The impact of socioeconomic and geographic factors on access to transoral robotic/endoscopic surgery for early stage oropharyngeal malignancy.

OBJECTIVE: To evaluate the role of social and geographic factors on the likelihood of receiving transoral robotic surgery (TORS) or non-robotic transoral endoscopic surgery treatment in early stage oropharyngeal squamous cell carcinoma (OPSCC). MATERIALS AND METHODS: The National Cancer Database was queried to form a cohort of patients with T1-T2 N0-N1 M0 OPSCC (AJCC v.7) who underwent treatment from 2010 to 2016. Demographics, tumor characteristics, treatment type, social, and geographic factors were all collected. Univariate analysis and multivariate logistic regression were then performed. RESULTS: Among 9267 identified patients, 1774 (19.1%) received transoral robotic surgery (TORS), 1191 (12.9%) received transoral endoscopic surgery, and 6302 (68%) received radiation therapy. We found that lower cancer stage, lower comorbidity burden and HPV- positive status predicted a statistically significant increased likelihood of receiving surgery. Patients who reside in suburban or small urban areas (>1 million population), were low-to- middle income, or rely on Medicaid were less likely to receive surgery. Patients that reside in Medicaid-expansion states were more likely to receive TORS (p > .0001). Patients that reside in states that expanded Medicaid January 2014 and after were more likely to receive non-robotic transoral endoscopic surgery (p > .0001). CONCLUSIONS: Poorer baseline health, lower socioeconomic status and residence in small urban areas may act as barriers to accessing minimally invasive transoral surgery while residence in a Medicaid-expansion state may improve access. Barriers to accessing robotic surgery may be greater than accessing non-robotic surgery.

Predictive Capacity of 3 Comorbidity Indices in Estimating Survival Endpoints in Women With Early-Stage Endometrial Carcinoma.

OBJECTIVE: The negative impact of comorbidity on survival in women with endometrial carcinoma (EC) is well-known. Few validated comorbidity indices are available for clinical use, such as the Charlson Comorbidity Index (CCI), the Age-Adjusted CCI (AACCI), and the Adult Comorbidity Evaluation-27 (ACE-27). The aim of the study is to determine which index best correlates with survival endpoints in women with EC. MATERIALS AND METHODS: We identified 1132 women with early-stage EC treated at an academic center. Three scores were calculated for each patient using CCI, AACCI, and ACE-27 at the time of hysterectomy. Univariate and multivariable modeling was used to determine predictors of survival. RESULTS: For each of the studied comorbidity indices, the highest scores were significantly correlated with poorer overall survival. The hazard ratio of death from any cause was 3.92 for AACCI, 2.25 for CCI, and 1.57 for ACE-27. All 3 indices were independent predictors of overall survival with a P value of less than 0.001 on multivariate analysis. In addition, lymphovascular space invasion, lower uterine segment involvement, and tumor grade were predictors of overall survival. Lymphovascular space invasion, grade (P < 0.001), and high AACCI score were the only significant predictors of recurrence-free survival (RFS). Lymphovascular space invasion and tumor grade were the only 2 predictors of disease-specific survival. CONCLUSIONS: Although all 3 studied comorbidity indices were significant predictors of overall survival in women with early-stage EC, AACCI showed a stronger association. It should be considered for evaluating comorbidity in women with early-stage EC.

Key factors for establishing and sustaining a successful palliative radiation oncology program: a survey of the Society for Palliative Radiation Oncology.

