Veterans RAND 12-Item Health Survey (VR-12) post 2006. Ordinary least squares regression was used to estimate mean difference (MD) in T scores and 95% confidence intervals (CIs) comparing treatment groups (surgery alone, adjuvant external beam radiation therapy [EBRT], or adjuvant vaginal brachytherapy [VBT]) after accounting for confounders using propensity score weighting. RESULTS: Overall, RT was not associated with physical health (MD = 0.97; 95% CI = - 1.13, 3.07) or mental health (MD = - 0.78; 95% CI = - 2.60, 1.05) relative to surgery alone. In analyses by RT type, adjuvant VBT was associated with better general health on the SF-36/VR-12 subscale (MD = 3.59; 95% CI = 0.56, 6.62) relative to surgery alone. No statistically significant associations were observed for adjuvant VBT and physical or mental health, or for adjuvant EBRT and any HRQOL domain. CONCLUSION: Older women with early-stage EC treated with adjuvant RT did not report worse physical and mental HRQOL scores compared to those treated with surgery alone, though relevant symptoms should be evaluated further to fully understand the disease and treatment specific aspects of the HRQOL.

Non-endometrioid endometrial cancer: analysis of recurrence pattern and identification of prognostic and treatment factors affecting recurrence and survival.

PURPOSE: We investigated the characteristics of recurrence pattern and survival of patients with non-endometrioid endometrial cancer (NEEC) and attempted to identify prognostic and treatment factors affecting disease-free survival (DFS) and overall survival (OS) of these patients. METHODS: Fifty-seven patients with histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stage IA-IVA NEEC from February 2003 to December 2021 were retrospectively analyzed. RESULTS: The 5­year DFS and OS rates of the total cohort were 50.6% and 56.1%, respectively. Recurrence occurred in 28 patients (49.1%) during follow-up, and the most common recurrence pattern was distant metastasis (DM; 78.6% of total recurrences). The occurrence of relapse significantly reduced 5­year OS (recurrence group vs. non-recurrence group: 12.5% vs. 100%; p < 0.001). In univariate analysis, adjuvant radiotherapy (RT) group showed significantly higher 5­year DFS (56.7% vs. 37.9%; p = 0.04), local recurrence-free survival (91.6% vs. 50.5%; p = 0.01), and regional recurrence-free survival (88.2% vs. 56.5%; p < 0.01) than the non-RT group. In multivariate analysis, advanced FIGO stage was identified as a negative prognostic factor for DFS and OS. Lymphovascular space invasion (LVSI) and adjuvant RT were independent prognostic factors for DFS. CONCLUSION: The most common recurrence pattern observed in patients with NEEC was DM. FIGO stage and LVSI were identified as prognostic factors for survival, and RT was identified as a therapeutic modality that could increase DFS. To improve the OS of patients with NEEC, the addition of effective chemotherapy that can reduce DM may be important.

Adjuvant radiation therapy in early-stage endometrial cancer with abnormal beta-catenin expression is associated with improved local control.

OBJECTIVES: Emerging data suggests that abnormal (nuclear) ß-catenin expression in some settings is associated with poorer outcomes. Our study aimed to verify the significance of abnormal ß-catenin expression in early-stage endometrial cancer patients and determine if adjuvant radiation therapy (RT) improves local control. METHODS: We identified 213 patients with FIGO 2018 stage I-II endometrioid endometrial cancer who underwent surgery from 2009 to 2021 with ß-catenin expression assessed. Vaginal, regional, and distant recurrences were analyzed using competing risk methods, and overall survival was analyzed using Kaplan-Meier. RESULTS: Median follow up was 53.2 months; 6.9% experienced vaginal, 8.2% regional, and 7.4% distant recurrence. For the entire cohort, abnormal ß-catenin expression was significantly associated with vaginal recurrence and remained significant on multivariate analysis (p = 0.03). There were 114 patients in the no specific molecular profile (NSMP) subgroup, and abnormal ß-catenin expression was present in 46.5%. In the NSMP subgroup, abnormal ß-catenin expression was associated with increased rates of vaginal recurrence (p = 0.06). Abnormal ß-catenin expression in the NSMP subgroup was significant on multivariate analysis for vaginal recurrence (p = 0.04). RT significantly decreased vaginal recurrences in the entire cohort in patients with abnormal ß-catenin expression (0%) versus wild type expression (17.5%; p = 0.03). In the NSMP subgroup 0% of patients who received RT versus 20.9% of patients who did not receive RT experienced a vaginal recurrence (p = 0.03). CONCLUSION: Use of adjuvant RT for stage I-II NSMP endometrial cancer with abnormal ß-catenin expression improved local control. RT should be considered in these patients to decrease risk of vaginal recurrences.

