Purpose/Objective(s) To examine the impact of MLH1 promoter hypermethylation (MLH1ph) on prognosis and recurrence patterns in stage I-II endometroid endometrial cancer (EEC) treated with adjuvant radiotherapy. Materials/Methods In a retrospective multi-institutional cohort study, patients with stage I-II EEC status post-surgical resection with known mismatch repair (MMR) status were included. Tumors with MSH2, MSH6, MLH1 or PMS2 mutations were classified as somatic deficient MMR (sdMMR), while tumors with epigenetic silencing of the MLH1 promoter were classified as MLH1ph. Recurrences were classified into 3 categories: vaginal, pelvic or distant (including para-aortic lymph nodes). Recurrence-free survival (RFS) and overall survival (OS) were calculated by the Kaplan Meier method. Univariate and multivariate analyses (UVA/MVA) were performed via Cox proportional hazard models. Statistical analyses were conducted using statistical software. Results A total of 823 patients were included with a median age at diagnosis of 65 (IQR = 58-71). Most patients had grade 2-3 disease (59.5%), ≥ 50% depth of myometrial invasion (56.4%), absence of lympho-vascular space invasion (57.5%), and no cervical stromal involvement (77.5%). Vaginal brachytherapy (VBT) was the most common adjuvant radiation modality for 643 (78.1%) patients, while 180 (21.9%) patients received external beam radiation (EBRT) +/- VBT. After a median follow up (MFU) of 38.2 months, OS and RFS for the entire cohort were 93.8% and 87.5%, respectively. MMR was proficient in 550 (66.8%) patients and deficient in 273 (33.2%) patients, most of which were MLH1ph (n = 171, 62.6%), while 93 (34.1%) were sdMMR; 9 could not be classified. The following prognostic factors were associated with decreased RFS on UVA and maintained significance on MVA: age ≥ 65 (P = 0.008, HR = 1.7), grade 2-3 (P = 0.046, HR = 1.6), and MMR status (P < 0.001, HR = 2.1). At MFU, patients with MLH1ph had inferior RFS compared to sdMMR and pMMR (73.5% vs 86% vs 92%, respectively, P < 0.001), but there was no difference in OS (92%, 92%, and 96%, respectively, P = 0.57). Of the 117 recurrences overall, the most common site of recurrence was distant regardless of MMR status, with overall breakdown as follows: 20 (2.4%) vaginal, 19 (2.3%) pelvic, and 78 (9.5%) distant. Patients with MLH1ph had a higher proportion of pelvic (28.2%) and vaginal (20.5%) recurrences, with only 51.3% distant recurrences compared to pMMR (73.2%) and sdMMR (76.5%) (P = 0.04). Conclusion This large multi-institutional study highlights the importance of MLH1 promoter hypermethylation testing when analyzing MMR status for patients with early-stage EEC treated with adjuvant radiotherapy. While MMR status did not impact OS, patients with MLH1ph dMMR had worse RFS and a higher proportion of locoregional recurrences compared to the pMMR and sdMMR patients which could hypothesize a need for escalation in locoregional therapy in patients with MLH1ph.

Preliminary data from 7 out of 11 participating institutions showed that dMMR status leads to significantly decreased RFS in patients with early-stage EEC. While awaiting the results of NRG GYN020 and RAINBO prospective trials, this large study suggests that treatment intensification could be warranted in patients with dMMR early-stage EEC.

We observed a statistically significant association between the dose to the RV-RP and VS G ≥ 2, when stratified by our median dose to the RV-RP of 51Gy, which is lower than the dose constraint of 65Gy previously reported by EMBRACE. These findings may be partially explained by differences in patient demographics or brachytherapy technique. Further investigation of the relationship between the dose to the RV-RP and development of VS G ≥ 2 across broader populations is warranted.