BACKGROUND: Dedicated palliative radiation oncology programs (PROPs) within radiation oncology (RO) practices have been shown to improve quality and decrease costs of radiation therapy (RT) in advanced cancer patients. Despite this, relatively few PROPs currently exist, highlighting an unmet need to understand characteristics of the few existing PROPs and the potential barriers and facilitators that exist in starting and maintaining a successful PROP. We sought to assess the attributes of existing PROPs, the facilitators and barriers to establishing these programs, and the resources needed to create and maintain a successful program. METHODS: A 15-item online survey was sent to 157 members of the Society of Palliative Radiation Oncology (SPRO) in July 2019. RESULTS: Of the 157 members, 48 (31%) responded. Most practiced in an academic center (71% at main center and 15% at satellite) and 75% were from a larger group practice (≥6 physicians). Most (89%) believed the development and growth of a dedicated PROPs was either important (50%) or most important (39%) to the field of RO. Only 36% of respondents had a PROP, 38% wanted to establish one, and 13% were currently developing one. Of those with PROPs (N=16), 75% perceived an increase in the number of referrals for palliative RT since starting the program. A majority had an ability to refer to an outside palliative care specialist (64%), an outpatient RO service (53%), and specialized clinical processes for managing palliative radiotherapy patients (53%), with 41% having an inpatient RO consult service. Resources considered most essential were access to specialist-level palliative care, advanced practice provider support, a radiation oncologist with an interest in palliative care, having an outpatient palliative RO clinic, an emphasis on administering short radiation courses, and opportunities for educational development. Of those with a PROP or those who have tried to start one, the greatest perceived barriers to initiating a PROP were committed resources (83%), blocked out clinical time (61%), challenges coordinating management of patients (61%), and support from leaders/colleagues (61%). Perceived barriers to sustaining a PROP were similar. For those without a PROP, the perceived most important resources for starting one included access to palliative care specialist by referral (83%), published guidelines with best practices (80%), educational materials for referring physicians and patients (80%), educational sessions for clinical staff (83%), and standardized clinical pathways (80%). CONCLUSIONS: PROPs are not widespread, exist mainly within academic centers, are outpatient, have access to palliative care specialists by referral, and have specialized clinical processes for palliative radiation patients. Lack of committed resources was the single most important perceived barrier for initiating or maintaining a PROP. Best practice guidelines, educational resources, access to palliative care specialists and standardized pathways are most important for those who wish to develop a PROP. These insights can inform discussions and help align resources to develop, grow, and maintain a successful PROP.

Impact of age-adjusted Charlson comorbidity score on outcomes for patients with early-stage endometrial cancer.

OBJECTIVES: To determine the impact of Age-Adjusted Charlson Comorbidity (AAC) index score on survival outcomes for patients with early stage endometrial cancer. METHODS: After IRB-approval, AAC score at time of hysterectomy was retrospectively tabulated by physician chart review for 671 patients with 2009 FIGO stage I-II endometrioid adenocarcinoma. Patients were grouped based on their AAC scores as follows: 0-1 (n=204), 2-3 (n=293) and >3 (n=174). Kaplan-Meier and log-rank test methods and univariate and multivariate modeling with Cox regression analysis was used to determine significant predictors of each survival endpoint. RESULTS: After a median follow-up of 85 months, 225 deaths were recorded (34 from EC and 191 from other causes) with a 7-year Overall (OS) and Disease-specific survival (DSS) of 77.6% and 94.0%, respectively. Based on AAC grouping, the 7-year OS, DSS, and Recurrence-free survival (RFS) were: 92.9%, 96.8%, and 94.9% for AAC 0-1; 81.7%, 95.3%, and 89.8% for AAC 2-3: and 56%, 88.2%, and 84.9% for AAC>3 (p<0.0001, p=0.005 and p=0.013, respectively). On multivariate analyses, higher AAC score, tumor grade, lower uterine segment involvement, and lymphovascular space invasion were significantly independent predictors for shorter OS, while for DSS and RFS, higher tumor grade and lymphovascular space invasion were significant predictors of worse outcome, but higher AAC score was not. CONCLUSIONS: Comorbidity score is as important as pathological features for predicting overall survival outcomes in patients with early-stage endometrioid endometrial carcinoma. Higher AAC scores accurately predicted for worse OS. Comorbidity score should be considered in prospective clinical trials of endometrial carcinoma.

The impact of race on outcomes of patients with early stage uterine endometrioid carcinoma.

OBJECTIVES: The purpose of the present study was to determine whether racial disparity exists between African American (AA) and non-African American (NAA) patients with uterine endometrioid carcinoma who received similar multidisciplinary management. METHODS: We identified 766 patients with endometrioid adenocarcinoma 2009 FIGO stages I-II who underwent hysterectomy. Patients were divided into two groups; AA and NAA. Recurrence-free survival (RFS), disease specific survival (DSS) and overall survival (OS) for two groups were calculated. RESULTS: Median follow-up was 5.1 years. 27% were AA and 73% were NAA. All patients underwent hysterectomy and oophorectomy. 80% had peritoneal cytology examination and 69% underwent lymphadenectomy. AA patients were more likely to have higher grade tumors, and higher incidence of lymphovascular space involvement (LVSI). Although the two groups were balanced with regards to surgical staging and adjuvant treatment received, the 5-year RFS and DSS were significantly lower in AA compared to NAA patients (91% vs 84%, p=0.030; 95% vs 88%, p=0.011, respectively). Overall survival was not significantly different between the two groups. On multivariate analysis, after adjusting for other prognostic factors, race (AA vs NAA) was not a significant predictor of outcome. Grade 3 tumors and the presence of LVSI were the only two independent predictors of RFS and DSS with p ≤ 0.001 and p ≤ 0.001, respectively. CONCLUSION: In this large hospital-based study, AA race was associated with a higher incidence of adverse pathological features and worse recurrence-free and disease-specific survival. However, on multivariate analysis race was not an independent prognostic factor. Further studies are needed to elucidate possible underlying molecular mechanisms for these poorer outcomes.