Prospective randomised phase II trial evaluating adjuvant pelvic radiotherapy using either IMRT or 3-Dimensional planning for endometrial cancer.

OBJECTIVE: To compare the incidence of grade ≥2 gastrointestinal (GI) or genitourinary (GU) toxicity for patients undergoing 3DRT versus IMRT in the postoperative setting for endometrial cancer. METHODS: Eligible patients were post-operatively randomly assigned to one of two parallel groups in a 1:1 ratio, to have their RT delivered using either a 3DRT technique or using IMRT. The prescription dose was 45 Gy in 25 fractions over 5 weeks followed by vaginal vault brachytherapy. Toxicity was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 3.0. Fisher's exact tests were used to test for associations between toxicity and arm. Differences in dosimetric parameters for patients with or without toxicity were tested using Mann-Whitney U-tests. RESULTS: 84 patients with a median age of 62 were evaluable for primary outcome. The median follow-up was 52 months. 14 (35%) participants from the 3DRT arm and 15 (34%) from the IMRT arm experienced acute grade ≥2 GI toxicity with older patients having a statistically higher risk of grade ≥2 acute GI toxicity. 20 (50%) participants from the 3DRT arm and 25 (57%) from the IMRT arm experienced acute grade ≥2 GI or GU toxicity (p = .662). 12 (30%) patients from the 3DRT arm and 17 (39%) from the IMRT arm experienced acute grade ≥2 GU toxicity (p = .493). CONCLUSION: Although IMRT can reduce dose to normal tissue, in this study no benefit in acute GI or GU toxicity outcome was seen.

The survival impact of adjuvant radiotherapy and chemotherapy in patients with non-endometrioid endometrial carcinomas: a PSM-IPTW analysis based on SEER database.

PURPOSE: To investigate outcomes of adjuvant treatments for non-endometrioid endometrial carcinomas (NEEC), as previous studies are limited by its rarity and heterogeneity. PATIENTS AND METHODS: Patients with endometrial serous carcinoma (SC), clear cell carcinoma (CCC) and carcinosarcoma were identified between 2004 and 2018 from SEER database. Propensity score matching (PSM) along with inverse probability treatment weighting (IPTW) technique were employed to balance confounding factors. Multivariate, exploratory subgroup and sensitivity analyses were conducted to evaluate the impact of adjuvant treatment on overall survival (OS) and cause-specific survival (CSS). RESULTS: The cohort comprised 5577 serous, 977 clear cell, and 959 carcinosarcomas. Combined chemotherapy and radiotherapy (CRT), chemotherapy alone, and radiotherapy alone were respectively administered in 42.21%, 47.27% and 10.58% of the whole cohort. Prior to adjusting, chemotherapy plus brachytherapy yielded the most beneficial effect among various strategies. After PSM-IPTW adjustment, CRT still demonstrated beneficial effect on OS and CSS. Subgroup analysis indicated CRT improved survival among various TNM stages, particularly with uterine carcinosarcoma. In the sensitivity analyses for serous histology, brachytherapy with or without chemotherapy appeared to benefit stage I-II patients. In stage III-IV SC patients, chemotherapy plus brachytherapy was still associated with improved survival outcomes. When nodal metastases were identified, additional external beam radiotherapy (EBRT) to CT was more utilized with survival improvement. CONCLUSION: In NEEC patients, combined CRT yielded beneficial effects than any single mode. Both chemotherapy and brachytherapy promoted survival in early stage SC patients. Late stage SC patients may benefit from chemotherapy plus either EBRT or brachytherapy.