Purpose/Objective(s) Cervical cancer remains a significant concern for both rural and urban populations in the US. Overall treatment time from the start of chemoradiation to completion of brachytherapy is known to correlate with local control and overall survival. Rural populations experience health disparities which are multi-factorial and vary by region, but a commonality is lack of healthcare access and distance to tertiary care centers. The purpose of this study is to examine the health disparities due to geographic location for women with locally advanced cervical cancer (LACC) presenting to tertiary care facilities and identify factors that influence their treatment and outcomes. Materials/Methods A multi-institutional retrospective cohort study was conducted including data from 5 tertiary care centers across the United States. Women with LACC defined as FIGO 2018 IB3-IVA treated with definitive intent RT ±chemotherapy from Jan 2011 to Jan 2021 were included. Clinical, pathologic, radiologic, demographic, and treatment parameters as well as disease outcomes were collected. Geographic location was collected, and zip code was used to determine urban (pop ≥10,000) or rural (pop <10,000) residency. Univariate analyses were used to determine the effects of these variables on disease outcomes. Overall survival (OS) and recurrence-free survival (RFS) were calculated using the Kaplan-Meier method. Results 613 patients were included from diverse regions of the country. Median OS was 27 months (range 0-133) and median RFS was 19.4 months (range 0-123.5). Urban (N=534, 87%) or rural (N=79, 13%) residence was not correlated with overall treatment time (p = 0.50) or cervical cancer specific survival (p = 0.32). The median time from diagnosis to start of RT was significantly shorter in the rural patient population than in the urban population (28 days v. 41 days, p = 0.002). There was no significant association between time from diagnosis to start of RT and cervical cancer specific survival (p = 0.07) or between overall treatment time and cervical cancer specific survival (p = 0.26). There was, however, a significant association between overall treatment time and time to recurrence, with each day of increase in treatment time leading to a 1.1% increased risk of recurrence (p = 0.03, HR = 1.011). Conclusion In this group of patients we found no differences in treatment time or outcomes between urban and rural residents and surprisingly, rural patients had a shorter median time from diagnosis to start of treatment when compared to the urban patient group. As is already known, there was a significant relationship between treatment time and time to recurrence, highlighting the importance of timely treatment in patients with LACC. We are adding data from several more centers and will be evaluating the populations with more granularity to identify challenges faced by our patients and resources that may be helpful.

Purpose/Objective(s) To report the impact of race on clinical outcomes in patients with stage IIIC endometrial carcinoma (EC). Materials/Methods A retrospective multi-institutional cohort study was conducted across 13 Northern American academic centers and included patients with stage IIIC endometrial carcinoma (EC) who received both chemotherapy and radiation in an adjuvant setting. Overall survival (OS) and recurrence-free survival (RFS) were calculated by Kaplan-Meier method. Univariable and multivariable analysis were performed by Cox proportional hazard models for RFS/OS. Propensity score matching was used to estimate the effect of race on survival outcomes. Statistical analyses were conducted using statistical software. Results A total of 90 Black and 568 non-Black patients (83%) were identified with a median age at diagnosis of 62 (Interquartile Range (IQR) 55-70). Median follow-up was 45.3 months (IQR 24-71 months). Black patients were significantly older (p<0.0001), had significantly more non-endometrioid histology (p<0.0001), grade 3 tumors (p<0.0001) and were more likely to have >1 positive paraaortic lymph nodes (PALN) compared to non-black patients. The presence of lymphovascular space invasion (LVSI), depth of myometrial involvement, number of total nodes involved, adnexal and cervical involvement and stage were not correlated with race (all p>0.1). As for treatment type, chemoradiotherapy sequencing approach was not correlated with race and no difference in number of chemotherapy cycles between Black and non-Black patients (p=0.32) was observed. Black patients were more often treated with external beam radiation therapy (EBRT) (43.3% and 24%, respectively) while a higher proportion of non-black patients received both EBRT and vaginal cuff brachytherapy (VBT) (65% vs. 38 %) (P<0.0001) despite similar cervical involvement. The 5-year estimated OS and RFS rates were 45% and 47% compared to 77% and 68% for Black patients vs. non-black patients, respectively (p<0.001). After propensity score matching, the 2 groups were well balanced for most of the covariates (age, histology, stage, grade, number of positive PALN, adnexal and cervical involvement) except for depth of myometrial invasion and radiation type. The estimated hazard ratios (HRs) of Black vs. non-Black patients were 1.613 (95% CI = (1.01, 2.575), p-value = 0.045) for OS and 1.487 (95% CI = (0.906, 2.440), p-value = 0.116) for RFS, indicating that Black patients have significantly worse OS. RFS differences did not reach statistical significance. Conclusion Compared to non-Black patients, Black patients have higher rates of non-endometrioid histology, grade 3 tumors and number of PALNs. After propensity score matching, Black patients had worse OS but no statistically significant difference in RFS. Racial disparities could be mitigated by better access to care, equitable inclusion on randomized trials, and identification of genomic/molecular differences to better tailor adjuvant treatment.

