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Background: Poor patients often reside in neighborhoods of lower socioeconomic status (SES) with high levels of airborne pollutants. They also have higher mortality from non–small cell lung cancer (NSCLC) than those living in wealthier communities. We investigated whether living in polluted neighborhoods is associated with somatic mutations linked with lower survival rates, i.e., TP53 mutations. Methods: In a retrospective cohort of 478 patients with NSCLC treated at a comprehensive cancer center between 2015 and 2018, we used logistic regression to assess associations between individual demographic and clinical characteristics, including somatic TP53 mutation status and environmental risk factors of annual average particulate matter (PM2.5) levels, and neighborhood SES. Results: 277 patients (58%) had somatic TP53 mutations. Of those, 45% lived in neighborhoods with “moderate” Environmental Protection Agency–defined PM2.5 exposure, compared with 39% of patients without TP53 mutations. We found significant associations between living in neighborhoods with “moderate” versus “good” PM2.5 concentrations and minority population percentage [OR, 1.06; 95% confidence interval (CI), 1.04–1.08]. There was a significant association between presence of TP53 mutations and PM2.5 exposure (moderate versus good: OR, 1.66; 95% CI, 1.02–2.72) after adjusting for patient characteristics, other environmental factors, and neighborhood-level SES. Conclusions: When controlling for individual- and neighborhood-level confounders, we find that the odds of having a TP53-mutated NSCLC are increased in areas with higher PM2.5 exposure. Impact: The link between pollution and aggressive biology may contribute to the increased burden of adverse NSCLC outcomes in individuals living in lower SES neighborhoods.

Our purpose was to analyze dose-volume parameters associated with genitourinary (GU) toxicity from a phase I clinical trial of prostate bed stereotactic body radiation therapy.Patients were treated in escalating dose levels of 35, 40, and 45 Gy, over 5 fractions. Data from all 26 patients enrolled in the protocol were analyzed using multiple dose-volume cut points for multiple GU organs at risk. Univariate logistical regression and Fisher exact test were used to assess statistical significance associated with incidence of toxicity.The median follow-up was 36 months for all patients. Acute GU toxicity was mild and resolved spontaneously. Eight out of 26 patients (30.7%) developed late GU toxicity of grade 2 or higher. Two patients developed grade 3 ureteral stenosis, 1 in the 35 Gy arm and the other in the 45 Gy arm. Three patients developed grade 2 or higher hematuria/cystitis, and 3 developed grade 2 or higher incontinence. Incidence of grade 3 ureteral stenosis was related to the absolute volume of bladder wall receiving greater than 20, 25, and 30 Gy (P.01). Grade 2 cystitis and hematuria were related to the volume of bladder wall receiving 20 Gy less than 34% and 35 Gy less than 25% (18.8% vs 60% and 23.8% vs 80%, respectively, P.05). Incontinence was related to mean urethral dose less than 35 Gy and 25 Gy (4.3% vs 66.7% and 0% vs 37.5%, respectively, P.05) and volume of urethra receiving 35 Gy less than 24% (8.3% vs 50%, P.05).This is the first analysis to report dose-volume thresholds associated with late GU toxicity in patients receiving prostate bed stereotactic body radiation therapy. We recommend limiting the bladder wall receiving 25 Gy to less than 18 cubic centimeters to reduce the risk for late grade 3 ureteral stenosis.

Lung cancer metastases comprise most of all brain metastases in adults and most brain metastases are diagnosed by magnetic resonance (MR) scans. The purpose of this study was to conduct an MR imaging-based radiomic analysis of brain metastatic lesions from patients with primary lung cancer to classify mutational status of the metastatic disease. We retrospectively identified lung cancer patients with brain metastases treated at our institution between 2009 and 2017 who underwent genotype testing of their primary lung cancer. Brain MR Images were used for segmentation of enhancing tumors and peritumoral edema, and for radiomic feature extraction. The most relevant radiomic features were identified and used with clinical data to train random forest classifiers to classify the mutation status. Of 110 patients in the study cohort (mean age 57.51 ± 12.32 years; M: F = 37:73), 75 had an EGFR mutation, 21 had an ALK translocation, and 15 had a KRAS mutation. One patient had both ALK translocation and EGFR mutation. Majority of radiomic features most relevant for mutation classification were textural. Model building using both radiomic features and clinical data yielded more accurate classifications than using either alone. For classification of EGFR, ALK, and KRAS mutation status, the model built with both radiomic features and clinical data resulted in area-under-the-curve (AUC) values based on cross-validation of 0.912, 0.915, and 0.985, respectively. Our study demonstrated that MR imaging-based radiomic analysis of brain metastases in patients with primary lung cancer may be used to classify mutation status. This approach may be useful for devising treatment strategies and informing prognosis.