Adjuvant radiation therapy for patients with type II endometrial carcinoma: impact on tumor recurrence and survival.

PURPOSE/OBJECTIVE: The optimal adjuvant treatment of type II endometrial carcinoma after hysterectomy remains controversial. The objective of this study was to determine the effect of adjuvant radiation therapy (RT) on recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival in patients with early-stage type II endometrial carcinoma. MATERIALS AND METHODS: In this institutional review board-approved study, our database of 1450 patients with endometrial cancer was reviewed. Seventy-nine surgically staged patients with 2009 International Federation of Gynecology and Obstetrics (FIGO) stages I and II serous and clear cell carcinoma were treated from 1991 to 2010. These patients were then divided into 2 groups; one group received adjuvant RT, and the other group included patients who did not receive adjuvant RT. RESULTS: The median age of the study cohort is 65 years, and the median follow-up is 47 months. Thirty-nine patients (49%) received adjuvant RT, and 40 patients did not. The 5-year RFS was significantly improved in patients who received RT (84% vs 58%; P = 0.002). Similarly, 5-year DSS was significantly improved in patients who received RT (87% vs 58%; P = 0.023) with a trend toward improved 5-year overall survival (74% vs 58%; P = 0.088). On multivariate analysis, lack of angiolymphatic invasion (P < 0.001 and P < 0.001), adjuvant RT (P < 0.001 and P = 0.004), and lack of lower uterine segment involvement (P = 0.007 and P = 0.009) were independent predictors of improved RFS and DSS, respectively. CONCLUSIONS: In the current study of surgically staged patients with type II endometrial carcinoma International Federation of Gynecology and Obstetrics stages I and II, adjuvant radiation therapy with or without chemotherapy resulted in a significant improvement in recurrence-free and disease-specific survival.

Phase 1 Randomized Trial of Stereotactic Body Radiation Therapy Followed by Nivolumab plus Ipilimumab or Nivolumab Alone in Advanced/Unresectable Hepatocellular Carcinoma.

PURPOSE: Immunotherapy has emerged as a promising therapeutic option for advanced or unresectable hepatocellular carcinoma (HCC). However, survival remains poor with only a subset of patients deriving benefit. This trial investigated the safety and efficacy of stereotactic body radiation therapy (SBRT) with immunotherapy in HCC. METHODS AND MATERIALS: In this multicenter phase 1 randomized trial, patients with advanced or unresectable HCC received liver SBRT (40 Gy in 5 fractions) followed by either nivolumab alone or nivolumab plus ipilimumab. The primary endpoint was dose-limiting toxicity occurring within 6 months of SBRT. Secondary endpoints included overall response rate, progression-free survival, overall survival (OS), distant disease control, and local control of the irradiated tumor. Disease status and response endpoints were assessed radiographically every 8 weeks until progression or initiation of nonprotocol therapy. Response was determined using both RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 and iRECIST. RESULTS: Fourteen patients were enrolled across 3 centers. Thirteen patients were evaluated for study endpoints. The study was closed early because of slow accrual. The median follow-up time was 42.7 months. Dose-limiting toxicities within 6 months occurred in 2 (15.4%) of 13 patients: 1 of 6 patients in the nivolumab arm (16.7%; 90% confidence interval [CI], 0.9%-58.2%) and 1 of 7 patients in the nivolumab plus ipilimumab arm (14.3%; 90% CI, 0.7%-52.1%). Grade 3 adverse events occurred in 8 (61.6%), 5 (71.4%), and 3 (50.0%) patients in the overall nivolumab plus ipilimumab and nivolumab cohorts. Grade 3 hepatotoxicity occurred in 4 (30.8%), 3 (42.9%), and 1 (16.7%) patients in the respective cohorts. Clinical outcomes favored the nivolumab plus ipilimumab arm compared with nivolumab alone, including an overall response rate of 57% (4 of 7 patients; 90% CI, 23%-87%) versus 0% (0 of 6 patients; 90% CI, 0%-39%), median progression-free survival of 11.6 months (90% CI, 4.5 months to not reached) versus 2.7 months (90% CI, 1.3-4.7 months), and median OS of 41.6 months (90% CI, 4.5 months to not reached) versus 4.7 months (90% CI, 2.0-16.2 months) (all P < .05). With combination immunotherapy, 3-year OS was 57% (90% CI, 23%-81%), with 2 patients alive after 42.7 months without progression and negative PET. CONCLUSIONS: In this first prospective trial investigating the combination of SBRT and immunotherapy for HCC, multimodal therapy demonstrated acceptable safety. SBRT with nivolumab plus ipilimumab compared favorably to outcomes of immunotherapy alone and warrants further investigation.

