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OBJECTIVES Lymphovascular space invasion (LVSI) is a known prognostic factor for endometrial carcinomas. However, LVSI as a determinant of treatment benefit has not been fully elucidated. METHODS AND MATERIALS Data from the National Cancer Database for endometrial cancer from 2004 to 2012 was obtained. Univariate and multivariate analysis was performed to assess the impact of LVSI on overall survival (OS). Survival analysis was performed utilizing log-rank and Kaplan-Meier analyses. The difference in OS between external beam radiation therapy (EBRT) and vaginal brachytherapy (VBT) in LVSI-positive patients was analyzed with propensity score matching. RESULTS A total of 32,150 patients with surgical stage I to III endometrial carcinomas were available for analysis with a median follow-up of 30 months. Twenty-nine percent were LVSI positive and received adjuvant radiotherapy (aRT) more often than if LVSI negative (57% vs. 37%). On multivariate analysis, LVSI (hazard ratio, 1.94; P

Parotid tumors are rare, and no clinical trial data exists to guide postoperative radiation therapy (PORT) usage. We sought to determine the impact of PORT on the overall survival (OS) of patients with parotid malignancies. Patient data was queried from the National Cancer Database. Patients with surgical resection of parotid gland carcinomas from 2004 to 2012 were analyzed. Kaplan-Meier and Cox proportional hazards were used to assess OS among those receiving PORT or not. Additionally, variables affecting OS and use of PORT were evaluated. A total of 12,439 patients were identified for analysis. Increasing T stage, N stage, tumor grade, and positive margin status were predictive of PORT. Survival for patients receiving PORT versus surgery only at 5 and 10 years was 65.5% and 50.3% versus 74.4% and 61.2% for surgery only (p ≤ 0.001). After multivariable adjustment, PORT improved OS (adjusted hazard ratio 0.79, 95% confidence interval 0.70–0.89). In subgroup analysis, PORT provided benefit for certain histologic subtypes and all other patient groups except those with T1 tumors and undifferentiated/anaplastic tumor grades. Our data suggests that PORT was associated with improved survival. Additionally, some subgroups may receive additional benefit and patients with small (T1), low-grade disease may be able to forgo PORT.

Radiation therapy (RT) may work synergistically with cancer immunotherapies but clinical trial data is needed to validate this paradigm. We isolated the portfolio of trials that investigate the primary immunomodulatory properties of RT and examined recent trends in clinical trials that combine immunotherapy and RT (ITRT). We queried clinicaltrials.gov for trials initiated since 2002 using both radiation and immunotherapy as mandated interventions. We designated the trials that examine the specific aspects of RT or its abscopal properties as “Primary RT Immunomodulation” trials. Chi-squared analysis determined differences between primary RT immunomodulation trials and those that incorporate RT as a secondary intervention. Joinpoint regression modeling determined the rate of change of the introduction of new trials over time. One hundred and ninety trials met inclusion criteria. Targeted immunostimulatory agents, including checkpoint inhibitors, were the most common immunotherapy (n = 79 [41.6%]). Sixty-six (34.7%) trials included RT as the primary intervention, with 50 (75.6%) of these utilizing stereotactic body radiation (SBRT). All ITRT trials increased at a rate of 14.8% per year. Primary RT immunomodulation trials increased at a rate of 26.8% per year. Primary RT immunomodulation trials were more likely to utilize targeted immunostimulatory agents (p

Objectives To investigate clinicopathologic and treatment factors associated with survival in adult head and neck sarcomas in the National Cancer Database (NCDB). To analyze whether treatment settings and therapies received influence survival outcomes and to compare trends in utilization via an aggregated national data set. Study Design Prospectively gathered data. Setting NCDB. Subjects and Methods The study comprised a total of 6944 adult patients treated for a head and neck sarcoma from January 2004 to December 2013. Overall survival (OS) was the primary outcome. Results Increased age and tumor size, nodal involvement, and poorly differentiated histology had significantly reduced OS ( P < .001). Angiosarcoma, malignant nerve sheath tumor, malignant fibrous histiocytoma, osteosarcoma, and rhabdomyosarcoma histologic subtypes had significantly reduced OS, while liposarcoma, chondrosarcoma, and chordoma had improved OS ( P < .001). Utilization of surgical therapy was associated with improved OS, while positive surgical margins were associated with treatment at a community-based cancer program and had reduced OS ( P < .001). On multivariate analysis, treatment with radiation and/or chemotherapy was not significantly associated with OS; however, primary treatment with definitive chemoradiotherapy had significantly reduced OS. Patients treated at academic/research cancer programs (n = 3874) had significantly improved 5- and 10-year OS (65% and 54%, respectively) when compared with patients treated at community-based cancer programs (n = 3027; 49% and 29%; P < .001). The percentage utilization of these programs (56% vs 44%) did not change over the study period. Conclusion For adult head and neck sarcomas, treatment at an academic/research cancer program was associated with improved survival; however, despite increasing medical specialization, the percentage utilization of these programs for this rare tumor remains constant.

We investigated the effect of neoadjuvant versus adjuvant chemoradiotherapy on overall survival as well as the impact of demographic and clinical factors for the selection of each approach utilizing the National Cancer Data Base. Adult patients with stage II and stage III adenocarcinoma of the rectum diagnosed from 2004 to 2013 were included. Chi-square analysis was used to compare demographic variables and clinical stage between the patients receiving neoadjuvant and adjuvant chemoradiotherapy. Univariate and multivariate logistic regression modeling was used to identify factors predictive of each treatment strategy. Kaplan-Meier and log-rank analysis and Cox proportional hazard modeling along with propensity score matching using variables known at the time of treatment sequence decision was performed to determine the effect on survival. A separate survival analysis was conducted including margin status to illustrate its effect on survival relative to adjuvant or neoadjuvant chemoradiation therapy. A total of 20,114 patients were identified: 17,612 (87.6%) received neoadjuvant chemoradiotherapy. Factors associated with receipt of neoadjuvant chemoradiotherapy on multivariate analysis include the following: income greater than $46,000 (p