The primary objectives of this study were to evaluate toxicity of escalating doses of prostate bed stereotactic body radiation therapy and to provide dose recommendations for a phase 2 study.Patients with organ-confined, node-negative prostate cancer who had biochemical failure (prostate-specific antigen [PSA] less than 2.0) after prostatectomy were eligible for this phase 1 dose-escalation trial. Doses delivered were 35 Gy, 40 Gy, and 45 Gy in 5 fractions, given every other day. Dose-limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events (version 4.0) grade 3 or higher gastrointestinal or genitourinary (GU) toxicity within 90 days of treatment. Maximum tolerated dose was the highest dose to be tested where fewer than 2 of the patients experienced DLT. Patients completed quality-of-life questionnaires at regular time intervals.Twenty-six patients completed treatment between October 2013 and December 2017. Three patients received 35 Gy, 8 patients received 40 Gy, and 15 patients received 45 Gy. The median follow-up was 60 months for 35 Gy, 48 months for 40 Gy, and 33 months for 45 Gy. No acute DLT events were observed. Late grade ≥2 and ≥3 gastrointestinal toxicity occurred in 11% and 0%, respectively, and late grade ≥2 and ≥3 GU toxicity occurred in 38% and 15%, respectively. No difference was observed in late GU toxicity between 40 Gy and 45 Gy. Sexual function scores were significantly lower in the patients receiving androgen deprivation therapy (P.01). In all patients, the crude rate of PSA control (0.2 ng/mL) was 11 out of 26 (42%).Dose escalation to 45 Gy did not result in acute DLT events, had similar rates of late grade 3 toxicity, and did not demonstrate higher rates of PSA control, compared with 40 Gy. While allowing for higher plan heterogeneity, the recommended dose for phase 2 study will be 40 Gy in 5 fractions.

Background: Brain metastases are associated with poor survival. Molecular genetic testing informs on targeted therapy and survival. The purpose of this study was to perform a MR imaging-based radiomic analysis of brain metastases from non-small cell lung cancer (NSCLC) to identify radiomic features that were important for predicting survival duration.Methods: We retrospectively identified our study cohort via an institutional database search for patients with brain metastases from EGFR, ALK, and/or KRAS mutation-positive NSCLC. We segmented the brain metastatic tumors on the brain MR images, extracted radiomic features, constructed radiomic scores from significant radiomic features based on multivariate Cox regression analysis (p < 0.05), and built predictive models for survival duration.Result: Of the 110 patients in the cohort (mean age 57.51 ± 12.32 years; range: 22–85 years, M:F = 37:73), 75, 26, and 15 had NSCLC with EGFR, ALK, and KRAS mutations, respectively. Predictive modeling of survival duration using both clinical and radiomic features yielded areas under the receiver operative characteristic curve of 0.977, 0.905, and 0.947 for the EGFR, ALK, and KRAS mutation-positive groups, respectively. Radiomic scores enabled the separation of each mutation-positive group into two subgroups with significantly different survival durations, i.e., shorter vs. longer duration when comparing to the median survival duration of the group.Conclusion: Our data supports the use of radiomic scores, based on MR imaging of brain metastases from NSCLC, as non-invasive biomarkers for survival duration. Future research with a larger sample size and external cohorts is needed to validate our results.

Lung cancer can be classified into two main categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which are different in treatment strategy and survival probability. The lung CT images of SCLC and NSCLC are similar such that their subtle differences are hardly visually discernible by the human eye through conventional imaging evaluation. We hypothesize that SCLC/NSCLC differentiation could be achieved via computerized image feature analysis and classification in feature space, as termed a radiomic model. The purpose of this study was to use CT radiomics to differentiate SCLC from NSCLC adenocarcinoma. Patients with primary lung cancer, either SCLC or NSCLC adenocarcinoma, were retrospectively identified. The post-diagnosis pre-treatment lung CT images were used to segment the lung cancers. Radiomic features were extracted from histogram-based statistics, textural analysis of tumor images and their wavelet transforms. A minimal-redundancy-maximal-relevance method was used for feature selection. The predictive model was constructed with a multilayer artificial neural network. The performance of the SCLC/NSCLC adenocarcinoma classifier was evaluated by the area under the receiver operating characteristic curve (AUC). Our study cohort consisted of 69 primary lung cancer patients with SCLC (n = 35; age mean ± SD = 66.91± 9.75 years), and NSCLC adenocarcinoma (n = 34; age mean ± SD = 58.55 ± 11.94 years). The SCLC group had more male patients and smokers than the NSCLC group (P < 0.05). Our SCLC/NSCLC classifier achieved an overall performance of AUC of 0.93 (95% confidence interval = [0.85, 0.97]), sensitivity = 0.85, and specificity = 0.85). Adding clinical data such as smoking history could improve the performance slightly. The top ranking radiomic features were mostly textural features. Our results showed that CT radiomics could quantitatively represent tumor heterogeneity and therefore could be used to differentiate primary lung cancer subtypes with satisfying results. CT image processing with the wavelet transformation technique enhanced the radiomic features for SCLC/NSCLC classification. Our pilot study should motivate further investigation of radiomics as a non-invasive approach for early diagnosis and treatment of lung cancer.

The tumor microenvironment affects the outcome of radiotherapy against head and neck squamous cell carcinoma (HNSCC). We recently found that tolerogenic myeloid cells accumulate in the circulation of HNSCC patients undergoing radiotherapy. Here, we analyzed tumor-containing lymph node biopsies collected from these patients. After 2 weeks of radiotherapy, we found an increase in tumor-associated macrophages (TAMs) with activated STAT3, while CD8(+) T cells were reduced as detected using multiplex IHC. Gene expression profiling indicated upregulation of M2 macrophage–related genes (CD163, CD206), immunosuppressive mediators (ARG1, LIF, TGFB1), and Th2 cytokines (IL4, IL5) in irradiated tumors. We next validated STAT3 as a potential target in human HNSCC-associated TAMs, using UM-SCC1 xenotransplants in humanized mice. Local injections of myeloid cell–targeted STAT3 antisense oligonucleotide (CpG-STAT3ASO) activated human DCs/macrophages and promoted CD8(+) T cell recruitment, thereby arresting UM-SCC1 tumor growth. Furthermore, CpG-STAT3ASO synergized with tumor irradiation against syngeneic HPV(+) mEERL and HPV(–) MOC2 HNSCC tumors in mice, triggering tumor regression and/or extending animal survival. The antitumor immune responses were CD8(+) and CD4(+) T cell dependent and associated with the activation of antigen-presenting cells (DCs/M1 macrophages) and increased CD8(+) to regulatory T cell ratio. Our observations suggest that targeted inhibition of STAT3 in tumor-associated myeloid cells augments the efficacy of radiotherapy against HNSCC.