Is time to recurrence after hysterectomy predictive of survival in patients with early stage endometrial carcinoma?

PURPOSE/OBJECTIVE(S): To determine the prognostic significance of time to recurrence (TTR) on overall survival (OS) and disease-specific survival (DSS) following recurrence in patients with stage I-II uterine endometrioid carcinoma. MATERIALS/METHODS: After IRB approval, we retrospectively identified 57 patients with recurrent endometrioid carcinoma who were initially treated for FIGO 1988 stages I-II between 1987 and 2009. The Kaplan-Meier approach and Cox regression analysis were used to estimate OS and DSS following recurrence and identify factors impacting outcomes. RESULTS: Median follow-up times were 54.8 months from hysterectomy and 19.8 months after recurrence. Median time to recurrence was 20.2 months. Twenty-eight (47%) patients had a recurrence<18 months after hysterectomy and 29 (53%) had a recurrence≥18 months. Both groups were evenly matched regarding initial pathological features and adjuvant treatments. The median OS and DSS in patients with TTR<18 months was shorter than those with TTR≥18 months, but not statistically significant (p=0.216). TTR did not impact outcomes after loco-regional recurrence, but for extrapelvic recurrence, a shorter TTR resulted in worse OS and DSS (p=0.03). On multivariate analysis, isolated loco-regional recurrence (HR 0.28, p=0.001) and salvage radiation therapy (HR 0.47, p=0.045) were statistically significant independent predictors of longer OS following recurrence. TTR as a continuous variable or dichotomized was not predictive of OS or DSS. CONCLUSIONS: In our study, the prognostic impact of time to recurrence was less important than the site of recurrence. While not prognostic for the entire cohort or for patients with loco-regional recurrence, TTR<18 months was associated with shorter OS and DSS after extrapelvic recurrence.

Palliative radiation for bone metastases from hepatocellular carcinoma: practice patterns and the amount of remaining life spent receiving treatment.

BACKGROUND: Palliative radiation therapy (RT) for bone metastases (BMs) is a common practice. Wide variation exists in clinically used dose schema despite numerous studies demonstrating palliative equipoise between single and multifraction courses. We hypothesize that fraction scheme for palliating BMs for hepatocellular carcinoma (HCC) significantly affects how patients spend their remaining time. METHODS: Patients with osseous HCC metastases who received RT were identified from the National Cancer Database [2004-2013]. The percentage of remaining life spent receiving radiation therapy (PRLSRT) and the number of incomplete RT courses were calculated. Kaplan-Meier analysis and Cox proportional hazards models were used to evaluate trends and predictors. RESULTS: A total of 1,331 patients met the inclusion criteria. Median overall survival (OS) was 3.3 months. Just 49 (3.7%) of patients received single fraction RT and 34% received >10 fractions. The mean and median PRLSRT were as follows: 1 fraction (8.9% and 3.0%), 2-5 fractions (32.9% and 24.3%), 6-10 fractions (27.2% and 15.9%), and >10 fractions (24.1% and 14.4%). Of the patients with PRLSRT >50%, 99.6% received multifraction RT. The proportion of incomplete RT courses increased as fraction size decreased from 17.6% with 4 Gy to 34% with 2 Gy. CONCLUSIONS: Single fraction palliative RT is vastly underutilized despite no additional palliative benefit with multifraction RT. PRLSRT significantly increased with multifraction RT. In the palliative treatment of painful BMs from HCC, single fraction treatment reduces time spent receiving radiation treatments and maximizes the number of patients who complete the prescribed treatment.

Retreatment of Recurrent or Second Primary Head and Neck Cancer After Prior Radiation: Executive Summary of the American Radium Society Appropriate Use Criteria.

