Thomas J. Dilling

This selection from the NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) focuses on targeted therapies and immunotherapies for metastatic NSCLC, because therapeutic recommendations are rapidly changing for metastatic disease. For example, new recommendations were added for atezolizumab, ceritinib, osimertinib, and pembrolizumab for the 2017 updates.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.

The NCCN Guidelines for Non–Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates in immunotherapy. For the 2020 update, all of the systemic therapy regimens have been categorized using a new preference stratification system; certain regimens are now recommended as “preferred interventions,” whereas others are categorized as either “other recommended interventions” or “useful under certain circumstances.”

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the targeted therapy and immunotherapy sections in the NCCN Guidelines. For the 2018 update, a new section on biomarkers was added.

Stage III non-small cell lung cancer (NSCLC) describes a heterogeneous population with disease presentation ranging from apparently resectable tumors with occult microscopic nodal metastases to unresectable, bulky nodal disease. This review updates the published clinical trials since the last American College of Chest Physicians guidelines to make treatment recommendations for this controversial subset of patients.Systematic searches were conducted through MEDLINE, Embase, and the Cochrane Database for Systematic Review up to December 2011, focusing primarily on randomized trials, selected meta-analyses, practice guidelines, and reviews.For individuals with stage IIIA or IIIB disease, good performance scores, and minimal weight loss, treatment with combined chemoradiotherapy results in better survival than radiotherapy alone. Consolidation chemotherapy or targeted therapy following definitive chemoradiation for stage IIIA is not supported. Neoadjuvant therapy followed by surgery is neither clearly better nor clearly worse than definitive chemoradiation. Most of the arguments made regarding patient selection for neoadjuvant therapy and surgical resection provide evidence for better prognosis but not for a beneficial impact of this treatment strategy; however, weak comparative data suggest a possible role if only lobectomy is needed in a center with a low perioperative mortality rate. The evidence supports routine platinum-based adjuvant chemotherapy following complete resection of stage IIIA lung cancer encountered unexpectedly at surgery. Postoperative radiotherapy improves local control without improving survival.Multimodality therapy is preferable in most subsets of patients with stage III lung cancer. Variability in the patients included in randomized trials limits the ability to combine results across studies and thus limits the strength of recommendations in many scenarios. Future trials are needed to investigate the roles of individualized chemotherapy, surgery in particular cohorts or settings, prophylactic cranial radiation, and adaptive radiation.

These NCCN Guidelines Insights focus on recent updates in the 2016 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC; Versions 1-4). These NCCN Guidelines Insights will discuss new immunotherapeutic agents, such as nivolumab and pembrolizumab, for patients with metastatic NSCLC. For the 2016 update, the NCCN panel recommends immune checkpoint inhibitors as preferred agents (in the absence of contraindications) for second-line and beyond (subsequent) therapy in patients with metastatic NSCLC (both squamous and nonsquamous histologies). Nivolumab and pembrolizumab are preferred based on improved overall survival rates, higher response rates, longer duration of response, and fewer adverse events when compared with docetaxel therapy.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC). Appropriate targeted therapy is very effective in patients with advanced NSCLC who have specific genetic alterations. Therefore, it is important to test tumor tissue from patients with advanced NSCLC to determine whether they have genetic alterations that make them candidates for specific targeted therapies. These NCCN Guidelines Insights describe the different testing methods currently available for determining whether patients have genetic alterations in the 2 most commonly actionable genetic alterations, notably anaplastic lymphoma kinase (ALK) gene rearrangements and sensitizing epidermal growth factor receptor (EGFR) mutations.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) focuses on the principles of radiation therapy (RT), which include the following: (1) general principles for early-stage, locally advanced, and advanced/metastatic NSCLC; (2) target volumes, prescription doses, and normal tissue dose constraints for early-stage, locally advanced, and advanced/palliative RT; and (3) RT simulation, planning, and delivery. Treatment recommendations should be made by a multidisciplinary team, including board-certified radiation oncologists who perform lung cancer RT as a prominent part of their practice.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for management of disease in patients with NSCLC. These NCCN Guidelines Insights focus on neoadjuvant and adjuvant (also known as perioperative) systemic therapy options for eligible patients with resectable NSCLC.

To report clinical and dosimetric factors predictive of radiation pneumonitis (RP) in patients receiving lung stereotactic body radiation therapy (SBRT) from a series of 240 patients.Of the 297 isocenters treating 263 patients, 240 patients (n=263 isocenters) had evaluable information regarding RP. Age, gender, current smoking status and pack-years, O2 use, Charlson Comorbidity Index, prior lung radiation therapy (yes/no), dose/fractionation, V5, V13, V20, Vprescription, mean lung dose, planning target volume (PTV), total lung volume, and PTV/lung volume ratio were recorded.Twenty-nine patients (11.0%) developed symptomatic pneumonitis (26 grade 2, 3 grade 3). The mean V20 was 6.5% (range, 0.4%-20.2%), and the average mean lung dose was 5.03 Gy (0.547-12.2 Gy). In univariable analysis female gender (P=.0257) and Charlson Comorbidity index (P=.0366) were significantly predictive of RP. Among dosimetric parameters, V5 (P=.0186), V13 (P=.0438), and Vprescription (where dose=60 Gy) (P=.0128) were significant. There was only a trend toward significance for V20 (P=.0610). Planning target volume/normal lung volume ratio was highly significant (P=.0024). In multivariable analysis the clinical factors of female gender, pack-years smoking, and larger gross internal tumor volume and PTV were predictive (P=.0094, .0312, .0364, and .052, respectively), but no dosimetric factors were significant.Rate of symptomatic RP was 11%. Our mean lung dose was <600 cGy in most cases and V20<10%. In univariable analysis, dosimetric factors were predictive, while tumor size (or tumor/lung volume ratio) played a role in multivariable and univariable and analysis, respectively.

Radiomics is being explored for potential applications in radiation therapy. How various imaging protocols affect quantitative image features is currently a highly active area of research. To assess the variability of image features derived from conventional [three-dimensional (3D)] and respiratory-gated (RG) positron emission tomography (PET)/computed tomography (CT) images of lung cancer patients, image features were computed from 23 lung cancer patients. Both protocols for each patient were acquired during the same imaging session. PET tumor volumes were segmented using an adaptive technique which accounted for background. CT tumor volumes were delineated with a commercial segmentation tool. Using RG PET images, the tumor center of mass motion, length, and rotation were calculated. Fifty-six image features were extracted from all images consisting of shape descriptors, first-order features, and second-order texture features. Overall, 26.6% and 26.2% of total features demonstrated less than 5% difference between 3D and RG protocols for CT and PET, respectively. Between 10 RG phases in PET, 53.4% of features demonstrated percent differences less than 5%. The features with least variability for PET were sphericity, spherical disproportion, entropy (first and second order), sum entropy, information measure of correlation 2, Short Run Emphasis (SRE), Long Run Emphasis (LRE), and Run Percentage (RPC); and those for CT were minimum intensity, mean intensity, Root Mean Square (RMS), Short Run Emphasis (SRE), and RPC. Quantitative analysis using a 3D acquisition versus RG acquisition (to reduce the effects of motion) provided notably different image feature values. This study suggests that the variability between 3D and RG features is mainly due to the impact of respiratory motion.

We previously developed a multigene expression model of tumor radiation sensitivity index (RSI) with clinical validation in multiple independent cohorts (breast, rectal, esophageal, and head and neck patients). The purpose of this study was to assess differences between RSI scores in primary colon cancer and metastases.Patients were identified from our institutional review board-approved prospective observational protocol. A total of 704 metastatic and 1362 primary lesions were obtained from a de-identified metadata pool. RSI was calculated using the previously published rank-based algorithm. An independent cohort of 29 lung or liver colon metastases treated with 60 Gy in 5 fractions stereotactic body radiation therapy (SBRT) was used for validation.The most common sites of metastases included liver (n=374; 53%), lung (n=116; 17%), and lymph nodes (n=40; 6%). Sixty percent of metastatic tumors, compared with 54% of primaries, were in the RSI radiation-resistant peak, suggesting metastatic tumors may be slightly more radiation resistant than primaries (P=.01). In contrast, when we analyzed metastases based on anatomical site, we uncovered large differences in RSI. The median RSIs for metastases in descending order of radiation resistance were ovary (0.48), abdomen (0.47), liver (0.43), brain (0.42), lung (0.32), and lymph nodes (0.31) (P<.0001). These findings were confirmed when the analysis was restricted to lesions from the same patient (n=139). In our independent cohort of treated lung and liver metastases, lung metastases had an improved local control rate compared to that in patients with liver metastases (2-year local control rate of 100% vs 73.0%, respectively; P=.026).Assessment of radiation sensitivity between primary and metastatic tissues of colon cancer histology revealed significant differences based on anatomical location of metastases. These initial results warrant validation in a larger clinical cohort.

For inoperable stage I (T1-T2N0) small cell lung cancer (SCLC), national guidelines recommend chemotherapy with or without conventionally fractionated radiation therapy. The present multi-institutional cohort study investigated the role of stereotactic ablative radiation therapy (SABR) for this population.The clinical and treatment characteristics, toxicities, outcomes, and patterns of failure were assessed in patients with histologically confirmed stage T1-T2N0M0 SCLC. Kaplan-Meier analysis was used to evaluate the survival outcomes. Univariate and multivariate analyses identified predictors of outcomes.From 24 institutions, 76 lesions were treated in 74 patients (median follow-up 18 months). The median age and tumor size was 72 years and 2.5 cm, respectively. Chemotherapy and prophylactic cranial irradiation were delivered in 56% and 23% of cases, respectively. The median SABR dose and fractionation was 50 Gy and 5 fractions. The 1- and 3-year local control rate was 97.4% and 96.1%, respectively. The median disease-free survival (DFS) duration was 49.7 months. The DFS rate was 58.3% and 53.2% at 1 and 3 years, respectively. The median, 1-year, and 3-year disease-specific survival was 52.3 months, 84.5%, and 64.4%, respectively. The median, 1-year, and 3-year overall survival (OS) was 17.8 months, 69.9%, and 34.0% respectively. Patients receiving chemotherapy experienced an increased median DFS (61.3 vs 9.0 months; P=.02) and OS (31.4 vs 14.3 months; P=.02). The receipt of chemotherapy independently predicted better outcomes for DFS/OS on multivariate analysis (P=.01). Toxicities were uncommon; 5.2% experienced grade ≥2 pneumonitis. Post-treatment failure was most commonly distant (45.8% of recurrence), followed by nodal (25.0%) and "elsewhere lung" (20.8%). The median time to each was 5 to 7 months.From the findings of the largest report of SABR for stage T1-T2N0 SCLC to date, SABR (≥50 Gy) with chemotherapy should be considered a standard option.

Frequently, three-dimensional (3D) conformal beams are used in lung cancer stereotactic body radiotherapy (SBRT). Recently, volumetric modulated arc therapy (VMAT) was introduced as a new treatment modality. VMAT techniques shorten delivery time, reducing the possibility of intrafraction target motion. However dose distributions can be quite different from standard 3D therapy. This study quantifies those differences, with focus on VMAT plans using unflattened photon beams.A total of 15 lung cancer patients previously treated with 3D or VMAT SBRT were randomly selected. For each patient, non-coplanar 3D, coplanar and non-coplanar VMAT and flattening filter free VMAT (FFF-VMAT) plans were generated to meet the same objectives with 50 Gy covering 95% of the PTV. Two dynamic arcs were used in each VMAT plan. The couch was set at ± 5° to the 0° straight position for the two non-coplanar arcs. Pinnacle version 9.0 (Philips Radiation Oncology, Fitchburg WI) treatment planning system with VMAT capabilities was used. We analyzed the conformity index (CI), which is the ratio of the total volume receiving at least the prescription dose to the target volume receiving at least the prescription dose; the conformity number (CN) which is the ratio of the target coverage to CI; and the gradient index (GI) which is the ratio of the volume of 50% of the prescription isodose to the volume of the prescription isodose; as well as the V20, V5, and mean lung dose (MLD). Paired non-parametric analysis of variance tests with post-tests were performed to examine the statistical significance of the differences of the dosimetric indices.Dosimetric indices CI, CN and MLD all show statistically significant improvement for all studied VMAT techniques compared with 3D plans (p < 0.05). V5 and V20 show statistically significant improvement for the FFF-VMAT plans compared with 3D (p < 0.001). GI is improved for the FFF-VMAT and the non-coplanar VMAT plans (p < 0.01 and p < 0.05 respectively) while the coplanar VMAT plans do not show significant difference compared to 3D plans. Dose to the target is typically more homogeneous in FFF-VMAT plans. FFF-VMAT plans require more monitor units than 3D or non-coplanar VMAT ones.Besides the advantage of faster delivery times, VMAT plans demonstrated better conformity to target, sharper dose fall-off in normal tissues and lower dose to normal lung than the 3D plans for lung SBRT. More monitor units are often required for FFF-VMAT plans.