Purpose: There are limited long-term data on patients treated with image guided intensity modulated radiation therapy (IG-IMRT) for prostate cancer recurrence or high-risk disease features after radical prostatectomy. We report single-institution results for patients treated with IG-IMRT and identify variables associated with outcome. Methods and materials: This is a retrospective chart review consisting of 313 consecutive patients who were treated with adjuvant or salvage IG-IMRT from 2004 to 2013. Cox proportional hazards analysis was used to identify factors related to survival and toxicity. Toxicity was graded using the Common Terminology Criteria for Adverse Events Version 4.0. Results: The median follow-up was 55 months (range, 6-131 months). The median pre-radiation therapy (RT) prostate-specific antigen (PSA) was 0.3 ng/mL (range, 0.2 ng/mL), biopsy Gleason score (≥7 [4+3]), and duration of ADT (>6 months) were significantly associated (P < .05) with biochemical progression-free survival. Actuarial late grade 3 genitourinary and gastrointestinal toxicities at 5 years were 10% and 2%, respectively. Conclusion: Our results suggest that lower pre-RT PSA level and longer duration of ADT are associated with improved biochemical control. The incidence of late grade 3 gastrointestinal toxicity was low, but late grade 3 genitourinary toxicity was higher than anticipated.

Purpose This study evaluates the feasibility and acceptability of a Self-Management Survivorship Care Planning (SM-SCP) intervention in colorectal and lung cancer survivors. Methods This is a single-group, pre- and post-mixed methods study of an advance practice nurse-driven survivorship care intervention that integrates a survivorship care plan with self-management skills coaching. Colorectal and lung cancer survivors with stage I-III disease were enrolled at 3–6 months after completing treatments, and the intervention was administered in one in-person or telephone session. Survivor outcome measures included depression, anxiety, self-efficacy, QOL, and satisfaction. Paired t- tests were used for exploratory evaluations of pre-to post-intervention score changes. Content analysis was conducted to analyze the qualitative data to describe survivors’ experience with the intervention. Results Thirty participants (15 colorectal, 15 lung) enrolled and completed the study (73% retention). It took an average of 40 min to complete the TS/CP and 34.2 min to deliver the intervention. Exploratory analysis revealed significant differences from baseline to post-intervention in depression, anxiety, self-efficacy, physical functioning, role limitations-physical, pain, general health, health transition, physical health summary, and total QOL. Three qualitative themes emerged: 1) Feeling empowered about having a plan; 2) Struggling with psychosocial concerns; and 3) Suggestions for intervention content and delivery. Conclusions The SM-SCP intervention was feasible and acceptable for colorectal and lung cancer survivors after treatment completion. Survivorship care interventions have potential to fulfill the unmet needs of colorectal and lung cancer survivors. Their effectiveness might be greater by integrating conceptually-based models of care, such as self-management skills building.

Introduction: Oropharyngeal squamous cell (OPSCC) is a subset of head and neck cancers and is known to be associated with human papillomavirus (HPV). We designed a retrospective analysis to determine differences in survival and functional outcomes of OPSCC patients treated at City of Hope (COH) Cancer Center’s main campus versus selected satellite sites with COH-associated faculty and facilities. Methods and Materials: A retrospective analysis was done on patients diagnosed with OPSCC and treated with concurrent chemoradiation therapy from May 2009 to February 2017 at COH main campus or satellite sites. Eligible patients (N=94) had available demographic data, treatment data, survival and functional outcomes, and recent follow-up at a COH site. Results: 50 patients underwent treatment at the COH main campus and 44 at its satellite sites. Majority of patients were Caucasian (38 patients at main campus, 32 patients at satellite sites), male (40 at main campus, 39 at satellite sites), diagnosed with stage IV locally advanced OPSCC by AJCC 7th edition (43 vs. 32 patients), and p16 positive (42 vs. 30 patients). There was an equal smoking history distribution within our cohort (50% never smokers, 50% former/current smokers at both sites). A small subset of patients at both sites underwent surgical resection prior to concurrent chemoradiation (N=23, 25%). Chemotherapy agents chosen for treatment included cisplatin, carboplatin, cetuximab, and platinum/paclitaxel. Cisplatin was highly favored at the main campus (N=39, 78%); cisplatin (N=21, 48%) and cetuximab (N=21, 48%) use was equally distributed at the satellite sites. Of the 60 cisplatin-treated patients, 58 (98%) received the recommended total minimum dose of 200 mg/m2. Majority of patients completed their prescribed cumulative radiation therapy dose (50-70 Gray) (49 [98%] at main campus, 43 [98%] at satellite sites) and had a complete response to treatment (35 [70%] at main campus, 37 [84%] at satellite sites). There were few hospitalizations during the course of treatment (6 at the main campus, 4 at the satellite sites). 12 patients (24%) at the main campus and 19 patients (43%) at the satellite sites underwent feeding tube placement. A trend toward significant difference in feeding tube dependency at 6 months was observed between the main campus (N=2) and satellite sites (N=11) (17% vs. 58%, p=0.08). No significant difference in the 2-year recurrence rate was observed between the main campus (N=5) and the satellite sites (N=7) (10% vs. 16%, p>0.05). Conclusion: Our retrospective analysis highlights comparable recurrence rates between a major tertiary cancer center and selected satellite sites with dedicated radiation and medical oncology faculty and facilities. Discrepancies in the feeding tube dependency rates could be potentially overcome by integration of supportive services between satellites and main campus. This study also highlights the importance of telehealth services in major institutions. Citation Format: Rebecca R. Pharaon, Ellie Maghami, Arya Amini, Atish Mohanty, Nayana Vora, Sue Chang, Thomas Gernon, Robert Kang, Lalit Vora, Samuel Chung, Sagus Sampath, Erminia Massarelli. Analysis and comparison of survival and functional outcomes in oropharyngeal squamous cell carcinoma patients within City of Hope Cancer Center sites [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B26.

