Adjuvant Vaginal Brachytherapy Research Articles

Mismatch repair status and surgical approach in apparent early-stage endometrial cancer

ObjectiveTo test the hypothesis that mismatch repair (MMR) status (as an accurate surrogate marker for microsatellite stability) modifies the effect of surgical approach on oncological outcome for apparent early-stage endometrial...

Novel FOXL2 Mutation in an Ovarian Adult Granulosa Cell Tumor: Report of a Case With Diagnostic and Clinicopathologic Implications.

Adult granulosa cell tumor, the most common malignant ovarian sex cord-stromal tumor, harbors the characteristic mutation c.402C>G (p.C134W) in the FOXL2 gene in ~90% to 95% of cases. To date, no other variants of FOXL2 mutations have been identified in these tumors. Here we report the first case of an adult granulosa cell tumor with a novel FOXL2 point mutation c.398C>T (p.A133V) presenting in a 64-year-old postmenopausal woman. The patient underwent total hysterectomy and bilateral salpingo-oophorectomy for atypical endometrial hyperplasia and gross examination revealed an incidental 3.2cm right ovarian mass with a solid, bright yellow, homogeneous cut surface. Microscopically, ~30% of the tumor showed a nested growth pattern composed of uniform tumor cells with oval nuclei and a moderate amount of pale cytoplasm, while the remaining areas consisted of a bland storiform fibromatous stroma. Reticulin stain demonstrated loss of the individual pericellular network within the nested areas, while the pericellular staining pattern was retained in the background stromal component. FOXL2 sequencing analysis was performed in both components and revealed a c.398C>T (p.A133V) mutation in the nested component, whereas wild-type FOXL2 sequence was identified in the fibromatous stroma. Sections from the uterus showed a low-grade endometrioid endometrial adenocarcinoma with superficial myometrial invasion. The patient underwent adjuvant vaginal cuff brachytherapy for the endometrial carcinoma and is alive and well at 8 months follow-up. This case illustrates that new FOXL2 mutations may be detected in ovarian sex cord-stromal tumors with increasing use of routine molecular testing, adding to the complexity of the pathologic diagnosis. In the right morphologic and clinical context, a FOXL2 mutation-even if it is different from the dominant hotspot mutation c.402C>G (p.C134W)-can support the diagnosis of adult granulosa cell tumor.

Isolated vaginal recurrence in women with stage I endometrial cancer

ObjectiveTo compare clinical and pathologic characteristics of women with surgical stage I endometrial carcinoma by location of first recurrence and describe characteristics of isolated vaginal recurrence. MethodsPatients with 2009 International Federation of Obstetrics and Gynecology (FIGO) stage I endometrial carcinoma treated at two large cancer centers from 1/1/2009–12/31/2017 were identified. Sarcoma histology was excluded. Recurrences were grouped into isolated vaginal or extravaginal. Isolated vaginal recurrences were localized by anatomic location within the vaginal vault. Clinical and pathologic variables were compared with chi-square analysis, and Kaplan-Meier curves with log-rank tests. ResultsOf 2815 women identified, 278 (10%) experienced a recurrence. Sixty-one patients (2%) had an isolated vaginal recurrence, including 42 (69%) at the vaginal apex; 217 (8%) had an extravaginal recurrence, including 18 with a vaginal component. Median time to recurrence was 11 months (range, 1–68) for isolated vaginal recurrence and 20 months (range, 1–98) for extravaginal recurrence (P < .004). Of 960 patients (34%) treated with adjuvant vaginal brachytherapy (VBT), 156 (16%) recurred; 19 (2%) had an isolated vaginal recurrence, including 16 (84%) at the vaginal apex. Three-year PFS rates for isolated vaginal recurrence were 97.6% (SE ± 0.4%) with minimally invasive surgery (MIS) versus 96.9% (SE ± 1.1%) with open (P = .8), and for extravaginal recurrence were 91.8% (SE ± 0.7%) with MIS versus 90.8% (SE ± 1.8%) with open (P = .8). ConclusionsIsolated vaginal recurrences in stage I endometrial cancer are detected earlier than non-vaginal recurrences. Surgical approach does not appear to impact recurrence. Adjuvant VBT after primary surgery carries a 1%–2% risk of isolated vaginal apex recurrence.

Comparison of Two Different Adjuvant High Dose Rate Vaginal Brachytherapy Fractionation Regimens in Early-Stage Endometrial Cancer

