Executive summary of the American Radium Society® Appropriate Use Criteria for management of uterine carcinosarcoma.

OBJECTIVE: Uterine carcinosarcomas (UCS) represent a rare but aggressive subset of endometrial cancers, comprising <5% of uterine malignancies. To date, limited prospective trials exist from which evidence-based management of this rare malignancy can be developed. METHODS: The American Radium Society Appropriate Use Criteria presented in this manuscript are evidence-based guidelines developed by a multidisciplinary expert panel for management of women with UCS. An extensive analysis of current medical literature from peer-reviewed journals was performed. A well-established methodology (modified Delphi) was used to rate the appropriate use of imaging and treatment procedures for the management of UCS. These guidelines are intended for the use of all practitioners who desire information about the management of UCS. RESULTS: The majority of patients with UCS will present with advanced extra uterine disease, with 10% presenting with metastatic disease. They have worse survival outcomes when compared to uterine high-grade endometrioid adenocarcinomas. The primary treatment for non-metastatic UCS is complete surgical staging with total hysterectomy, salpingo-oophorectomy and lymph node staging. Patients with UCS appear to benefit from adjuvant multimodality therapy to reduce the chance of tumor recurrence with the potential to improve overall survival. CONCLUSION: Women diagnosed with uterine UCS should undergo complete surgical staging. Adjuvant multimodality therapies should be considered in the treatment of both early- and advanced stage patients. Long-term surveillance is indicated as many of these women may recur. Prospective clinical studies of women with UCS are necessary for optimal management.

Racial disparities in brachytherapy administration and survival in women with locally advanced cervical cancer.

OBJECTIVE: Black women have the highest incidence and mortality from cervical cancer in the United States. This study evaluated whether racial disparities in the receipt of brachytherapy (BT) for locally advanced cervical cancer mediate survival differences by race using the National Cancer Database. METHODS: A retrospective cohort study was performed using 16,116 women with stage IB2-IVA cervical cancer treated from 2004 to 2014. Women who did not receive external beam radiation therapy, those with unknown survival data or stage, and those status post hysterectomy or pelvic exenteration were excluded. Multivariate logistic regression was performed to evaluate factors associated with BT use. Using a propensity score adjusted model with inverse probability treatment weighting, adjusted hazard ratios for overall survival were calculated, including an interaction term between BT and race. RESULTS: Of 16,116 patients, 19.2% were black and 55.8% received BT. Black women were significantly less likely to receive BT (AOR 0.87, 95% confidence interval [CI] 0.79-0.96, p = 0.007) and had worse all-cause mortality (median survival 3.9 years [95% CI 3.6-4.6] versus 5.2 years [95% CI 4.9-5.5] for non-black women, p < 0.001). In the adjusted model, black patients had an increased risk of death compared to non-black patients (AHR 1.14, 95% CI 1.05-1.24; p = 0.002) among women who did not receive BT. However, there was no difference in survival by race when both groups received BT (AHR 1.04, 95% CI 0.95-1.13, p = 0.42; p-interaction = 0.005). CONCLUSIONS: Black women with locally advanced cervical cancer are less likely to receive brachytherapy, which mediates survival differences by race. Improving access to brachytherapy may improve overall survival.

Palliative Radiation Therapy for Recurrent Ovarian Cancer: Efficacy and Predictors of Clinical Response.