Key Points Question Can the duration of phase 1 studies using either the 3 + 3 or rolling 6 designs be substantially reduced without exceeding the patient risk limits or changing the operating characteristics of the parent design? Findings This decision analytical model found that the modified study designs were associated with reduced expected study durations. The modified designs were associated with minimal changes in the number of patients treated and the determination of the maximum tolerated dose, without changing the operating characteristics or exceeding the risk limits of the parent design. Meaning Per this analysis, a substantial reduction in the time required to bring new advances to the clinic can be accomplished by simple modifications of 2 commonly used phase 1 trial designs., This decision analytical model assesses a queuing approach to modify the design of phase 1 oncology trials., Importance Phase 1 cancer studies, which guide dose selection for subsequent studies, are almost 3 times more prevalent than phase 3 studies and have a median study duration considerably longer than 2 years, which constitutes a major component of drug development time. Objective To discern a method to reduce the duration of phase 1 studies in adult and pediatric cancer studies without violating risk limits by better accommodating the accrual and evaluation process (or queue). Design The process modeled, the phase 1 queue (IQ), includes patient interarrival time, screening, and dose-limiting toxicity evaluation. For this proof of principle, the rules of the 3 + 3 and rolling 6 phase 1 designs were modified to improve patient flow through the queue without exceeding the maximum risk permitted in the parent designs. The resulting designs, the IQ 3 + 3 and the IQ rolling 6, were each compared with their parent design by simulations in 12 different scenarios. Main Outcomes and Measures (1) The time from study opening to determination of the maximum tolerated dose (MTD), (2) the number of patients treated to determine the MTD, and (3) the association of the design with the dose selected as the MTD. Results Based on 800 simulations, for all 12 scenarios considered, the IQ 3 + 3 and the IQ rolling 6 designs were associated with reduced expected study durations compared with the parent design. The expected IQ 3 + 3 reduction ranged from 1.6 to 10.4 months (with 3.7 months for the standard scenario), and the expected reduction associated with IQ rolling 6 ranged from 0.4 to 10.5 months (with 3.4 months for the standard scenario). The increase in the mean number of patients treated in the IQ 3 + 3 compared with the 3 + 3 ranged from 0.6 to 3.2 patients. No increase in the number of patients was associated with the IQ rolling 6 compared with the rolling 6 design. The probability of selecting a dose level as the MTD changed by less than 3% for all dose levels and scenarios in both parent designs. Conclusions and Relevance This study found that IQ designs were associated with reduced mean duration of phase 1 studies compared with their parent designs without changing the risk limits or MTD selection operating characteristics. These approaches have been successfully implemented in both hematology and solid tumor phase 1 studies.

Background: Early mortality is a major deterrent to oncologic management, often preventing delivery of therapy or leading to administration of treatment that offers limited benefit from aggressive interventions. Due to more recent progress in therapeutic options for stage IV non-small cell lung cancer (NSCLC) patients, identifying those at high risk of early mortality (within 30 days) could have implications for treatment selection. Because early mortality following diagnosis of metastatic non-small cell lung cancer (NSCLC) is not well-characterized, this investigation evaluated national trends and predictors thereof. Material and methods: The National Cancer Database was queried for cases of pathologically confirmed metastatic NSCLC with complete vital status and clinical information, diagnosed between 2006 and 2014. Multivariable logistic regression ascertained factors associated with 30-day mortality. Results: Of 346,681 patients, 45,861 (13%) experienced early mortality over the past decade, which remained relatively constant over time. Predictors of early mortality included advancing age (>65 years), male gender, Caucasian race, non-private insurance, lower income, greater comorbidities, residence in metropolitan and/or lesser-educated areas, treatment at community centers, patients with no prior history of cancer and regional differences (p Conclusions: A fair proportion of NSCLC patients experience early mortality, which has not decreased over time. The majority of patients with early mortality do not receive treatment. Prognostic factors for early mortality should be considered during initial evaluation and subsequent follow-up of these patients. Doing so may impact systemic treatment selection by medical oncologists, management of (oligo)metastatic disease by radiation and surgical oncologists and cost-effective administration of these therapies in the stage IV NSCLC population.