The goal of this study was to assess the survival differences seen in early-stage and advanced-stage nodular lymphocytic predominant Hodgkin lymphoma (NLPHL) based on treatment modality.The National Cancer Database was queried to identify patients diagnosed with NLPHL between 2004 and 2012. Overall survival (OS) was determined using univariate and multivariate Cox regression analysis. Kaplan-Meier and log-rank analysis were used to estimate differences in OS between treatment groups.A total of 1968 patients were identified for analysis, consisting of stage I (40.4%), stage II (29.3%), stage III (22.3%), and stage IV (8.0%) disease. The median age of patients was 46 years. The following factors were predictive of radiotherapy (RT) omission in treatment: increasing age, black race, Medicare insurance, chemotherapy use, stage II to IV disease, and the presence of B-symptoms. On survival analysis, RT was associated with prolonged OS in all stages of NLPHL (50.1 vs. 42.4 months; P .01). The OS benefit of RT persisted on multivariate analysis (hazard ratio, 0.37; P .01). On subset analysis, RT was associated with prolonged OS in early disease (49.8 vs. 45.5 months; P .01), whereas a trend towards an OS benefit was observed in advanced-stage (54.1 vs. 39.6 months; P = .06) NLPHL. Radiotherapy was also associated with prolonged OS among patients with B-symptoms (49.0 vs. 42.6 months; P .01).The use of RT in NLPHL is less likely among those with advanced-stage disease and B-symptoms. However, we found RT to be associated with prolonged OS in all stages of NLPHL, including those with B-symptoms.

Unresected extrahepatic cholangiocarcinoma (uEHCC) remains a deadly disease. Guidelines for uEHCC recommend either chemotherapy alone (CT) or chemoradiotherapy (CRT). This study used the National Cancer Database (NCDB) to compare outcomes for patients treated with CT and those who underwent CRT. Patients with initially diagnosed non-metastatic uEHCC from 2004 to 2014 were identified. Using Chi square analysis, patients who underwent CT were compared with those who received CRT. Uni- and multivariate Cox regression analyses were used to compare characteristics related to survival. Propensity score matching and shared frailty analysis were undertaken to correct for baseline differences between the two groups. Additional analyses were performed to compare survival for the minority of patients who underwent surgery and advanced-stage patients. The study identified 2996 patients with uEHCC. Chemoradiation was associated with better survival (median survival [MS], 14.5 months; hazard ratio [HR] 0.84; p

BACKGROUND The role of chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC) is uncertain after multiple randomized clinical trials have yielded mixed results. The authors used the National Cancer Data Base (NCDB) to determine whether CRT yields a survival benefit compared with chemotherapy alone (CT). METHODS Patients with nonmetastatic LAPC diagnosed during 2004 through 2014 were identified in the NCDB. Patients who received CT were compared with those who received CRT using chi-square analysis. Univariate and multivariate Cox regression analyses were used to compare demographic, clinical, and treatment characteristics that were predictive of survival. Propensity score matching and shared frailty analysis were done. Subgroup analyses were undertaken to examine patients who underwent pancreatectomy and cohorts of patients who received different CT or CRT regimens. RESULTS In total, 8689 patients with LAPC were identified. CRT was associated with improved survival (median survival [MS], 13.5 months) compared with CT (MS, 10.6 months) on multivariate analysis (hazard ratio [HR], 0.80; P < .001). Induction chemotherapy before CRT (HR, 0.67; P < .001) and multiagent chemotherapy (HR, 0.72; P < .001) were also identified as independent predictors of survival compared with concurrent CRT and single-agent CT, respectively. Patients in the CRT group who received multiagent induction chemotherapy had superior MS and pancreatectomy rates (MS, 17.5 months; HR, 0.70; P < .001; pancreatectomy rate, 10%) compared with those who received multiagent CT alone (MS, 12.4 months; pancreatectomy rate, 3.3%). Patients who underwent pancreatectomy experienced improved survival (MS, 22 vs 10.6 months; HR, 0.39; P < .001). CONCLUSIONS In this NCDB analysis, maximizing systemic chemotherapy before CRT improved survival compared with CT alone in patients with LAPC. Continued analysis of CRT in properly selected patients after maximized systemic therapy is needed. Cancer 2017;123:3816-24. © 2017 American Cancer Society.

Early-stage high-risk endometrial cancer (HREC) treated with adjuvant radiotherapy (aRT) alone has been associated with an increased risk of distant relapse. The addition of chemotherapy to radiotherapy (aCRT) may benefit overall survival (OS). We investigated the patterns-of-care and OS benefit of aCRT in HREC by analyzing a large national registry.Our query was limited to patients with the International Federation of Gynecology and Obstetrics stage IB and II HREC with either papillary serous, clear cell, or grade 3 adenocarcinoma, diagnosed between 2004 and 2012. Logistic and Cox regression analyses were utilized to identify predictors of aCRT use and OS, respectively. Survival analysis was performed with Kaplan Meier and log-rank methods. Propensity score matching was employed to decrease the potential influence of selection bias.A total of 11,746 patients were identified for analysis with 8206 (69.9%) receiving aCRT, and 3540 (30.1%) received aRT. Predictors of aCRT included International Federation of Gynecology and Obstetrics stage II (odds ratio [OR], 1.39; 95% confidence interval [CI], 1.22-1.57), papillary serous (OR, 9.44; 95% CI, 8.22-10.85) or clear cell (OR, 3.21; 95% CI, 2.59-3.97) histology, lymph nodes removed (OR, 1.48; 95% CI, 1.31-1.69), and receipt of brachytherapy alone (OR, 1.55; 95% CI, 1.36-1.78). Estimated 5-year OS was 75.2% for patients receiving aRT only and 79.2% for those receiving aCRT (P0.001). When compared with aRT, aCRT was associated with improved OS on multivariate (hazard ratio, 0.78; 95% CI, 0.61-0.99) analysis. A univariate shared-frailty Cox regression after propensity score matching revealed persistence of the OS benefit with aCRT (hazard ratio, 0.74; 95% CI, 0.65-0.84).The addition of adjuvant chemotherapy to radiation in HREC is associated with improved OS. Multiple demographic and clinical factors significantly influence the choice of adjuvant therapy in this setting.