Vaginal brachytherapy (VB) for early stage endometrial cancer (EC) has technologically evolved with the incorporation of 3D imaging into treatment planning. When our institution transitioned from phantom-based 2D template planning to 3D CT-based planning, we implemented selective optimization of standard dwell times for cases with bowel adhered to the vaginal apex. Our hypothesis was that optimizing 3D plans with unfavorable bowel dosimetry would result in no detriment to local control and potentially improve treatment tolerability. We reviewed records of patients with stage I-II EC treated with VB at our institution from 1/2017-6/2019 (3D group). We compared patient, tumor, and treatment characteristics to a historic cohort treated at our institution between 2011-2015 (2D group). Patients had minimum 6 months follow-up. Patients with stage III-IV disease, prior or concurrent pelvic radiation, or synchronous pelvic primary were excluded. Recurrence-free survival (RFS), local control, and treatment tolerability (any acute toxicity recorded prospectively on treatment) were analyzed. Statistical analyses were performed in Stata and included Chi-square and Wilcoxon Rank Sum tests to compare between-group characteristics and Cox proportional hazards analysis to assess RFS. A total of 403 patients were included (n = 99/3D and n = 304/2D). The 3D vs. 2D groups were similar in age, weight, gravidity, cylinder sizes, histology, and chemotherapy, though differed in race (p = 0.004) and % stage IA/IB/II (p = 0.022). VB dose was similar, with majority receiving either 18Gy/3 fractions (46% vs. 46%) or 21Gy/3 fractions (40% vs. 38%) to 5mm depth. In the 3D cohort, however, the proportion of vagina treated was less (3D median 50%, IQ range 43-56% vs. 2D median 60%, IQ range 50-67%; p<0.001). and standard dwell times were decreased to improve bowel dosimetry in 21%. Median follow-up times were 524 and 903 days in the 3D and 2D groups, respectively. There was no significant difference in RFS (HR 0.48, 95% CI 0.19-1.22, p = 0.122). Vaginal recurrence occurred in 1 and 2 patients, respectively, with recurrence distal to treated mucosa in all cases. There were no significant differences between groups in rates of acute GI (14.1% vs. 10.9%, p = 0.376), GU (8.1% vs. 11.2%, p = 0.380), or vaginal (20.2% vs. 19.4%, p = 0.827) toxicities. All toxicities were mild (grade 1-2). In the 3D patients, there were no significant differences (p>0.05) in bowel, rectal, or bladder Dmax or D2cc values between those with vs. without symptoms on treatment. 3D vs. 2D planning maintained excellent local control despite selectively reducing the volume of prescription isodose overlapping with bowel. Treatment tolerability was favorable in both groups with no benefit observed in the short term, however, longer follow-up is needed to compare late outcomes.

In GOG-258, patients who received upfront chemoradiotherapy had more distant relapses compared to those treated with systemic chemotherapy alone, although vaginal and nodal recurrence rates were lower with the addition of adjuvant radiotherapy (RT). Given the importance of both systemic and local therapies, this study evaluates clinical outcomes by the sequence and type of adjuvant therapy for patients with stage IIIC endometrial cancer (EC). In a multi-institutional retrospective cohort study, clinical and treatment data from 12 academic centers were collected for patients with stage IIIC EC treated with curative intent. All patients had surgical staging and received chemotherapy and radiation. Adjuvant treatment (AT) regimens were classified as: adjuvant chemotherapy followed by sequential radiation (ACTRT), concurrent chemoradiation followed by chemotherapy (CCTRT), systemic chemotherapy before and after RT (Sandwich), adjuvant RT followed by chemotherapy (ARTCT) or chemotherapy concurrent with vaginal cuff brachytherapy alone (CCTBT). Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by Kaplan-Meier method and covariates were compared by log-rank test. Chi-square tests were used to compare categorical variables. A total of 670 eligible patients were included (Table) with a median follow-up of 44.1 months. The estimated 5-year OS and RFS rates were 71.5% and 65.5%, respectively. On univariate analysis (UVA) for OS, older age, non-white race, non-endometrioid histology, grade 3 tumor, 2 or more positive nodes, adnexal involvement, cervical involvement, stage IIIC2 vs. IIIC1, and in-field recurrence were associated with worse OS (all p<0.02). On UVA for RFS, older age, non-endometrioid histology, grade 3 tumor, lymphovascular invasion, adnexal involvement, cervical involvement and stage IIIC2 were associated with recurrence. The sequence and type of adjuvant therapy was not correlated with OS or RFS (p = 0.08 and 0.8, respectively). The most common pattern of recurrence was distant metastasis only (66%). Site of first recurrence was significantly different by adjuvant treatment regimen (p = 0.02): ACTRT, CCTRT and Sandwich had a higher proportion of distant metastasis whereas ARTCT and CCTBT had more para-aortic nodal recurrences. Pelvic control was highest for ACTRT. The sequence and type of adjuvant therapy did not impact OS or RFS rates, which were comparable to those of the prospective GOG 258 and PORTEC-3 studies. Adjuvant radiotherapy resulted in excellent pelvic control. Most recurrences were distant despite upfront systemic chemotherapy given in most patients, highlighting the need for novel regimens.Abstract 102; TableFactornAge, Median62Race Caucasian African-American Other480 83 47Stage IIIC1 IIIC2430 240Histology Endometrioid Non-endometrioid441 229Grade 1-2 3320 346RT EBRT BT Both176 94 400Adjuvant therapy ACTRT CCTRT Sandwich ARTCT CCTBT290 112 165 26 77 Open table in a new tab