OBJECTIVE: This study aimed to report response rates and predictors of response to palliative radiotherapy (RT) for recurrent ovarian cancer. METHODS/MATERIALS: Database review identified 64 patients with symptomatic ovarian cancer recurrence who received a total of 76 courses of RT for 103 indications from March 2003 to August 2014. Radiotherapy indications were pain (44%), bleeding (32%), obstruction (15%), and other (9%). Responses were categorized as complete, partial, or none; all response (AR) was the sum of complete and partial responses. Response rates were compared using a χ test. Multivariate analysis was performed using logistic regression. Patients were followed up for symptom recurrence and death. RESULTS: Response rates were significantly higher for pain (AR, 87%) and bleeding (93%) than for obstruction (62%) and other (60%; P < 0.01). Patients treated for pain at nonbony sites had higher response rates (AR 96%) compared with those treated at bony sites (75%; P = 0.04). Patients with clear cell histology had the lowest response rates (AR, 60%) compared with those with serous (82%), endometrioid (95%), or other Müllerian histology (85%; P = 0.01). Platinum status at diagnosis or the time of RT was not associated with response, nor was tumor size or number of prior chemotherapy regimens. On multivariate analysis, histology, RT indication, and RT dose were independent predictors of response (all P < 0.01). CONCLUSIONS: Palliative RT provides relief of pain and bleeding in most patients with ovarian cancer recurrence. Patients with symptomatic obstruction, bony involvement, and clear cell histology may experience lower clinical response rates.

Differentiated exophytic vulvar intraepithelial lesions are genetically distinct from keratinizing squamous cell carcinomas and contain mutations in PIK3CA.

Human papillomavirus-negative keratinizing vulvar cancers typically harbor TP53 mutations as do their precursors, differentiated vulvar intraepithelial neoplasia. However, atypical verruciform proliferations are also associated with these malignancies and their pathogenesis is poorly understood. This study compared 11 atypical verruciform lesions, including atypical verruciform hyperplasia, vulvar acanthosis with altered differentiation, and verruciform lichen simplex chronicus, with 14 human papillomavirus-negative keratinizing squamous cell carcinomas. Extracted tissue DNA was subjected to targeted massively parallel sequencing of the exonic regions of 300 genes. Eight (73%) and six (55%) of eleven atypical verruciform lesions contained mutations in PIK3CA and ARID2, respectively. No TP53 mutations were identified. Eleven (79%) and five (36%) of fourteen keratinizing squamous cell carcinomas tested contained TP53 and CDKN2A mutations, respectively. Keratinizing squamous cell carcinomas displayed the majority of copy number variations with some variations (7p gain and 8p loss) shared by some cases in both groups. One patient developed atypical verruciform lesions with PIK3CA mutations followed by a keratinizing carcinoma with mutations in both PIK3CA and TP53. This study, for the first time segregates atypical verruciform lesions by virtue of a unique genotype (PIK3CA mutant/TP53 wild type) illustrating an example of progression to a TP53-mutated keratinizing carcinoma. The findings indicate that although PIK3CA mutations are found in <10% of vulvar squamous cell carcinomas, they may be specific for a particular pathway involving atypical verruciform lesions, which could function as either a direct precursor or a risk factor for vulvar squamous cell carcinoma. Given the presence of a molecular signature, we propose the term 'differentiated exophytic vulvar intraepithelial lesion' for this group. Whether they function as direct precursors to a less common form of squamous cell carcinoma will require further study, but carcinomas associated with these lesions might warrant testing for PIK3CA mutations to address this question.

Sentinel lymph node mapping reduces practice pattern variations in surgical staging for endometrial adenocarcinoma: A before and after study.

OBJECTIVE: To examine the effects of universal sentinel lymph node mapping on the use of nodal staging in endometrial adenocarcinoma. METHODS: Two approaches to laparoscopic staging for endometrial adenocarcinoma were compared using a before and after study design. The before cohort underwent selective lymphadenectomy from January 1, 2014-October 1, 2015 while the after cohort underwent universal sentinel lymph node (SLN) mapping from October 2, 2015-September 29, 2016. RESULTS: The before cohort comprised 215 patients and the after cohort 166 patients. In women undergoing SLN mapping, a sentinel node was identified at least unilaterally in 146/153 cases (95.4%), and bilaterally in 114/153 (74.5%) of cases. Pelvic nodes were removed in 35.8% of the before cohort versus 92.2% of the after cohort (p<0.0001) with more nodal evaluation among both low risk (9.6% vs. 91%, p<0.0001) and high risk cases (66% vs. 94%, p<0.0001). While the proportion of low risk cases diagnosed with nodal involvement did not significantly change (0.9% to 3.1%, p=0.32), there was a trend toward more diagnoses of nodal involvement in high risk cases (5% to 13.2%, p=0.06). Mean number of pelvic lymph nodes removed (15 vs. 4, p<0.0001), mean operative time (181min vs. 137min, p<0.0001), estimated blood loss (80ml vs. 56ml, p=0.004), and rate of post-operative complications (13% vs. 5.2%, p=0.04) all decreased after the adoption of SLN dissection. CONCLUSIONS: Universal sentinel lymph node dissection for laparoscopic endometrial cancer staging reduces heterogeneity in surgeon staging practice, increases nodal detection, and lowers post-operative complications.