To evaluate the survival benefit of adding vaginal brachytherapy (BT) to pelvic external beam radiation therapy (EBRT) in women with stage III endometrial cancer.The National Cancer Data Base was used to identify patients with stage III endometrial cancer from 2004 to 2013. Only women who received adjuvant EBRT were analyzed. Women were grouped according to receipt of BT. Logistic regression modeling was used to identify predictors of receiving BT. Log-rank statistics were used to compare survival outcomes. Cox proportional hazards modeling was used to evaluate the effect of BT on survival. A propensity score-matched analysis was also conducted among women with cervical involvement.We evaluated 12,988 patients with stage III endometrial carcinoma, 39% of whom received EBRT plus BT. Women who received BT were more likely to have endocervical or cervical stromal involvement (odds ratios 2.03 and 1.77; P.01, respectively). For patients receiving EBRT alone, the 5-year survival was 66% versus 69% with the addition of BT at 5 years (P.01). Brachytherapy remained significantly predictive of decreased risk of death (hazard ratio 0.86; P.01) on multivariate Cox regression. The addition of BT to EBRT did not affect survival among women without cervical involvement (P=.84). For women with endocervical or cervical stromal invasion, the addition of BT significantly improved survival (log-rank P.01). Receipt of EBRT plus BT was associated with improved survival in women with positive and negative surgical margins, and receiving chemotherapy did not alter the benefit of BT. Propensity score-matched analysis results confirmed the benefit of BT among women with cervical involvement (hazard ratio 0.80; P=.01).In this population of women with stage III endometrial cancer the addition of BT to EBRT was associated with an improvement in survival for women with endocervical or cervical stromal invasion.

Proton beam therapy (PBT) potentially allows for improved sparing of normal tissues, hopefully leading to decreased late side effects in children. Using a national registry, we sought to perform a patterns-of-care analysis for children receiving PBT for primary malignancies of the central nervous system (CNS).Using the National Cancer Data Base, we identified pediatric patients with primary CNS malignancies that were diagnosed between 2004 and 2012. We used a standard t test for comparison of means and χWe identified 4637 pediatric patients receiving radiation therapy from 2004 to 2012, including a subset of 267 patients treated with PBT. We found that PBT use increased with time from1% in 2004 to 15% in 2012. In multivariate logistical regression, we found the following to be predictors of receipt of PBT: private insurance, the highest income bracket, younger age, living in a metropolitan area, and residing200 miles from a radiation treatment facility (P.05).We noted the proportion of children receiving PBT to be significantly increasing over time from1% to 15% from 2004 to 2012. We also observed important disparities in receipt of PBT based on socioeconomic status. Children from higher-income households and with private insurance were more likely to use this expensive technology. As we continue to demonstrate the potential benefits of PBT in children, efforts are needed to expand the accessibility of PBT for children of all socioeconomic backgrounds and regions of the country.

In endometrial cancer, the appropriate sequence of adjuvant chemotherapy (aCT) and adjuvant radiation therapy (aRT) is unclear. We aim evaluated whether early chemotherapy is associated with improved overall survival (OS) and cancer-specific survival (CSS).Endometrial cancer patients that received aCT and aRT were selected from the SEER-Medicare database. Early chemotherapy was defined as receiving aCT before aRT, with or without additional aCT ("sandwich" regimens). All other patients received a full course of aRT before chemotherapy with or without concurrent chemotherapy. Univariate and multivariate Cox proportional hazards regression was utilized to assess the impact of clinical and demographic factors on OS.We selected 597 patients for analysis. Median age and was 72 years; 85% of patients were white. Overall, 68% of women had FIGO (International Federation of Gynecology and Obstetrics) stage III disease and 77% received 4 to 6 cycles of chemotherapy. Five-year OS (66.6% vs. 62.4%, P=0.46) and 5-year CSS (71.1% vs. 71.2%, P=0.88) was not significantly improved among those receiving early chemotherapy. In addition, early chemotherapy did not improve OS (hazard ratio [HR]=0.87; 95% confidence interval [CI]: 0.56-1.34, P=0.53) or CSS (HR=1.21; 95% CI: 0.82-1.79, P=0.34) on multivariate analysis. Compared with 1 to 3 cycles, receiving 4 to 6 (HR=0.48, 95% CI: 0.26-0.87, P=0.02), and ≥7 cycles (HR=0.42, 95% CI: 0.20-0.89, P=0.02) of chemotherapy was associated with improved OS.No differences in OS or CSS were noted among endometrial patients receiving early chemotherapy. However, the number of chemotherapy cycles was associated with prolonged survival.

Purpose: Clinical trials (CTs) in proton beam therapy (PBT) are important for determining its benefits relative to other treatments. An analysis of PBT trials is, thus, warranted to understand the current state of PBT CTs and the factors affecting current and future trials. Materials and Methods: We queried the clinicaltrials.gov Website using the search terms: proton beam therapy, proton radiation, and protons. A total of 152 PBT CTs were identified. We used χ2 analysis and logistic regression to evaluate trial characteristics. Results: Most CTs were recruiting (n = 79; 52.0%), phase II (n = 95; 62.5%), open label (n = 134; 88.2%), single-group assignment (n = 84; 55.3%), and with primary treatment endpoints of safety and efficacy (n = 94; 61.8%). The primary treatment sites included gastrointestinal (n = 32; 21.1%), central nervous system (n = 31; 20.4%), lung (n = 21; 13.8%), prostate (n = 19; 12.5%), sarcoma (n = 15; 9.9%), and others (n = 24; 15.8%). Comparison studies between radiation modalities involved PBT and intensity-modulated photon therapy (n = 11; 7.2%), PBT and general photon therapy (n = 8; 5.3%), and PBT and carbon-ion therapy (n = 7; 4.6%). The PBT CTs underwent substantial growth after 2008 but now appear to be in decline. Nongovernmental institutions, comprising university centers, hospital systems, and research groups, have funded the greatest number of CTs (n= 106; 69.7%). The National Institutes of Health (NIH) were more likely to fund CTs involving the central nervous system ( P = 0.02). Trials involving NIH funding were more likely to result in successful trial completion ( P = 0.02). Conclusion: Among PBT CTs, most were phase II trials, with a very few being phase III CTs. Funding of PBT CTs originating from industry or the NIH is limited. Recently, there has been a declining trajectory of newly initiated PBT trials. It is not yet clear whether this represents a true trend or just a pause in CT implementation. Despite multiple impediments to PBT CTs, the particle therapy community continues to work toward evidence generation.