Adjuvant vaginal brachytherapy (VBT) as monotherapy is commonly used as treatment for early-stage uterine cancer following hysterectomy. No ABS guidelines existed at the onset of our institution's high dose rate (HDR) brachytherapy program, so a regimen of 30 Gy in six fractions was adopted in this setting. Due to the COVID pandemic in 2020, we implemented the use of 22 Gy in four fractions as our primary regimen to reduce overall treatment duration and healthcare exposure risks. In this analysis, we seek to compare outcomes and toxicities between the two treatment regimens. This is a single institution retrospective review of patients with Stage I-II endometrial cancer who received adjuvant VBT as monotherapy between 1998 and 2022. HDR VBT was delivered via a vaginal cylinder prescribed to a depth of 5 mm, to a dose of 22 or 30 Gy in four or six fractions, respectively. We evaluated maximum acute and chronic toxicities, defined as ≤6 months and ≥ 6 months following treatment completion, respectively. Toxicities were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) criteria. We evaluated clinical outcomes including local recurrence (LR), distant metastasis (DM), cause-specific survival (CSS) and overall survival (OS). P-values <0.05 were considered significant. A total of 270 patients were included in our analysis, with a median follow up of 4.98 years (7.7 and 1.3 years for six-fraction and 4-fraction regimen, respectively, p<0.001). The median age at the time of treatment was 66 (range 31-89). 195 patients (72.2%) were treated with six fractions and 75 (27.8%) were treated with four fractions. There was significantly less chronic vaginal dryness (p = 0.017) and vaginal stenosis (p<0.001) with the four-fraction compared to the 6-fraction regimen. There was no difference in acute toxicity (p = 0.468). There were no grade ≥3 toxicities in either group. The 2-year LR, DM, CSS, and OS rates for four/six fractions were 2.4%/3.7%, 6.8%/3.7%, 95.8%/97.9%, and 95.8%/95.8%, respectively. There were no significant differences in outcomes between the two groups. Our experience supports that VBT in four fractions is well tolerated with minimal acute and chronic toxicities. When comparing to our institution's historical data for a six-fraction regimen, the use of a four-fraction regimen resulted in less chronic vaginal dryness and stenosis, supporting its continued use. The clinical outcomes have been similar thus far. Further analysis with a longer follow-up duration and a match-pair analysis is warranted.

Financial Improvements from Short Course Adjuvant Vaginal Cuff Brachytherapy (VCB) in Early Endometrial Cancer Compared to Standard of Care, “SAVE” Trial

Early-stage endometrial cancer is often managed with hysterectomy followed by adjuvant VCB. Financial toxicity from cancer treatment is a strong driver of adherence. The SAVE trial is a multicenter, prospective randomized trial of standard of care (SoC) VCB doses delivered in 3-5 fractions per physician discretion compared to a 2-fraction course. We report on secondary cost endpoints, quantifying the financial impacts of shorter treatment courses on institutions and participating patients. Technical (TechCs), professional (PCs), and total charges (TotCs) were collected prospectively and are reported as raw and Medicare-adjusted charges per patient. Geographic variations were standardized with CMS Geographic Practice Cost Indices (GPCI), and inflation was adjusted using the Consumer Price Index (CPI): Medical Care. Distance to treatment center was calculated from the patient's zip code to the corresponding treatment center. Cost of commutes was estimated through round-trip travel distance multiplied by average gas MPG for new vehicles by treatment year and state. Median income for each patient's zip code was estimated using 5-year Household income in 2021 inflation-adjusted dollars from the US Census. Mann-Whitney U, T- and Chi-square tests were used to compare characteristics between the two groups. One hundred eight patients were analyzed. SoC VCB was delivered in 3, 4 and 5 fractions for 27/54 (50%), 11/54 (20%), and 16/54 (30%), respectively. Median total distance traveled per patient for SoC vs. experimental arms was 213 vs 137 miles (p = .12), and median cost of commute for patients was 36.3 vs 18.0 USD (p = .11). Compared to 2-fraction treatment, 5-fraction treatment resulted in longer travel distances (median 462 vs. 137 miles, p < 0.01) and increased travel costs (median 59.3 v. 18.0 USD, p = < 0.01). Median income by zip code for SoC v. experimental arms was 79,704 vs. 79,671 USD (p = 1.0). For SoC v. experimental arms, 11 (20%) vs 7 (13%) of patients had zip codes with median income in the lowest or second lowest quintiles (p = 0.5). Adjusted raw PCs per patient did not differ between SoC vs. experimental arms (9,159$ vs. 7,532$, p = 0.19). TechCs were significantly higher on the SoC arm (35,734$ vs. 24,696$ p = < 0.01), as were TotCs (44,892$ vs. 32,228$, p < 0.01;). Medicare-adjusted PCs, TechCs, and TotCs were higher for the SoC arm (Table 1). Two-fraction VCB resulted in fewer treatments per patient, reduced cost of travel compared to longer courses, and an adjusted reduction in healthcare expenditures compared to standard of care. Ongoing work will include assessment of patient-reported financial toxicities.

Short Course Adjuvant Vaginal Cuff Brachytherapy (VCB) in Early Endometrial Cancer: Primary Endpoint Results of the SAVE Randomized Clinical Trial