Objective: Evaluation and treatment of the paraaortic lymph nodes (PAN) in locally advanced cervical cancer (LACC) remains an active area of investigation. Pelvic lymph node involvement at the time of diagnosis is an important prognostic factor. The purpose of this study was to determine the risks of PAN failures after chemoradiotherapy for patients with pelvic node-positive PAN-negative LACC receiving pelvic radiotherapy (RT) without extended field.

To examine patient outcomes of stage III uterine serous carcinoma (USC) in a modern and prior treatment era. We hypothesized that contemporary treatment incorporating external beam radiotherapy (EBRT) is associated with improved outcomes. We performed a retrospective review of FIGO (2009) stage III USC patients who received radiotherapy as a component of treatment at our institution between 1/2003-5/2018. Fifty patients were identified and divided into two cohorts: 20 comprised the early cohort (2003-2010), for whom vaginal brachytherapy (VB) was considered the radiotherapy modality of choice per institutional standard. Thirty were included in the modern cohort (2011-2018), for whom EBRT was considered. Patient, tumor, and treatment characteristics were compared using χ2 tests for categorical variables and t-tests for continuous variables. Recurrence free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards. There were no differences in clinicopathologic characteristics between the two cohorts. All patients underwent complete surgical staging and 3-7 cycles of carboplatin/paclitaxel chemotherapy. The modern era differed from the early era in the increased use of volume-directed EBRT as opposed to VB alone (33.3% vs 5.0%, p=0.048). Reasons for non-use of EBRT in the modern era included patient refusal, poor performance status, or enrollment on clinical protocols not permissive of EBRT. Other management differences between the cohorts included increased use of minimally invasive surgery (56.7% vs. 25%, p=0.027), sentinel node sampling (26.7% vs. 0%, p=0.012), CT imaging in the perioperative period (63.3% vs. 30%, p=0.044), and HER2/neu testing (96.7% vs. 55%, p=0.001). Median follow-up for the early and modern eras was 37.27 months and 33.23 months, respectively. The early and modern treatment era 3-year RFS was 33% and 64% (P=0.039), respectively, while the 3-year OS was 55% and 90% (P=0.034). There were no vaginal recurrences in either time period. In the early and modern eras, 50% and 23% of patients, respectively, had a regional nodal component of recurrence (p=0.051). Of the 11 patients who received EBRT, only one patient had a regional nodal recurrence (9%), whereas among the 39 patients who received VB only, 16 patients (41%) had a recurrence with a regional nodal component (p=0.048). Modern era treatment was associated with improved RFS and OS in patients with stage III USC. Regional nodal recurrences were significantly reduced in patients who received EBRT. EBRT should thus be considered for locoregional control, which becomes even more valuable as the prognosis for this population continues to improve in the modern era.