Three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) are both utilized in rectal cancer treatment. We investigated the impact of demographic and clinical factors for the selection of each modality utilizing the National Cancer Database. Adult patients with stage II and stage III adenocarcinoma of the rectum diagnosed from 2004 to 2013 were included. Chi-squared analysis was used to compare demographic and clinical variables in the 3DCRT and IMRT treatment groups. Univariate and multivariate logistic regression modeling was used to identify factors predictive of receipt of each radiation therapy (RT) modality. A total of 9027 patients were identified: 8141 in the neoadjuvant RT group and 886 in the adjuvant RT group. In both cohorts, the utilization of IMRT increased over the study period (p 5400 centigray (cGy) (OR 2.07, 95 % CI 1.69–2.53). The use of IMRT for locally advanced rectal cancer is increasing and surpassed 3DCRT as the most common radiation modality at the beginning of 2010. Intensity-modulated radiotherapy was given more commonly for adjuvant treatment than for neoadjuvant treatment and was associated with higher RT doses and treatment at an academic institution in the neoadjuvant setting.

We aimed to evaluate if use of brachytherapy (BT) is associated with improved survival in patients with oral cavity cancer who do not receive surgery and to analyze patterns of care.We queried the Surveillance, Epidemiology, and End Results database for patients who received radiation therapy for squamous cell carcinoma of the oral cavity between 1973 and 2012. Patients were grouped by treatment modality: external beam radiotherapy alone vs. external beam radiotherapy + BT. Surgical patients were excluded. Trends in BT utilization over the study period and patterns of care were analyzed. Propensity scores were generated, and a nearest-neighbor matching algorithm was used to balance the 2 groups. Cox regression modeling was used to estimate the effect of BT on overall survival. Sensitivity analysis was conducted to estimate the effect of unmeasured confounders on the analysis.Of 5,161 patients with squamous cell carcinoma of the oral cavity who received radiotherapy, 12% of patients received BT. The rate of BT use has decreased by 0.58% per year (p 0.001). Factors that predicted for omission of radiation therapy included age ≥ 65 years (adjusted odds ratio [aOR], 0.56; p0.001), regional nodal disease (aOR, 0.57; p0.001), and black race (aOR, 0.45; p0.001). Use of BT was associated with a decreased risk of death (hazard ratio, 0.75; p0.001).The use of BT is associated with improved survival in oral cavity tumors treated with definitive radiotherapy. Rates of BT utilization have declined by 0.58% per year and are currently very low.

Background: Extrahepatic cholangiocarcinoma (EHC) is a rare malignancy with a relatively poor prognosis. There are no randomized, prospective data to help define the optimal method of radiation delivery for unresectable EHC. The purpose of this study was to evaluate the benefit of adding brachytherapy to external beam radiation therapy (EBRT) for unresectable EHC. Methods: A retrospective review of 1,326 patients with unresectable EHC using the Surveillance, Epidemiology, and End Results (SEER) database was completed. Kaplan-Meier methods were used to analyze the primary endpoint, overall survival. Univariate and multivariate analysis was performed to identify and control for potential confounding variables, including age at diagnosis, sex, stage, grade, histology, race, year of diagnosis, and reason for no surgery. Results: Of the 1,326 patients with unresectable EHC, 1,188 (92.9%) received EBRT only, while 91 (7.1%) received both EBRT and brachytherapy. Patients receiving combined modality radiation therapy were more likely to be treated prior to the year 2000. Median overall survival for patients receiving EBRT and EBRT plus brachytherapy was 9 and 11 months, respectively (P=0.04). Cause specific survival was 12 months for those receiving EBRT only, and 15 months for those who received EBRT + brachytherapy (P=0.10). Survival analysis performed on patients with locoregional disease only revealed a trend towards prolonged overall survival with those receiving EBRT + brachytherapy (P=0.08). Multivariate analysis revealed grade and stage of disease were correlated with both overall survival and cause specific survival (P≤0.05). Conclusions: Among patients with unresectable EHC, the addition of brachytherapy to EBRT is associated with a prolonged median overall survival. However, the use of brachytherapy boost decreased in the last decade of the study.

Prospective, randomized data does not exist to guide treatment in primary vaginal cancer (PVC). We evaluated the impact of brachytherapy on survival in women with PVC.Women who received radiotherapy for PVC were identified using the Surveillance, Epidemiology, and End Result database. Two retrospective cohorts were created; women who received external beam radiotherapy (EBRT) alone and those who received brachytherapy (alone or in combination of EBRT). Nearest-neighbor propensity score matching was used to balance the groups according to measured covariates. Cox proportional hazard regression modeling was used to estimate the effect of receipt of brachytherapy on survival.Two thousand five hundred seventeen vaginal cancer patients were identified. Squamous cell carcinoma made up 75% of tumors. Median overall survival (OS) for patients receiving EBRT alone was 3.6years (95% CI, 3.0-4.2years) versus 6.1years (95% CI 5.2-7.2years) for patients receiving brachytherapy (p=0.001). Cox proportional hazard model revealed decrease risk of death among patients that received brachytherapy in the matched cohort (HR 0.77; 95% CI 0.68-0.86). Brachytherapy reduced risk of death among patients in all stage groups. No patient demographic or tumor variables favored the use of EBRT alone. Brachytherapy was associated with a decreased risk of death for all FIGO stages. Brachytherapy benefited patients with squamous cell carcinoma (HR 0.80; 95% CI 0.70-0.92) and adenocarcinoma (HR 0.69; 95% CI 0.49-0.95). Tumors larger than 5cm had the greatest benefit from brachytherapy (HR 0.68; 95% CI 0.50-0.91).Brachytherapy should be encouraged for all suitable patients with PVC.