Prognostic importance of human papillomavirus (HPV) and p16 positivity in squamous cell carcinoma of the vulva treated with radiotherapy.

OBJECTIVE: HPV status is an important prognostic factor for patients with oropharyngeal, anal and cervical cancers treated with radiotherapy. This study evaluates the association between HPV and p16 status and outcome in a radiation-treated cohort with vulvar squamous cell carcinoma (SCC). METHODS: Patients with vulvar SCC who received radiotherapy with or without surgical resection between 1985 and 2011 were identified retrospectively. Immunostaining for p16 and multiplex PCR for HPV genotyping were performed using archival tumor tissue from 57 patients. Actuarial estimates of PFS, OS and in-field recurrence were calculated using the Kaplan-Meier method. Cox proportional hazards models were used for multivariable analysis. Median follow-up was 58months among the 57 patients with an available tumor specimen. RESULTS: HPV prevalence was implied in 37% by (diffuse linear) p16 immunostaining and confirmed in 27% by HPV PCR with good agreement (κ=0.7). HPV-16 was identified in 80% of HPV-positive tumors. Women with p16-positive tumors had significantly higher 5-year PFS (65% vs. 16%, p<0.01) and OS (65% vs. 22%, p=0.01) rates, as well as lower in-field relapse rates (19% vs. 75%, p<0.01) compared to those with p16-negative disease. On multivariable analysis adjusted for age and stage, p16 positivity was significantly associated with better PFS (HR 0.4, 95% CI 0.2-0.9) and lower rates of in-field relapse (HR 0.2, 95% CI 0.06-0.6). Results were similar when analyzed by HPV DNA status. CONCLUSION: In this study, the presence of HPV or its surrogate of p16 immunostaining was an independent prognostic factor for in-field relapse and survival in women with vulvar SCC treated with radiotherapy. This finding warrants validation in larger cohorts or the prospective setting.

ACR Appropriateness Criteria® Adjuvant Management of Early-Stage Endometrial Cancer.

These consensus guidelines on adjuvant radiotherapy for early-stage endometrial cancer were developed from an expert panel convened by the American College of Radiology. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method; and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. After a review of the published literature, the panel voted on three variants to establish best practices for the utilization of imaging, radiotherapy, and chemotherapy after primary surgery for early-stage endometrial cancer.

ACR Appropriateness Criteria® Adjuvant Therapy in Vulvar Cancer.

These American College of Radiology consensus guidelines were formed from an expert panel on the appropriate use of adjuvant therapy in vulvar cancer after primary treatment with surgery. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. The panel reviewed the pertinent literature in vulvar cancer and voted on three variants to establish appropriate use of imaging, adjuvant radiation, including dose, fields, and technique, as well as adjuvant chemotherapy. This report will aid clinicians in selecting appropriate patients for adjuvant treatment and will provide guidelines for the optimal delivery of adjuvant radiation therapy and chemotherapy.

Complications of pelvic radiation in patients treated for gynecologic malignancies.