Retreatment of recurrent or second primary head and neck cancers occurring in a previously irradiated field is complex. Few guidelines exist to support practice. We performed an updated literature search of peer-reviewed journals in a systematic fashion. Search terms, key questions, and associated clinical case variants were formed by panel consensus. The literature search informed the committee during a blinded vote on the appropriateness of treatment options via the modified Delphi method. The final number of citations retained for review was 274. These informed 5 key questions, which focused on patient selection, adjuvant reirradiation, definitive reirradiation, stereotactic body radiation, and reirradiation to treat nonsquamous cancer. Results of the consensus voting are presented along with discussion of the most current evidence. This provides updated evidence-based recommendations and guidelines for the retreatment of recurrent or second primary cancer of the head and neck.

Hysterectomy for uterine adenocarcinoma in the elderly: tumor characteristics, and long-term outcome.

OBJECTIVES: To evaluate the tumor recurrences and survival in elderly patients ≥75 years of age with uterine endometrioid carcinoma treated with surgical staging with/without adjuvant radiation therapy (RT). METHODS: We identified 675 surgically staged patients with FIGO stage I-II uterine endometrioid carcinoma who were treated between 1985 and 2009. Their medical records were retrospectively reviewed in this IRB-approved study. Patients were classified as ≥75 years vs. <75 years and compared regarding tumor recurrence and survival. Following a univariate analysis, multivariable modeling was done using Cox regression analysis. RESULTS: 121 patients (18%) were ≥75 years old at the time of hysterectomy. For this group of elderly patients, median age was 79. All patients were surgically staged and some received adjuvant RT. Older patients were found to have higher FIGO stages (p<0.001), higher grade tumors (p<0.001), more frequent deep myometrial involvement (p<0.001), and more frequent lower uterine segment involvement (p<0.001). There was no significant difference found between older and younger patients with respect to lymphovascular space involvement (LVSI) (p=0.415), number of lymph nodes dissected (p=0.440), or adjuvant RT received (p=0.089). Older patients had more tumor recurrence (15% vs 7%) (p=0.005) and lower five year relapse-free survival of 80% compared to 90% in younger patients (p=0.0016). Multivariate analysis confirmed the significance of LVSI, grade 3 tumors, and deep myometrial invasion as prognostic factors for recurrence. After adjusting for other poor prognostic factors, age was not found to be an independent prognostic factor for recurrence. CONCLUSION: Despite similar surgical staging and adjuvant radiation treatment, patients ≥75 years old diagnosed with FIGO stage I-II uterine endometrioid carcinoma were found to have more adverse pathologic features and worse relapse-free, disease-specific and overall survival than younger patients. Age ≥75 years alone may not be an independent significant prognostic factor affecting tumor recurrence.

Dosimetry Comparison of Palliative Radiation Plans Generated From Available Diagnostic CT Images Versus Dedicated CT Simulation for Inpatients.

Introduction The morbidity sequelae of advanced cancer are often irreversible. Early palliative radiation can prevent, delay, and even improve these consequences. Treatment may be delayed due to a packed computed tomography (CT) simulation schedule or other logistics, including the cost and burden of arranging ambulance transportation when radiation centers are off-site. Objectives The primary objective was to determine the feasibility of using a recent diagnostic CT scan in lieu of a dedicated simulation CT to generate an adequate plan without sacrificing dosimetric goals and subsequent efficacy or tolerability. Secondary objectives included how much the lesion has grown, and how much earlier treatment could start if planned on a diagnostic CT scan. Materials/Methods For each inpatient treated with palliative radiation, a prior recent diagnostic CT scan was imported into the RayStation (RaySearch Laboratories, Stockholm, Sweden) planning system. From these diagnostic scans, planning treatment volumes (PTV) and organs at risk (OAR) were contoured using the same technique as the patient's actual treatment. The primary outcome was to compare both the PTV coverage and OAR dose between the plan generated from the diagnostic CT compared to that from the simulation CT. Our secondary outcomes include the mean time between CT simulation and first treatment, change in tumor volume between diagnostic scan and CT simulation, and the hottest 1% of each plan (D1). Results Between May and August 2019, a total of 22 inpatients were treated palliatively. Of those 22 patients, 10 patients (ages 32-92 years, median 64.5 years, 50% spine) met study criteria and had a diagnostic CT scan that was obtained within 14 days of simulation CT that was also compatible with our planning software. In the plans that were delivered, a mean of 98.8% (range 94.4-100%) of PTV was covered by at least 95% prescription dose. In the diagnostic CT plans, a mean of 95.4% (range 84.5-100%) of PTV was covered by at least 95% prescription dose. The difference between plans trended towards significance (p=0.061). When looking at patients receiving treatment to the spine or having a diagnostic CT within four days of the simulation CT, there was no statistically significant difference between the two plans (p=0.032 and 0.030, respectively). The OARs received, on average, 1.4% less mean radiation dose in the hypothetical plans (p=0.911). All OAR constraints were met in both groups. The mean time between diagnostic CT and CT simulation was 5.9 days and between CT simulation and first treatment was 1.9 days (range 0-5 days). The mean change in tumor volume was 22.64% smaller in the diagnostic CT scan plan. The D1 was an average 1% hotter in the hypothetical plans (p=0.16). Conclusion In hospitalized patients with an indication for palliative radiation, treatment planning on a pre-existing recent diagnostic CT scan produces comparable dose distributions without increases in dose to OARs when compared to the use of CT simulation scans, particularly for the treatment of the spine or when a very recent diagnostic CT is available. Bypassing CT simulation in select cases allows for earlier delivery of radiation with less patient and logistical burden. In combination with daily image guidance, this may translate to more timely delivery of radiation, less cost and burden to critically ill patients, and improved palliative benefit.