Prospective trials in early stage endometrial cancer demonstrate increased locoregional control with adjuvant radiotherapy for patients with high risk features. VCB is widely utilized, yet there is substantial practice variation and limited randomized data examining optimal dose/fractionation. We aimed to study the safety and efficacy of short course VCB compared to commonly used regimens. We conducted a prospective, randomized, multicenter trial examining short course adjuvant VCB (11 Gy x 2 fractions at the surface) compared with other standard regimens (7 Gy x 3 fractions at 0.5 cm depth, 6 Gy x 5 fractions at the surface, or 5-5.5 Gy x 4 fractions at 0.5 cm depth). Eligible patients underwent hysterectomy and had pathologically confirmed endometrioid adenocarcinoma, serous, clear cell, or carcinosarcoma. Patients with stage I and II cancers were included, with lymphovascular invasion (LVI) required for stage IAG1. The primary outcome was Global Health Status measured by the EORTC QLQ-C30 with a pre-specified non-inferiority margin of 15 points. Secondary outcomes included patient-reported outcomes, toxicities as assessed by CTCAEv5, and patterns of recurrence. Data were collected at each brachytherapy fraction and at 1-, 6-, and 12-month follow-up. One hundred eight patients were enrolled, 54 in each study arm. Data completion was 94%, 91%, and 77% at 1 month, 6 months, and 12 months, respectively. 70% of patients had endometrioid adenocarcinoma, 18% serous carcinoma, and 12% other histologies. 23% were FIGO grade 1, 33% grade 2, and 43% grade 3 or high risk histologies. The majority of patients were stage I (56% IA, 38% IB). 22% of patients had LVI. The QLQ-C30 Global Health Status for the experimental arm was within the predefined boundary and thus 2 fractions were non-inferior to standard of care at one month (p = 0.000005) and 12 months (p = 0.0005). Using EORTC EN24 for patient reported vaginal/sexual, urologic, and gastrointestinal symptoms, the change in mean patient reported symptom score from baseline to 1 month and baseline to 12 months were not significantly different between arms. Using CTCAEv5, 51 patients experienced short-term AEs related to study treatment, 20 in the experimental arm and 31 in the control arm (p = 0.053). All study treatment-related AEs were grade 1-2, except for two grade 3-4 AEs, both on the control arm. At median follow-up of 19 months, the isolated vaginal control rate in each arm was 100%. There was no significant difference in the total number of recurrences between study arms, with 3 distant and 3 distant/pelvic/vaginal recurrences in the experimental arm, and 2 distant, 2 pelvic, and 1 pelvic/vaginal recurrence in the control arm. Short course VCB is safe with acceptable acute toxicity and non-inferior patient reported outcomes. Short course VCB improves patient convenience and may improve access to care for rural or underserved populations while providing similar local control.

Clinical outcomes and recurrence patterns of high‐intermediate‐risk and high‐risk early‐stage endometrial cancer treated with postoperative intracavitary brachytherapy

AbstractObjectiveTo investigate the clinical outcomes and recurrence patterns of high‐intermediate‐risk (HIR)‐ and high‐risk (HR) early‐stage endometrial cancer (EC) treated with postoperative intracavitary brachytherapy alone.MethodsWe included 152 patients with International Federation of Gynecology and Obstetrics (FIGO) stage I‐II endometrial cancer with HIR and HR factors who received vaginal brachytherapy alone after surgery in our center between April 2008 and December 2017. The irradiation area was the top and upper halves of the vagina. The reference point was defined as 0.5 cm below the vaginal mucosa. The radiation dose was 25–30 Gy 5–6 times. The Kaplan–Meier method was used to calculate the survival rate; differences were assessed using the log‐rank test, and univariate and multivariate prognostic analyses were performed using the Cox regression model.ResultThe median follow‐up was 49.2 months (range 3–132 months). The 5‐year overall survival (OS), disease‐free survival (DFS), locoregional failure‐free survival time (LRFS), and distant metastasis‐free survival (DMFS) rates were 93.2%, 83.4%, 87.9%, and 86.6%, respectively. Treatment failure occurred in 18 patients, locoregional recurrence in 11, and distant metastasis in 14 (four with locoregional recurrence). Distant metastasis is the main recurrence pattern in patients at HIR and HR. Univariate and multivariate analyses revealed that age was an independent prognostic factor for OS, DFS, DMFS, and LRFS.ConclusionThe main recurrence pattern after adjuvant vaginal brachytherapy alone was distant metastasis in patients with HIR and HR early‐stage EC. Age at onset was an independent prognostic factor for survival. Vaginal brachytherapy alone is an acceptable treatment option for patients with HIR and HR early‐stage endometrial cancer.

Applicator-guided proton therapy versus multichannel brachytherapy for vaginal vault irradiation.

To dosimetrically compare applicator-guided intensity-modulated proton therapy(IMPT) and multichannel brachytherapy (MC-BRT) for vaginal vault irradiation(VVI) with special focus on dose to organs at risk (OARs) and normal tissues. Ten patients with uterine confined endometrial cancer who received adjuvant vaginal cuff brachytherapy were included in this study. For each patient an additional IMPT treatment plan was created using the same computed tomography dataset and contours segmented for MC-BRT plans. Clinical target volume (CTV) was defined as the proximal 3.5 cm of the vagina including the entire thickness of vaginal wall. Planning target volume for IMPT plans was generated from the CTV with an addition isotropic 3 mm margin. OARs included rectum, bladder, sigmoid, small bowel and femoral heads. The prescribed dose was 21 Gy in 3 fractions. For simplicity, all doses were expressed in Gy and a constant relative biological effectiveness of 1.1 was used for IMPT plans. Plan comparison was performed using dose-volume histogram and treatment planning parameters. A significant improvement of the D98% coverage for CTV was reached by the applicator-guided IMPT plans (p < 0.01). IMPT also provided a dose reduction in all OARs except for femoral heads due to the lateral beam direction, especially significant reduction of V5Gy, D2cc, D0.1 cc, Dmean, V95% values for the rectum and Dmean, D0.1 cc to bladder, sigmoid, small bowel. Additionally, IMPT plans showed a significant reduction of integral dose to normal tissue with respect to MC-BRT (221.5 cGy.L vs. 653.6 cGy.L, p < 0.01). Applicator-guided IMPT has the potential for improving plan quality in VVI while maintaining the high conformity afforded by the state-of-the-art intracavitary brachytherapy.