Radiation therapy is a critical treatment modality in the management of patients with gynecologic tumors. New highly conformal external-beam and brachytherapy techniques have led to important reductions in recurrence and patient morbidity and mortality. However, patients who receive pelvic radiation for gynecologic malignancies may experience a unique constellation of toxicity because of the anatomic locations, combination with concurrent chemotherapy and/or surgery, as well as potential surgical interventions. Although side effects are often categorized into acute versus late toxicities, several late toxicities represent continuation and evolution of the same pathologic process. Comorbidities and radiation dose can significantly increase the risk of morbidity. Current understanding of the incidence of various morbidities in patients treated with current radiation techniques for gynecologic malignancies, the impact of chemotherapy and surgery, treatment options for those effects, and future areas of research are highlighted.

Outcome of triple negative breast cancer: comparison of sporadic and BRCA1-associated cancers.

The majority of breast cancers developing in BRCA1 mutation carriers are triple negative breast cancers (TNBC), an aggressive subtype that accounts for 15-20 % of sporadic breast cancer. We compare the clinical outcome and sites of relapse of TNBC in BRCA1 mutation carriers and non-carriers who received adjuvant chemotherapy. Women with stage I-III TNBC who had BRCA1 testing within 36 months of diagnosis and received adjuvant chemotherapy were identified from clinical databases at two academic institutions. Sites of relapse, freedom from distant metastasis (FFDM), and breast cancer-specific survival (BCSS) were determined. RCA1 carriers (n = 89) were significantly younger at diagnosis (P < 0.0001) than non-carriers (n = 175). FFDM at 5 years was 80.5 % for carriers and 76.9 % for non-carriers; with median follow-up of 55 months, hazard ratio (HR) was 0.90, P = 0.71. Sites of recurrence, including brain, did not differ significantly. BCSS at 5 years was 88.1 % for carriers and 81.4 % for non-carriers; HR 0.60; P = 0.15 at 55 months follow-up. BRCA1 carriers who underwent oophorectomy had a significantly lower rate of death from TNBC, with an adjusted HR of 0.30 (95 % CI 0.10-0.94). Adjusting for age, oophorectomy, and prophylactic mastectomy, BRCA1 mutation status was not an independent predictor of survival (HR 2.1; P = 0.13). BRCA1 mutation carriers with TNBC had similar survival rates and sites of recurrence to non-carriers after treatment with conventional chemotherapy. Carriers who underwent oophorectomy had a significantly lower rate of breast cancer-related death; this finding should be studied further in all women with TNBC.

Clinical predictors of long-term survival for stage IVB uterine papillary serous carcinoma confined to the abdomen.

OBJECTIVE: To identify clinical predictors of long-term survival in women with FIGO Stage IVB uterine papillary serous carcinoma (UPSC) confined to the abdomen METHODS: Records were reviewed for 48 patients with Stage IVB UPSC diagnosed from 1/1980 to 12/2011. Study inclusion required hysterectomy, salpingo-oophorectomy and negative chest imaging. Disease-free (DFS) and overall (OS) survival rates were calculated using the Kaplan-Meier method. Multivariate analysis (MVA) was performed using Cox proportional hazards. RESULTS: Median age at diagnosis was 70 years (range, 53-87). Optimal cytoreduction (Opt) to <1cm residual disease was performed in 36 patients (75%). With a median follow-up of 21 months for all patients and 99 months for survivors, 36 (75%) experienced disease progression or relapse, most commonly intraperitoneal (16, 44%). At 5 years, DFS and OS rates were 12% and 19%, respectively. Five patients (10%) were long-term survivors without relapse at a median of 124 months. All 5 had Opt and carboplatin/paclitaxel chemotherapy, and 4 received radiotherapy (2 pelvic, 1 whole-abdominal, 1 brachytherapy). On MVA in the chemotherapy-treated population, Opt (HR 0.09, 95% CI 0.02-0.35) and radiotherapy (HR 0.36, 0.15-0.80) were associated with decreased rates of recurrence or progression. Opt (HR 0.09, 0.02-0.38) was prognostic for OS when adjusted for age. CONCLUSIONS: Clinical predictors of long-term survival for Stage IVB UPSC confined to the abdomen include optimal cytoreduction and adjuvant platinum and paclitaxel chemotherapy. Radiotherapy may decrease rates of recurrence or progression. Despite intra-abdominal involvement, disease remission and long-term survival may be achieved in some patients.