Using a large national registry, we investigated patterns of care and overall survival (OS) for metastatic rectal cancer patients treated with chemotherapy or radiotherapy (RT), or with a multimodal approach.Adult patients with metastatic rectal cancer who did not undergo resection diagnosed from 2004 to 2014 were included. Kaplan-Meier, log-rank, and Cox regression analyses were performed.We identified 2385 patients. Of these, 1020 patients (43%) received chemotherapy alone, 228 (10%) received RT alone, 850 (36%) received chemotherapy and RT, and 287 (12%) received no treatment. Receipt of chemotherapy alone increased over the study period, and receipt of chemoradiotherapy decreased (P .01). The only factor predictive of receiving any RT on multivariate analysis was clinical stage T3 disease. Factors predictive of OS on multivariate analysis included receipt of chemotherapy, Hispanic race, income greater than $46,000, and presence of lung metastasis. The OS for patients treated with chemotherapy and RT was not significantly different than chemotherapy alone. Five-year OS with chemotherapy alone, RT alone, chemoradiotherapy, and no treatment were, respectively, 84%, 56%, 79%, and 46%.Metastatic rectal cancer patients with T3 tumors were more likely to receive RT. Local RT does not improve survival for patients with metastatic rectal cancer who do not also undergo surgery. The use of chemotherapy alone for metastatic rectal cancer is increasing, and chemotherapy is associated with higher OS compared to no treatment and RT alone. This remained true even in patients older than 80 years.

To evaluate clinically significant radiotherapy (RT) dose to draining lymph nodes (LN) in patients treated with SBRT.Early stage non-small cell lung cancer patients treated with SBRT were selected for analysis. Patients received SBRT if they were not considered eligible for surgical resection. RT plans for 29 patients (32 lesions) were analyzed. For each patient, ipsilateral and contralateral levels 2, 3, 4, 5, 6, 7 and ipsilateral hilar LN stations were contoured. Dose volume histograms and dosimetric coverage of each lymph node region were obtained for each patient. There were 14 males and 15 females. Median age was 75 (range 60-89). Clinically significant RT was received at the corresponding draining lymph node station depending on the primary tumor location. Friedman's non-parametric test revealed a statistically significant difference in RT dose to LN stations depending on the location of the tumor (p0.0001).SBRT for early stage lung cancer results in significant RT dose to the draining LN. This RT dose may be sufficient to eliminate subclinical microscopic disease despite being a highly conformal treatment. Prospective studies are needed to evaluate if SBRT is comparable to lobectomy plus mediastinal lymph node dissection as a treatment option.

The purpose of the study was to determine predictors of recurrence for patients treated with neoadjuvant chemotherapy (NAC) and mastectomy according to the use of postmastectomy radiation therapy (PMRT).An analysis of 161 clinically staged T1 to T3/N0 to N3 patients treated with NAC and mastectomy with and without PMRT at our institution from 2003 to 2010 was conducted. The Kaplan-Meier product limit method was used to estimate survival and time to recurrence rates and the log-rank test was used to compare groups. A Cox proportional hazard regression analysis was carried out for time to recurrence, radiation therapy, and their interaction in the model.The median follow-up period was 48 months and 18 patients developed a recurrence. The 5-year recurrence rate and overall survival was 16.1% (95% confidence interval [CI], 9.6%-26.3%) and 93.6% (95% CI, 88.2%-97.0%), respectively. Patients who underwent PMRT had a decreased risk of recurrence compared with patients who did not (hazard ratio [HR], 0.25; 95% CI, 0.097-0.661; P.005). The 5-year disease-free survival (DFS) rate for those who received PMRT was 91.3% (95% CI, 82.8%-95.7%) and 64.8% (95% CI, 37.8%-82.4%) for those who did not (P = .0126). Among all clinicopathologic factors examined, pathologic T stage (ypT) and pathological N stage (ypN) significantly correlated with the risk of recurrence (P.05). Patients with any pathological nodal disease had an increased risk of recurrence compared with patients who were pathologically node-negative (HR, 7.196; 95% CI, 2.05-25.264; P.002).Patients treated with NAC and mastectomy, but without PMRT had a higher risk recurrence with increasing ypT and ypN stages. PMRT might increase DFS.

Background: The outcomes, complications, and rates of secondary malignancies from radiation therapy (RT) are not known for patients with familial adenomatous polyposis (FAP). Methods: We queried the Hereditary Gastrointestinal Cancer Registry (HGCR) for patients with FAP who received RT. Outcomes assessed included acute and late treatment toxicity and secondary malignancies. Results: We identified 15 patients undergoing 18 treatment courses. Median follow-up was 3.1 years after RT. Treated sites included rectal cancer, desmoid, prostate cancer, breast cancer, melanoma, medulloblastoma, gastric cancer, and glioma. Secondary tumors occurred in two patients: a medulloblastoma was diagnosed in a patient treated for glioma, and a desmoid tumor was diagnosed in a patient treated for rectal cancer. All nine patients treated with intra-abdominal or pelvic RT had prior prophylactic proctocolectomies, yet only one patient experienced grade 3 gastrointestinal toxicity. Common Terminology Criteria for Adverse Events version 4 (CTCAE v4) toxicities were grade 1 in seven treatment courses (39%), grade 2 in five courses (28%), and grade 3 in two courses (11%). Conclusions: In this cohort, RT was well tolerated with adverse effects comparable with non-FAP patients. Secondary in-field tumors occurred in 2 of 15 patients and their increased risk in this cohort was likely due to prior predilection from FAP itself, although an increased role of RT cannot be ruled out.