Purpose: The effects of respiratory motion on the tumor dose can be divided into the gradient and interplay effects. While the interplay effect is likely to average out over a large number of fractions, it may play a role in hypofractionated [stereotactic body radiation therapy (SBRT)] treatments. This subject has been extensively studied for intensity modulated radiation therapy but less so for volumetric modulated arc therapy (VMAT), particularly in application to hypofractionated regimens. Also, no experimental study has provided full four‐dimensional (4D) dose reconstruction in this scenario. The authors demonstrate how a recently described motion perturbation method, with full 4D dose reconstruction, is applied to describe the gradient and interplay effects during VMAT lung SBRT treatments. Methods: VMAT dose delivered to a moving target in a patient can be reconstructed by applying perturbations to the treatment planning system‐calculated static 3D dose. Ten SBRT patients treated with 6 MV VMAT beams in five fractions were selected. The target motion (motion kernel) was approximated by 3D rigid body translation, with the tumor centroids defined on the ten phases of the 4DCT. The motion was assumed to be periodic, with the period T being an average from the empirical 4DCT respiratory trace. The real observed tumor motion (total displacement ≤8 mm) was evaluated first. Then, the motion range was artificially increased to 2 or 3 cm. Finally, T was increased to 60 s. While not realistic, making T comparable to the delivery time elucidates if the interplay effect can be observed. For a single fraction, the authors quantified the interplay effect as the maximum difference in the target dosimetric indices, most importantly the near‐minimum dose (D 99% ), between all possible starting phases. For the three‐ and five‐fractions, statistical simulations were performed when substantial interplay was found. Results: For the motion amplitudes and periods obtained from the 4DCT, the interplay effect is negligible (&lt;0.2%). It is also small (0.9% average, 2.2% maximum) when the target excursion increased to 2–3 cm. Only with large motion and increased period (60 s) was a significant interplay effect observed, with D 99% ranging from 16% low to 17% high. The interplay effect was statistically significantly lower for the three‐ and five‐fraction statistical simulations. Overall, the gradient effect dominates the clinical situation. Conclusions: A novel method was used to reconstruct the volumetric dose to a moving tumor during lung SBRT VMAT deliveries. With the studied planning and treatment technique for realistic motion periods, regardless of the amplitude, the interplay has nearly no impact on the near‐minimum dose. The interplay effect was observed, for study purposes only, with the period comparable to the VMAT delivery time.

Predicting recurrence after stereotactic body radiotherapy (SBRT) in non-small cell lung cancer (NSCLC) patients is problematic, but critical for the decision of following treatment. This study aims to investigate the association of imaging features derived from the first follow-up computed tomography (CT) on lung cancer patient outcomes following SBRT, and identify patients at high risk of recurrence.Fifty nine biopsy-proven non-small cell lung cancer patients were qualified for this study. The first follow-up CTs were performed about 3 months after SBRT (median time: 91 days). Imaging features included 34 manually scored radiological features (semantics) describing the lesion, lung and thorax and 219 quantitative imaging features (radiomics) extracted automatically after delineation of the lesion. Cox proportional hazard models and Harrel's C-index were used to explore predictors of overall survival (OS), recurrence-free survival (RFS), and loco-regional recurrence-free survival (LR-RFS). Five-fold cross validation was performed on the final prognostic model.The median follow-up time was 42 months. The model for OS contained Eastern Cooperative Oncology Group (ECOG) performance status (HR = 3.13, 95% CI: 1.17-8.41), vascular involvement (HR = 3.21, 95% CI: 1.29-8.03), lymphadenopathy (HR = 3.59, 95% CI: 1.58-8.16) and the 1st principle component of radiomic features (HR = 1.24, 95% CI: 1.02-1.51). The model for RFS contained vascular involvement (HR = 3.06, 95% CI: 1.40-6.70), vessel attachment (HR = 3.46, 95% CI: 1.65-7.25), pleural retraction (HR = 3.24, 95% CI: 1.41-7.42), lymphadenopathy (HR = 6.41, 95% CI: 2.58-15.90) and relative enhancement (HR = 1.40, 95% CI: 1.00-1.96). The model for LR-RFS contained vascular involvement (HR = 4.96, 95% CI: 2.23-11.03), lymphadenopathy (HR = 2.64, 95% CI: 1.19-5.82), circularity (F13, HR = 1.60, 95% CI: 1.10-2.32) and 3D Laws feature (F92, HR = 1.96, 95% CI: 1.35-2.83). Five-fold cross-validated the areas under the receiver operating characteristic curves (AUC) of these three models were all above 0.8.Our analysis reveals disease progression could be prognosticated as early as 3 months after SBRT using CT imaging features, and these features would be helpful in clinical decision-making.

Purpose Pencil beam (PB) and collapsed cone convolution (CCC) dose calculation algorithms differ significantly when used in the thorax. However, such differences have seldom been previously directly correlated with outcomes of lung stereotactic ablative body radiation (SABR). Methods and Materials Data for 201 non-small cell lung cancer patients treated with SABR were analyzed retrospectively. All patients were treated with 50 Gy in 5 fractions of 10 Gy each. The radiation prescription mandated that 95% of the planning target volume (PTV) receive the prescribed dose. One hundred sixteen patients were planned with BrainLab treatment planning software (TPS) with the PB algorithm and treated on a Novalis unit. The other 85 were planned on the Pinnacle TPS with the CCC algorithm and treated on a Varian linac. Treatment planning objectives were numerically identical for both groups. The median follow-up times were 24 and 17 months for the PB and CCC groups, respectively. The primary endpoint was local/marginal control of the irradiated lesion. Gray's competing risk method was used to determine the statistical differences in local/marginal control rates between the PB and CCC groups. Results Twenty-five patients planned with PB and 4 patients planned with the CCC algorithms to the same nominal doses experienced local recurrence. There was a statistically significant difference in recurrence rates between the PB and CCC groups (hazard ratio 3.4 [95% confidence interval: 1.18-9.83], Gray's test P=.019). The differences (Δ) between the 2 algorithms for target coverage were as follows: ΔD99GITV = 7.4 Gy, ΔD99PTV = 10.4 Gy, ΔV90GITV = 13.7%, ΔV90PTV = 37.6%, ΔD95PTV = 9.8 Gy, and ΔDISO = 3.4 Gy. GITV = gross internal tumor volume. Conclusions Local control in patients receiving who were planned to the same nominal dose with PB and CCC algorithms were statistically significantly different. Possible alternative explanations are described in the report, although they are not thought likely to explain the difference. We conclude that the difference is due to relative dosimetric underdosing of tumors with the PB algorithm. Pencil beam (PB) and collapsed cone convolution (CCC) dose calculation algorithms differ significantly when used in the thorax. However, such differences have seldom been previously directly correlated with outcomes of lung stereotactic ablative body radiation (SABR). Data for 201 non-small cell lung cancer patients treated with SABR were analyzed retrospectively. All patients were treated with 50 Gy in 5 fractions of 10 Gy each. The radiation prescription mandated that 95% of the planning target volume (PTV) receive the prescribed dose. One hundred sixteen patients were planned with BrainLab treatment planning software (TPS) with the PB algorithm and treated on a Novalis unit. The other 85 were planned on the Pinnacle TPS with the CCC algorithm and treated on a Varian linac. Treatment planning objectives were numerically identical for both groups. The median follow-up times were 24 and 17 months for the PB and CCC groups, respectively. The primary endpoint was local/marginal control of the irradiated lesion. Gray's competing risk method was used to determine the statistical differences in local/marginal control rates between the PB and CCC groups. Twenty-five patients planned with PB and 4 patients planned with the CCC algorithms to the same nominal doses experienced local recurrence. There was a statistically significant difference in recurrence rates between the PB and CCC groups (hazard ratio 3.4 [95% confidence interval: 1.18-9.83], Gray's test P=.019). The differences (Δ) between the 2 algorithms for target coverage were as follows: ΔD99GITV = 7.4 Gy, ΔD99PTV = 10.4 Gy, ΔV90GITV = 13.7%, ΔV90PTV = 37.6%, ΔD95PTV = 9.8 Gy, and ΔDISO = 3.4 Gy. GITV = gross internal tumor volume. Local control in patients receiving who were planned to the same nominal dose with PB and CCC algorithms were statistically significantly different. Possible alternative explanations are described in the report, although they are not thought likely to explain the difference. We conclude that the difference is due to relative dosimetric underdosing of tumors with the PB algorithm.

IntroductionWe assessed the radiosensitivity of lung metastases on the basis of primary histologic type by using a validated gene signature and model lung metastases for the gnomically adjusted radiation dose (GARD).MethodsTissue samples were identified from our prospective observational protocol. The radiosensitivity index (RSI) 10-gene assay was run on samples and calculated alongside the GARD by using the previously published algorithms. A cohort of 105 patients with 137 lung metastases treated with stereotactic body radiation therapy (SBRT) at our institution was used for clinical correlation.ResultsA total of 138 unique metastatic lung lesions from our institution’s tissue biorepository were identified for inclusion. There were significant differences in the RSI of lung metastases on the basis of histology. In order of decreasing radioresistance, the median RSIs for the various histologic types of cancer were endometrial adenocarcinoma (0.49), soft-tissue sarcoma (0.47), melanoma (0.44), rectal adenocarcinoma (0.43), renal cell carcinoma (0.33), head and neck squamous cell cancer (0.33), colon adenocarcinoma (0.32), and breast adenocarcinoma (0.29) (p = 0.002). We modeled the GARD for these samples and identified the biologically effective dose necessary to optimize local control. The 12- and 24-month Kaplan-Meier rates of local control for radioresistant versus radiosensitive histologic types from our clinical correlation cohort after lung SBRT were 92%/87% and 100%, respectively (p = 0.02).ConclusionsIn this analysis, we have noted significant differences in radiosensitivity on the basis of primary histologic type of lung metastases and have modeled the biologically effective dose necessary to optimize local control. This study suggests that primary histologic type may be an additional factor to consider in selection of SBRT dose to the lung and that dose personalization may be feasible.

To investigate whether imaging features from pretreatment planning CT scans are associated with overall survival (OS), recurrence-free survival (RFS), and loco-regional recurrence-free survival (LR-RFS) after stereotactic body radiotherapy (SBRT) among nonsmall-cell lung cancer (NSCLC) patients.A total of 92 patients (median age: 73 yr) with stage I or IIA NSCLC were qualified for this study. A total dose of 50 Gy in five fractions was the standard treatment. Besides clinical characteristics, 24 "semantic" image features were manually scored based on a point scale (up to 5) and 219 computer-derived "radiomic" features were extracted based on whole tumor segmentation. Statistical analysis was performed using Cox proportional hazards model and Harrell's C-index, and the robustness of final prognostic model was assessed using tenfold cross validation by dichotomizing patients according to the survival or recurrence status at 24 months.Two-year OS, RFS and LR-RFS were 69.95%, 41.3%, and 51.85%, respectively. There was an improvement of Harrell's C-index when adding imaging features to a clinical model. The model for OS contained the Eastern Cooperative Oncology Group (ECOG) performance status [Hazard Ratio (HR) = 2.78, 95% Confidence Interval (CI): 1.37-5.65], pleural retraction (HR = 0.27, 95% CI: 0.08-0.92), F2 (short axis × longest diameter, HR = 1.72, 95% CI: 1.21-2.44) and F186 (Hist-Energy-L1, HR = 1.27, 95% CI: 1.00-1.61); The prognostic model for RFS contained vessel attachment (HR = 2.13, 95% CI: 1.24-3.64) and F2 (HR = 1.69, 95% CI: 1.33-2.15); and the model for LR-RFS contained the ECOG performance status (HR = 2.01, 95% CI: 1.12-3.60) and F2 (HR = 1.67, 95% CI: 1.29-2.18).Imaging features derived from planning CT demonstrate prognostic value for recurrence following SBRT treatment, and might be helpful in patient stratification.