Adjuvant chemotherapy with external beamradiation therapy for high-grade, node-positive endometrial cancer.

OBJECTIVE: The objective of this study was to evaluate clinical outcomes including disease-free survival (DFS) and overall survival (OS) for women with node-positive, high-grade adenocarcinoma of the uterus. METHODS: Database review identified 73 patients with International Federation of Gynecology and Obstetrics stage IIIC 1/2 grade 3 endometrial cancer diagnosed from 1995 to 2009. Study inclusion required total abdominal hysterectomy/bilateral salpingo-oophorectomy and negative chest imaging. Histologic subtypes were endometrioid (22, 30%), papillary serous (20, 27%), clear cell (9, 12%), mixed (21, 29%), and undifferentiated (1, 1%). Adjuvant treatment was chemotherapy with external beam radiation therapy (EBRT) in 55 patients (75%), EBRT alone in 14 (19%), chemotherapy in 2 (3%), and no adjuvant therapy in 2 (3%). RESULTS: With a median follow-up of 50 months, DFS/OS rates at 5 years were 44%/53%, respectively. Intraperitoneal relapse was more common in patients with positive cytology (30% vs 6%, P = 0.02) and nonendometrioid histology (16% vs 4%, P = 0.3). By histologic subtype, 5-year DFS/OS rates were 59%/82% for grade 3 endometrioid, 25%/30% for serous, 22%/17% for clear cell, and 50%/51% for mixed histology (P = 0.1/P < 0.001). The 5-year DFS/OS rates were 56%/68% for those who received both chemotherapy and EBRT. Among patients treated with adjuvant EBRT, pelvic control was 93%. CONCLUSIONS: For node-positive, high-grade endometrial cancer, patients with endometrioid and mixed histologic subtypes had better clinical outcomes than did those with serous and clear cell cancers. Distinct patterns of relapse were observed with a greater risk of intraperitoneal failure for nonendometrioid histologic subtypes. Future studies are needed to define the optimal chemotherapy regimen and radiation fields.

Clinical outcomes following 3D image-guided brachytherapy for vaginal recurrence of endometrial cancer.

PURPOSE: To evaluate clinical outcomes for women with recurrent endometrial cancer treated with 3D image-guided brachytherapy METHODS AND MATERIALS: 44 women, of whom 13 had received prior RT, received salvage RT for vaginal recurrence from 9/03 to 8/11. HDR or LDR interstitial brachytherapy was performed under MR or CT guidance in 35 patients (80%); 9 (20%) had CT-guided HDR cylinder brachytherapy. The median cumulative dose in EQD2 was 75.5 Gy. Actuarial estimates of local failure (LF), disease-free (DFS) and overall survival (OS) were calculated by Kaplan-Meier. RESULTS: Histologic subtypes were endometrioid (EAC, 33), papillary serous/clear cell (UPSC/CC, 5) and carcinosarcoma (CS, 6). The 2-year DFS/OS rates were 75%/89% for EAC and 11%/24% for UPSC/CC/CS (both p<0.01). On MVA, high tumor grade was associated with recurrence (HR 3.2 for grade 2, 9.6 for grade 3, p<0.01). The LF rate at 2 years was 4% for patients without versus 39% for those with prior RT (p=0.1). Patients who had prior RT received lower cumulative doses at recurrence (66.5 Gy vs. 74.4 Gy, p<0.01). The 2-year DFS/OS rates with and without prior RT were 26%/55% and 72%/80% (both p=0.1). Four patients (9%) experienced grade 3 late toxicity, including 3 of 13 (23%) in the re-irradiation setting and 1 of 31 (3%) with no prior radiotherapy. DISCUSSION: 3D image-guided brachytherapy results in excellent local control for women with recurrent endometrial cancer, particularly with cumulative EQD2 doses greater than 70 Gy. Successful salvage of vaginal recurrence is related to tumor grade and histologic subtype.