BACKGROUND The available literature to guide treatment decision making in esthesioneuroblastoma (ENB) is limited. OBJECTIVE To define treatment patterns and outcomes in ENB according to treatment modality using a large national cancer registry. METHODS This study is a retrospective cohort analysis of 931 patients with a diagnosis of ENB who were treated with surgery, radiation therapy, and/or chemotherapy in the United States between the years of 2004 and 2012. Log-rank statistics were used to compare overall survival by primary treatment modality. Logistic regression modeling was used to identify predictors of receipt of postoperative radiotherapy (PORT). Cox proportional hazards modeling was used to determine the survival benefit of PORT. Subgroup analyses identified subgroups that derived the greatest benefit of PORT. RESULTS Primary surgery was the most common treatment modality (90%) and resulted in superior survival compared to radiation (P < .01) or chemotherapy (P < .01). On multivariate analysis, PORT was associated with decreased risk of death (hazard ratio [HR] 0.53, P < .01). PORT showed a survival benefit in Kadish stage C (HR 0.42, P < .01) and D (HR 0.09, P = .01), but not Kadish A (HR 1.17, P = .74) and B (HR 1.37, P = .80). Patients who received chemotherapy derived greater benefit from PORT (HR 0.22, P < .01) compared with those who did not (HR 0.68, P = .13). Predictors of PORT included stage, grade, extent of resection, and chemotherapy use. CONCLUSION Best outcomes were obtained in patients undergoing primary surgery. The benefit of PORT was driven by patients with stages C and D disease, and by those also receiving chemotherapy.

Elderly women with endometrial cancer are at increased risk of local recurrence and cancer-specific death compared to younger women. We sought to investigate adjuvant radiotherapy (RT) practice patterns and effects on survival in elderly women with endometrial cancer.Women from the National Cancer Data Base (NCDB) with FIGO IA grade 3 to FIGO IVA endometrial cancer diagnosed from 2004-2013 were included. Chi square analysis was used to compare the elderly (80+) and non-elderly women (18-79) and women who received RT and those that did not. Univariate and multivariate logistic regression were used to determine predictors of receipt of oncologic surgery and adjuvant RT. Univariate and multivariate Cox survival analyses were performed to examine the effect of radiotherapy on survival. Propensity score matching and shared frailty analysis were done in the elderly cohort.We identified 48,871 women for analysis. Rates of oncologic surgery were higher in the women 80+ compared with rates of adjuvant RT (95% versus 34%). Rates of RT receipt were higher in non-elderly women (48% versus 34%, p0.001). Age over 80 was a negative predictive factor (OR 0.62, p0.001) for receipt of adjuvant RT and oncologic surgery (OR 0.81, p=0.03). Adjuvant RT was associated with a decreased risk of death in elderly (HR 0.79, p0.001) and non-elderly women (HR 0.77, p0.001).Endometrial cancer patients over age 80 have similar rates of oncologic surgery as younger women but are significantly less likely to receive adjuvant RT, and this negatively impacts their survival.

Uterine carcinosarcoma (UCS) is a rare and aggressive cancer with poor survival. Our purpose was to evaluate the patterns-of-care and overall survival (OS) benefit of adjuvant chemoradiation (aCRT) compared with adjuvant chemotherapy (aCT) among UCS patients.A query was made in the National Cancer Database to identify patients with UCS diagnosed between 2004 and 2012. Factors predictive of OS were determined using univariate and multivariate Cox regression analysis, as well as Kaplan-Meier and log-rank analysis. Propensity-score matching was employed to decrease the potential influence of selection bias.A total of 3538 patients were identified for analysis, consisting of 1787 patients (50.5%) receiving aCT and 1751 (49.5%) receiving aCRT. The median age of patients was 65 years. The majority of patients in our cohort were white (68.6%), on Medicare insurance (47.9%), with5 cm tumor size (59.9%), and received a lymph node surgery (87.9%). The following factors were predictive of aCRT use: undergoing lymph node surgery (odds ratio, 1.59, P=0.01), and FIGO stage II (odds ratio, 1.71, P=0.01). Median survival for the aCT and aCRT groups was 24 months and 31.3 months, respectively. When compared with aCT alone, aCRT was associated with a benefit in OS on multivariate analysis (hazard ratio, 0.65, P0.01).When compared with aCT alone, the use of aCRT in UCS patients was associated with a significant OS benefit. Multiple demographic and clinical factors significantly influence the choice of adjuvant therapy in this setting.

The role of chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC) is uncertain after multiple randomized clinical trials have yielded mixed results. The authors used the National Cancer Data Base (NCDB) to determine whether CRT yields a survival benefit compared with chemotherapy alone (CT).Patients with nonmetastatic LAPC diagnosed during 2004 through 2014 were identified in the NCDB. Patients who received CT were compared with those who received CRT using chi-square analysis. Univariate and multivariate Cox regression analyses were used to compare demographic, clinical, and treatment characteristics that were predictive of survival. Propensity score matching and shared frailty analysis were done. Subgroup analyses were undertaken to examine patients who underwent pancreatectomy and cohorts of patients who received different CT or CRT regimens.In total, 8689 patients with LAPC were identified. CRT was associated with improved survival (median survival [MS], 13.5 months) compared with CT (MS, 10.6 months) on multivariate analysis (hazard ratio [HR], 0.80; P.001). Induction chemotherapy before CRT (HR, 0.67; P.001) and multiagent chemotherapy (HR, 0.72; P.001) were also identified as independent predictors of survival compared with concurrent CRT and single-agent CT, respectively. Patients in the CRT group who received multiagent induction chemotherapy had superior MS and pancreatectomy rates (MS, 17.5 months; HR, 0.70; P.001; pancreatectomy rate, 10%) compared with those who received multiagent CT alone (MS, 12.4 months; pancreatectomy rate, 3.3%). Patients who underwent pancreatectomy experienced improved survival (MS, 22 vs 10.6 months; HR, 0.39; P.001).In this NCDB analysis, maximizing systemic chemotherapy before CRT improved survival compared with CT alone in patients with LAPC. Continued analysis of CRT in properly selected patients after maximized systemic therapy is needed. Cancer 2017;123:3816-24. © 2017 American Cancer Society.