Cervical cancer (CC) brachytherapy (BT) has evolved from Point A to volumetric MRI-based prescriptions. At our institution, in transitioning to MRI-guided BT, an inpatient (IP) rather than outpatient (OP) paradigm was adopted due to resource considerations. The IP regimen mandated a pre-procedure bowel prep (BP) to improve logistics and comfort; the OP regimen did not. We hypothesized that use of BP may theoretically displace rectum and sigmoid walls away from the applicators and thereby improve BT dosimetry. We included locally advanced CC patients treated with HDR intra-cavitary BT over a 5-year period. Earlier patients were treated with 4-5 individually planned OP fractions (5-7Gy), with prescription to point A. Later patients were treated IP, generally in 4 fractions (6.8-7Gy) from two individually planned implant insertions, with MRI performed with applicator in situ. Most (98%) fractions were done with tandem and ring. Data collected from each individually planned fraction included % D2cc rectum, % D2cc sigmoid, treated volume (defined as the volume in cc covered by the 100% prescription isodose), and use of BP. Per-patient cumulative doses (EQD2, Gy) to the rectum and sigmoid were recorded. Median values were compared with the Wilcoxon Rank Sum test. Univariable and multivariable linear regression was performed to assess impact of BP. Statistical analyses were performed in Stata. Data from 140 individually planned fractions (66 OP, 74 IP) from 53 patients were analyzed. The median OP vs IP fractional %D2cc rectum and %D2cc sigmoid were 44.2% vs 24.7% (p<0.001) and 57.4% vs 50.8% (p=0.007). The resulting median cumulative D2cc values for OP vs IP rectum and sigmoid were 58.1 Gy vs 50.3 Gy (p<0.001) and 64 Gy vs 62 Gy (p=0.51). Median treated volume for all fractions was 51.0cc (IQ: 41.8-64.4). OP vs IP median treated volume was 58.2cc (IQ: 48.9-70.4) and 45.6cc (IQ: 35.7-53.0), respectively (p<0.001). On univariable analyses, both IP treatment with BP, and smaller treated volume, were associated with significantly lower %D2cc rectum and %D2cc sigmoid. On multivariable analyses, IP treatment with BP (Coef -0.15, CI -0.19 to -0.11, P<0.001) and smaller treated volume (Coef 0.06, CI 0.02 to 0.11, P=0.002) both remained significantly associated with lower %D2cc rectum, but only treated volume remained significant for %D2cc sigmoid (Coef 0.12, CI 0.05 to 0.17, p<0.001); IP treatment with BP did not (Coef -0.02, CI -0.08 to 0.04, p=0.4). On sensitivity analysis, IP treatment with BP resulted in significantly lower %D2cc rectum for both smaller (<51cc) (Coef -0.19, CI -0.24 to -0.14, P<0.001) and larger (≥51cc) (Coef -0.12, CI -0.17 to -0.05, P=0.001) treated volumes. The transition from point A to MRI-guided BT was associated with improved dosimetry. Further, we observed an independent association between IP treatment with BP and reduced rectal D2cc for both larger and smaller volume tumors.

Objective: Optimal adjuvant treatment of patients with FIGO 2009 stage IB grade 2 or 3 endometrioid endometrial cancer (EEC) is controversial. We sought to assess the outcomes of patients with FIGO 2009 stage IB grade 2 or 3 EEC treated with comprehensive surgical staging (CSS) and vaginal brachytherapy (VBT) as sole adjuvant treatment.

A randomized phase II trial has recently demonstrated that anti-HER2 therapy in combination with cytotoxic chemotherapy improves outcomes for HER2 positive advanced FIGO stage III-IV or recurrent uterine serous carcinoma (USC). Whether such treatment is beneficial for early FIGO stage I-II USC is unknown. We examined whether HER2 overexpression was associated with an increased recurrence risk in a large cohort of early stage USC patients treated with multi-modality therapy (without anti-HER2 therapy) at a single institution. The cohort consisted of 117 patients with FIGO stage I-II USC treated between 2000-2015 in a consistent manner with carboplatin and paclitaxel chemotherapy and high-dose-rate intravaginal brachytherapy following surgical staging. HER2 status was available in patients treated after 2009. HER2 positivity was defined as overexpression of HER2 at a level of 3+ by immunohistochemistry (IHC) and/ or HER2 gene amplification with a HER2/CEP17 ratio of >2.1 by fluorescence in situ hybridization (FISH). For the total cohort, we analyzed clinical, pathologic, and treatment-related factors influencing recurrence-free survival (RFS). In the cohort of patients with known HER2 status, we examined the impact of HER2 positivity on RFS. Kaplan-Meier statistics were performed, and the log-rank test was used for univariable statistical comparisons. Multivariate analyses were not performed due to few events. This retrospective study was granted approval by the institutional human investigations committee. Stage IA, IB and II comprised 75%, 17%, and 8% of patients, respectively. Histology was pure serous in 68% and mixed serous in 32%. Treatment included pelvic and para-aortic dissections in 96%, brachytherapy in 100%, and full chemotherapy (6 cycles) in 91%. For the total cohort, the median follow-up time was 4.85 years (range: 0.26 – 16.68), the 5-year RFS was 86.3%, and the median time to recurrence was 32.8 months. Factors associated with worse RFS were higher stage (p=0.025) and lymphovascular invasion (LVI) (p=0.0092). Stage IB versus IA was associated with higher recurrence (HR 4.4; 95% CI 1.3-14.4; p=0.015). Among the 52 patients with known HER2 status, IHC levels were 0 (21%), 1+ (40%), 2+ (21%), and 3+ (17%). In combination with FISH results, a total of 13 patients (25%) were HER2 positive. HER2 overexpression was associated with worse RFS (p=0.005). The estimated 5-year RFS was 94.6% and 41.1% in the HER2 negative and Her2 positive populations, respectively. Our results indicate that HER2 overexpression is associated with increased risk of recurrence. These data, in combination with other published trials, may support the use of anti-HER2 therapy in early stage disease, especially when other poor prognostic features (+LVI, deep myometrial invasion) are present.