Consolidative thoracic radiation therapy (TRT) has been shown to improve outcomes for patients with extensive stage small cell lung cancer. We hypothesized that the addition of ipilimumab (IPI) and nivolumab (NIVO) after TRT would improve outcomes for patients with extensive stage small cell lung cancer.Eligibility required stable disease or better after platinum doublet chemotherapy. Study therapy included consolidative TRT to 30 Gy in 10 fractions, targeting residual primary tumor and initially involved regional lymph nodes. Two weeks after TRT, patients received concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks for 4 doses followed by NIVO monotherapy (480 mg) every 4 weeks until progression or up to 1 year.The study enrolled 21 patients, with 6-month progression-free survival (PFS) of 24% (90% confidence interval [CI], 11%-40%) and a median PFS of 4.5 months (95% CI, 2.7%-4.6%). The 12-month overall survival (OS) was 48% (95% CI, 29%-64%) with a median OS of 11.7 months (95% CI, 4.7%-16.0%). Fifty-two percent of patients had ≥1 possibly related grade 3 to 4 immune-related adverse event. Grade 3 pulmonary and gastrointestinal immune-related adverse events were recorded in 19% and 24% of patients, respectively. Exploratory analysis showed increased cytotoxic T cell (CD3+CD8+) tumor infiltration was associated with favorable PFS (P = .01) and OS (P = .02). Reduction in peripheral blood CD3+CD8+ from baseline to after first dose of IPI/NIVO was associated with improved PFS (P = .02) and OS (P = .02).Consolidative IPI and NIVO after platinum-based chemotherapy and TRT demonstrated a toxicity profile consistent with the known adverse events attributable to IPI and NIVO. Although the study regimen did not significantly improve PFS, the OS was higher than historic expectations. CD3+CD8+ tumor infiltration and migration may identify patients most likely to have improved outcomes in small cell lung cancer.

Cancer sequencing efforts have revealed that cancer is the most complex and heterogeneous disease that affects humans. However, radiation therapy (RT), one of the most common cancer treatments, is prescribed on the basis of an empirical one-size-fits-all approach. We propose that the field of radiation oncology is operating under an outdated null hypothesis: that all patients are biologically similar and should uniformly respond to the same dose of radiation.We have previously developed the genomic-adjusted radiation dose, a method that accounts for biological heterogeneity and can be used to predict optimal RT dose for an individual patient. In this article, we use genomic-adjusted radiation dose to characterize the biological imprecision of one-size-fits-all RT dosing schemes that result in both over- and under-dosing for most patients treated with RT. To elucidate this inefficiency, and therefore the opportunity for improvement using a personalized dosing scheme, we develop a patient-specific competing hazards style mathematical model combining the canonical equations for tumor control probability and normal tissue complication probability. This model simultaneously optimizes tumor control and toxicity by personalizing RT dose using patient-specific genomics.Using data from two prospectively collected cohorts of patients with NSCLC, we validate the competing hazards model by revealing that it predicts the results of RTOG 0617. We report how the failure of RTOG 0617 can be explained by the biological imprecision of empirical uniform dose escalation which results in 80% of patients being overexposed to normal tissue toxicity without potential tumor control benefit.Our data reveal a tapestry of radiosensitivity heterogeneity, provide a biological framework that explains the failure of empirical RT dose escalation, and quantify the opportunity to improve clinical outcomes in lung cancer by incorporating genomics into RT.

The recent results from the Nordic-HILUS study indicate stereotactic body radiation therapy (SBRT) is associated with high-grade toxicity for ultracentral (UC) tumors. We hypothesized that magnetic resonance-guided SBRT (MRgSBRT) or hypofractionated radiation therapy (MRgHRT) enables the safe delivery of high-dose radiation to central and UC lung lesions.Patients with UC or central lesions were treated with MRgSBRT/MRgHRT with real-time gating or adaptation. Central lesions were defined as per the Radiation Therapy Oncology Group and UC as per the HILUS study definitions: (1) group A or tumors less than 1 cm from the trachea and/or mainstem bronchi; or (2) group B or tumors less than 1 cm from the lobar bronchi. The Kaplan-Meier estimate and log-rank test were used to estimate survival. Associations between toxicities and other patient factors were tested using the Mann-Whitney U test and Fisher's exact test.A total of 47 patients were included with a median follow-up of 22.9 months (95% confidence interval: 16.4-29.4). Most (53%) had metastatic disease. All patients had central lesions and 55.3% (n = 26) had UC group A. The median distance from the proximal bronchial tree was 6.0 mm (range: 0.0-19.0 mm). The median biologically equivalent dose (α/β = 10) was 105 Gy (range: 75-151.2). The most common radiation schedule was 60 Gy in eight fractions (40.4%). Most (55%) had previous systemic therapy, 32% had immunotherapy and 23.4% had previous thoracic radiation therapy. There were 16 patients who underwent daily adaptation. The 1-year overall survival was 82% (median = not reached), local control 87% (median = not reached), and progression-free survival 54% (median = 15.1 mo, 95% confidence interval: 5.1-25.1). Acute toxicity included grade 1 (26%) and grade 2 (21%) with only two patients experiencing grade 3 (4.3%) in the long term. No grade 4 or 5 toxicities were seen.Previous studies noted high rates of toxicity after SBRT to central and UC lung lesions, with reports of grade 5 toxicities. In our cohort, the use of MRgSBRT/MRgHRT with high biologically effective doses was well tolerated, with two grade 3 toxicities and no grade 4/5.

Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor antibody, has been approved in the second-line treatment of metastatic squamous NSCLC.1 However, only a minority of patients respond to anti–PD-1 immunotherapy, and the mechanisms of de novo and adaptive resistance to nivolumab are unclear. There are limited treatment options to rescue immunotherapy-refractory patients. We herein describe a patient who was nivolumab refractory and subsequently demonstrated global response after a course of palliative thoracic radiotherapy (RT).

Modern radiation therapy is delivered with great precision, in part by relying on high-resolution multidimensional anatomic imaging to define targets in space and time. The development of quantitative imaging (QI) modalities capable of monitoring biologic parameters could provide deeper insight into tumor biology and facilitate more personalized clinical decision-making. The Quantitative Imaging Network (QIN) was established by the National Cancer Institute to advance and validate these QI modalities in the context of oncology clinical trials. In particular, the QIN has significant interest in the application of QI to widen the therapeutic window of radiation therapy. QI modalities have great promise in radiation oncology and will help address significant clinical needs, including finer prognostication, more specific target delineation, reduction of normal tissue toxicity, identification of radioresistant disease, and clearer interpretation of treatment response. Patient-specific QI is being incorporated into radiation treatment design in ways such as dose escalation and adaptive replanning, with the intent of improving outcomes while lessening treatment morbidities. This review discusses the current vision of the QIN, current areas of investigation, and how the QIN hopes to enhance the integration of QI into the practice of radiation oncology. Modern radiation therapy is delivered with great precision, in part by relying on high-resolution multidimensional anatomic imaging to define targets in space and time. The development of quantitative imaging (QI) modalities capable of monitoring biologic parameters could provide deeper insight into tumor biology and facilitate more personalized clinical decision-making. The Quantitative Imaging Network (QIN) was established by the National Cancer Institute to advance and validate these QI modalities in the context of oncology clinical trials. In particular, the QIN has significant interest in the application of QI to widen the therapeutic window of radiation therapy. QI modalities have great promise in radiation oncology and will help address significant clinical needs, including finer prognostication, more specific target delineation, reduction of normal tissue toxicity, identification of radioresistant disease, and clearer interpretation of treatment response. Patient-specific QI is being incorporated into radiation treatment design in ways such as dose escalation and adaptive replanning, with the intent of improving outcomes while lessening treatment morbidities. This review discusses the current vision of the QIN, current areas of investigation, and how the QIN hopes to enhance the integration of QI into the practice of radiation oncology.

We hypothesized that concurrent ipilimumab with chemoradiationtherapy (chemoRT) followed by maintenance nivolumab would be safe for patients with unresectable stage III non-small cell lung cancer (NSCLC). We aimed to assess the safety (phase 1) and the 12-month progression-free survival (PFS) (phase 2) in a multi-institution prospective trial.Eligible patients had unresectable stage III NSCLC. The treatment included platinum doublet chemotherapy with concurrent thoracic radiation therapy to 60 Gy in 30 fractions and ipilimumab (1 mg/kg) delivered during weeks 1 and 4. After chemoRT, maintenance nivolumab (480 mg) was given every 4 weeks for up to 12 cycles. Adverse events (AEs) were assessed according to the Common Terminology Criteria for Adverse Events, version 5.0. Survival analyses were performed with Kaplan Meier (KM) methods and log-rank tests.The trial was discontinued early after enrolling 19 patients without proceeding to the phase 2 component because of unacceptable toxicity. Sixteen patients (84%) had grade ≥3 (G3+) possible treatment-related toxicity, most commonly pulmonary AEs (n = 8, 42%). Fourteen patients (74%) discontinued study therapy early because of AEs (n = 12, 63%) or patient choice (n = 2, 11%). Eleven patients (58%) experienced G2+ pulmonary toxicity with median time to onset 4.1 months (95% CI 2.6-not reached [NR]), and 12-month freedom from G2+ pulmonary toxicity 37% (95% CI, 16-59). Five patients had G5 AEs, including 3 with G5 pulmonary AEs (1 respiratory failure with pneumonitis and pulmonary embolism, 1 pneumonia/chronic obstructive pulmonary disease exacerbation, 1 pulmonary fibrosis). Despite toxicities, the median PFS was 19.2 months (95% CI 6.1-NR) and the median overall survival was NR (95% CI 6.1-NR) with median follow-up of 30.1 months by the reverse KM method.Concurrent ipilimumab with chemoRT for unresectable stage III NSCLC is associated with pulmonary toxicity that may limit opportunities for improved outcomes. Future studies aiming to incorporate ipilimumab or other anti-CTLA4 therapies into management of unresectable stage III NSCLC should consider careful measures to minimize toxicity risk.

Evans, S. M., Jenkins, K. W., Jenkins, W. T., Dilling, T., Judy, K. D., Schrlau, A., Judkins, A., Hahn, S. M. and Koch, C. J. Imaging and Analytical Methods as Applied to the Evaluation of Vasculature and Hypoxia in Human Brain Tumors. Radiat. Res. 170, 677–690 (2008).Tissue hypoxia results from the interaction of cellular respiration, vascular oxygen carrying capacity, and vessel distribution. We studied the relationship between tumor vasculature and regions of low pO2 using quantitative analysis of binding of the 2-nitroimidazole EF5 given to patients intravenously (21 mg/kg) approximately 24 h preceding surgery. We describe new computer algorithms for determining EF5 binding as a function of radial distance from individual blood vessels and converting this value to tissue pO2. Tissues from six human brain tumors were assessed. In a hemangiopericytoma, a WHO Grade 2 and WHO Grade 3 glial brain tumor, all tissue pO2 values calculated by EF5 binding were >20 mmHg (described as “physiologically oxygenated”). In these three tumors, EF5 binding gradients (measured as a function of distance from each observed vessel) were low, with small positive and negative values averaging close to zero. Much lower tissue oxygen levels were found, including near some vessels, in glioblastomas. Gradients of EF5 binding away from vessels were larger in glioblastomas than in the low-grade tumors, but positive and negative values again averaged to near zero. Based on these preliminary data, we hypothesize a new paradigm for tumor blood flow in human brain tumors whereby in-flowing and out-flowing blood patterns may have contrasting effects on average tissue EF5 (and by inference, oxygen) gradients. Our studies also imply that neither distance to the nearest blood vessel nor distance from each observed blood vessel provide reliable estimates of tissue pO2.

Conventionally fractionated radiotherapy is delivered in 1.8- to 2.0-Gy fractions. With increases in understanding of radiation and tumor biology, various alterations of radiotherapy schedules have been tested in clinical trials and are now regarded by some as standard treatment options. Hyperfractionation is delivered through a greater number of smaller treatment doses. Accelerated fractionation decreases the amount of time over which radiotherapy is delivered typically by increasing the number of treatments per day. Hypofractionation decreases the number of fractions delivered by increasing daily treatment doses. Furthermore, many of these schedules have been tested with concurrent chemotherapy regimens. In this review, we summarize the major clinical studies that have been conducted on altered fractionation in various disease sites.

This report evaluates stereotactic body radiotherapy (SBRT) in the treatment of early-stage non-small-cell lung cancer (NSCLC). Stereotactic refers to precise positioning of the target volume in three dimensions. The target volume is usually localized by using some external frame of reference related to the treatment delivery system. The term “body” is used to distinguish the technique from treatments performed in the brain and skull base called intracranial stereotactic radiosurgery (SRS) or intracranial stereotactic RT (SRT).