Improving normal tissue sparing using scripting in endometrial cancer radiation therapy planning.

The aim of this study was to improve the protection of organs at risk (OARs), decrease the total planning time and maintain sufficient target doses using scripting endometrial cancer external beam radiation therapy (EBRT) planning. Computed tomography (CT) data of 14 endometrial cancer patients were included in this study. Manual and automatic planning with scripting were performed for each CT. Scripts were created in the RayStation™ (RaySearch Laboratories AB, Stockholm, Sweden) planning system using a Python code. In scripting, seven additional contours were automatically created to reduce the OAR doses. The scripted and manual plans were compared to each other in terms of planning time, dose-volume histogram (DVH) parameters, and total monitor unit (MU) values. While the mean total planning time for manual planning was 368 ± 8 s, it was only 55 ± 2 s for the automatic planning with scripting (p < 0.001). The mean doses of OARs decreased with automatic planning (p < 0.001). In addition, the maximum doses (D2% and D1%) for bilateral femoral heads and the rectum were significantly reduced. It was observed that the total MU value increased from 1146 ± 126 (manual planning) to 1369 ± 95 (scripted planning). It is concluded that scripted planning has significant time and dosimetric advantages over manual planning for endometrial cancer EBRT planning.

Treatment outcomes of early-stage endometrial cancer patients: A propensity score matching of vaginal brachytherapy versus pelvic radiotherapy.

OBJECTIVES: This study aimed to report the treatment outcomes of radiation therapy for early-stage endometrial cancer patients. In addition, this study intended to identify high-risk factors that require pelvic radiotherapy (PRT) in addition to vaginal brachytherapy (VBT) for intermediate-risk endometrial cancer patients. METHODS: Patients with early-stage endometrial cancer receiving postoperative VBT alone or with PRT were included. Propensity score matching was used to balance the two study groups. The primary endpoint was locoregional recurrence (LRR). Age-adjusted Charlson comorbidity index and substantial lymphovascular space invasion were selected for subgroup analyses to identify the benefits of PRT over VBT alone. RESULTS: From 2005 to 2017, a total of 288 patients underwent analysis following propensity score matching. Of these, 144 received VBT and 144 received PRT. There was no significant difference in 5-year LRR between VBT and PRT for both intermediate (0% vs. 0%) and high-intermediate risk patients (3.5% VBT vs. 5.4% PRT; HR 0.54: 0.05-6.00; p = 0.616). The subgroup analyses revealed no significant factors favoring PRT over VBT. Patients with high comorbidities may have higher risks of non-cancer death after receiving PRT. CONCLUSIONS: Postoperative VBT alone is sufficient for early-stage intermediate-risk endometrial cancer patients.

Does the addition of radiation improve survival compared to chemotherapy alone in women with stage IV endometrial carcinoma? Analysis of the NCDB and SEER databases.

OBJECTIVE: To evaluate whether the addition of radiation to adjuvant chemotherapy is associated with improved survival in women with stage IV endometrial cancer following surgery. METHODS: The National Cancer Database (NCDB) and Surveillance, Epidemiology, and End Results Program (SEER) registries were queried for patients with stage IV endometrial cancer from 2004 to 2017. Treatment was categorized as chemotherapy alone, chemotherapy with external beam radiation therapy (EBRT), chemotherapy with vaginal brachytherapy (VBT), or chemotherapy with EBRT+VBT. Multivariable Cox regression models assessed associations between treatment modality and overall survival (OS). RESULTS: This analysis included 17,890 (NCDB: 12,812, SEER: 5078) women with stage IV endometrial cancer, including 1757 (9.8%) with IVA disease and 16,133 (90.2%) with IVB. The majority of stage IV patients received chemotherapy alone (NCDB 78.8%, SEER 77.0%). When radiation was utilized in addition to chemotherapy, EBRT was most common (NCDB 15.8%, SEER: 15.4%). In both databases, use of any radiation in addition to chemotherapy was associated with improved OS. Stage IV patients treated with chemotherapy plus EBRT had better survival than those receiving chemotherapy alone [NCDB: HR 0.75 (95% CI 0.70, 0.79), SEER: HR 0.85 (95% CI 0.77, 0.94)]. This benefit was more pronounced in patients with IVA disease [NCDB: HR 0.66 (95% CI 0.55, 0.79), SEER: HR 0.63 (95% CI 0.46, 0.85)]. In histology-stratified analyses, the addition of radiation to chemotherapy was associated with improved OS in all histologies, except clear cell. CONCLUSIONS: In this analysis of the NCDB and SEER registries, the use of multimodality treatment with radiation and chemotherapy was associated with improved OS compared to chemotherapy alone in women with stage IVA and IVB endometrial cancer.