ObjectivesOncology has become more reliant on new testing methods and a greater use of electronic medical records, which provide a plethora of information available to physicians and researchers. However, to take advantage of vital clinical and research data for precision medicine, we must initially make an effort to create an infrastructure for the collection, storage, and utilization of this information with uniquely designed disease-specific registries that could support the collection of a large number of patients.Materials and methodsIn this study, we perform an in-depth analysis of a series of lung adenocarcinoma patients (n = 415) with genomic and clinical data in a recently created thoracic patient registry.ResultsOf the 415 patients with lung adenocarcinoma, 59% (n = 245) were female; the median age was 64 (range, 22-92) years with a median OS of 33.29 months (95% CI, 29.77-39.48). The most common actionable alterations were identified in EGFR (n = 177/415 [42.7%]), ALK (n = 28/377 [7.4%]), and BRAF V600E (n = 7/288 [2.4%]). There was also a discernible difference in survival for 222 patients, who had an actionable alteration, with a median OS of 39.8 months as compared to 193 wild-type patients with a median OS of 26.0 months (PConclusionThe use of patient registries, focused genomic panels and the appropriate use of clinical guidelines in community and academic settings may influence cohort selection for clinical trials and improve survival outcomes.

Response assessment with computed tomography after stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC) is challenging because myriad anatomic changes can occur after treatment. Diffusion-weighted magnetic resonance imaging (MRI) may provide additional data to guide therapy response. The primary objective was to evaluate the effect of SBRT on the mean apparent diffusion coefficient (ADC).This is a prospective clinical study of patients with NSCLC who received SBRT to the primary lung lesion. Patients underwent MRI scans before and at 1 month after completion of SBRT. MRI consisted of T1- and T2-weighted sequences, along with postcontrast, dynamic-contrast, and diffusion-weighted sequences with construction of ADC maps. Two blinded radiologists generated the ADC. SBRT was given over 5 fractions.A total of 13 patients were enrolled. Twelve patients were eligible for analysis. An average increase of 50% and 46% in mean single-plane ADC was observed after treatment by readers 1 and 2, respectively (P.01, both reviewers). There was good interobserver agreement of single-plane ADC values between the 2 radiologists (Pearson correlation of 0.85 [baseline] and 0.89 [1-month post-SBRT], P.001 for both). There was also a significant 18% increase in mean volumetric ADC on the 1-month scan (Wilcoxon P = .02). Two patients developed a local failure after SBRT, 1 at 6 months and the other at 34 months. Using a threshold of volumetric ADC increase of greater than 40%, 2 of 2 patients demonstrated local failure compared with 0 of 10 patients below this limit.A statistically significant increase in ADC was observed 1 month after treatment. An ADC increase of 40% at 1 month was associated with a higher rate of local failure. This pilot study provides impetus for studying ADC as a radiomic biomarker in patients receiving lung SBRT for NSCLC.

BACKGROUND: The purpose of this analysis is to evaluate whether postoperative radiotherapy (PORT) at the same facility as surgery portends to better survival outcomes compared to PORT given at a different facility. METHODS: Patients underwent upfront surgery at the National Cancer Database reporting facility followed by PORT. PORT was coded as performed at either the same facility or at a different facility as surgery. RESULTS: A total of 10 832 patients were selected. Five-year overall survival (OS) was higher in patients undergoing PORT at the same facility: 52.5% vs 48.4% (P < 0.001). PORT performed at the same facility was associated with improved OS under multivariate (HR, 0.92; P = 0.01) and propensity score matched (hazard ratio, 0.90; P = 0.004) analyses. CONCLUSIONS: OS was better among patients with head and neck cancer who received PORT at the same facility as surgery.

Radiation therapy for head and neck malignancies has made remarkable advances in treatment technology, resulting in improved clinical and functional outcomes. It is necessary for the radiation oncologist to have a complex understanding of the patient’s tumor and its relationship to the surrounding normal anatomy, in order to safely limit dose to normal tissues. Complications following radiation can be managed with timely intervention, usually on an outpatient basis. This chapter will discuss the technological advances in the field, the impact of human papillomavirus (HPV)-mediated disease on radiation treatment, efforts to limit dose to critical salivary and swallowing structures, and management of certain radiation-related toxicities.

Immunomodulation contributes to the antitumor efficacy of the fractionated radiation therapy (RT). Here, we describe immune effects of RT with concurrent systemic cisplatin or cetuximab treatment of patients with stage III-IV head and neck squamous cell carcinoma (HNSCC). Using longitudinally collected blood samples, we identified significant changes in cytokines/chemokines and immune cell populations compared to immune-related gene expression profiles in peripheral blood mononuclear cells (PBMCs). The 7-week combinatorial RT resulted in gradual elevation of proinflammatory mediators (IFNγ, IL-6, TNFɑ, CCL2), while levels of IL-12, cytokine essential for antitumor immune responses, were decreased. These effects correlated with progressive accumulation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) with detectable activity of STAT3 and PD-L1 expression, underscoring tolerogenic effects of MDSCs. Correspondingly, gene expression analysis of PBMCs harvested after two weeks of combinatorial RT, found upregulation of several immunosuppressive mediators. These included IL6, IL6R, STAT3 and PDL1, which could represent IL-6/STAT3-driven tolerogenic signaling, which inhibits T cell and NK activity. Overall, our results suggest that potential immunostimulatory effects of combinatorial RT in HNSCC patients are likely limited by tolerogenic STAT3 signaling and PD-L1 upregulation in myeloid immune cells. Further studies will clarify whether STAT3 targeting could augment RT efficacy and durability of antitumor responses.