Purpose We investigated the impact of race, in conjunction with gender and partner status, on locoregional control (LRC) and overall survival (OS) in three head and neck trials conducted by the Radiation Therapy Oncology Group (RTOG). Methods and Materials Patients from RTOG studies 9003, 9111, and 9703 were included. Patients were stratified by treatment arms. Covariates of interest were partner status (partnered vs. non-partnered), race (white vs. non-white), and sex (female vs. male). Chi-square testing demonstrated homogeneity across treatment arms. Hazards ratio (HR) was used to estimate time to event outcome. Unadjusted and adjusted HRs were calculated for all covariates with associated 95% confidence intervals (CIs) and p values. Results A total of 1,736 patients were analyzed. Unpartnered males had inferior OS rates compared to partnered females (adjusted HR = 1.22, 95% CI, 1.09–1.36), partnered males (adjusted HR = 1.20, 95% CI, 1.09–1.28), and unpartnered females (adjusted HR = 1.20, 95% CI, 1.09–1.32). White females had superior OS compared with white males, non-white females, and non-white males. Non-white males had inferior OS compared to white males. Partnered whites had improved OS relative to partnered non-white, unpartnered white, and unpartnered non-white patients. Unpartnered males had inferior LRC compared to partnered males (adjusted HR = 1.26, 95% CI, 1.09–1.46) and unpartnered females (adjusted HR = 1.30, 95% CI, 1.05–1.62). White females had LRC superior to non-white males and females. White males had improved LRC compared to non-white males. Partnered whites had improved LRC compared to partnered and unpartnered non-white patients. Unpartnered whites had improved LRC compared to unpartnered non-whites. Conclusions Race, gender, and partner status had impacts on both OS and locoregional failure, both singly and in combination. We investigated the impact of race, in conjunction with gender and partner status, on locoregional control (LRC) and overall survival (OS) in three head and neck trials conducted by the Radiation Therapy Oncology Group (RTOG). Patients from RTOG studies 9003, 9111, and 9703 were included. Patients were stratified by treatment arms. Covariates of interest were partner status (partnered vs. non-partnered), race (white vs. non-white), and sex (female vs. male). Chi-square testing demonstrated homogeneity across treatment arms. Hazards ratio (HR) was used to estimate time to event outcome. Unadjusted and adjusted HRs were calculated for all covariates with associated 95% confidence intervals (CIs) and p values. A total of 1,736 patients were analyzed. Unpartnered males had inferior OS rates compared to partnered females (adjusted HR = 1.22, 95% CI, 1.09–1.36), partnered males (adjusted HR = 1.20, 95% CI, 1.09–1.28), and unpartnered females (adjusted HR = 1.20, 95% CI, 1.09–1.32). White females had superior OS compared with white males, non-white females, and non-white males. Non-white males had inferior OS compared to white males. Partnered whites had improved OS relative to partnered non-white, unpartnered white, and unpartnered non-white patients. Unpartnered males had inferior LRC compared to partnered males (adjusted HR = 1.26, 95% CI, 1.09–1.46) and unpartnered females (adjusted HR = 1.30, 95% CI, 1.05–1.62). White females had LRC superior to non-white males and females. White males had improved LRC compared to non-white males. Partnered whites had improved LRC compared to partnered and unpartnered non-white patients. Unpartnered whites had improved LRC compared to unpartnered non-whites. Race, gender, and partner status had impacts on both OS and locoregional failure, both singly and in combination.

The effect of noise on image features has yet to be studied in depth. Our objective was to explore how significantly image features are affected by the addition of uncorrelated noise to an image. The signal-to-noise ratio and noise power spectrum were calculated for a positron emission tomography/computed tomography scanner using a Ge-68 phantom. The conventional and respiratory-gated positron emission tomography/computed tomography images of 31 patients with lung cancer were retrospectively examined. Multiple sets of noise images were created for each original image by adding Gaussian noise of varying standard deviation equal to 2.5%, 4.0%, and 6.0% of the maximum intensity for positron emission tomography images and 10, 20, 50, 80, and 120 Hounsfield units for computed tomography images. Image features were extracted from all images, and percentage differences between the original image and the noise image feature values were calculated. These features were then categorized according to the noise sensitivity. The contour-dependent shape descriptors averaged below 4% difference in positron emission tomography and below 13% difference in computed tomography between noise and original images. Gray level size zone matrix features were the most sensitive to uncorrelated noise exhibiting average differences >200% for conventional and respiratory-gated images in computed tomography and 90% in positron emission tomography. Image feature differences increased as the noise level increased for shape, intensity, and gray-level co-occurrence matrix features in positron emission tomography and for gray-level co-occurrence matrix and gray-level size zone matrix features in conventional computed tomography. Investigators should be aware of the noise effects on image features.

Background: Adaptive treatment strategies that can dynamically react to individual cancer progression can provide effective personalized care. Longitudinal multi-omics information, paired with an artificially intelligent clinical decision support system (AI-CDSS) can assist clinicians in determining optimal therapeutic options and treatment adaptations. However, AI-CDSS is not perfectly accurate, as such, clinicians' over/under reliance on AI may lead to unintended consequences, ultimately failing to develop optimal strategies. To investigate such collaborative decision-making process, we conducted a Human-AI interaction case study on response-adaptive radiotherapy (RT). Methods: We designed and conducted a two-phase study for two disease sites and two treatment modalities—adaptive RT for non-small cell lung cancer (NSCLC) and adaptive stereotactic body RT for hepatocellular carcinoma (HCC)—in which clinicians were asked to consider mid-treatment modification of the dose per fraction for a number of retrospective cancer patients without AI-support (Unassisted Phase) and with AI-assistance (AI-assisted Phase). The AI-CDSS graphically presented trade-offs in tumor control and the likelihood of toxicity to organs at risk, provided an optimal recommendation, and associated model uncertainties. In addition, we asked for clinicians' decision confidence level and trust level in individual AI recommendations and encouraged them to provide written remarks. We enrolled 13 evaluators (radiation oncology physicians and residents) from two medical institutions located in two different states, out of which, 4 evaluators volunteered in both NSCLC and HCC studies, resulting in a total of 17 completed evaluations (9 NSCLC, and 8 HCC). To limit the evaluation time to under an hour, we selected 8 treated patients for NSCLC and 9 for HCC, resulting in a total of 144 sets of evaluations (72 from NSCLC and 72 from HCC). Evaluation for each patient consisted of 8 required inputs and 2 optional remarks, resulting in up to a total of 1440 data points. Results: AI-assistance did not homogeneously influence all experts and clinical decisions. From NSCLC cohort, 41 (57%) decisions and from HCC cohort, 34 (47%) decisions were adjusted after AI assistance. Two evaluations (12%) from the NSCLC cohort had zero decision adjustments, while the remaining 15 (88%) evaluations resulted in at least two decision adjustments. Decision adjustment level positively correlated with dissimilarity in decision-making with AI [NSCLC: ρ = 0.53 (p &lt; 0.001); HCC: ρ = 0.60 (p &lt; 0.001)] indicating that evaluators adjusted their decision closer towards AI recommendation. Agreement with AI-recommendation positively correlated with AI Trust Level [NSCLC: ρ = 0.59 (p &lt; 0.001); HCC: ρ = 0.7 (p &lt; 0.001)] indicating that evaluators followed AI's recommendation if they agreed with that recommendation. The correlation between decision confidence changes and decision adjustment level showed an opposite trend [NSCLC: ρ = -0.24 (p = 0.045), HCC: ρ = 0.28 (p = 0.017)] reflecting the difference in behavior due to underlying differences in disease type and treatment modality. Decision confidence positively correlated with the closeness of decisions to the standard of care (NSCLC: 2 Gy/fx; HCC: 10 Gy/fx) indicating that evaluators were generally more confident in prescribing dose fractionations more similar to those used in standard clinical practice. Inter-evaluator agreement increased with AI-assistance indicating that AI-assistance can decrease inter-physician variability. The majority of decisions were adjusted to achieve higher tumor control in NSCLC and lower normal tissue complications in HCC. Analysis of evaluators' remarks indicated concerns for organs at risk and RT outcome estimates as important decision-making factors. Conclusions: Human-AI interaction depends on the complex interrelationship between expert's prior knowledge and preferences, patient's state, disease site, treatment modality, model transparency, and AI's learned behavior and biases. The collaborative decision-making process can be summarized as follows: (i) some clinicians may not believe in an AI system, completely disregarding its recommendation, (ii) some clinicians may believe in the AI system but will critically analyze its recommendations on a case-by-case basis; (iii) when a clinician finds that the AI recommendation indicates the possibility for better outcomes they will adjust their decisions accordingly; and (iv) When a clinician finds that the AI recommendation indicate a worse possible outcome they will disregard it and seek their own alternative approach.

Abstract Thoracic cancer treatment presents dosimetric difficulties due to respiratory motion and lung inhomogeneity. Monte Carlo and deformable image registration techniques have been proposed to be used in four-dimensional (4D) dose calculations to overcome the difficulties. This study validates the 4D Monte Carlo dosimetry with measurement, compares 4D dosimetry of different tumor sizes and tumor motion ranges, and demonstrates differences of dose-volume histograms (DVH) with the number of respiratory phases that are included in 4D dosimetry. BEAMnrc was used in dose calculations while an optical flow algorithm was used in deformable image registration and dose mapping. Calculated and measured doses of a moving phantom agreed within 3% at the center of the moving gross tumor volumes (GTV). 4D CT image sets of lung cancer cases were used in the analysis of 4D dosimetry. For a small tumor (12.5 cm 3 ) with motion range of 1.5 cm, reduced tumor volume coverage was observed in the 4D dose with a beam margin of 1 cm. For large tumors and tumors with small motion range (around 1 cm), the 4D dosimetry did not differ appreciably from the static plans. The dose-volume histogram (DVH) analysis shows that the inclusion of only extreme respiratory phases in 4D dosimetry is a reasonable approximation of all-phase inclusion for lung cancer cases similar to the ones studied, which reduces the calculation in 4D dosimetry.

Purpose Current guidelines recommend surgery as standard of care for primary lung neuroendocrine tumor (LNET). Given that LNET is a rare clinical entity, there is a lack of literature regarding treatment of LNET with stereotactic body radiation therapy (SBRT). We hypothesized that SBRT could lead to effective locoregional tumor control and long-term outcomes. Methods and Materials We retrospectively reviewed 48 tumors in 46 patients from 11 institutions with a histologically confirmed diagnosis of LNET, treated with primary radiation therapy. Data were collected for patients treated nonoperatively with primary radiation therapy between 2006 and 2020. Patient records were reviewed for lesion characteristics and clinical risk factors. Kaplan-Meier analysis, log-rank tests, and Cox multivariate models were used to compare outcomes. Results Median age at treatment was 71 years and mean tumor size was 2 cm. Thirty-two lesions were typical carcinoid histology, 7 were atypical, and 9 were indeterminate. The most common SBRT fractionation schedule was 50 to 60 Gy in 5 daily fractions. Overall survival at 3, 6, and 9 years was 64%, 43%, and 26%, respectively. Progression-free survival at 3, 6, and 9 years was 88%, 78%, and 78%, respectively. Local control at 3, 6, and 9 years was 97%, 91%, and 91%, respectively. There was 1 regional recurrence in a paraesophageal lymph node. No grade 3 or higher toxicity was identified. Conclusions This is the largest series evaluating outcomes in patients with LNET treated with SBRT. This treatment is well tolerated, provides excellent locoregional control, and should be offered as an alternative to surgical resection for patients with early-stage LNET, particularly those who may not be ideal surgical candidates. Current guidelines recommend surgery as standard of care for primary lung neuroendocrine tumor (LNET). Given that LNET is a rare clinical entity, there is a lack of literature regarding treatment of LNET with stereotactic body radiation therapy (SBRT). We hypothesized that SBRT could lead to effective locoregional tumor control and long-term outcomes. We retrospectively reviewed 48 tumors in 46 patients from 11 institutions with a histologically confirmed diagnosis of LNET, treated with primary radiation therapy. Data were collected for patients treated nonoperatively with primary radiation therapy between 2006 and 2020. Patient records were reviewed for lesion characteristics and clinical risk factors. Kaplan-Meier analysis, log-rank tests, and Cox multivariate models were used to compare outcomes. Median age at treatment was 71 years and mean tumor size was 2 cm. Thirty-two lesions were typical carcinoid histology, 7 were atypical, and 9 were indeterminate. The most common SBRT fractionation schedule was 50 to 60 Gy in 5 daily fractions. Overall survival at 3, 6, and 9 years was 64%, 43%, and 26%, respectively. Progression-free survival at 3, 6, and 9 years was 88%, 78%, and 78%, respectively. Local control at 3, 6, and 9 years was 97%, 91%, and 91%, respectively. There was 1 regional recurrence in a paraesophageal lymph node. No grade 3 or higher toxicity was identified. This is the largest series evaluating outcomes in patients with LNET treated with SBRT. This treatment is well tolerated, provides excellent locoregional control, and should be offered as an alternative to surgical resection for patients with early-stage LNET, particularly those who may not be ideal surgical candidates.

Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term "malignant" is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.