Dosimetric Evaluation of Organs at Risk From SAVE Protocol

The objective of this work was to evaluate dosimetric characteristics to organs at risk (OARs) from short-course adjuvant vaginal cuff brachytherapy (VCB) in early endometrial cancer compared with standard of care (SOC) in a multi-institutional prospective randomized trial. SAVE (Short Course Adjuvant Vaginal Brachytherapy in Early Endometrial Cancer Compared to Standard of Care) is a prospective, phase 3, multisite randomized trial in which 108 patients requiring VCB were randomized to an experimental short-course arm (11 Gy×2 fractions [fx] to surface) and SOC arm. Those randomized to the SOC arm were subdivided into treatment groups based on treating physician discretion as follows: 7 Gy×3 fx to 5 mm, 5 to 5.5 Gy×4 fx to 5 mm, and 6 Gy×5 fx to surface. To evaluate doses to OARs of each SAVE cohort, the rectum, bladder, sigmoid, small bowel, and urethra were contoured on planning computed tomography, and doses to OARs were compared by treatment arm. Absolute doses for each OAR and from each fractionation scheme were converted to 2 Gy equivalent dose (EQD23). Each SOC arm was compared with the experimental arm separately using 1-way analysis of variance, followed by pairwise comparisons using Tukey's honestly significant difference test. The experimental arm had significantly lower doses for rectum, bladder, sigmoid, and urethra compared with the 7 Gy×3 and 5 to 5.5 Gy×4 fractionation schemes; however, the experimental arm did not differ from the 6 Gy×5 fractionation scheme. For small bowel doses, none of the SOC fractionation schemes were statistically different than the experimental. The highest EQD23 doses to the examined OARs were observed to come from the most common dose fractionation scheme of 7 Gy×3 fx. With a short median follow-up of 1 year, there have been no isolated vaginal recurrences. Experimental short-course VCB of 11 Gy×2 fx to the surface provides a comparable biologically effective dose to SOC courses. Experimental short-course VCB was found to reduce or be comparable to D2cc and D0.1cc EQD23 doses to rectum, bladder, sigmoid, small bowel, and urethra critical structures. This may translate into a comparable or lower rate of acute and late adverse effects.

Is Substantial Lymphovascular Space Invasion Prognostic in Patients With Pathologically Lymph Node-Negative Endometrial Cancer?

Lymphovascular space invasion (LVSI) predicts for higher rates of recurrence and increased mortality in endometrial cancer. Using three-tier LVSI scoring, a PORTEC 1&2 trials analysis demonstrated that substantial LVSI was associated with worse locoregional (LR-DFS) and distant metastasis disease free survival (DM-DFS), and these patients possibly benefited from external beam radiation therapy (EBRT). Furthermore, LVSI is a predictor for lymph node (LN) involvement, but the significance of substantial LVSI is unknown in patients with a pathologically negative LN assessment. We aimed to evaluate clinical outcomes of these patients in relation to the three-tier LVSI scoring system. We performed a single-institutional retrospective review of patients with stage I endometrioid-type endometrial cancer who underwent surgical staging with pathologically negative LN evaluation from 2017 - 2019 with three-tier LVSI scoring (none, focal or substantial). Clinical outcomes (LR-DFS, DM-DFS, and overall survival [OS]) were analyzed using Kaplan-Meier method. A total of 335 patients with pathologically LN negative stage 1 endometrioid-type endometrial carcinoma were identified. Substantial LVSI was present in 17.6% of patients. 39.7% of patients received adjuvant vaginal brachytherapy, and 6.9% of patients received EBRT. Adjuvant radiation treatment varied by LVSI status. In patient with focal LVSI, 81.0% received vaginal brachytherapy. Among patients with substantial LVSI, 57.9% received vaginal brachytherapy alone, and 31.6% of patients received EBRT. The 2-year LR-DFS rates were 92.5%, 98.0%, and 91.4% for no LVSI, focal LVSI, and substantial LVSI, respectively. The 2-year DM-DFS rates were 95.5%, 93.3%, and 93.8% for no LVSI, focal LVSI, and substantial LVSI, respectively. In our institutional study, patients with pathologically LN negative stage I endometrial cancer with substantial LVSI had similar rates of LR-DFS and DM-DFS compared to patients with none/focal LVSI. These findings highlight the need for multi-institutional studies to validate the prognostic value of substantial LVSI in this patient population.

A longitudinal study of sexual health and quality of life in endometrial carcinoma survivors

ObjectivesThis study aimed to assess sexual health and quality of life (QoL) in endometrial cancer survivors and the factors influencing these variables.MethodsA mixed method design comprising quantitative (cohort design) and...

Lymph-vascular Space Involvement and/or p53 Overexpression Correlated With the Clinical Outcome of Early-stage Endometrial Cancer Patients Treated With Adjuvant Vaginal Brachytherapy.