Systematic review of postoperative therapy for resected squamous cell carcinoma of the head and neck: Executive summary of the American Radium Society appropriate use criteria.

BACKGROUND: The aims of this systematic review are to (a) evaluate the current literature on the impact of postoperative therapy for resected squamous cell carcinoma of the head and neck (SCCHN) on oncologic and non-oncologic outcomes and (b) identify the optimal evidence-based postoperative therapy recommendations for commonly encountered clinical scenarios. METHODS: An analysis of the medical literature from peer-reviewed journals was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Prospective studies and methodology-based systematic reviews and meta-analyses of postoperative therapy for SCCHN were identified by searching Medline (OVID) and EMBASE (Elsevier) using controlled vocabulary terms (ie, National Library of Medicine Medical Subject Headings [MeSH], EMTREE). Study screening and selection was performed with Covidence software and full-text review. The RAND/UCLA appropriateness method was used by the expert panel to rate the appropriate use of postoperative therapy, and the modified Delphi method was used to come to consensus. RESULTS: A total of 5660 studies were identified and screened using the title and abstract, leading to 201 studies assessed for relevance using full-text review. After limitation to the eligibility criteria, 101 studies from 1977 to 2020 were identified, including 77 with oncologic endpoints and 24 with function and quality of life endpoints. All studies reported staging prior to the implementation of American Joint Committee on Cancer (AJCC-8). CONCLUSIONS: Prospective clinical studies and systematic reviews identified through the PRISMA systematic review provided good evidence for consensus statements regarding the appropriate use of postoperative therapy for resected SCCHN. Further research is needed in domains where consensus by the expert panel could not be achieved for the appropriateness of specific postoperative therapeutic interventions.

The influence of breast cancer subtype on survival after palliative radiation for osseous metastases.

BACKGROUND: Among patients with osseous metastases, breast cancer (BC) patients typically have the best prognosis. In the palliative setting, BC is often considered a single disease, but based on receptor status there are four distinct subtypes: luminal A (LA), luminal B (LB), triple negative (TN), and HER2-enriched (HER2). We hypothesize that survival and palliative outcomes following palliative RT for osseous metastases correlate with breast cancer subtype (BCS). METHODS: We identified 3,895 BC patients with known receptor status who received palliative RT for osseous metastases from 2004-2013 in the National Cancer Database. Kaplan-Meier method with log-rank testing and univariate/multivariate Cox-regression was used to identify survival factors. Incomplete radiation courses, 30-day mortality rate, and percentage remaining life spent receiving RT (PRLSRT) were calculated. RESULTS: Subtypes were 54% LA, 33% LB, 8% TN, and 5% HER2 with median survival of 34.1, 28.2, 5.3, and 15.7 months, respectively (p < 0.001). Overall 82% of patients received ≥10 fractions. Although BCS had limited effect on radiation regimens, TN received nearly twice as many single or hypofractionated (≤5 fractions) treatments, but the overall rate of these fraction schemes was low at 3.7 and 13.7%, respectively. Compared to LA and LB, TN and HER2 patients had worse palliative outcomes; higher rates of incomplete courses at 18.8% and 18.3% versus 12.7%-14.4%; higher 30-day mortality post-radiotherapy at 21.5% and 16.0% versus 6.3%-7.9%, and higher median PRLSRT of 7.7% and 3.7% versus 2.2%-2.4% for LA and LB. On multivariate analysis, BCS was associated with overall survival with TN (HR 3.7), HER2 (HR 1.75), and LB (HR 1.28) fairing worse than LA (p < 0.001). CONCLUSIONS: BCS correlated with survival and palliative outcome following radiation to osseous metastases. BCS should be considered by physicians when planning palliative RT to maximize quality-of-life, avoid unnecessary treatment, and ensure palliative benefits.