Introduction Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. However, the optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown. Methods In this multi-institutional international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary endpoint) and overall survival (OS, secondary endpoint). Treatment-related adverse events (trAE) during consolidation treatment were defined using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Multivariable Cox regression analysis was used. Results Of 136 patients with stage III EGFRmut NSCLC treated with definitive concurrent CRT, 56 received consolidation durvalumab, 33 received consolidation osimertinib, and 47 received observation alone. Baseline characteristics were similar across the 3 cohorts. With a median follow-up of 46 months for the entire cohort, the median duration of treatment was not reached (NR) for osimertinib (Inter-quartile range [IQR]: NR-NR) and was 5.5 (IQR:2.4-10.8) months with durvalumab. After adjusting for nodal status, stage III A/B/C, and age, patients treated with consolidation osimertinib had significantly longer 24-month rwPFS compared to those in the durvalumab or observation cohorts (osimertinib: 86%, durvalumab: 30%, observation: 27%, p<0.001 for both comparisons). There was no difference in rwPFS between durvalumab and the observation cohort. No significant difference in OS across the 3 cohorts was detected, possibly due to the limited follow-up. Any grade trAE occurred in 52% (2 [6.1%] grade ≥3) and 48% (10 [18%] grade ≥3) of patients treated with osimertinib and durvalumab, respectively. Of 45 patients who progressed on consolidation durvalumab, 37 (82%) subsequently received EGFR tyrosine kinase inhibitors (TKIs). Of these, 14 (38%) patients developed trAEs including 5 pneumonitis (14%; 2 [5.4%] grade ≥3) and 5 diarrhea (14%; 1 [2.7%] grade ≥3). Conclusions This study suggests that among patients with stage III unresectable NSCLC with a sensitizing EGFR mutation, consolidation osimertinib was associated with significantly longer rwPFS than durvalumab or observation. No unanticipated safety signals were observed with consolidation osimertinib.

Radiotherapy outcome modelling often suffers from class imbalance in the modelled endpoints. One of the main options to address this issue is by introducing new synthetically generated datapoints, using generative models, such as Denoising Diffusion Probabilistic Models (DDPM). In this study, we implemented DDPM to improve performance of a tumor local control model, trained on imbalanced dataset, and compare this approach with other common techniques.A dataset of 535 NSCLC patients treated with SBRT (50 Gy/5 fractions) was used to train a deep learning outcome model for tumor local control prediction. The dataset included complete treatment planning data (planning CT images, 3D planning dose distribution and patient demographics) with sparsely distributed endpoints (6-7 % experiencing local failure). Consequently, we trained a novel conditional 3D DDPM model to generate synthetic treatment planning data. Synthetically generated treatment planning datapoints were used to supplement the real training dataset and the improvement in the model's performance was studied. Obtained results were also compared to other common techniques for class imbalanced training, such as Oversampling, Undersampling, Augmentation, Class Weights, SMOTE and ADASYN.Synthetic DDPM-generated data were visually trustworthy, with Fréchet inception distance (FID) below 50. Extending the training dataset with the synthetic data improved the model's performance by more than 10%, while other techniques exhibited only about 4% improvement.DDPM introduces a novel approach to class-imbalanced outcome modelling problems. The model generates realistic synthetic radiotherapy planning data, with a strong potential to increase performance and robustness of outcome models.

Patients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce.In this retrospective study, data were collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at nine institutions. Patients were classified into: Cohort 1 (pre-existing PNS before ICI initiation), cohort 2 (PNS during ICI treatment), and cohort 3 (PNS after ICI discontinuation). Patients with metastatic non-small cell lung cancer (NSCLC) (mNSCLC) from cohort 1 were matched to patients who were PNS-free at each institution up to a 1:3 ratio for age, sex, type of ICI, use of concurrent chemotherapy, and number of lines of systemic therapy prior to ICI initiation. Kaplan-Meier method was used to assess overall survival (OS) and time-to-next treatment (TTNT).Among 109 patients with PNS treated with ICIs, median age at ICI initiation was 67 years (IQR: 58-74). The most represented cancer type was NSCLC (n=39, 36%). In cohort 1 (n=55), PNS exacerbations occurred in 16 (29%) patients with median time to exacerbation after ICI of 1.1 months (IQR: 0.7-3.3). Exacerbation or de novo PNS prompted temporary/permanent interruption of ICIs in 14 (13%) patients. For cohort 2 (n=16), median time between ICI initiation and de novo PNS was 1.2 months (IQR: 0.4-3.5). Treatment-related adverse events (trAEs) occurred in 43 (39%) patients. Grade ≥3 trAEs occurred in 18 (17%) patients. PNS-directed immunosuppressive therapy was required in 55 (50%) patients. We matched 18 patients with mNSCLC and PNS (cohort 1) to 40 without PNS, treated with ICIs. There was no significant difference in OS or TTNT between patients with mNSCLC with and without PNS, although a trend was seen towards worse outcomes in patients with PNS. TrAEs occurred in 6/18 (33%) and 14/40 (35%), respectively. Grade ≥3 trAEs occurred in 4 (22%) patients with PNS and 7 (18%) patients without PNS.Exacerbations of pre-existing PNS occurred in 29% of patients treated with ICIs and both exacerbations and de novo PNS occur early in the ICI course. TrAE from ICIs were similar between patients with and without PNS. Our data suggest that pre-existing PNS should not preclude consideration of ICI therapy although patients may not derive the same clinical benefit compared with patients without PNS.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.

An active arena for technological advancement in radiation oncology treatment delivery has focused on the motion inherent in target structures and normal organs. With the advances over the last decade (and more so within the last few years), in intensity modulated radiation therapy (IMRT), stereotactic radiosurgery (SRS)/radiotherapy and stereotactic body radiotherapy (SBRT), and image-guided radiation therapy, it has become critical to position patients in the treatment positions precisely and reproducibly.

Outcome modeling plays an important role in personalizing radiotherapy and finds applications in specialized areas such as adaptive radiotherapy. Conventional outcome models that are based on a simplified understanding of radiobiological effects or empirical fitting often only consider dosimetric information. However, it is recognized that response to radiotherapy is multi-factorial and involves a complex interaction of radiation therapy, patient and treatment factors, and the tumor microenvironment. Recently, large pools of patient-specific biological and imaging data have become available with the development of advanced biotechnology and multi-modality imaging techniques. Given this complexity, artificial intelligence (AI) and machine learning (ML) are valuable to make sense of such a plethora of heterogeneous data and to aid clinicians in their decision-making process. The role of AI/ML has been demonstrated in many retrospective studies and more recently prospective evidence has been emerging as well to support AI/ML for personalized and precision radiotherapy.

Quantum noise is common in CT images and is a persistent problem in accurate ventilation imaging using 4D-CT and deformable image registration (DIR). This study focuses on the effects of noise in 4D-CT on DIR and thereby derived ventilation data. A total of six sets of 4D-CT data with landmarks delineated in different phases, called point-validated pixel-based breathing thorax models (POPI), were used in this study. The DIR algorithms, including diffeomorphic morphons (DM), diffeomorphic demons (DD), optical flow and B-spline, were used to register the inspiration phase to the expiration phase. The DIR deformation matrices (DIRDM) were used to map the landmarks. Target registration errors (TRE) were calculated as the distance errors between the delineated and the mapped landmarks. Noise of Gaussian distribution with different standard deviations (SD), from 0 to 200 Hounsfield Units (HU) in amplitude, was added to the POPI models to simulate different levels of quantum noise. Ventilation data were calculated using the ΔV algorithm which calculates the volume change geometrically based on the DIRDM. The ventilation images with different added noise levels were compared using Dice similarity coefficient (DSC). The root mean square (RMS) values of the landmark TRE over the six POPI models for the four DIR algorithms were stable when the noise level was low (SD <150 HU) and increased with added noise when the level is higher. The most accurate DIR was DD with a mean RMS of 1.5 ± 0.5 mm with no added noise and 1.8 ± 0.5 mm with noise (SD = 200 HU). The DSC values between the ventilation images with and without added noise decreased with the noise level, even when the noise level was relatively low. The DIR algorithm most robust with respect to noise was DM, with mean DSC = 0.89 ± 0.01 and 0.66 ± 0.02 for the top 50% ventilation volumes, as compared between 0 added noise and SD = 30 and 200 HU, respectively. Although the landmark TRE were stable with low noise, the differences between ventilation images increased with noise level, even when the noise was low, indicating ventilation imaging from 4D-CT was sensitive to image noise. Therefore, high quality 4D-CT is essential for accurate ventilation images.

Ventilation imaging using 4D CT is a convenient and low-cost functional imaging methodology which might be of value in radiotherapy treatment planning to spare functional lung volumes. Deformable image registration (DIR) is needed to calculate ventilation imaging from 4D CT. This study investigates the dependence of calculated ventilation on DIR methods and ventilation algorithms. DIR of the normal end expiration and normal end inspiration phases of the 4D CT images was used to correlate the voxels between the two respiratory phases. Three different DIR algorithms, optical flow (OF), diffeomorphic demons (DD), and diffeomorphic morphons (DM) were retrospectively applied to ten esophagus and ten lung cancer cases with 4D CT image sets that encompassed the entire lung volume. The three ventilation extraction methods were used based on either the Jacobian, the change in volume of the voxel, or directly calculated from Hounsfield units. The ventilation calculation algorithms used are the Jacobian, , and HU method. They were compared using the Dice similarity coefficient (DSC) index and Bland-Altman plots. Dependence of ventilation images on the DIR was greater for the and the Jacobian methods than for the HU method. The DSC index for 20% of low-ventilation volume for was between OF and DM, between OF and DD, and between DM and DD. The similarity comparisons for Jacobian were , and , respectively, and for HU they were , and , respectively. Dependence of extracted ventilation on the ventilation algorithm used showed good agreement between the and Jacobian methods, but differed significantly for the HU method. DSC index for using OF as DIR was between and Jacobian, between and HU, and between Jacobian and HU, respectively. When using DM or DD as DIR, similar values were obtained when comparing the different ventilation calculation methods. The similarity values for the 20% high-ventilation volume were close to those found for the 20% low-ventilation volume. The results obtained with DSC index were confirmed when using the Bland-Altman plots for comparing the ventilation images. Our data suggest that ventilation calculated from 4D CT depends on the DIR algorithm employed. Similarities between and Jacobian are higher than between and HU, and Jacobian and HU. PACS number: 87.57.nj

The appropriate follow-up frequency after definitive chemoradiotherapy (CRT) for locally advanced non-small-cell lung cancer patients is unknown. Although surveillance guidelines have been proposed, very few data support current recommendations. Here we analyze relapse events after CRT and investigate whether symptomatic relapses versus those detected by surveillance imaging influences outcomes.Stage III non-small-cell lung cancer patients treated with CRT at our institution between 2005 and 2014 were retrospectively analyzed. Relapse events were grouped into posttreatment intervals and analyzed with cumulative tables. Time to relapse and overall survival (OS) were compared between patients with relapse detection via symptomatic presentation versus surveillance imaging.A total of 211 patients were identified for analysis. The median follow-up was 43 months for patients alive at the time of analysis. The median age was 63 years, and equal proportions had IIIA or IIIB disease. A total of 135 patients (64%) experienced disease relapse, and of these, 74% did so within 12 months. In those who did not experience relapse at ≤ 12 months, 16%, 6%, and < 5% experienced relapse during 12 to 24, 24 to 36, and > 36 months of follow-up, respectively. In patients with relapse, 56% presented symptomatically, which led to inferior median OS compared to those identified by surveillance imaging (23 vs. 36 months; P = .013).This study identified that most relapses occur within 1 year of completing CRT, and approximately half of these occur within 6 months. A symptomatic relapse led to inferior OS. More aggressive surveillance imaging may therefore identify asymptomatic relapses that are amenable to earlier salvage therapy.

BackgroundLung cancer is the No. 1 cancer killer of both men and women in the United States. Radiotherapy is frequently employed as part of the treatment. However, radiation must traverse surrounding regions of normal lung, potentially inducing pulmonary toxicity. Because these patients frequently have underlying lung disease, a radiation-induced decrement in lung function could be highly morbid or even fatal. It is well known that lung function is not uniform, with wide ranges of ventilation and perfusion levels throughout the lung. Currently radiation oncologists do not have the ability to account for this variation when generating treatment plans.MethodsThis article reviews some techniques used to assess pulmonary ventilation and perfusion, including nuclear medicine, magnetic resonance imaging (MRI) and computed tomography (CT).ResultsMany techniques have the potential to be used in radiotherapy treatment planning for thoracic cancer patients to spare normal functional lung volumes while delivering adequate radiation dose to the tumors. The article outlines a promising new technique to generate 3-D ventilation maps by using deformable image registration of 4-D CT image sets.ConclusionsWhile there are some technical challenges to overcome before pulmonary functional imaging can be routinely employed clinically in radiation oncology, there is the potential to preferentially spare better perfused/ventilated regions of normal lung, which promises to reduce pulmonary toxicity.

Intracranial delivery of high-dose radiation treatment with stereotactic techniques has paved the way for treatment of extracranial sites.The authors review the evolution of stereotactic body radiation therapy (SBRT) and its application to tumors in the lung and abdomen, addressing both the technical concerns associated with treatment delivery and the emerging clinical data.Radiation delivery systems have overcome the obstacles with immobilization, respiration, visualization, and daily reproducible imaging. Lung SBRT has been associated with local control rates of over 90%, and liver SBRT has ranged from 55% to 93%. SBRT is being explored in other sites such as the pancreas and kidney. Mature data from ongoing trials will be available in the next 5 years.Modern stereotactic radiation treatment techniques allow the safe delivery of high doses to extracranial sites with minimal toxicity, which results in improved outcomes.