Vaginal brachytherapy for early stage uterine papillary serous and clear cell endometrial cancer.

OBJECTIVE: To report clinical outcomes following adjuvant high-dose-rate (HDR) vaginal brachytherapy (VB) for early-stage uterine papillary serous (UPSC) and clear cell (CC) endometrial cancer. METHODS: A retrospective study of Stage I and II papillary serous and clear cell endometrial cancer treated with post-operative HDR VB between October 2005 and May 2012 was performed. A total of 37 patients were identified, 26 with UPSC, 9 with CC and 2 with mixed UPSC/CC. After total hysterectomy and bilateral salpingo-oophorectomy, VB was administered without external-beam radiation with a dose of 24 Gy in 6 fractions prescribed to the vaginal surface. Chemotherapy was given to 30 patients (75%). RESULTS: The median follow up time was 24.8 months (range, 2.0 to 71.5 months). Four patients relapsed, 2 with UPSC and 2 with CC. The initial site of relapse was concurrent vagina, pelvic/para-aortic nodes and abdominal wall (1), pelvic/para-aortic nodes (1) and para-aortic nodes alone (2). The 2-year vaginal-control rate was 96.8%. The pelvic-control rate including vaginal and nodal relapse was 93.5%. The 2-year disease-free and overall survival rates were 89.3% and 100%, respectively. CONCLUSION: HDR VB as the sole adjuvant treatment modality for early-stage UPSC/CC is associated with a low rate of vaginal relapse and excellent survival outcomes. This novel low-dose regimen for VB is safe and effective.

Acr appropriateness Criteria management of vaginal cancer.

Due to its rarity, treatment guidelines for vaginal cancer are extrapolated from institutional reports and prospective studies of cervical and anal cancer. An expert panel was convened to reach consensus on the selection of imaging and therapeutic modalities. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) used by the panel to rate the appropriateness of imaging and treatment procedures. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Four variants were developed to represent clinical scenarios in vaginal cancer management. Group members reached consensus on the appropriateness of the pretreatment evaluation and therapeutic interventions. This article represents the consensus opinion of an expert panel and may be used to inform clinical recommendations in vaginal cancer management.

The Impact of Racial Disparities on Outcome in Patients With Stage IIIC Endometrial Carcinoma: A Pooled Data Analysis.

OBJECTIVE: To report the impact of race on clinical outcomes in patients with stage IIIC endometrial carcinoma. MATERIALS AND METHODS: A retrospective multi-institutional study included 90 black and 568 non-black patients with stage IIIC endometrial carcinoma who received adjuvant chemotherapy and radiation treatments. Overall survival (OS) and recurrence-free survival (RFS) were calculated by the Kaplan-Meier method. Propensity score matching (PSM) was conducted. Statistical analyses were conducted using SPSS version 27. RESULTS: The Median follow-up was 45.3 months. black patients were significantly older, had more nonendometrioid histology, grade 3 tumors, and were more likely to have >1 positive paraaortic lymph nodes compared with non-black patients (all P <0.0001). The 5-year estimated OS and RFS rates were 45% and 47% compared with 77% and 68% for black patients versus non-black patients, respectively ( P <0.001). After PSM, the 2 groups were well-balanced for all prognostic covariates. The estimated hazard ratios of black versus non-black patients were 1.613 ( P value=0.045) for OS and 1.487 ( P value=0.116) for RFS. After PSM, black patients were more likely to receive the "Sandwich" approach and concurrent chemoradiotherapy compared with non-black ( P =0.013) patients. CONCLUSIONS: Black patients have higher rates of nonendometrioid histology, grade 3 tumors, and number of involved paraaortic lymph nodes, worse OS, and RFS, and were more likely to receive the "Sandwich" approach compared with non-black patients. After PSM, black patients had worse OS with a nonsignificant trend in RFS. Access to care, equitable inclusion on randomized trials, and identification of genomic differences are warranted to help mitigate disparities.