Advancements in radiation planning and delivery have resulted in the ability to safely deliver higher doses per fraction to the tumor while also sparing normal tissue. Known as hypofractionated radiation therapy (HRT), or stereotactic ablative radiation therapy (SABR), this technique has been developed in multiple sites outside the brain, including lung, prostate, and pancreas. Accompanying such treatment is some form of image guided radiation therapy (IGRT). Localization of these tumors requires high quality soft tissue imaging, in addition to the ability to ascertain tumor location during radiation delivery. This chapter will outline the role of IGRT as it pertains to HRT treatment schemes for various malignancies.

We aimed to compare gross tumor volumes (GTV) in 3-dimensional computed tomography (3DCT) simulation and daily cone beam CT (CBCT) with the internal target volume (ITV) in 4-dimensional CT (4DCT) simulation in stereotactic body radiotherapy (SBRT) treatment of patients with early-stage non–small cell lung cancer (NSCLC) under abdominal compression. We retrospectively selected 10 patients with NSCLC who received image-guided SBRT treatments under abdominal compression with daily CBCT imaging. GTVs were contoured as visible gross tumor on the planning 3DCT and daily CBCT, and ITVs were contoured using maximum intensity projection (MIP) images of the planning 4DCT. Daily CBCTs were registered with 3DCT and MIP images by matching of bony landmarks in the thoracic region to evaluate interfractional GTV position variations. Relative to MIP-based ITVs, the average 3DCT-based GTV volume was 66.3 ± 17.1% (range: 37.5% to 92.0%) (p < 0.01 in paired t-test), and the average CBCT-based GTV volume was 90.0 ± 6.7% (daily range: 75.7% to 107.1%) (p = 0.02). Based on bony anatomy matching, the center-of-mass coordinates for CBCT-based GTVs had maximum absolute shift of 2.4 mm (left-right), 7.0 mm (anterior-posterior [AP]), and 5.2 mm (superior-inferior [SI]) relative to the MIP-based ITV. CBCT-based GTVs had average overlapping ratio of 81.3 ± 11.2% (range: 45.1% to 98.9%) with the MIP-based ITV, and 57.7 ± 13.7% (range: 35.1% to 83.2%) with the 3DCT-based GTV. Even with abdominal compression, both 3DCT simulations and daily CBCT scans significantly underestimated the full range of tumor motion. In daily image-guided patient setup corrections, automatic bony anatomy-based image registration could lead to target misalignment. Soft tissue-based image registration should be performed for accurate treatment delivery.

Uterine sarcomas are rare and, consequently, data supporting the use of adjuvant radiotherapy in uterine sarcomas consist of few randomised studies and multiple single-institution retrospective reports. It is becoming increasingly clear that each histologic subtype of uterine sarcoma is a distinct entity for which tailored treatment recommendations are needed. In this review, we analysed the effect of adjuvant radiotherapy for the main histologic subtypes of uterine sarcomas. When grouping all histologies, adjuvant radiotherapy has been shown in most studies to reduce local-regional failure without an overall survival advantage, as distant failure is the predominant pattern of relapse. Carcinosarcomas have the strongest indication for adjuvant radiotherapy, especially in early stage disease. Women with leiomyosarcomas and endometrial stromal sarcomas receiving adjuvant radiotherapy have improved local control compared with women undergoing surgery alone. As distant failure rates decrease with improvements in systemic therapies, there may be a broader indication for adjuvant radiotherapy.

To assess the impact of radiotherapy (RT) sequencing with surgery on overall survival (OS), cause-specific survival (CSS), local failure, and distant failure in soft-tissue sarcoma (STS).A retrospective analysis was conducted using the National Oncology Database, a proprietary database of aggregated tumor registries owned by IMPAC Medical Systems (Sunnyvale, CA). Patients with STS of all major anatomic sites who received definitive surgery and either preoperative (preop) or postoperative (postop) RT were included. Patients were also required to have known stage and grade. Prognostic factors for survival were identified using multivariate techniques. Survival was calculated using the Kaplan-Meier method, and compared for statistical significance (p0.05) using the log-rank test.A total of 821 patients met inclusion criteria. The median follow-up time was 63 months. Age, stage, histology, gender, tumor size, and RT sequence were independent predictors for OS (p0.05). Preop RT was associated with significantly improved OS and CSS compared with postop RT (hazard ratio [HR] = 0.72, 95% confidence interval [CI] 0.56-0.91, p0.01, and HR = 0.64, 95% CI 0.46-0.88, p0.01, respectively). The 5-year CSS was 79% and 74%, in favor of preop RT (log-rank, p0.05). Preop RT was also significantly associated with a reduced risk for local and distant relapse compared with postop RT.Preoperative RT is associated with a reduced cancer-specific mortality compared with postoperative RT in STS. The results of this study may serve as motivation to conduct future prospective studies with larger patient numbers.

Background and Objective To examine the impact of adjuvant radiotherapy (RT) and surgical technique on survival in retroperitoneal soft-tissue sarcoma. Methods A retrospective analysis was conducted using the National Oncology Database, a proprietary database of aggregated tumor registries owned by IMPAC® Medical Systems (Sunnyvale, CA). Patients who received definitive surgery with negative or microscopic-positive margins were included. Multivariate analysis was performed using the Cox proportional hazards model. Survival curves were estimated by the Kaplan–Meier method and were compared for statistical significance (P

Radiation therapy (RT) is an integral part of treating all stages of lung cancer. Stereotactic ablative radiation therapy (SABR) has emerged as a standard treatment option for stage I–II patients with medically inoperable disease. Stage IIIA–IIIB disease is typically managed with definitive concurrent chemo-radiotherapy (CRT). Intensity modulated radiation therapy (IMRT) has enabled delivery of more potent RT dose while greatly limiting dose to surrounding normal organs, including lung, esophagus, and heart. SABR may have an expanding role in the treatment of stage IV patients, with new clinical trials exploring its combination with systemic immuotherapies.