Cellular and molecular bases of the initiation of fever.

All phases of lipopolysaccharide (LPS)-induced fever are mediated by prostaglandin (PG) E2. It is known that the second febrile phase (which starts at approximately 1.5 h post-LPS) and subsequent phases are mediated by PGE2 that originated in endotheliocytes and perivascular cells of the brain. However, the location and phenotypes of the cells that produce PGE2 triggering the first febrile phase (which starts at approximately 0.5 h) remain unknown. By studying PGE2 synthesis at the enzymatic level, we found that it was activated in the lung and liver, but not in the brain, at the onset of the first phase of LPS fever in rats. This activation involved phosphorylation of cytosolic phospholipase A2 (cPLA2) and transcriptional up-regulation of cyclooxygenase (COX)-2. The number of cells displaying COX-2 immunoreactivity surged in the lung and liver (but not in the brain) at the onset of fever, and the majority of these cells were identified as macrophages. When PGE2 synthesis in the periphery was activated, the concentration of PGE2 increased both in the venous blood (which collects PGE2 from tissues) and arterial blood (which delivers PGE2 to the brain). Most importantly, neutralization of circulating PGE2 with an anti-PGE2 antibody both delayed and attenuated LPS fever. It is concluded that fever is initiated by circulating PGE2 synthesized by macrophages of the LPS-processing organs (lung and liver) via phosphorylation of cPLA2 and transcriptional up-regulation of COX-2. Whether PGE2 produced at the level of the blood-brain barrier also contributes to the development of the first phase remains to be clarified.

Stereotactic body radiation therapy for hepatocellular carcinoma: Practice patterns, dose selection and factors impacting survival.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is an emerging option for unresectable hepatocellular carcinoma (HCC) without consensus regarding optimal dose schemas. This analysis identifies practice patterns and factors that influence dose selection and overall survival, with particular emphasis on dose and tumor size. MATERIALS/METHODS: Query of the National Cancer Database (NCDB) identified patients with unresectable, nonmetastatic HCC who received SBRT from 2004 to 2013. Biological Effective Dose (BED) was calculated for each patient in order to uniformly analyze different fractionation regimens. RESULTS: A total of 456 patients met the inclusion criteria. The median BED was 100 Gy (22.5-208.0), which corresponded to the most common dose fractionation (50 Gy in five fractions). Various factors influenced dose selection including tumor size (P < 0.001), tumor stage (P = 0.002), and facility case volume (<0.001). On multivariate analysis, low BED (<75 Gy, HR 2.537, P < 0.001; 75-100 Gy, HR 1.986, P = 0.007), increasing tumor size (HR 1.067, P = 0.032), elevated AFP (HR 1.585, P = 0.019), stage 3 (HR 1.962, P < 0.001), low-volume facilities (1-5 cases HR 1.687, P = 0.006), and a longer time interval from diagnosis to SBRT (>2 to ≤4 months, HR 1.456, P = 0.048; >4 months, HR 2.192, P < 0.001) were associated with worse survival. CONCLUSION: SBRT use is increasing for HCC, and multiple regimens are clinically employed. Although high BED was associated with improved outcomes, multiple factors contributed to the dose selection with favorable patients receiving higher doses. Continued efforts to enhance radiation planning and delivery may help improve utilization, safety, and efficacy.

The Dosimetric Impact of Interfractional Organ-at-Risk Movement During Liver Stereotactic Body Radiation Therapy.