Background Recursive partitioning analysis has shown that Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≥2, male sex, and age ≥70 years are prognostic of poor outcome in locally advanced non-small cell lung cancer (LA-NSCLC) patients. Concurrent chemoradiation therapy (CRT) improves survival, but toxicity is a concern in this frail patient cohort. We therefore opened this trial of concurrent definitive thoracic radiation therapy (XRT) and cetuximab, followed by consolidation docetaxel plus cetuximab. Methods and Materials Eligible patients had pathologically proven, unresectable LA-NSCLC (stage IIA-“dry” IIIB). They had ECOG PS 2 or weight loss ≥5% in 3 months or were aged ≥70 years. The primary objective was progression-free survival (PFS). Secondary objectives included overall survival (OS) and overall response rate (ORR). Results From May 2008 to November 2010, a total of 32 patients were evaluated in our single-institution, institutional review board–approved prospective clinical trial. Three patients were screen failures and 2 more withdrew consent before treatment, leaving 27 evaluable patients. One was removed because of poor therapy compliance, and 2 were taken off trial because of grade 3 cetuximab-related toxicities but were followed up under intent-to-treat analysis. The median follow-up and OS were 10.5 months. The median PFS was 7.5 months. The ORR was 59.3%. Eight early/sudden deaths were reported. Upon review, 6 patients developed severe pulmonary complications. Conclusions Patients enrolled in this trial had improved OS compared with poor-PS historical controls (10.5 vs 6.4 months) and comparable OS to good-PS historical controls (10.5 vs 11.9 months) treated with XRT alone. However, pulmonary toxicity is a concern. Consolidative cetuximab/docetaxel, in conjunction with high-dose radiation therapy, is a putative cause. Recursive partitioning analysis has shown that Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≥2, male sex, and age ≥70 years are prognostic of poor outcome in locally advanced non-small cell lung cancer (LA-NSCLC) patients. Concurrent chemoradiation therapy (CRT) improves survival, but toxicity is a concern in this frail patient cohort. We therefore opened this trial of concurrent definitive thoracic radiation therapy (XRT) and cetuximab, followed by consolidation docetaxel plus cetuximab. Eligible patients had pathologically proven, unresectable LA-NSCLC (stage IIA-“dry” IIIB). They had ECOG PS 2 or weight loss ≥5% in 3 months or were aged ≥70 years. The primary objective was progression-free survival (PFS). Secondary objectives included overall survival (OS) and overall response rate (ORR). From May 2008 to November 2010, a total of 32 patients were evaluated in our single-institution, institutional review board–approved prospective clinical trial. Three patients were screen failures and 2 more withdrew consent before treatment, leaving 27 evaluable patients. One was removed because of poor therapy compliance, and 2 were taken off trial because of grade 3 cetuximab-related toxicities but were followed up under intent-to-treat analysis. The median follow-up and OS were 10.5 months. The median PFS was 7.5 months. The ORR was 59.3%. Eight early/sudden deaths were reported. Upon review, 6 patients developed severe pulmonary complications. Patients enrolled in this trial had improved OS compared with poor-PS historical controls (10.5 vs 6.4 months) and comparable OS to good-PS historical controls (10.5 vs 11.9 months) treated with XRT alone. However, pulmonary toxicity is a concern. Consolidative cetuximab/docetaxel, in conjunction with high-dose radiation therapy, is a putative cause.

Objectives Although treatment of superior sulcus tumors with induction chemoradiotherapy (CRT) followed by surgery employed in the Intergroup INT-0160 trial is widely adopted as a standard of care, there may be significant associated morbidity and mortality. We describe our experience using standard and alternative induction regimens to assess survival rates and treatment toxicity in these patients. Materials and methods Electronic medical records of all patients who underwent multimodality treatment including resection of lung cancer invading the superior pulmonary sulcus between 1994 and 2016 were retrospectively reviewed. Multivariable Cox Proportional Hazards model was constructed. Results Of 102 consecutive patients, 53 (52%) underwent induction CRT, 34 (33%) underwent induction chemotherapy only (Ch) followed by adjuvant radiotherapy, and 15 (15%) underwent no induction therapy followed by adjuvant therapy. There were 2 postoperative deaths (1.9%). To date, 42 patients are alive with a median follow-up 72.5 months. Overall 5-year survival rate was 45.4%. Survival was significantly influenced by age, FEV1, positive resection margins, surgical complications, but not the induction regimen. CRT resulted in higher complete pathological response rate than Ch: 38% vs. 3% (p < 0.001). CRT was associated with higher post-operative re-intubation rate: 13% vs. 0% (p = 0.03). Conclusions Our single-institutional experience indicated that while induction CRT produced greater complete pathological response than Ch, it also increased the risk of post-operative complications. With careful patient selection, induction Ch followed by adjuvant radiotherapy may provide comparable survival outcomes to induction CRT. Since induction Ch is associated with lower risk of complications, it may be a particularly desirable choice for patients with impaired performance status.

Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. Whether durvalumab is an appropriate consolidation therapy in patients (pts) with EGFR-mutant (EGFRmut) NSCLC remains unknown.

Non-small cell lung cancer (NSCLC) stereotactic body radiation therapy with 50 Gy/5 fractions is sometimes considered controversial, as the nominal biologically effective dose (BED) of 100 Gy is felt by some to be insufficient for long-term local control of some lesions. In this study, we analyzed such patients using explainable deep learning techniques and consequently proposed appropriate treatment planning criteria. These novel criteria could help planners achieve optimized treatment plans for maximal local control.A total of 535 patients treated with 50 Gy/5 fractions were used to develop a novel deep learning local response model. A multimodality approach, incorporating computed tomography images, 3-dimensional dose distribution, and patient demographics, combined with a discrete-time survival model, was applied to predict time to failure and the probability of local control. Subsequently, an integrated gradient-weighted class activation mapping method was used to identify the most significant dose-volume metrics predictive of local failure and their optimal cut-points.The model was cross-validated, showing an acceptable performance (c-index: 0.72, 95% CI, 0.68-0.75); the testing c-index was 0.69. The model's spatial attention was concentrated mostly in the tumors' periphery (planning target volume [PTV] - internal gross target volume [IGTV]) region. Statistically significant dose-volume metrics in improved local control were BED Dnear-min ≥ 103.8 Gy in IGTV (hazard ratio [HR], 0.31; 95% CI, 015-0.63), V104 ≥ 98% in IGTV (HR, 0.30; 95% CI, 0.15-0.60), gEUD ≥ 103.8 Gy in PTV-IGTV (HR, 0.25; 95% CI, 0.12-0.50), and Dmean ≥ 104.5 Gy in PTV-IGTV (HR, 0.25; 95% CI, 0.12-0.51).Deep learning-identified dose-volume metrics have shown significant prognostic power (log-rank, P = .003) and could be used as additional actionable criteria for treatment planning in NSCLC stereotactic body radiation therapy patients receiving 50 Gy in 5 fractions. Although our data do not confirm or refute that a significantly higher BED for the prescription dose is necessary for tumor control in NSCLC, it might be clinically effective to escalate the nominal prescribed dose from BED 100 to 105 Gy.

Intensity-modulated radiation therapy (IMRT) is evolving for the treatment of gastrointestinal cancers. The purpose of this study is to analyze our outcomes utilizing IMRT chemoradiation for esophageal cancer. IMRT was incorporated into esophageal cancer treatment at our center in 2006. Patients treated between 2006 and 2011 with either preoperative or definitive IMRT chemoradiation to 50–60 Gy prescribed to the gross tumor volume and 45–50.4 Gy to the clinical target volume concurrently with chemotherapy were evaluated. IMRT techniques included multifield segmented step and shoot, compensator-based, and volumetric arc therapy. Overall survival (OS) and disease-free survival (DFS) were analyzed by Kaplan–Meier and log-rank analysis. Multivariate analysis (MVA) for OS and DFS were performed with a Cox proportional hazard ratio model. We identified 108 patients with a median follow-up of 19 months. Median OS and DFS were 32 and 21.6 months, respectively. Fifty-eight (53.7 %) patients underwent surgical resection. There was no difference in OS or DFS in patients who underwent surgery compared to patients treated definitively without surgery. Median weight loss was 5.5 %. Rates of hospital admissions, feeding tube placement, stent placement, dilation, and radiation pneumonitis were 15.7, 7.4 4.6, 12, and 1.9 %, respectively. Long-term radiation pneumonitis was observed in six (5.6 %) patients. MVA revealed that age, stage, and surgery were prognostic for DFS, while gender and histology were not. Gender, histology, and stage were prognostic of OS on MVA, while surgery and age were not. IMRT chemoradiation for esophageal cancer is safe and effective when compared to published series of 2D or 3D conformal radiation therapy. This is the largest single institutional series with long-term follow-up, confirming that IMRT is a viable treatment option for the curative treatment of esophageal cancer.

Studies have demonstrated that deformable image registration (DIR) driven atlas-based auto-contouring can save time and improve consistency. However, variations in contouring style between treatment centers exist and hence many studies use atlases defined at the assessing institution. This study investigates the performance of a single atlas-based auto-contouring system across multiple institutions. Six clinical experts from four different institutions were asked to rate the performance of an atlas-based auto-contouring system using an atlas defined independently at a sixth institution. Two of the institutions provided two assessors each. The system was evaluated over 18 cases including a range of treatment sites using a single atlas per treatment site: 5 Head and Neck (33 structures), 5 Thoracic (16 structures), 4 Male and 4 Female Pelvis (8 structures). Thus a total of 108 case assessments were performed. Each assessor was asked to rate each case as a whole numerically from 1 meaning “No useable contours, no time saving compared to manual contouring” to 4 meaning “most contours useful, significant time saving compared to manual contouring”. The Table shows the mean and standard deviation by institution and treatment site. The average score over all institutions was 2.9 (std = 0.89). The highest average scores were obtained for the thorax (3.5), head and neck (3.0), and male pelvis (3.0) and the lowest for the female pelvis (1.9). The most consistent scores across institutions were for the thorax (std = 0.46). For the institutions with two assessors, the overall scores were for Institution 3: 3.6 (std = 0.38) and 3.2 (std = 0.79) and for Institution 4: 2.5 (std = 0.77) and 2.5 (std = 0.86). There was no statistical difference between overall ratings within an institution. There was a statistical difference in the overall ratings between all institutions except between 1 and 3 and between 2 and 4. All institutions agreed that atlas-based auto-contouring would save time for the cases assessed with an average score close to 3 which means “many of the contours useable” on the assessment scale. However, opinions differed between institutions on the degree of utility and/or potential time saved. Scores from assessors at the same institution were consistent which implies that the differences between institutions reflect a difference in contouring style. Locally edited or defined atlases may address this variation.Poster Viewing Abstract 3338; TableMean (SD) assessment scores by institutionCombinedInstitution 1Institution 2Institution 3Institution 4Overall2.9 (0.89)3.4 (0.78)2.3 (0.86)3.4 (0.51)2.5 (0.80)Head and neck3.0 (0.78)3.8 (0.45)2.2 (0.57)3.4 (0.22)2.5 (0.50)Thoracic3.5 (0.46)3.8 (0.45)3.2 (0.27)3.7 (0.33)3.3 (0.53)Male pelvis3.0 (0.80)3.5 (0.58)2.3 (0.87)3.6 (0.52)2.6 (0.38)Female pelvis1.9 (0.70)2.3 (0.50)1.3 (0.29)2.7 (0.38)1.4 (0.29) Open table in a new tab

The 4D-CT data used for comparing a patient's ventilation distributions before and after lung radiotherapy are acquired at different times. As a result, an additional variable--the tidal volume (TV)--can alter the results. Therefore, in this paper we propose to normalize the ventilation to the same TV to eliminate that uncertainty.Absolute ventilation (AV) data were generated for 6 stereotactic body radiation therapy (SBRT) cases before and after treatment, using the direct geometric algorithm and diffeomorphic morphons deformable image registration (DIR). Each pair of AV distributions was converted to TV-normalized, percentile ventilation (PV) and low-dose well-ventilated-normalized ventilation (LDWV) distributions. The ventilation change was calculated in various dose regions based on the treatment plans using the DIR-registered before and after treatment data sets. The ventilation change based on TV-normalized ventilation was compared with the AV as well as the data normalized by PV and LDWV.AV change may be misleading when the TV differs before and after treatment, which was found to be up to 6.7%. All three normalization methods produced a similar trend in ventilation change: the higher the dose to a region of lung, the greater the degradation in ventilation. In low dose regions (<5 Gy), ventilation appears relatively improved after treatment due to the relative nature of the normalized ventilation. However, the LDWV may not be reliable when the ventilation in the low-dose regions varies. PV exhibited a similar ventilation change trend compared to the TV-normalized in all cases. However, by definition, the ventilation distribution in the PV is significantly different from the original distribution.Normalizing ventilation distributions by the TV is a simple and reliable method for evaluation of ventilation changes.