Objectives There is a paucity of data on non-surgical outcomes specific to stage II non-small cell lung cancer (NSCLC) patients receiving definitive chemotherapy and radiation therapy (CRT). This study reports population-based outcomes for this subgroup, and investigates a radiation dose–response for overall survival. Materials and methods The National Oncology Data Alliance (NODA), a merging of multiple tumor registries maintained by Elekta ® medical systems, was queried for stage II patients and CRT. Only curative cases (RT doses ≥59Gy) were included. Both sequential and concurrent CRT were allowed. Univariate and Cox multivariate techniques were used to assess factors significant for overall survival. These factors included: gender, age, race, radiation dose, radiation total treatment time, stage, histology, tumor size, and chemotherapy sequence. Results A total of 568 patients were included in the analysis, with a median follow-up of 12.9 months for surviving patients. Patients were treated between 2004 and 2014. Median survival was 20.5 months (95% confidence interval (CI) 18–23 months), with 16% patients alive at 5 years. Only gender was found to be significantly associated with survival in the Cox model. Although median survival was higher in patients receiving greater than 60Gy (21 months, 95% CI 18–24 moths) compared to 59–60Gy (16.5 months 95% CI 10–23 months), this was not statistically significant ( p =0.6). Conclusions This is the first report on outcomes for stage II NSCLC patients receiving CRT as definitive therapy. Survival approximates stage III CRT patients from historical phase III trials. As an increasing aging population may parallel a rise in medically inoperable stage II patients, this study can provide useful information when reviewing treatment options.

Purpose: Total body irradiation (TBI) and chemotherapy are common components of conditioning regimens for bone marrow transplantation. Interstitial pneumonitis (IP) is a known regimen-related complication. Using published data of IP in a multivariate logistic regression, this study sought to identify the parameters in the bone marrow transplantation conditioning regimen that were significantly associated with IP and to establish a radiation dose-response function. Methods and Materials: A retrospective review was conducted of articles that reported IP incidence along with lung dose, fractionation, dose rate, and chemotherapy regimen. In the final analysis, 20 articles (n = 1090 patients), consisting of 26 distinct TBI/chemotherapy regimens, were included in the analysis. Multivariate logistic regression was performed to determine dosimetric and chemotherapeutic factors that influenced the incidence of IP. Results: A logistic model was generated from patients receiving daily fractions of radiation. In this model, lung dose, cyclophosphamide dose, and the addition of busulfan were significantly associated with IP. An incidence of 3%-4% with chemotherapy-only conditioning regimens is estimated from the models. The {alpha}/{beta} value of the linear-quadratic model was estimated to be 2.8 Gy. The dose eliciting a 50% incidence, D {sub 50}, for IP after 120 mg/kg of cyclophosphamide was 8.8 Gy; inmore » the absence of chemotherapy, the estimated D {sub 50} is 10.6 Gy. No dose rate effect was observed. The use of busulfan as a substitute for radiation is equivalent to treating with 14.8 Gy in 4 fractions with 50% transmission blocks shielding the lung. The logistic regression failed to find a model that adequately fit the multiple-fraction-per-day data. Conclusions: Dose responses for both lung radiation dose and cyclophosphamide dose were identified. A conditioning regimen of 12 Gy TBI in 6 daily fractions induces an IP incidence of about 11% in the absence of lung shielding. Shielding the lung to receive 50% of this dose lowers the estimated incidence to about 2.3%. Because the lungs can be adequately shielded, we recommend against using busulfan as a substitute for fractionated TBI with cyclophosphamide.« less