Long-term survival following definitive radiation therapy for recurrence or oligometastases in gynecological malignancies: A landmark analysis.

OBJECTIVE: Radiation therapy (RT) may improve outcomes for patients with oligometastatic cancer. We sought to determine if there are long-term survivors treated with definitive RT for recurrent or oligometastatic gynecological cancer (ROMGC), and to evaluate the clinical and disease characteristics of these patients. METHODS: We performed a landmark analysis in 48 patients with ROMGC who survived for ≥5 years following definitive RT of their metastasis. Patient characteristics were extracted from the medical record. DFS was modeled using the Kaplan-Meier method. RESULTS: This cohort included 20 patients (42%) with ovarian cancer, 16 (33%) with endometrial cancer, 11 (23%) with cervical cancer, and one (2%) with vaginal cancer. The sites of ROMGC were the pelvic (46%), para-aortic (44%), supraclavicular (7%), mediastinal (4%), axillary (4%) lymph nodes and the lung (5.5%). Median total RT dose and fractionation were 62.1 Gy and 2.1 Gy/fraction; one patient was treated with SBRT. 32 patients (67%) received chemoradiation; these patients had higher rates of median DFS than those treated with RT alone (93 vs. 34 months, P = 0.05). At median follow-up of 11.7 years, 11 (23%) patients had progression of disease. 20 (42%) patients had died, 9 (19%) died from non-gynecologic cancer and 8 (17%) from gynecologic cancer (three were unknown). 25 (52%) patients were alive and disease-free (10 initially had endometrial cancer [63% of these patients], eight had cervical cancer [73%], six had ovarian cancer [30%], one had vaginal cancer [100%]). CONCLUSIONS: Long-term survival is possible for patients treated with definitive RT for ROMG, however randomized data are needed to identify which patients derive the most benefit.

Not all stage I and II endometrial cancers are created equal: Recurrence-free survival and cause-specific survival after observation or vaginal brachytherapy alone in all subgroups of early-stage high-intermediate and high-risk endometrial cancer.

OBJECTIVE: To evaluate recurrence-free survival (RFS) and cause-specific survival (CSS) after observation or vaginal brachytherapy (VB) alone in all subgroups of early-stage high-intermediate (HIR) and high-risk endometrial cancer (EC). METHODS: We identified patients with stage I HIR (GOG-249 criteria) and stage II endometrioid EC, and stage I and II non-endometrioid EC who underwent surgery at Mayo Clinic and Cleveland Clinic between 1999 and 2016. Three-year RFS and CSS after observation or VB only were estimated in 16 subgroups defined by risk factors. RESULTS: Among 4156 ECs, we identified 447 (10.8%) stage I endometrioid HIR, 52 (1.3%) stage II endometrioid, 350 (8.4%) stage I non-endometrioid, and 17 (0.4%) stage II non-endometrioid ECs; observation or VB alone was applied in 349 (78.1%), 24 (46.2%), 187 (53.4%), and 2 (11.8%) patients, respectively. After observation or VB, stage I HIR endometrioid EC subgroups with <2 factors among grade 3, LVSI, or stage IB had a 3-year CSS >95% (lower 95% confidence intervals limit: 89.8%), whereas subgroups with ≥2 factors had poorer outcomes. No EC-related deaths after 3 years were reported in 97 stage IA non-endometrioid ECs without myometrial invasion. Stage II ECs had poor outcomes regardless of histology. CONCLUSIONS: Observation or VB only may be sufficient in stage I endometrioid HIR ECs with <2 factors among grade 3, LVSI, or IB and in stage IA non-endometrioid ECs without myometrial invasion. Stratification of early-stage HIR and high-risk ECs into risk subgroups potentially alleviates the overtreatment and undertreatment risk and should be considered in future research.