When prescribing adjuvant high-dose-rate intra-vaginal brachytherapy (IVB) for endometrial cancer, in terms of equivalent dose in 2 Gy fractions (EQD2), there is growing data to support surface doses as low as 30-40 Gy as compared to more traditional surface doses of 50-55 Gy. Such lower dose regimens may be especially advantageous when IVB is combined with chemotherapy. Since 2000, patients with stage I-II uterine papillary serous carcinoma (UPSC) at our institution have been treated with 6 cycles of adjuvant carboplatin-paclitaxel chemotherapy along with 2 fractions of IVB (7 Gy each), with the first fraction typically delivered one week prior to and the second fraction one week following the second cycle of chemotherapy. IVB is delivered via an Ir-192 source. Prescription depth is 5mm from the cylinder surface, and the estimated total EQD2 surface dose is approximately 36 Gy. We performed a retrospective chart review in order to evaluate the effectiveness of this regimen. We identified 56 patients with FIGO 2009 stage I-II UPSC treated with this regimen between 2000 and 2010. Patients who had received single modality therapy, external beam radiation therapy, or other brachytherapy fractionation were excluded. All patients underwent total hysterectomy and the majority had undergone comprehensive surgical staging including pelvic dissection (96%, median nodes removed = 18, range, 6-47) and para-aortic dissection (80%, median nodes removed = 3, range, 1-37). Patients were followed by routine clinical examination, Pap smears, and tumor markers. Kaplan-Meier methods were used to estimate recurrence-free survival (RFS) and overall survival (OS). All 56 patients completed 2 IVB fractions, and 53 patients (95%) completed all 6 cycles of chemotherapy. The median time from surgery to first IVB fraction was 50 days (range, 30-113 days). There were no delays in administering subsequent cycles of chemotherapy due to IVB. The median follow-up time was 49 months (range, 9-145 months). The 5-yr RFS and OS were 85% and 93%, respectively. In all cases of recurrence (n = 8), the first site of failure was extra-pelvic. The para-aortic region was an isolated failure site in 1 patient. There were no pelvic recurrences. There were no isolated vaginal recurrences, however, there was one vaginal apex recurrence recorded at 19 months in a patient with simultaneous lung metastases. Thus, the 2-year vaginal RFS was 98%. For stage I-II UPSC, 2 fractions of adjuvant IVB to a total dose of 14 Gy with 6 cycles of carboplatin-paclitaxel chemotherapy resulted in excellent disease control and very low rates of vaginal/pelvic failure. Whether this lower dose regimen translates into improvements in patient-centered outcomes compared to more traditional higher dose fractionation schemes is a subject on ongoing prospective investigation.