Background and Objectives: While radiation therapy (RT) and certain types of chemotherapy are potentially immunogenic, they rarely generate antitumor immune responses. Our previous studies in mice showed that effects of RT on solid tumors are limited by the activation of tumor-promoting and immunosuppressive protein STAT3 in tumor-associated myeloid cells. Current study focused on determining whether STAT3 plays similar role in promoting immune evasion and therapeutic resistance in patients with head and neck squamous cell carcinoma (HNSCC) undergoing chemo-radiation therapy. Patients, Materials, and Methods: 15 patients with stage III-IV HNSCC who received CRT with curative intent consented to collect blood and tissue biopsy (IRB#14255). Before and during week 2 of RT, tissue biopsies were collected of a cancer-involved lymph node that received full dose radiation. Blood specimens were collected from patients before and during RT on weeks 1, 2, 4, 6, and 7, as well as 6-12 weeks after treatment completion. After isolation, PBMCs and plasma samples were cryopreserved and stored in liquid nitrogen for no longer than 12 months. For flow-cytometric analysis, PBMC were thawed in 37°C water bath, washed and pre-incubated in RPMI1640 media supplemented with 20% of autologous plasma for 2 h. Cells were then stained with fluorescently-labeled antibodies specific for CD14, CD15, CD33, and HLA-DR (eBioscience). For intracellular staining of phosphorylated-STAT3 (pSTAT3), cells were fixed, permeablized and then stained with fluorescently-labeled antibodies specific to tyrosine 705-phosphorylated STAT3 (pSTAT3; BD Biosciences) or an isotype control. mRNA was isolated from PBMC from baseline and Week 2 draw during RT from 6 patients. Expression of 730 genes selected for immune profiling was evaluated by nCounter Immune Cell Profiling Assay (Nanostring) and data was analyzed using nSolver software (Nanostring). Results: CRT resulted in the accumulation of potently immunosuppressive polymorphonuclear-myeloid-derived suppressor cells (PMN-MDSCs; HLA-DRloCD14-CD15+) in circulation of HNSCC patients. The PMN-MDSCs had high levels of activated STAT3, which correlated with the expression of immune checkpoint inhibitor, programmed death-ligand 1 (PD-L1). The analysis of gene expression in patients' PBMC indicated increased expressions of multiple protein mediators that promote immune suppression and MDSC functions such as IL-1β (20.7 fold, p=1.59E-5), IDO (3.6 fold, p=0.1) and VEGF (13.2 fold, p=7.97E-6) during RT. Pathway analysis using KEGG data base predicted that RT enhanced NF-κB signaling in PBMC. In contrast, number of circulating CD3+ T cell was significantly reduced and expression of genes involved in T-cell cytotoxicity including Granzymes A/K/M and Perforin-1 were decreased by greater than twice (p Conclusion: The data suggest that RT induces accumulation of PMN-MDSC in circulation and activation of STAT3 which positively regulates suppressive function of MDSC. Correspondingly, the percentage of T cells in circulation and the expression level of genes regulating cytotoxic functions were significantly reduced during RT. Taken together, the results suggest that RT could induce tolerogenic effects in HNSCC patients. Our further studies will test the feasibility of using the TLR9-targeted STAT3 inhibitors, alone or combination with checkpoint inhibitors, to overcome immune suppression and improve RT efficacy in syngeneic mouse models of HNSCC. Citation Format: Haejung Won, Sagus Sampath, Erminia Massarelli, Ellie Maghami, Marcin Kortylewski. Chemo-radiotherapy induces tolerogenic STAT3 signaling in circulating myeloid-derived suppressor cells in patients with head and neck squamous cell carcinoma (HNSCC) [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 35.

About 15%-20% of patients with non-small-cell lung cancer (NSCLC) present with early-stage disease without clinical evidence of lymph node metastasis.1 It is noteworthy that up to 80% of screen-detected lung cancers are detected as stage I disease.2 Surgical resection has been the traditional therapy for these patients, but recently, stereotactic body radiotherapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), has emerged as an alternative for patients who are either medically unfit for surgery or who choose not to undergo surgery. Numerous studies have demonstrated good rates of local control for SBRT in lung cancer.3-6 Despite the increasing use of SBRT as standard of care in early-stage lung cancer, there is limited information about patients' quality of life (QoL) with this treatment modality. For this patient population with substantial comorbid disease, the impact of treatment on QoL is of particular importance. Dutch investigators examined QoL before and after SBRT in 39 patients with lung cancer who received SBRT.7 There was no significant change in QoL scores except for an increase in emotional function after treatment. Respiratory symptoms, including dyspnea, chest pain, and cough were not significantly different. Another study from the Netherlands of 382 patients with lung cancer found no significant difference in quality of life scores after SBRT.8 Likewise, a prospective study of 21 patients from the Cleveland Clinic found no significant change in QoL and shortness of breath scores, despite a decrease in measured diffusion capacity on pulmonary function tests.9 Current published studies on SBRT are limited in their depth of QoL assessment. For example, the EORTC-QLQ-C30 has been used in several studies as the only main QoL instrument,6,7 while another study used only the FACT-L and UCSD shortness of breath questionnaire.9 The inclusion of symptom, social well-being, and functional well-being measures allows for a more in-depth perspective of overall QoL in SBRT patients. The purpose of this prospective study was to describe comprehensive QoL, symptoms and functional status in a cohort of early-stage, non-small-cell lung cancer (NSCLC) patients who were treated with SBRT.

Purpose: It is unknown whether established dose-volume parameters predictive of radiation pneumonitis (RP) are applicable to multiple disease sites. We investigated the factors associated with RP in a heterogeneous population of patients receiving thoracic radiation. Methods and materials: Ninety-nine patients who received thoracic radiation with helical tomotherapy were included in this retrospective chart review. Correlation studies were performed and significant clinical and dosimetric factors predictive for grade ≥ 3 RP were assessed using Cox multivariate analysis (MVA). Results: Fifty-two patients developed RP (grade 1-5), the majority having grade 1 toxicity. Five patients experienced grade ≥ 3 RP. Eleven patients developed ≥ 2 RP. The mean time to RP was 3 months. The sole predictor of RP on MVA was a lung volume receiving a maximum of 20 Gy (VS20) < 1600 cc’s (hazard ratio=14.7, p

Standard breast conservation therapy consists of lumpectomy and whole breast radiation with boost. The effectiveness of radiation in cases of positive margins is controversial. Two potential treatment-related factors are time to initiation of radiation and localization of the boost. Here, we examine long-term outcomes of positive margin cases treated with an upfront interstitial brachytherapy boost. This particular treatment arrangement may reduce those treatment-related effects on local control. Historically, a low dose interstitial implant was a common boost technique. One approach administered the boost before external beam. A review of 521 cases treated at our institution was conducted. Patients were selected for this study if they received an upfront brachytherapy boost and had close or positive margins. Forty-four breast cancers were identified. Median follow-up of survivors was 11.3 years (8.1-21.7). Implant was performed at lumpectomy (12) or axillary dissection (32). Margin statuses were: focal carcinoma at ink (37), multifocal carcinoma at ink (1), carcinoma