Comparison between Pelvic IMRT and 3D-CRT in Combination with Chemotherapy via Nrf2 Expression on the High-Risk Endometrial Cancer.

This study aimed to explore the clinical efficacy of pelvic intensity-modulated radiation therapy (IMRT) and 3-dimensional conformal radiotherapy (3D-CRT) in combination with chemotherapy on high-risk endometrial cancer. The effect of these methods is evaluated via Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression, the levels of chitinase protein 40 (YKL-40), human epididymis protein 4 (HE4), and prolactin (PRL) in serum. For this purpose, between August 2014 and July 2017, 114 endometrial cancer patients admitted to this hospital for treatment were randomized into the observation group (n=60) and control group (n=54). Following the surgery, patients in these two groups received the chemotherapy of taxol and carboplatin (TC). Based on the chemotherapy, patients in the observation underwent the IMRT, while those in the control group adopted the 3D-CRT. The Nrf2 expression was performed based on the Real-time PCR technique. The incidence rate of adverse reactions was a 3-year recurrence rate and mortality rate. Results showed that after treatment, levels of YKL-40, HE4, and PRL in the serum of patients in two groups decreased compared to those before treatment (all P < 0.05). In comparison, the difference between the two groups showed no statistical significance (P > 0.05). The evaluation of Nrf2 transcription factor expression showed significant differences started in comparisons of the Nrf2 Expression between two groups (P > 0.05), and this enhancement was significant in the control group after treatment. Comparison of the incidence rates of the bone marrow suppression during treatment showed no significant difference (P > 0.05). However, the incidence rates of radiation enteritis and radio-cystitis in the observation group were much lower than those in the control group (P < 0.05). During the follow-up, there were five patients in the control group and 7 in the observation group losing to the follow-up, and among the remaining subjects, no significant difference was identified in the comparison of the recurrence rate or mortality rate between the two groups (all P > 0.05). In general, Pelvic IMRT in combination with chemotherapy is a promising and safe candidate for high-risk endometrial cancer with mild radiation injury; besides, YKL-40, HE4, and PRL are the effective indicator for the prediction of efficacy in chemotherapy for endometrial cancer.

Adjuvant chemotherapy and radiation for patients with high-risk stage I endometrial cancer treated with curative intent surgery: impact on recurrence and survival.

BACKGROUND: Survival benefits of post-operative systemic and radiation therapy in high-risk stage I endometrial cancer are uncertain. OBJECTIVE: To compare recurrence patterns and survival outcomes of post-surgical treatment in patients with high-risk stage I endometrial cancer and to determine whether adjuvant therapy significantly improves outcomes. METHODS: High-risk stage I endometrial cancer was defined as either stage IB grade 3 endometrioid histology or myoinvasive non-endometrioid histology. Consecutive patients diagnosed between January 2000 and December 2010 in eight cancer centers were included. Patients, disease, and treatment characteristics were summarized by descriptive statistics. Overall survival, disease-specific survival, and relapse-free survival were examined using Cox's proportional hazards regression and log-rank test. Survival curves were estimated using the Kaplan-Meier method. RESULTS: Of 2317 patients with stage I endometrial cancer, 414 patients had high-risk disease. Use of chemotherapy did not improve overall survival (relative risk (RR) 0.70, 95% CI 0.46 to 1.14, p=0.13) or disease-specific survival (RR 1.06, 95% CI 0.61 to 1.85, p=0.84). Significant improvement in recurrence-free survival was observed in patients who received chemotherapy (RR 0.61, 95% CI 0.39 to 0.95, p=0.03). Use of radiation therapy did not improve overall survival, recurrence-free survival, or disease-specific survival. Patients who received four cycles or fewer of chemotherapy versus five to six cycles had similar overall survival, disease-specific survival, and recurrence-free survival. CONCLUSIONS: Post-operative chemotherapy or radiation in stage I high-risk endometrial cancer is not associated with improved cancer-specific or overall survival. More than four cycles of chemotherapy did not improve survival compared with four cycles or fewer.