The majority of patients with endometrial cancer (EC) are diagnosed at an early stage and undergo primary surgery, followed by observation or adjuvant therapy according to risk factors on surgical samples. The objective of this study was to assess the correlation between a risk profile represented by the presence of substantial lymph-vascular space involvement (LVSI) and/or p53 overexpression and the clinical outcome of patients with early-stage endometrial cancer (EC) who received adjuvant vaginal brachytherapy (BT). This investigation assessed 79 patients who underwent hysterectomy, bilateral salpingo-oophorectomy, and pelvic and/o aortic lymphadenectomy or sentinel lymph node biopsy followed by hypofractionated (HDR)-vaginal BT, using 192Ir source, for stage I-II endometrioid (n=70) or non-endometrioid (n=9) EC. Thirty-four patients (43.0%) were considered to have an unfavorable risk profile defined by the presence of substantial LVSI and /or p53 overexpression. Five-year disease-free survival (DFS) and five-year overall survival (OS) were 93.7% and 95%, respectively. There was a significant correlation between unfavorable risk-profile and pelvic recurrence rate (p=0.002) and distant recurrence rate (p=0.017). Patients with abnormal p53 had a higher risk of local relapse (p=0.041). Substantial LVSI was strongly associated with pelvic recurrence (p=0.001) and distant metastasis (p<0.001). The presence of substantial LVSI and/or p53 overexpression strictly correlated with poor outcome of patients with early-stage EC and should be taken into consideration for better planning adjuvant treatment in this clinical setting.

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

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. 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 ≥ 65years 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. 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. 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.

Impact of Adjuvant Pelvic External Beam Radiotherapy or Vaginal Brachytherapy on Clinical Outcomes for Early-Stage Uterine Carcinosarcoma

<h3>Purpose/Objective(s)</h3> Uterine carcinosarcoma (UCS) is an uncommon but aggressive malignancy with poor prognosis. There is no clear consensus regarding adjuvant radiotherapy (RT) following surgical management for patients (pts) with early stage UCS. We compared outcomes for pts with early stage UCS who underwent adjuvant pelvic external beam RT (EBRT) vs. vaginal brachytherapy (VBT) alone. <h3>Materials/Methods</h3> We conducted an Institutional Review Board-approved single institution retrospective study of 98 pts diagnosed with FIGO stage I-II UCS from 2002 to 2020 and received adjuvant RT, with or without chemotherapy (CT), following definitive surgery. EBRT dose was 45-50.4 Gy alone or followed by VBT boost of 10-18 Gy in 2-4 fractions (fx). Dose for adjuvant VBT alone was 21 Gy in 3 fx or 24 Gy in 6 fx, prescribed to the vaginal surface. We recorded clinical and treatment characteristics and clinical outcomes, including dates and location of progression. Fisher exact tests were used for categorical variables. PFS and OS were analyzed by Kaplan-Meier method and log-rank test. Univariate analyses (UVA) were performed using Cox proportional hazards modeling. <h3>Results</h3> 38 received CT+EBRT, 31 received CT+VBT, and 29 received RT alone (18 EBRT, 11 VBT). Fewer pts in the CT+EBRT and RT-alone groups received nodal sampling compared to pts in the CT+VBT group (<i>P</i>=0.02). Other factors including age, comorbidities, FIGO stage, and pathology were not different between the three groups. Median follow up was 93.5, 50.2, and 143.0 months for CT+EBRT, CT+VBT, and RT-alone groups, respectively. 3-year PFS was 78.7%, 67.6%, and 58.2% for CT+EBRT, CT+VBT, and RT alone, respectively. EBRT+CT significantly improved PFS (P=0.01) compared to RT alone (P=0.01), but not compared to CT+VBT (P=0.22). In terms of locoregional recurrences, 1 pt had a vaginal recurrence and 3 had pelvic nodal recurrences after CT+EBRT. In the CT+VBT cohort, 4 pts had vaginal recurrences, 3 had pelvic nodal recurrences, and 1 had a pelvic soft-tissue recurrence. In the RT-alone group, 1 pt receiving VBT suffered a vaginal recurrence, and 4 pts receiving EBRT had pelvic nodal recurrences. UVA showed that compared to CT+EBRT, RT alone was associated with shorter time to progression (HR 2.50, 95% CI 1.08-5.79, <i>P</i>=0.03) but CT+VBT was not (HR 1.82, 95% CI 0.74-4.50, <i>P=</i>0.20). Other factors including age, stage, nodal sampling, and lymphovascular invasion were not significant on UVA. <h3>Conclusion</h3> In one of the largest retrospective cohorts of early stage UCS, we found adjuvant EBRT+CT improved outcomes compared to RT alone, but not CT+VBT. There were 5 vaginal recurrences in pts undergoing VBT, suggesting that VBT alone at the doses prescribed in this study may not be sufficient. Larger prospective studies and longer follow up are needed to further investigate differences in radiation modalities for the treatment of early-stage UCS. †In Memoriam: LJL, deceased June 23, 2021.