PURPOSE: Stereotactic body radiation therapy (SBRT) is an effective therapy for treating liver malignancies. However, little is known about interfractional dose variations to adjacent organs at risk (OARs). We examine the effects of interfractional organ movement and setup variation on dose delivered to OARs in patients receiving liver SBRT. METHODS AND MATERIALS: Thirty patients treated with liver SBRT were analyzed. Daily image guidance with diagnostic quality computed tomography-on-rails imaging was performed before each fraction. In phase 1, these daily images were used to delineate all OARs including the liver, heart, right kidney, esophagus, stomach, duodenum, and large bowel in 10 patients. In phase 2, only OARS in close proximity to the target were contoured in 20 additional patients. Dose distribution on each daily computed tomography was generated, and daily doses to each OAR were recorded and compared with clinical thresholds to determine whether a daily dose excess (DDE) occurred. RESULTS: In phase 1, significant interfractional dose differences between planned and delivered dose to OARs were observed, but differences were rarely clinically significant, with just 1 DDE. In phase 2, multiple DDEs were recorded for OARs close to the target, mainly involving the stomach, heart, and esophagus. Tumors in the hilum and liver segments I, IV, and VIII were the most common locations for DDEs. On root cause analysis, 3 etiologies of DDE emerged: craniocaudal shift (69.2%), anatomic changes (28.2%), and anteroposterior shifts (2.6%). CONCLUSIONS: OARs close to liver lesions may receive higher doses than expected during SBRT owing to interfractional variations in OARs relative to the target. These differences in planned versus expected dose can lead to toxicity. Efforts to better evaluate OARs with daily image guidance may help reduce risks. Application of adaptive replanning and improved and real-time image guidance could mitigate risks of toxicity, and further study into their applications is warranted.

Neoadjuvant chemotherapy improves survival compared with concurrent chemoradiation alone in nasopharyngeal carcinoma patients with N3 disease.

BACKGROUND: Neoadjuvant chemotherapy (NAC) trials in endemic regions of nasopharyngeal carcinoma (NPC) found improved survival, but studies are lacking in nonendemic regions. We assessed whether adding NAC to concurrent chemoradiation (CRT) improves overall survival (OS), especially in high-risk nonendemic patients. METHODS: Definitively treated NPC patients (n = 5424) from the National Cancer Database were analyzed for predictors of NAC and NAC effects on OS with multivariate Cox proportional hazards analysis (multivariate analysis [MVA]). Propensity score matched (1:2) survival analysis of NAC (n = 968) and CRT alone (n = 1914) was also performed. Effects on OS were stratified by risk group. RESULTS: On MVA, NAC-improved OS among the total cohort (hazard ratio [HR] 0.89, P = .049), particularly among stratified keratinizing histology (HR 0.82, P = .015) and N3 disease (HR 0.73, P = .046). Among propensity matched patients, NAC improved OS in patients with N3 disease (n = 336; HR 0.71, P = .046). CONCLUSIONS: NAC may improve OS among nonendemic NPC patients at higher risk of distant micrometastases, particularly N3 disease and those with unfavorable histology.

Technical Note: Enhancing soft tissue contrast and radiation-induced image changes with dual-energy CT for radiation therapy.

PURPOSE: The purpose of this work is to investigate the use of low-energy monoenergetic decompositions obtained from dual-energy CT (DECT) to enhance image contrast and the detection of radiation-induced changes of CT textures in pancreatic cancer. METHODS: The DECT data acquired for 10 consecutive pancreatic cancer patients during routine nongated CT-guided radiation therapy (RT) using an in-room CT (Definition AS Open, Siemens Healthcare, Malvern, PA) were analyzed. With a sequential DE protocol, the scanner rapidly performs two helical acquisitions, the first at a tube voltage of 80 kVp and the second at a tube voltage of 140 kVp. Virtual monoenergetic images across a range of energies from 40 to 140 keV were reconstructed using an image-based material decomposition. Intravenous (IV) bolus-free contrast enhancement in pancreas patient tumors was measured across a spectrum of monoenergies. For treatment response assessment, the changes in CT histogram features (including mean CT number (MCTN), entropy, kurtosis) in pancreas tumors were measured during treatment. The results from the monoenergetic decompositions were compared to those obtained from the standard 120 kVp CT protocol for the same subjects. RESULTS: Data of monoenergetic decompositions of the 10 patients confirmed the expected enhancement of soft tissue contrast as the energy is decreased. The changes in the selected CT histogram features in the pancreas during RT delivery were amplified with the low-energy monoenergetic decompositions, as compared to the changes measured from the 120 kVp CTs. For the patients studied, the average reduction in the MCTN in pancreas from the first to the last (the 28th) treatment fraction was 4.09 HU for the standard 120 kVp and 11.15 HU for the 40 keV monoenergetic decomposition. CONCLUSIONS: Low-energy monoenergetic decompositions from DECT substantially increase soft tissue contrast and increase the magnitude of radiation-induced changes in CT histogram textures during RT delivery for pancreatic cancer. Therefore, quantitative DECT may assist the detection of early RT response.