To report a single institution experience utilizing adjuvant carboplatin/paclitaxel (C/T) chemotherapy and vaginal brachytherapy (VB) without external beam radiation therapy (EBRT) for locally advanced endometrial cancer (EC). From 2004-2010, 80 women with locally advanced endometrial adenocarcinoma were treated with comprehensive surgical staging, followed by concurrent carboplatin (AUC = 5) and paclitaxel (175 mg/m2) chemotherapy given every 3 weeks for 6 planned cycles. Two or 3 fractions of high dose rate VB using Ir-192 (7 Gy per fraction, 0.5cm from cylinder surface) was planned within 6-8 weeks of surgery. Locally advanced disease was defined as FIGO 2009 stage IIIA-IIIC2 or stage I-II with positive cytology (FIGO 1988 Stage IIIA). Patients with stage IV or sub-optimal surgical debulking were excluded. For analysis, patients were grouped into Type 1 (FIGO grade 1-2 endometrioid histology, n=40) or Type 2 (FIGO grade 3, clear cell, papillary serous, or mixed histologies, n=40). Kaplan-Meier methods were used to estimate survival and log-rank was used for comparison between groups. Mean age at diagnosis was 63 years (range 27-89). Surgery was hysterectomy and bilateral salpingoophorectomy (70% open, 15% laparoscopic, and 15% robotic), pelvic washings, omentectomy (36%), pelvic lymph node dissection (97.5%, median 20, range 2-60), and paraortic node sampling (85%, median 4, range 1-28). The pathologic sub-stages according to Type 1/Type 2 histology were: IIIA (n=8/n=13); IIIB (n=0/n=0); IIIC1 (n=11/n=13); IIIC2 (n=9/n=8); stage I-II + positive cytology (n=12/n=6). Seventy seven (96.3%) patients completed 6 cycles of C/T. VB total dose was 21 Gy, 14 Gy, or 7 Gy in 22 (27.5%), 57 (71.3%), and 1 (1.2%) patients, respectively. Median follow up was 35.1 months (range 10.1-89.0). Median time to recurrence was 12.3 months (range 4.0-34.6). The 3-year estimated overall (OS) and disease-free survival rates (DFS) were 85.3% and 76.7%, respectively. Type 1 compared to Type 2 patients had significantly improved 3-year OS (100% vs 71%; p=0.002) and DFS (92% vs 61%; p=0.001). Thirteen of 18 patients with recurrence had initial failure in the pelvis and/or paraortics (Type 1, n=2; Type 2, n=11). There were no isolated vaginal relapses in either Type 1 or Type 2; however, 3 Type 2 patients developed subsequent vaginal recurrence in the setting of prior distant or paraortic disease. In this study, Type I EC patients with locally advanced disease who had comprehensive surgical staging appeared to have excellent disease control with adjuvant C/T and VB without EBRT. Type 2 EC, however, remains a therapeutic challenge, although recent regimens combining tumor-directed EBRT + chemotherapy may be promising.

Verrucous carcinoma of the vulva is an unusual variant of squamous cell carcinoma, and it is believed to have a distinct clinical behavior. The case reports available suggest this entity is indolent and rarely metastasizes to lymph nodes. However, there has been no large population based analysis of this histologic subtype. A SEER Database analysis was performed to analyze survival by stage, age, and race. The National Cancer Institute Surveillance Epidemiology and End Results (SEER) database was analyzed to evaluate outcomes for patients with verrucous carcinoma of the vulva treated from 1994 to 2008. Patients were excluded for prior or subsequent malignant diagnoses. Overall and population matched relative survival were calculated. Predictors of survival were analyzed using Cox proportional hazards analysis. A total of 143 women were identified as having verrucous carcinoma of the vulva. Median age was 77 years (range 27-94 years). Stage I disease was 34.9% of the cases, stage II comprised 32.2%, stage III (histologically node positive by either of staging systems used) was 15.4%, and stage was unknown in 16.7%. Only 0.7% of patients (n=1) were stage IV. This differs favorably from 25.7% stage III cases seen among all histologies of vulvar cancer, and 6.6% stage IV cases seen in the SEER database. White race was present in 86.7% of the patients, followed by black race in 7.7%, with other or unknown comprising the remaining 5.6%. Surgery alone was the management in 94.4%, with the remaining 5.6% receiving surgery and radiation. The 10-year overall survival was 89.3% [95% confidence interval (CI) 81.4-94.0%]. US census population-matched relative survival was 90.2% at 5 years [95% CI 62.6-74.8%]. The 5 and 10-year cancer specific survival were identical at 89.3% [95% CI 81.4-94.0%]. On multivariate analysis, stage III disease and age > 80 were each independently associated with decreased overall survival. Race was not related to survival in multivariate analysis. Verrucous carcinoma is an uncommon malignancy. Radiation treatment, although possibly under-recorded in SEER, was rarely used, which may be related to the early stage at presentation and case reports of anaplastic transformation after radiation therapy of verrucous type vulvar cancer. Surgery alone results in excellent relative and cancer specific survival.