PO29 Presentation Time: 7:40 AM: Dosimetric Review to Organs at Risk from Short Course Adjuvant Vaginal Cuff Brachytherapy in Early Endometrial Cancer Compared to Standard of Care (SAVE)

<h3>Purpose</h3> To evaluate dosimetric characteristics to organs at risk (OARs) from short course adjuvant vaginal cuff brachytherapy (VCB) in early endometrial cancer compared to standard of care in a multi-institutional prospective randomized trial. <h3>Materials and Methods</h3> 108 patients requiring VCB were randomized to an experimental short course arm (11 Gy x 2Fx to surface) and standard of care arms: 7 Gy x 3Fx to 5mm, 5-5.5 Gy x 4Fx to 5mm, and 6 Gy x 5Fx to surface. Rectum, bladder, sigmoid, small bowel, and urethra were contoured retrospectively on the planning CT and doses to OARs were compared by arm. Absolute doses for each OAR (D2cc and D0.1cc), and from each fractionation scheme, were converted to 2 Gy equivalent dose (EQD2; α/β=3 Gy). Each standard of care arm was compared to the experimental arm separately using a one-way analysis of variance, followed by pairwise comparisons using Tukey's HSD test. Additionally, treatment planning system reported point doses (mid cylinder) to the vaginal mucosa was converted to EQD2 (α/β=10 Gy) and evaluated. <h3>Results</h3> The experimental arm had significantly lower doses for rectum, bladder, sigmoid, and urethra when compared to the 7 Gy x3 and 5-5.5 Gy x4 fractionation schemes; however, the experimental arm did not differ statistically from the 6 Gy x5 fractionation scheme. For small bowel doses, none of the standard of care fractionation schemes were statistically different than the experimental arm (see fig. 1f). The highest D2cc EQD2 doses to the examined critical structures were observed to come from the most common dose fractionation scheme of 7 Gy x 3Fx (see fig. 1a-e). The data revealed similar results for the D0.1cc EQD2 doses for the urethra. Furthermore, average reported EQD2 doses to the vaginal mucosa were 40.32 Gy (σ=1.97 Gy) for 11 Gy x2, 56.53 Gy (σ=6.29 Gy) for 7 Gy x3, 47.81 Gy (σ=2.97 Gy) for 5-5.5 Gy x 4, and 41.69 Gy (σ=1.29 Gy) for 6 Gy x 5. With a short median follow up of one year, there have been no isolated vaginal recurrences. <h3>Conclusions</h3> Doses to OARs were generally low; however, in the highest quintile significant doses can be delivered with VCB. Experimental short course VCB of 11 Gy x 2Fx to the surface provides a comparable biologic effective dose to standard of care courses. Experimental short course VCB was found to reduce or be comparable to D2cc and D0.1cc EQD2 doses to rectum, bladder, sigmoid, small bowel, and urethra critical structures. This may translate into a comparable or lower rate of acute and late side effects.

PO23 Presentation Time: 7:40 AM: Dosimetric Effects of Model-Based TG-186 Vaginal Cylinder Treatment Plans

<h3>Purpose</h3> The vaginal cuff is the main location of relapse after curative surgery for early-stage endometrial cancer. Adjuvant vaginal cylinder brachytherapy is increasingly used to decrease the risk of postoperative recurrence due to low vaginal cuff recurrence rates and low gastrointestinal toxicity. Current clinical treatment planning follows TG-43 guidance, which assumes that all material is water. Cylinder composition can vary substantially from water equivalent materials, highlighting the importance of investigations into the dosimetric impact of cylinder composition. In the present study, we evaluated dosimetric characteristics of plans utilizing TG-186, which provides a model-based calculation approach to account for heterogeneities in cylinder configuration. <h3>Materials and Methods</h3> Ten graphically planned vaginal cylinder plans were retrospectively evaluated in this study. Each patient was fitted with an Elekta cylinder (part# 084350) comprised primarily of polysulfone (PSU, 1.29g/cc) and secondarily of stainless steel (8.00g/cc) for the stem and rings. Cylinder diameters ranged from 2.5cm to 3.5cm, and treatment lengths from 4.0cm to 7.5cm. Dose prescription was 7Gy/fx x 3fx at 5mm depth for the most proximal 2cm of the cylinder and at cylinder surface for the remainder of the treatment length. Treatment planning was conducted in Oncentra Brachy 4.5.3. The original TG-43 plans (which assume a water-equivalent material, 1.00g/cc) were recalculated using Oncentra's Advanced Collapsed-Cone Engine (ACE) according to TG-186's guidance to account for differences in density. Dwell times were unchanged, so heterogeneity correction accounts for any dosimetric changes. Points placed at the middle of the 5mm depth portion and the middle of the surface depth portion - prescription dose for TG-43 - were compared, as were rectum points. In addition, all isodose lines were converted to contours and compared for the following metrics: percent volume change, Hausdorff distance (HD), mean distance to agreement (MDA), and Dice coefficient. A paired Wilcoxon signed-rank test assessed for significance. <h3>Results</h3> Recalculated TG-186 plans were found to have consistently and statistically significantly (p<0.05) less dose: 5mm depth: -10.5% +/- 2.4%, surface: -15.9% +/- 3.5%, and rectum: -12.1% +/- 3.4% average dose reduction. Compared to TG-43, the TG-186 100% isodose lines as contours show an average volume decrease of 22.2% +/- 2.5%, HD 4.6mm +/- 1.2mm, MDA 1.5mm +/- 0.3mm, and Dice 0.87 +/- 0.02. The high dose region as defined by 150% of prescription (25.7% volume decrease, HD 4.4mm, MDA 1.3mm) and the low dose region of 50% prescription (19.5% volume decrease, HD 8.2mm, MDA 1.9mm) show similar trends. <h3>Conclusions</h3> Ten TG-43 graphical vaginal cylinder plans were recalculated using TG-186 to account for the material composition of the cylinders. ACE calculations show that the dose delivered to target prescription points and to OARs may be less than originally planned, although the impact on treatment efficacy is presently unclear. Further studies on other cylinder models will be useful to evaluate the generalizability of these findings, as well as any potential effect on treatment.