To examine a relationship between serum transforming growth factor β -1 (TGF-β1) values and radiation-induced fibrosis (RIF).We conducted a prospective analysis of the development of RIF in 39 women with American Joint Committee on Cancer stage 0-I breast cancer treated with lumpectomy and accelerated partial breast irradiation via intracavitary brachytherapy (IBAPBI). An enzyme-linked immunoassay (Quantikine, RD, Minneapolis, MN) was used to measure serum TGF-β1 before surgery, before IBAPBI, and during IBAPBI. Blood samples for TGF-β1 were also collected from 15 healthy, nontreated women (controls). The previously validated tissue compliance meter (TCM) was used to objectively assess RIF.The median time to follow-up for 39 patients was 44 months (range, 5-59 months). RIF was graded by the TCM scale as 0, 1, 2, and 3 in 5 of 20 patients (25%), 6 of 20 patients (30%), 5 of 20 patients (25%), and 4 of 20 patients (20%), respectively. The mean serum TGF-β1 values were significantly higher in patients before surgery than in disease-free controls, as follows: all cancer patients (30,201 ± 5889 pg/mL, P=.02); patients with any type of RIF (32,273 ± 5016 pg/mL, P.0001); and women with moderate to severe RIF (34,462 ± 4713 pg/mL, P0.0001). Patients with moderate to severe RIF had significantly elevated TGF-β1 levels when compared with those with none to mild RIF before surgery (P=.0014) during IBAPBI (P≤0001), and the elevation persisted at 6 months (P≤.001), 12 months (P≤.001), 18 months (P≤.001), and 24 months (P=.12). A receiver operating characteristic (ROC) curve of TGF-β1 values predicting moderate to severe RIF was generated with an area under the curve (AUC)ROC of 0.867 (95% confidence interval 0.700-1.000). The TGF-β1 threshold cutoff was determined to be 31,000 pg/mL, with associated sensitivity and specificity of 77.8% and 90.0%, respectively.TGF-β1 levels correlate with the development of moderate to severe RIF. The pre-IBAPBI mean TGF-β1 levels can serve as an early biomarker for the development of moderate to severe RIF after IBAPBI.

Background. Cerebral radiation necrosis (RN) is a difficult to treat complication of stereotactic radiosurgery (SRS) that can result in progressive neurologic decline. Currently, steroids are the standard of care treatment for brain RN despite their adverse effect profile and limitedefficacy.Thepurposeofthisstudywastoevaluate the treatment efficacy of cerebral RN to bevacizumab in patients with brain metastases previously treated with SRS. Methods. We retrospectively reviewed 14 lesions in 11 patients treated with bevacizumab for brain RN secondary to SRS for their brain metastases. Steroid dosing, RN-associated symptoms, and magnetic resonance imaging (MRI) scans were examined before, during, and after bevacizumab administration. Results. Of the 11 patients included, 6 had metastatic non‐small cell lung cancer, and 5 had metastatic breast cancer. The mean percentage decrease in RN volume seen on T1 post-Gadolinium and fluid-attenuated inversion recovery (FLAIR) MRI at first follow-up, at a mean of 26 days (range, 15‐43 days), was 64.4% and 64.3%, respectively. MRI changes were sustained on follow-up MRI scans, obtained at a mean of 33 days (range, 7‐58 days)afterbevacizumabdiscontinuation.Afterbevacizumabtreatment,allpatientsinitiallyreceivingsteroidshad areductioninsteroidrequirement, andallbutone hadan improvement in or stability of RN-associated symptoms. No patients experienced intratumoral bleeds or other adverse effects related to their bevacizumab treatment. Conclusions. Bevacizumab is effective and safe for the treatment of RN after SRS for brain metastasis. In this context, bevacizumab offers symptomatic relief, a reduction in steroid requirement, and a dramatic radiographic response.

Clinical trials (CTs) involving brachytherapy (BT) are crucial in establishing the role of BT in the evolving landscape of cancer treatment. An analysis of BT trials is warranted to understand the factors driving their success and the future direction of the field.We queried the clinicaltrials.gov website using the search terms: Radiation Therapy, Brachytherapy, and associated terms. This yielded 10,417 CTs between 2000 and 2015. Trials not using BT were excluded; yielding 319 CTs. Characteristics of individual CTs were obtained. Least squared linear regression, χThe majority of the CTs were phase II (37%), involving interstitial BT (45%), and treating the prostate (36%). Nongovernmental institutions (NGIs) have funded the greatest number of CTs. New CTs involving radiotherapy of all types showed increase over time (p0.05), whereas no corresponding increase was seen in BT trials. New BT trials independently funded by industry have declined (p = 0.01). Collaboration between industry and NGIs was associated with greater likelihood of trial completion. Industry funding was associated with Phase IV trials, usage of surface BT, among others. NIH/government funding was associated with Phase I trials, intracavitary BT, trials focused on systemic therapy, among others.Trials examining radiotherapy have increased, whereas trials incorporating BT have remained unchanged. Collaboration between industry and NGIs was associated with a greater likelihood for successful trial completion. The role of BT can be better realized with greater incorporation into CTs.

Zyxin is an adhesion protein that regulates actin assembly by binding to VASP family members through N-terminal proline-rich motifs. Evidence suggests that zyxin’s C-terminal LIM domains function as a negative regulator of zyxin–VASP complexes. Zyxin LIM domains access to binding partners is negatively regulated by an unknown mechanism. One possibility is that zyxin LIM domains mediate a head–tail interaction, blocking interactions with other proteins. Such a mechanism might prevent both zyxin–VASP complexes activity and LIM domain access. In this report, the effect of LIM domains on zyxin–VASP complex assembly is defined. We find that zyxin LIM domains associate with zyxin’s VASP binding sites, preventing zyxin from binding to PKA-phosphorylated VASP. Unphosphorylated VASP overcomes the head–tail interaction, a result of a direct interaction with the LIM domain region. Zyxin, like a growing number of actin regulators, is controlled by intramolecular interactions.