Vaginal stenosis in women with cervical or endometrial cancer after pelvic radiotherapy: a cross-sectional study of vaginal measurements, risk for sexual dysfunction and quality of life.

INTRODUCTION AND HYPOTHESIS: Radiotherapy (RT) for cervical (CC) and endometrial cancer (EC) is known to lead to vaginal stenosis (VS), but the comparison between vaginal anatomical measurements and the risk of sexual dysfunction presents a wide variety of results among the literature. Thus, we sought to assess the prevalence of VS, vaginal measurements, sexual dysfunction and QOL in women with CC and EC submitted to pelvic RT with or without previous surgery. METHODS: Cross-sectional study that included 61 women with CC and 69 with EC. VS was classified by the Common Terminology Criteria for Adverse Effects version 5.0 (CTCAE v5.0), sexual function by the validated Female Sexual Function Index (FSFI) and QOL by the validated World Health Organization questionnaire (WHOQOL-BREF). Acrylic cylinders were used for vaginal measurements. Uni-/multivariate analyses to address factors associated with VC in both groups were performed. RESULTS: The prevalence of VS was 79% and 67% within patients with CC and EC, respectively. Vagina length was decreased in both groups without statistical difference (7.2 ± 1.7 vs. 6.6 ± 1.8;p = 0.072). Vaginal diameter was significantly higher (p = 0.047) in women with EC (25.4 ± 6.3) than in those with CC (23.1 ± 5.7). Sexual dysfunction was highly prevalent for both CC and EC (88% vs. 91%; p = 0.598). There was no difference in all WHOQOL-BREF domains between women with CC and EC. CONCLUSIONS: VS is highly prevalent in CC and EC patients, with vaginal length decreased in both groups but with a higher vaginal diameter in those with EC. Nevertheless, sexual dysfunction is highly prevalent in both groups.

Blocking PARP activity with the inhibitor veliparib enhances radiotherapy sensitivity in endometrial carcinoma.

OBJECTIVE: Our study aimed to investigate the potential clinical utility of a poly(ADP-ribose) polymerase (PARP) inhibitor, veliparib (ABT-888), as a radiosensitizer in the medication of endometrial carcinoma (EC). METHODS: Human Ishikawa endometrial adenocarcinoma cells were treated with veliparib, radiotherapy (RT), or combination treatment. The viabilities, radiosensitivity enhancement ratio (sensitizer enhancement ratio (SER), and apoptosis of Ishikawa cells were, respectively, evaluated by Cell Counting Kit-8 (CCK-8), colony formation experiment, and flow cytometry. The tumor growth was assessed by xenograft mice models. Western blot assay investigated the expression of DNA damage and apoptosis-related proteins in vivo and in vitro. RESULTS: Cell Counting Kit-8 revealed that the 10% inhibition concentration (IC10 ) and 50% inhibition concentration (IC50 ) values of veliparib-treated Ishikawa cells were 1.7 and 133.5 µM, respectively. The SER of veliparib combined with RT was 1.229 in vitro. Flow cytometry analysis results indicated that the apoptosis rate of the veliparib + RT group was markedly higher than that of the RT group in vitro (p < 0.05). Furthermore, in vivo data revealed that veliparib + RT treatment significantly decreased tumor growth compared with single treatments of veliparib or RT and with the control group (p < 0.05). Then western blot confirmed the levels of anti-phospho-histone (γH2AX), caspase-3, and B-cell lymphoma 2 (Bcl-2) associated protein X (Bax) were significantly higher in the veliparib + RT group, while the level of Bcl-2 was lower compared with that of the RT group (p < 0.05), both in vivo and in vitro. CONCLUSION: Our results indicate that veliparib in combination with RT markedly improved the therapeutic efficiency in human endometrial carcinoma.