Immune checkpoint inhibitors (ICPIs) are changing systemic management of lung cancer. Pneumonitis can lead to dose-limiting toxicity. There are limited published data on the use of thoracic radiation therapy (TRT) before, during, or after administration of these agents. The goal of this study was to assess safety and tolerability among patients receiving TRT within 6 months before or after receipt of ICPIs. For all patients, ICPIs were delivered until disease progression. We identified 29 patients who received TRT between February 2012 and May 2016 to 29 unique intrathoracic sites within 6 months of either single agent ICPI (n=14 anti-PD-1, n=3 anti-PD-L1) or combined ICPIs (n=7 anti-PD-1/CTLA-4, n= 5 anti-PD-L1/CTLA-4). TRT-associated toxicities were defined qualitatively based on careful review of the clinical chart. Kaplan-Meier (KM) estimates of progression-free survival (PFS) and overall survival (OS) were calculated from the date of ICPI initiation. The median age at time of ICPI study enrollment was 64 years (range 41-77) with 16 females (55%). The majority of patients had an ECOG 1 performance status (69%), were of non–small cell lung cancer (NSCLC) histology (79%), with a median of 3 metastatic sites (range 2-8). Fifteen lesions (52%) were treated with TRT concurrent with or after ICPI therapy. The median interval between ICPI and TRT administration was 2.2 months (range 0.4-5.5 month) in lesions treated with TRT before or after ICPI. Median PFS and OS was 3.8 months (1.9, 8-95% CI) and 9.2 months (5.1, not reached-95% CI), respectively, with a median PFS/toxicity follow-up of 6.6 months (range: 0.5-40.4 months). TRT doses ranged between 10 to 70 Gy in 1 to 35 fractions. One patient experienced possible TRT/ICPI related grade 5 pulmonary toxicity 2 weeks following completion of TRT (4 Gy x 5 to right hilum/lung), which was initiated 1 month after the last dose of anti-PD-1 therapy. Two cases of possible grade 3 TRT/ICPI related pneumonitis were noted approximately 2 and 4 months following palliative TRT to the mediastinum and right lower lobe, respectively. In these cases, anti-PD-L1/CTLA-4 and anti-PD-L1 therapy were completed approximately 1 and 2 months before starting RT. Additionally, two cases of grade 2 and grade 3 pneumonitis related to anti-PD-1 agent alone were noted prior to initiation of TRT. In both cases, patients were treated with steroid therapy and subsequently received TRT without additional pulmonary toxicity. In this analysis of TRT delivered among lung cancer patients treated with ICPIs, 3 of 29 patients experienced possible grade ≥3 pneumonitis, which may have been related to TRT while two patients developed pneumonitis from ICPIs alone and were subsequently treated with TRT without increased toxicity. Further prospective safety data is necessary with combination TRT and ICPI therapy.

Although many researchers talk about a "patient database," they typically are not referring to a database at all, but instead to a spreadsheet of curated facts about a cohort of patients. This article describes relational database systems and how they differ from spreadsheets. At their core, spreadsheets are only capable of describing one-to-one (1:1) relationships. However, this article demonstrates that clinical medical data encapsulate numerous one-to-many relationships. Consequently, spreadsheets are very inefficient relative to relational database systems, which gracefully manage such data. Databases provide other advantages, in that the data fields are "typed" (that is, they contain specific kinds of data). This prevents users from entering spurious data during data import. Because each record contains a "key," it becomes impossible to add duplicate information (ie, add the same patient twice). Databases store data in very efficient ways, minimizing space and memory requirements on the host system. Likewise, databases can be queried or manipulated using a highly complex language called SQL. Consequently, it becomes trivial to cull large amounts of data from a vast number of data fields on very precise subsets of patients. Databases can be quite large (terabytes or more in size), yet still are highly efficient to query. Consequently, with the explosion of data available in electronic health records and other data sources, databases become increasingly important to contain or order these data. Ultimately, this will enable the clinical researcher to perform artificial intelligence analyses across vast amounts of clinical data in a way heretofore impossible. This article provides initial guidance in terms of creating a relational database system.

Locally advanced non-small cell lung cancer patients represent around one third of newly diagnosed lung cancer patients. There remains a large unmet need to find treatment strategies that can improve the survival of these patients while minimizing therapeutical side effects. Increasing the availability of patients' data (imaging, electronic health records, patients' reported outcomes, and genomics) will enable the application of AI algorithms to improve therapy selections. In this review, we discuss how artificial intelligence (AI) can be integral to improving clinical decision support systems. To realize this, a roadmap for AI must be defined. We define six milestones involving a broad spectrum of stakeholders, from physicians to patients, that we feel are necessary for an optimal transition of AI into the clinic.

In ITV-based 3D-planning, the information of volume occupancy versus respiratory phase is not utilized. We propose a motion-weighted CTV (mwCTV) delineation method, which carries some 4D-information into planning. This method allows plan optimization based on occupancy-weighting and generation of motion-weighted DVH (mwDVH) that approximate the DVHs of full 4D-dose accumulation.Occupancy information from contours in 4D-CT is incorporated in the mwCTV generation. Higher-occupancy volumes receive higher dosimetric priority in planning. The temporally-weighted mwCTV is converted to a spatially-weighted mwCTV incorporating the temporal-weighting in mwDVH generation using the 3D-dose distribution. The mwDVHs were compared with DVHs of deformable-image-registration (DIR)-based 4D-dose accumulation and 3D-method for 10 cases.For all the cases, the mwDVH curves are closer to the 4D-calculated DVH than the 3D-DVHs are, indicating a better approximation of the 4D-DVH. The 70 Gy-covered percentage-CTV volume differed by -2.8% ± 0.8% between 3D and 4D, and 0.3% ± 0.7% between mwDVH and 4D-methods. The mean RMS values of the percentage-volume differences for the 4D-3D is 1.7 ± 1.1, while for the 4D-mwDVH is 0.4 ± 0.3.The mwCTV and mwDVH method, which is simple in implementation and does not require DIR, is a practical approximation of DIR-based 4D-planning and evaluation.

Introduction:The survival for patients with locally advanced, unresectable non-small cell lung cancer receiving standard of care concomitant chemoradiation remains disappointingly low. A reduction in both local and distant recurrence is needed to improve patients' outcome. Performing molecular studies on serially collected tumor specimens may result in a better selection of therapeutic options.Methods:We conducted a phase II single-institution trial of two cycles of induction chemotherapy with gemcitabine and carboplatin followed by high-dose conformal radiation concomitant with weekly paclitaxel and carboplatin in 39 patients. The trial required a dedicated tumor biopsy before treatment initiation. In addition, tumor biopsies were requested, if safely feasible, before initiation of chemoradiation and 2 months after completion all therapy.Results:Induction chemotherapy was well tolerated, and 38 patients proceeded with chemoradiation. The mean delivered radiation dose was 70.2 Gy, 23 patients received the full dose of 74 Gy, and 19 patients completed all treatment on schedule without dose reductions or delays. Median overall and progression-free survivals were 22.7 and 14.3 months, respectively. A total of 82 procedures, including 46 transthoracic core needle biopsies, were performed. Thirteen patients had all three serial tumor biopsies. Three of these procedures resulted in complications that required an intervention; all for the treatment of a biopsy-induced pneumothorax.Conclusions:We conclude that induction gemcitabine/carboplatin followed by concurrent paclitaxel/carboplatin with conformal radiation to 74 Gy is safe and tolerable with promising efficacy. We demonstrated that dedicated and serial tumor collections are safe, feasible, and acceptable for patients with non-small cell lung cancer.

With the technologic advancements in image guidance and dose delivery, stereotactic body radiotherapy (SBRT) is being widely used for cancer treatment in various anatomical locations as a noninvasive alternative to surgery.To deliver ablative doses to tumors with limited normal tissue toxicity, SBRT requires high accuracy in treatment setup which requires taking tumor motion into account.Techniques are also applied in SBRT to minimize tumor motion during dose delivery.This paper reviews techniques for motion management in SBRT.

Adenocarcinoma of the esophagus is frequently associated with Barrett's esophagus (BE). The response of esophageal adenocarcinoma to chemoradiation therapy is well described; however, the effect of chemoradiation on tumor-associated BE has not been specifically reported.To determine the response of tumor-associated BE to chemoradiation therapy.Retrospective cohort study.A single National Cancer Institute Comprehensive Cancer Care Center experience.The study cohort consisted of 43 patients with stage I to IVA esophageal adenocarcinoma associated with BE who received either neoadjuvant or definitive chemoradiation therapy and underwent either esophagectomy or surveillance at our institution.The presence and extent of BE after chemoradiation therapy of esophageal adenocarcinoma associated with endoscopically documented pretreatment BE.BE persisted after chemoradiation therapy in 93% (40/43) of cases (95% CI, 83%-99%). Twenty-seven patients received neoadjuvant chemoradiation therapy before esophagectomy. Persistent BE was detected in all 27 surgical specimens (100%). In 59% (16/27) of the cases, there was complete pathologic tumor response. Sixteen patients received definitive chemoradiation therapy. Persistent pretreatment BE was identified in 88% (14/16) by surveillance endoscopy (95% CI, 60%-98%). The mean length of BE before and after chemoradiation was 6.6 cm and 5.8 cm, respectively (P = .38).Retrospective design, small sample size, and single-site data collection.Chemoradiation therapy of esophageal adenocarcinoma does not eliminate tumor-associated BE, nor does it affect the length of the BE segment.

This paper will demonstrate that deriving ventilation data from four-dimensional (4-D) CT is less expensive, easier to perform, and quantitatively more accurate than standard nuclear medicine techniques. The ventilation data could be utilized in thoracic cancer treatment planning to spare normal lung volumes, without requiring additional imaging procedures and cost. The voxel-to-voxel deformation matrices between CT scans from different respiratory phases are calculated using deformable image registration (optical flow technique). The matrices are used to calculate local volume change ΔV for each voxel. The ΔV/V matrices yield three-dimensional (3-D) high-resolution pulmonary ventilation images. Ventilation images were generated for twelve lung patients using this method. Tidal volumes calculated from the ventilation images were, on average, within 2.6% of those derived using 4-D CT automated lung segmentation and, in the worst case, the agreement was within 4.9%. Tidal volume difference between the left and right lungs (noticeable on 4-D CT) was quantifiable in the ventilation image set. Low ventilation regions distal to lung tumors were observed on some generated ventilation images. This ventilation calculation algorithm demonstrates reduced image noise and decreased edge artifacts when compared to another published method using Hounsfield Units (HU). This proposed algorithm provides a practical method for ventilation imaging from 4-D CT data.

Patients with extensive stage small cell lung cancer (ES-SCLC) typically receive first line treatment with platinum doublet chemotherapy (CT). Consolidative thoracic radiotherapy (TRT) has also been shown to improve outcomes for patients with ES-SCLC. We hypothesized that the addition of ipilimumab (IPI) and nivolumab (NIVO) after TRT would improve the 6 month progression free survival (PFS, primary endpoint) and 12 month overall survival (OS, secondary endpoint) for patients with ES-SCLC and stable disease or better after at least 4 cycles of platinum CT. This prospective single arm Phase I/II study enrolled 21 patients. Eligible patients demonstrated stable disease or better following platinum CT. Study therapy included consolidative TRT to a total dose of 30Gy in 10 fractions targeting any residual primary tumor and all initially involved regional lymph node stations. Two weeks after TRT, patients received concurrent IPI (3mg/kg) and NIVO (1mg/kg) every 3 weeks for 4 planned doses followed by NIVO monotherapy (480mg) every 4 weeks until progression or up to 1 year. Archival tissue from initial diagnosis (n=15) and peripheral blood (n=20) were collected at serial time points for research purposes. The study planned to enroll up to 52 patients but was discontinued early due to a planned interim analysis after 21 patients had enrolled. The initial 6 patient safety lead in demonstrated an acceptable toxicity profile with the study therapy. The 6 month (mo) PFS estimate was 24% (95% CI: 9%-43%). The median PFS estimate was 4.5 mo (95% CI: 2.7-4.6). The median PFS follow up for those patients who have not progressed is 11.1 mo. The 12 mo OS estimate was 47% (95% CI 25%-66%). The median OS estimate was 11.7 mo (95% CI: 4.7-16.0). The median OS follow up for patients who remain alive is 14.4 mo. 52% of patients had at least 1 grade 3 or higher immune related adverse event (IRAE) possibly or definitely attributable to study therapy. Grade 3 pulmonary and GI IRAEs possibly or definitely attributable to study therapy were recorded in 19.1% and 23.8% of patients respectively. The only grade 4 IRAE toxicity was thrombocytopenia. One patient died without progression at 4.6 mo due to lung aspergillosis infection secondary to steroid and infliximab therapy delivered for treatment of study related grade 3 diarrhea. Consolidative IPI and NIVO after platinum based CT and TRT demonstrated a toxicity profile consistent with the known AEs attributable to IPI and NIVO. The study regimen did not significantly improve the 6 mo PFS compared to historic estimates. The OS estimate at 1 year compares favorably with historic estimates. Biomarkers including tissue PD-L1 and estimation of tumor mutational burden, as well as flow cytometric characterization of the peripheral T cells and myeloid cells at baseline and during the treatment course will be presented.