GPP03 Presentation Time: 8:20 AM: Short Course Adjuvant Vaginal Cuff Brachytherapy (VCB) in Early Endometrial Cancer: Preliminary Results of the SAVE Randomized Clinical Trial

<h3>Purpose</h3> Prospective randomized trials in early stage endometrial cancer demonstrate increased locoregional control with adjuvant radiotherapy for patients with select high risk features. Vaginal cuff brachytherapy (VCB) is widely utilized, yet there is substantial practice variation and limited randomized data examining optimal dose/fractionation. We aimed to study the safety and efficacy of short course VCB compared to commonly used regimens, and herein report on short-term adverse events, patient reported outcomes, and recurrences. <h3>Materials and Methods</h3> We conducted a prospective, multi-center, randomized trial examining short course adjuvant VCB (11 Gy x 2 fractions at the surface delivered in 2 weeks) compared with the commonly used regimens (7 Gy x 3 fractions at 0.5 cm depth, 6 Gy x 5 fractions at the surface, or 5-5.5 Gy x 4 fractions at 0.5 cm depth). Eligible patients underwent hysterectomy and had pathologically confirmed endometrioid adenocarcinoma, serous, clear cell, or carcinosarcoma histology. Patients with stage I and II cancers were included, with additional risk factors required for stage IA (IAG1 with LVSI). The primary outcome was Global Health Status measured by the EORTC QLQ-C30. Secondary outcomes included differences in patient-reported outcomes using the EORTC EN24 for vaginal, bladder, and bowel symptoms, cost effectiveness, toxicities as assessed by CTCAEv4, and patterns of recurrence. Data were collected at each brachytherapy fraction and at 1, 6 and 12 month follow-up with a compliance rate of 94% at 1 month. <h3>Results</h3> 108 patients were enrolled. Of these, 52 patients experienced short-term AEs related to study treatment, 21 in the experimental arm and 31 in the control arm (p=0.05). All study treatment-related AEs were grade 1-2, except for 1 grade 3 urinary symptom in the control arm. In the experimental arm, the most frequent short-term AEs were fatigue (n=6), diarrhea (n=4), vaginal discharge (n=3), and vaginal dryness (n=3). In the control arm, the most frequent short-term AEs were vaginal dryness (n=8), urinary incontinence (n=6), urinary tract infection (n=5), and pelvic pain (n=5). At median follow-up of 12 months, 5 patients experienced recurrence including 2 distant recurrences and 1 distant and pelvic recurrence in the experimental arm and 2 pelvic recurrences in the control arm. There have been no isolated vaginal recurrences in either arm. The QLQ-C30 Global Health Status for the experimental arm was within the predefined boundary and thus 2 fractions was non-inferior to standard of care (p=0.00002) at one month. <h3>Conclusions</h3> Short course VCB is safe and well-tolerated with acceptable acute toxicity and non-inferior patient reported outcomes. Although longer follow-up data is pending, short course VCB shows promise to improve patient convenience and access to care for rural or underserved populations while providing similar local control and toxicity profile.

8136 Robotic Interval Debulking with Radical Hysterectomy and Partial Urinary Bladder Resection for Locally Advanced Uterine Carcinosarcoma

<h3>Study Objective</h3> Demonstrate an interval debulking where meticulous retroperitoneal dissection, ureterolysis and intentional cystotomy with ureteral stenting were performed robotically in a patient with large volume uterine carcinosarcoma to avoid pelvic exenteration. <h3>Design</h3> Demonstration of robotic radical hysterectomy, retroperitoneal dissection, ureterolysis, and intentional cystotomy with ureteral stenting. <h3>Setting</h3> Tertiary referral center in New Haven, Connecticut. <h3>Patients or Participants</h3> Surgical video case presentation. <h3>Interventions</h3> 47-year-old with locally advanced uterine carcinosarcoma underwent neoadjuvant chemotherapy with TAP (paclitaxel, doxorubicin, and cisplatin), followed by an interval debulking surgery. The uterus was enlarged with lower uterine segment tumor replacing the majority of the ectocervix. The posterior supratrigonal wall of the urinary bladder was extensively involved with the tumor. Extensive ureterolysis was performed from above the pelvic brim to the ureterovesical junctions in order to safely lateralize bilateral ureters. Tedious bladder dissection was performed to prevent thermal injury. A modified (Type B) radical hysterectomy was performed, sacrificing the bladder pillars, distal ureterosacral ligaments, and 2 cm of upper vagina. The posterior urinary bladder wall had clinically questionable residual tumor, therefore intentional cystotomy was performed to resect the involved segment. Six French, 24 cm double-J stents were placed to decrease the risk of ureteral fistula and stricture, given anticipation of postoperative pelvic radiation. The bladder was repaired in two layers. The patient was discharged home on postoperative day 2, and received adjuvant chemotherapy and vaginal brachytherapy, per tumor board recommendations. <h3>Measurements and Main Results</h3> N/A. <h3>Conclusion</h3> Locally advanced uterine carcinosarcoma can be managed on an individualized basis with neoadjuvant therapy followed by non-exenterative interval laparoscopic/robotic radical surgery, with emphasis on quality-of-life.