Combined chemotherapy and radiation improves survival for node-positive endometrial cancer.

OBJECTIVE: To evaluate the clinical outcomes for women with node-positive endometrioid adenocarcinoma of the uterus METHODS: Records were reviewed for 66 patients with Stage IIIC endometrioid adenocarcinoma diagnosed between 1/1995 and 12/2009. Study inclusion required TAH, BSO and negative chest imaging. Papillary serous and clear cell histologies were excluded. Adjuvant treatment was external beam radiation (RT) alone in 18 patients (27%), combined chemotherapy and RT in 44 (67%), chemotherapy alone in 1 (2%), and no adjuvant therapy in 3 (5%). The median follow-up was 48 months. RESULTS: Of 66 patients, 56 (85%) had positive pelvic nodes only, 5 (8%) had positive para-aortic nodes only, and 5 (8%) had both. Of the 62 patients who received adjuvant RT, only 4 (6%) had an in-field recurrence, including 2 with residual disease after surgery. Disease-free (DFS) and overall (OS) survival rates at 5 years were 71% and 81%, respectively. By adjuvant treatment modality, 5-year DFS and OS rates were 63% and 67% for RT alone and 79% and 90% for combined modality therapy (p=0.15 and p<0.01). On multivariate analysis, combined modality therapy significantly improved DFS (HR 0.12, 95% CI 0.03-0.49, p<0.01) and OS (HR 0.20, 95% CI 0.05-0.75, p=0.02) compared to adjuvant RT alone. CONCLUSIONS: Compared to RT alone, combined modality therapy decreased recurrence and improved survival in patients with node-positive endometrioid adenocarcinoma of the uterus. In addition, external beam RT resulted in excellent local and regional control. Future studies are needed to define the optimal chemotherapy regimen, sequencing, and radiation fields.

Clinical outcomes and dosimetric predictors of toxicity for re-irradiation of vaginal recurrence of endometrial cancer.

OBJECTIVE: To report clinical outcomes and dosimetric predictors of late toxicity for patients with vaginal recurrence of endometrial cancer treated with brachytherapy in the re-irradiation setting. METHODS: On retrospective review, 32 patients with vaginal recurrence of endometrial cancer received salvage brachytherapy with or without pelvic radiotherapy (RT) from 06/2003-12/2017. Prior RT modalities were vaginal brachytherapy (19, 59%), pelvic RT (7, 22%) or both (6, 19%). Image-guided brachytherapy was performed with CT- (25, 78%) or MR-guidance (7, 22%). Vaginal control, recurrence-free survival (RFS) and overall survival (OS) were estimated by Kaplan-Meier method. Late toxicity was graded by Common Toxicity Criteria for Adverse Events. RESULTS: Median time from prior RT to re-irradiation was 22 months (range, 4-140). Salvage RT modalities were pelvic RT and brachytherapy (25, 78%) or brachytherapy alone (7, 22%). With median follow-up of 47 months, 3/5-year vaginal control, RFS and OS rates were 64/56%, 47/41% and 68/42%, respectively. Six patients (19%) had no evidence of disease at 85-155 months. Late grade 2/3 GI, GU and vaginal toxicity rates were 13%/16%, 19%/13%, and 9%/16%. Cumulative D2cc rectum (sum of prior and salvage RT courses) was predictive of grade 2+ and grade 3 GI toxicity. Cumulative D2cc rectum for an estimated 10% risk of late grade 2+ and 3 GI toxicity was 86 Gy and 92 Gy, respectively. CONCLUSIONS: Salvage image-guided brachytherapy in the re-irradiation setting results in modest local control and increased late toxicity for localized recurrent endometrial cancer. With long-term disease control, cumulative D2cc rectum may be used to reduce late GI complication risk.