To evaluate the risk of heart disease related death (HDRD) following radiation therapy (RT) for esophageal cancer (EC).Using the Surveillance, Epidemiology, and End Results (SEER) database, two cohorts of patients with EC were created: (I) patients who received RT with their initial therapy; and (II) those who did not. Heart disease specific survival (HDSS) was analyzed using Kaplan-Meier methods. Cox proportional-hazards regression methods were used for univariate and multivariate analyses.We identified 40,778 patients with EC. A total of 26,377 patients received RT and 14,401 did not. HDSS analysis revealed increased risk of HDRD in those receiving RT (P0.05), with an absolute risk of HDRD of 2.8%, 5.3% and 9.4% at 5-, 10- and 20-year, respectively. Log rank test of HDSS revealed the risk of HDRD became significant at 8 months (P0.05). The following were associated with HDRD: RT, age, race, stage at presentation, time period of diagnosis, and known comorbid condition keeping one from esophagectomy. On multivariate analysis, RT remained predictive of HDRD [hazard ratio (HR) 1.46, P0.05]. When considering only candidates for definitive therapy, RT remained predictive of HDRD on univariate (HR 1.53, P0.0001) and multivariate (HR 1.62, P0.0001) analyses.The use of RT leads to increased risk of HDRD that is detectable as early as eight months from diagnosis. More research is needed to define optimal dose volume parameters to prevent cardiac death. Consideration should be given to this risk in relation to prognosis and the expected benefits of RT.

686 Background: Neoadjuvant chemoradiotherapy (NCRT) is generally accepted as the optimal treatment strategy compared to adjuvant chemoradiotherapy (ACRT) for locally advanced rectal cancer due to improvement in local control and reduced toxicity. However, NCRT has not been shown to improve overall survival (OS). We investigated the effect of NCRT versus ACRT on OS as well as the impact of demographic factors and clinical stage for the selection of each treatment approach utilizing the National Cancer Data Base. Methods: Adult patients with stage II and stage III adenocarcinoma of the rectum diagnosed from 2004-2013 were included. Chi-square analysis was used to compare demographic variables and clinical stage between the NCRT and ACRT treatment groups. Univariate and multivariate logistic regression modeling was used to identify factors predictive of each treatment strategy. Kaplan Meier and log-rank analysis along with propensity score matching was performed to determine the effect on OS. Results: A total of 20,262 patients were identified: 17,737 (87.5%) received NCRT and 2,525 (12.5%) received ACRT. Utilization of NCRT increased over the study period (p < 0.01). Factors associated with receipt of NCRT on multivariate analysis include: treatment at an academic institution (OR 0.76, 95% CI 0.68-0.85), income greater than $46,000 (OR 0.79, 95% CI 0.67-0.92), and living greater than 50 miles from a treatment facility. Factors associated with receipt of ACRT on multivariate analysis include: female sex (OR 1.12, 95% CI 1.01-1.24), Charlson comorbidity index of 1 (OR 1.18, 95% CI 1.04-1.34), and radiotherapy dose greater than 5040 centigray (OR 1.76, 95% CI 1.56-1.98). Compared to ACRT, NCRT was associated with a decreased risk of death on multivariate analysis (HR 0.91, 95% CI 0.84-1.00), which persisted after propensity score analysis. Conclusions: The use of NCRT for locally advanced rectal cancer is increasing and is associated with an OS benefit compared to ACRT.

To evaluate the tolerability and toxicity of administering vaginal brachytherapy (VB) concurrently during chemotherapy compared with the sequential approach for patients with endometrial cancer.A retrospective analysis of 372 surgically staged patients with endometrial cancer American Joint Committee on Cancer 2009 stages I to IV treated with adjuvant postoperative radiation therapy (RT) at our institution from 2001 to 2012 was conducted. All patients received VB+external beam RT (EBRT)+6 cycles of adjuvant carboplatin- and paclitaxel-based chemotherapy. The VB mean dose was 15.08 Gy (range, 15-20 Gy), with 3 to 4 weekly applications, and the EBRT mean dose was 45 Gy delivered with 3-dimensional or intensity modulated RT techniques. Hematologic, gastrointestinal (GI), and genitourinary (GU) toxicities were assessed by Common Toxicity Criteria (CTC) and compared between sequential and concurrent chemotherapy and VB schedules.Among patients who received RT and adjuvant chemotherapy, 180 of 372 patients (48%) received RT sandwiched between cycles 3 and 4 of chemotherapy. A separate group of 192 patients (52%) were treated with VB during the first 3 cycles of chemotherapy, with a weekly application on nonchemotherapy days, and received the EBRT portion in a sandwiched fashion. Patients treated with VB during chemotherapy had a decreased overall treatment time by 4 weeks (P.001; 95% confidence interval: 3.99-4.02) and sustained no difference in CTC-graded acute hematologic, GI, or GU toxicities in comparison with the patients treated with VB and chemotherapy in a sequential manner (P.05). CTC grade 3 or 4 hematologic, GI, and GU toxicities were zero.VB during chemotherapy is well tolerated, decreases overall treatment time, and does not render more toxicity than the sequential regimen.

Celiac disease (CD) is a unique autoimmune disorder in which the genetic factors (DQ2/DQ8) and the environmental trigger (gluten) are known and necessary but not sufficient for its development. Other environmental components contributing to CD are poorly understood. Studies suggest that aspects of gluten intake might influence the risk of CD occurrence and timing of its onset, i.e., the amount and quality of ingested gluten, together with the pattern of infant feeding and the age at which gluten is introduced in the diet. In this study, we hypothesize that the intestinal microbiota as a whole rather than specific infections dictates the switch from tolerance to immune response in genetically susceptible individuals. Using a sample of infants genetically at risk of CD, we characterized the longitudinal changes in the microbial communities that colonize infants from birth to 24 months and the impact of two patterns of gluten introduction (early vs. late) on the gut microbiota and metabolome, and the switch from gluten tolerance to immune response, including onset of CD autoimmunity. We show that infants genetically susceptible to CD who are exposed to gluten early mount an immune response against gluten and develop CD autoimmunity more frequently than at-risk infants in which gluten exposure is delayed until 12 months of age. The data, while derived from a relatively small number of subjects, suggest differences between the developing microbiota of infants with genetic predisposition for CD and the microbiota from infants with a non-selected genetic background, with an overall lack of bacteria of the phylum Bacteriodetes along with a high abundance of Firmicutes and microbiota that do not resemble that of adults even at 2 years of age. Furthermore, metabolomics analysis reveals potential biomarkers for the prediction of CD. This study constitutes a definite proof-of-principle that these combined genomic and metabolomic approaches will be key to deciphering the role of the gut microbiota on CD onset.