GPP02 Presentation Time: 8:10 AM: Evaluating the Relationship Between Vaginal Apex ``Dog Ears'' and Patterns of Recurrence in Endometrial Cancer Following Adjuvant Image Guided Vaginal Cuff Brachytherapy

<h3>Purpose</h3> The vaginal cuff is a common site of tumor recurrence following surgery for endometrial cancer, and adjuvant vaginal cuff brachytherapy (VCB) is indicated to reduce the risk of local recurrence. Following hysterectomy, many patients have redundant tissue at the lateral apex of the vaginal cuff ("dog ears"). This extra tissue may extend irregularly beyond the typical cylindrical dose distribution of radiation delivered during single channel VCB and it is hypothesized that they are a potential site of local treatment failure even after VCB. The effects of the presence and size of vaginal cuff "dog ears" on tumor recurrence is not yet fully understood. The aim of this study is to evaluate the prevalence and size of extra tissue at the vaginal apex, and whether these factors predict disease recurrence in patients treated with adjuvant VCB for endometrial cancer. <h3>Materials and Methods</h3> We retrospectively reviewed the medical records of 219 patients with early-stage endometrial cancer treated with image-guided single channel VCB at our institution from 2012 - 2021 with available brachytherapy planning CT simulation images. "Dog ears" were defined as the presence of additional soft tissue extending at least 10 mm from the apex of the vaginal cuff perpendicular to the surface of the brachytherapy applicator as defined on a coronal or axial CT simulation. Patient characteristics and outcomes including stage, size and laterality of dog ears, presence of air gaps, and patterns of failure were collected. Vaginal cuff recurrence (VCR) failure free survival was calculated from time of first brachytherapy to VCR and was estimated by the product limit method of Kaplan and Meier. Fisher's exact test was used to compare categorical variables and a multivariate logistic regression model was developed to evaluate the association of overall treatment failure with various factors of interest. <h3>Results</h3> We found that 57.5% of patients (n = 126) met our criteria for having "dog ears," which, on average, extended 23.8 mm (SD = 6.4) from the brachytherapy applicator. In total, 13 patients (5.9%) developed a VCR, 12 (5.5%) developed a regional recurrence, and 16 (7.3%) developed distant recurrence. There was no statistically significant difference in VCRs between patients with dog ears and those without dog ears (7.1% vs 4.3%, p=0.56). The various surgical approaches (abdominal, laparoscopic, transvaginal) did not have an increased propensity to result in dog ears (p=0.74). The 3-year probability of VCR failure-free survival is 86%. On multivariate analysis (MVA), no factors predicted for overall treatment failure including the presence of dog ears, maximum dimension of dog ears, FIGO stage, presence of air gaps at the applicator surface on post insertion CT images, or brachytherapy duration. There was a trend toward increased risk of recurrence with higher grade histology on MVA (p=0.0805). <h3>Conclusions</h3> In this investigation of a single institution experience with single-channel image-guided VCB, the presence of "dog ears" at the vaginal apex is prevalent; however, VCR remains low with distant metastases being the predominant site of failure. While dog ears appear to have little impact on overall recurrence patterns, these may be a factor to consider when planning adjuvant brachytherapy including choosing alternate applicators.

Improving locoregional outcome in high-intermediate-risk and high-risk stage I endometrial cancer with surgical staging followed by brachytherapy.

PurposeThis study aims to assess the locoregional efficacy of postoperative vaginal brachytherapy (VBT) alone in patients undergoing surgical staging for early-stage high-intermediate-risk (HIR) and high-risk (HR) endometrial cancer. Materials and MethodsOne hundred and four patients with early-stage HIR and HR endometrial cancer who underwent surgical staging were treated with adjuvant VBT alone. The patients with stage Ib, grade I–III, stage Ia, grade III, lower uterine segment involvement, and lymphovascular invasion (LVI) were included to study. ResultsThe 5- and 10-year overall survival (OS) rates were 87% and 76%, respectively. The 5- and 10-year DFS rates were 86% and 86%, respectively. Among the patients, 92% had endometrioid adenocarcinoma, 2% had undifferentiated carcinoma, 2% had serous papillary carcinoma, and 4% had clear-cell carcinoma. Of the patients, 63% had stage Ib disease, while 37% had stage Ia disease. None of the patients had vaginal or pelvic lymph node recurrence, whereas two had para-aortic lymph node metastasis, one had surgical scar recurrence, one had para-aortic lymph node and brain metastasis, and one had lung metastasis. The presence of lymphatic invasion was found to be a statistically significant prognostic factor for increased distant metastasis rates (p = 0.020). Lymphatic invasion was also regarded as an independent prognostic factor for metastasis-free survival (p = 0.044). ConclusionOur study results suggest that postoperative VBT alone is an effective and safe treatment modality with low complication in patients undergoing surgical staging for HIR and HR endometrial cancer.