To evaluate outcomes in patients with recurrent paraspinal metastases who were re-irradiated with two different schemes of hypo-fractionated, image-guided, intensity-modulated radiation therapy (IG-IMRT). A retrospective analysis was performed on 89 recurrent paraspinal metastases in 86 patients who were re-irradiated with IG-IMRT in 5 daily fractions to a total dose of either 20Gy (n = 34) or 30Gy (n = 55) from August 2001 to August 2008. Institutional practice was 20Gy prior to 01/01/06 and was escalated to 30Gy subsequently. All patients received previous spine radiation (RT) (median dose 30Gy in 10 fractions). Following IG-IMRT, patients underwent dedicated cross-sectional spine imaging and clinic visits every 3 months. Local recurrence (LR) was defined as radiographic progression of disease within the RT field, and functional outcomes were measured by the American Spinal Injury Association (ASIA) impairment score. Treatment characteristics analyzed included total dose (30Gy vs. 20Gy), performance status, surgical decompression prior to 2nd RT, interval between first RT and first failure, tumor histology, and both volume and D95 of the GTV and PTV. To assess for association between treatment characteristics and local control following IG-IMRT, an actuarial cumulative competing risks analysis was performed with death as a competing risk event. Cox proportional hazards regression models were used to investigate predictors for overall survival (OS). Fisher's exact test was used to evaluate association between variables. With a median follow-up of 12.4 months (range 0.2 - 102), 29/34 and 28/55 have died in the 20Gy and 30Gy cohorts, respectively. At one year, the cumulative incidence of LR was 30% and OS survival was 66%. At the time of last follow-up, the ASIA score was stable or improved in 76% of cases. Of treatment characteristics examined for association with local control, only dose (30Gy vs. 20Gy) was statistically significant (p = 0.02, unadjusted HR 0.46, 95% CI 0.24-0.90). Higher dose was also more likely to be associated with a stable or improved ASIA score (88% with 30Gy vs. 59% with 20Gy, p = 0.004). Dose did not significantly impact OS (p = 0.20). There were minimal acute toxicities and no serious late complications including no myelopathy. There are limited treatment options available for patients whose paraspinal metastases recur following an initial course of RT. Re-irradiation with hypo-fractionated IG-IMRT was effective, and a significant dose response for local control was demonstrated. 30Gy resulted in significantly better local control and functional outcomes compared to 20Gy, without greater toxicity. Further dose escalation with IG-IMRT may be warranted.

Radiation is an important component of the multimodality treatment approach for patients with inflammatory breast cancer (IBC). Various fractionation protocols exist, including daily and BID schedules. Randomized prospective studies comparing protocols will never be possible, as this diagnosis represents less than 5% of all breast cancers. Over the past decade, IBC patients at our center have been treated with anthracycline and taxane-containing chemotherapy, modified radical mastectomy (MRM), and adjuvant radiation using standard fractionation and daily bolus to ensure 100% dose coverage of the skin. Our objective was to evaluate the outcomes of IBC patients treated with this regimen. One hundred twenty-three patients with a clinical diagnosis of IBC between May 1995 and December 2006 underwent radiation as part of multimodality therapy. Patients with metastatic disease or disease progression throughout treatment were excluded. The majority of patients received neoadjuvant chemotherapy (89%) and MRM (96%). Neoadjuvant chemotherapy was predominantly anthracycline-based. Taxanes were incorporated into the chemotherapy regimen of 94% of all patients, either in the neoadjuvant setting (59%), or following definitive surgery (41%). A median dose of 5040 cGy was delivered to the chest wall utilizing either electrons (54%) or photons (46%), in 180-200 cGy daily fractions. Supraclavicular nodes were treated in all cases. Posterior axillary boost and internal mammary node irradiation were given in 28% and 20% of patients, respectively. Thirteen percent of patients received an additional boost to the mastectomy scar (600-1400 cGy). For all patients, skin bolus was applied on a daily basis to the entire chest wall. The Kaplan-Meier method was used for survival analysis. Median follow-up was 46 months. Median duration of radiation treatment was 39 days (range, 34-64). Eighty-nine percent of patients completed the full planned course of radiation. Twelve patients discontinued treatment between 4,600-4,980 cGy and 1 patient at 3,800 cGy secondary to intolerable moist desquamation. The 5-year locoregional control was 86%. Of 14 locoregional failures, 7 occurred in the skin or chest wall and 7 occurred in the regional lymph nodes. Three of these were isolated recurrences, while the remaining cases also presented with distant failures. The 5-year disease-free survival and overall survival rates were 44%, and 63%, respectively. Multimodality therapy with anthracycline and taxane-containing chemotherapy, MRM, and adjuvant radiation achieves excellent locoregional control in IBC patients. Standard fractionation with daily bolus is a well-tolerated and effective method of treating these high risk patients.