Effect of Mismatch Repair Status on Outcome of Early-Stage Grade 1 to 2 Endometrial Cancer Treated With Vaginal Brachytherapy.

OBJECTIVES: The objective of this study was to determine if deficiency of mismatch repair (dMMR) proteins in patients with early-stage favorable endometrial cancer treated with vaginal brachytherapy (VB) is associated with increased recurrence. MATERIALS AND METHODS: A multi-institutional retrospective cohort study of 141 patients with stage I to II grade 1 and 2 endometrioid adenocarcinoma treated with surgery and adjuvant VB was performed to compare recurrence risk in dMMR (n=41) versus MMR-preserved (pMMR) (n=100). Additional clinical and pathologic risk factors were also collected. Univariate analysis and multivariable analysis Cox regression analysis was performed to identify factors associated with any recurrence. Kaplan-Meier method and log rank test were used to compare recurrence free survival and overall survival (OS). RESULTS: Median follow up was 42 months. Forty-one patients (29%) were dMMR. There were 7 recurrences (17%) in dMMR versus 4 recurrences (4%) in pMMR (P=0.009). On univariate analysis of any recurrence, both dMMR (hazard ratio: 5.3, P=0.008) and stage (hazard ratio: 3.8, P=0.05) were statistically significantly associated with time to first recurrence. The 5-year recurrence free survival was 90% (95% CI: 73%-96%) in pMMR versus 61.0% (95% CI: 19%-86%) in dMMR (P=0.003). Five-year OS was 96% (95% CI: 76%-99%) in pMMR versus 86% (95% CI: 62%-95%) in dMMR (P=0.03). CONCLUSIONS: MMR deficiency in stage I to II grade 1 to 2 endometrial cancer patients treated with adjuvant VB alone was associated with statistically significant increased risk for any recurrence and worse OS. MMR status may be an important prognosticator in this cohort of patients warranting adjuvant treatment intensification in the clinical trial setting.

Does Prophylactic Paraortic Lymph Node Irradiation Improve Outcomes in Women With Stage IIIC1 Endometrial Carcinoma?

PURPOSE: To evaluate the impact of prophylactic paraortic lymph node (PALN) radiation therapy (RT) on clinical outcomes in patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 endometrial cancer (EC). METHODS AND MATERIALS: A multi-institutional retrospective study included patients with International Federation of Obstetrics and Gynecology 2018 stage IIIC1 EC lymph node assessment, status postsurgical staging, followed by adjuvant chemotherapy and RT using various sequencing regimens. Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. Univariable and multivariable analysis were performed by Cox proportional hazard models for RFS/OS. In addition, propensity score matching was used to estimate the effect of the radiation field extent on survival outcomes. RESULTS: A total of 378 patients were included, with a median follow-up of 45.8 months. Pelvic RT was delivered to 286 patients, and 92 patients received pelvic and PALN RT. The estimated OS and RFS rates at 5 years for the entire cohort were 80% and 69%, respectively. There was no difference in the 5-year OS (77% vs 87%, P = .47) and RFS rates (67% vs 70%, P = .78) between patients treated with pelvic RT and those treated with pelvic and prophylactic PALN RT, respectively. After propensity score matching, the estimated hazard ratios (HRs) of prophylactic PALN RT versus pelvic RT were 1.50 (95% confidence interval, 0.71-3.19; P = .28) for OS and 1.24 (95% confidence interval, 0.64-2.42; P = .51) for RFS, suggesting that prophylactic PALN RT does not improve survival outcomes. Distant recurrence was the most common site of first recurrence, and the extent of RT field was not associated with the site of first recurrence (P = .79). CONCLUSIONS: Prophylactic PALN RT was not significantly associated with improved survival outcomes in stage IIIC1 EC. Distant metastasis remains the most common site of failure despite routine use of systemic chemotherapy. New therapeutic approaches are necessary to optimize the outcomes for women with stage IIIC1 EC.