Immune checkpoint inhibitors (ICPIs) are revolutionizing systemic management of non-small cell lung cancer (NSCLC). There is limited published data on the use of radiation therapy (RT) before, during, or after administration of these agents. The goal of this study was to assess safety and tolerability among patients receiving extracranial external beam RT within 6 months before or after enrollment on prospective clinical studies of ICPIs for metastatic NSCLC. A total of 213 patients with Stage 4 NSCLC were enrolled in prospective ICPI trials at our institution. For all patients, ICPIs were delivered until disease progression. Of these patients, we identified 29 patients who received palliative RT between February 2012 and December 2015 to 39 unique osseous or intrathoracic sites within 6 months before or after enrollment on one of 9 prospective clinical studies evaluating safety and/or efficacy of either single agent ICPI (n = 7 anti-PD-1, n = 8 anti-PD-L1) or combined ICPIs (n = 5 anti-PD-1/CTLA-4, n = 9 anti-PD-L1/CTLA-4). RT associated toxicities were defined qualitatively based on review of the clinical chart. Kaplan-Meier (KM) estimates of progression-free survival (PFS) and overall survival (OS) were calculated from date of ICPI initiation. Among patients treated with RT, the median age at time of ICPI study enrollment was 64 years (range 47-75) with 15 males included (52%). The majority of patients had an ECOG 1 performance status (79%) with a median of 4 metastatic sites (range 2-9). Eight lesions (21%) were treated concurrently with systemic treatment. The median interval between ICPI and RT administration was 2.4 months (range 0.2-5.6 months) in lesions treated with RT before or after ICPI. Median PFS and OS were 3.6 months (2.6, not reached-95% CI) and 8.7 months (5.2, 10.8-95% CI), respectively with a median PFS/toxicity follow-up of 5.6 months (range: 0.5-39.7 months). Ten lesions (26%) were treated to thoracic sites and 29 lesions (74%) were treated to osseous sites. The most common osseous dose and fractionation schedules were 30 Gy in 10 fractions (52%) and 20 Gy in 5 fractions (34%) (range: 8-45 Gy in 1-15 fractions). Response to osseous palliative radiation could be qualitatively assessed in 26 lesions; symptomatic improvement either partial or full was noted in 20 lesions (77%). Thoracic RT doses ranged between 10 to 70 Gy in 1 to 35 fractions. One patient experienced possible RT related grade 5 pulmonary toxicity 2 weeks following completion of RT (4 Gy x 5 to right hilum/lung), which was initiated 1 month after last dose of anti-PD-1 therapy. There were no other unexpected RT associated toxicities. In this analysis of RT among NSCLC patients treated on prospective clinical studies with ICPIs, RT directed at osseous metastases was well tolerated. Among patients treated with thoracic RT, there was 1 possible grade 5 RT associated toxicity. ICPI and RT for intrathoracic disease should be further studied to better understand safety and tolerability.

Classic teaching states that treatment of limited-stage small cell lung cancer (L-SCLC) requires large treatment fields covering the entire mediastinum. However, a trend in modern thoracic radiotherapy is toward more conformal fields, employing positron emission tomography/computed tomography (PET/CT) scans to determine the gross tumor volume (GTV). This analysis evaluates the dosimetric results when using selective nodal irradiation (SNI) to treat a patient with L-SCLC, quantitatively comparing the results to standard Intergroup treatment fields. Sixteen consecutive patients with L-SCLC and central mediastinal disease who also underwent pretherapy PET/CT scans were studied in this analysis. For each patient, we created SNI treatment volumes, based on the PET/CT-based criteria for malignancy. We also created 2 ENI plans, the first without heterogeneity corrections, as per the Intergroup 0096 study (ENIoff) and the second with heterogeneity corrections while maintaining constant the number of MUs delivered between these latter 2 plans (ENIon). Nodal stations were contoured using published guidelines, then placed into 4 “bins” (treated nodes, 1 echelon away, >1 echelon away within the mediastinum, contralateral hilar/supraclavicular). These were aggregated across the patients in the study. Dose to these nodal bins and to tumor/normal structures were compared among these plans using pairwise t-tests. The ENIon plans demonstrated a statistically significant degradation in dose coverage compared with the ENIoff plans. ENI and SNI both created a dose gradient to the lymph nodes across the mediastinum. Overall, the gradient was larger for the SNI plans, although the maximum dose to the “1 echelon away” nodes was not statistically different. Coverage of the GTV and planning target volume (PTV) were improved with SNI, while simultaneously reducing esophageal and spinal cord dose though at the expense of modestly reduced dose to anatomically distant lymph nodes within the mediastinum. The ENIon plans demonstrate that intergroup-style treatments, as actually delivered, had statistically reduced coverage to the mediastinum and tumor volumes than was reported. Furthermore, SNI leads to improved tumor coverage and reduced esophageal/spinal cord dose, which suggests the possibility of dose escalation using SNI.

For an institution that already owns the licenses, it is economically advantageous and technically feasible to use Pinnacle TPS (Philips Radiation Oncology Systems, Fitchburg, WI) with the BrainLab Novalis delivery system (BrainLAB A.G., Heimstetten, Germany). This takes advantage of the improved accuracy of the convolution algorithm in the presence of heterogeneities compared with the pencil beam calculation, which is particularly significant for lung SBRT treatments. The reference patient positioning DRRs still have to be generated by the BrainLab software from the CT images and isocenter coordinates transferred from Pinnacle. We validated this process with the end‐to‐end hidden target test, which showed an isocenter positioning error within one standard deviation from the previously established mean value. The Novalis treatment table attenuation is substantial (up to 6.2% for a beam directed straight up and up to 8.4% for oblique incidence) and has to be accounted for in calculations. A simple single‐contour treatment table model was developed, resulting in mean differences between the measured and calculated attenuation factors of 0.0%–0.2%, depending on the field size. The maximum difference for a single incidence angle is 1.1%. The BrainLab micro‐MLC (mMLC) leaf tip, although not geometrically round, can be represented in Pinnacle by an arch with satisfactory dosimetric accuracy. Subsequently, step‐and‐shoot (direct machine parameter optimization) IMRT dosimetric agreement is excellent. VMAT (called “SmartArc” in Pinnacle) treatments with constant gantry speed and dose rate are feasible without any modifications to the accelerator. Due to the 3 mm‐wide mMLC leaves, the use of a 2 mm calculation grid is recommended. When dual arcs are used for the more complex cases, the overall dosimetric agreement for the SmartArc plans compares favorably with the previously reported results for other implementations of VMAT: γ(3%,3mm) for absolute dose obtained with the biplanar diode array passing rates above 97% with the mean of 98.6%. However, a larger than expected dose error with the single‐arc plans, confined predominantly to the isocenter region, requires further investigation PACS numbers: 87.55Qr, 87.56Nk

Background and purpose The study objective was to determine whether longitudinal changes in patient-reported outcomes (PROs) were associated with survival among early-stage, non-small cell lung cancer (NSCLC) patients undergoing stereotactic body radiation therapy (SBRT). Materials and methods Data were obtained from January 2015 through March 2020. We ran a joint probability model to assess the relationship between time-to-death, and longitudinal PRO measurements. PROs were measured through the Edmonton Symptom Assessment Scale (ESAS). We controlled for other covariates likely to affect symptom burden and survival including stage, tumor diameter, comorbidities, gender, race/ethnicity, relationship status, age, and smoking status. Results The sample included 510 early-stage NSCLC patients undergoing SBRT. The median age was 73.8 (range: 46.3–94.6). The survival component of the joint model demonstrates that longitudinal changes in ESAS scores are significantly associated with worse survival (HR: 1.04; 95% CI: 1.02–1.05). This finding suggests a one-unit increase in ESAS score increased probability of death by 4%. Other factors significantly associated with worse survival included older age (HR: 1.04; 95% CI: 1.03–1.05), larger tumor diameter (HR: 1.21; 95% CI: 1.01–1.46), male gender (HR: 1.87; 95% CI: 1.36–2.57), and current smoking status (HR: 2.39; 95% CI: 1.25–4.56). Conclusion PROs are increasingly being collected as a part of routine care delivery to improve symptom management. Healthcare systems can integrate these data with other real-world data to predict patient outcomes, such as survival. Capturing longitudinal PROs—in addition to PROs at diagnosis—may add prognostic value for estimating survival among early-stage NSCLC patients undergoing SBRT.

Abstract The objective of this study was to assess the toxicity and potential efficacy of the adjuvant administration of an iodine 125 ( 125 I)‐labeled monoclonal antibody 425 for primary glioblastoma multiforme. From January 29, 1987, to October 1, 1993, 60 patients with a diagnosis of glioblastoma multiforme received an average of three intravenous or intraarterial injections of 125 I‐labeled antiepidermal growth factor receptor monoclonal antibody ( 125 1425). All patients had biopsy or resection followed by postoperative radiation therapy. Patients were included who had either stereotactic irradiation or brachytherapy (5 patients), or who were not candidates for these treatments. Stratification was made by Karnofsky performance status (KPS) and age. Treatments were administered on an outpatient basis. The mean KPS was 78, and the total cumulative dose of 125 I 425 was approximately 150 mCi. Among this entire group were 6 patients who received 10–80 mg of unlabeled “blocking” 425 to block binding sites on non‐tumor cells prior to the second intravenous infusion of 125 I 425. No patients were excluded from the statistical analysis. The median actuarial survival for all patients treated adjuvantly for glioblastoma multiforme was 13 months. Both age and KPS correlated positively with survival, as would be expected. The toxicity from the administration of repeated doses of 125 I 425 was low. No patient had chronic toxicity attributed to the monoclonal antibody therapy. Acute toxicity was observed in 1 patient who received a single dose &gt;60 mCi. We conclude that the repeated administration of 125 1425 is safe and may have some benefit in the management of primary glioblastoma multiforme. This may be especially true for patients who do not qualify for other forms of more aggressive management. A prospective randomized trial should be performed. © 1995 Wiley‐Liss, Inc.

Patients who present for radiation treatment with a history of prior radiation pose a difficult challenge if there is overlap between the treatment fields. In the era of conformal therapy, new options offer re-treatment to small volumes of previously irradiated tissue.

When contemplating the literature of the past year or two in non-small cell lung cancer, surely the topic of radiation dose has proved to be one of the most talked-about (and thorny). Some preliminary results of the Radiation Therapy Oncology Group (RTOG) 0617 study have been presented, with another presentation pending as I write this. What this and other studies demonstrate, ultimately, is how comparatively little we understand about radiation dose in nonsmall cell lung cancer (NSCLC). To that end, I thought that a review of the known (and unknown) RTOG 0617 findings would be useful as background. Within that general milieu of higher dose being detrimental, however, some researchers are nonetheless attempting to escalate dose “differently” via hypofractionation. Many recent publications explore the concept of reirradiation and suggest that it can be done safely, despite the classical teaching about normal tissue toxicity secondary to the cumulative radiation exposure. How do we reconcile these disparate findings?

A previous meta-analysis (MA) found postoperative radiotherapy (PORT) in lung cancer patients to be detrimental in N0/N1 patients and equivocal in the N2 setting. We hypothesized that treatment plans generated using MA protocols had worse dosimetric outcomes compared to modern plans.We retrieved plans for 13 patients who received PORT with modern planning. A plan was recreated for each patient using the 8 protocols included in MA. Dosimetric values were then compared between the modern and simulated MA plans.A total of 104 MA plans were generated. Median prescribed dose was 50.4 (range, 50-60) Gy in the modern plans and 53.2 (30-60) Gy in the MA protocols. Median planning volume coverage was 96% (93%-100%) in the modern plans, versus 58% (0%-100%) in the MA plans (P < .001). Internal target volume coverage was 100% (99%-100%) versus 65% (0%-100%), respectively (P < .001). Organs at risk received the following doses: spinal cord maximum dose, 36.8 (4.6-50.4) Gy versus 46.8 (2.9-74.0) Gy (P < .001); esophageal mean dose, 22.9 (5.5-35) Gy versus 30.5 (11.1-52.5) Gy (P = .003); heart V30 (percentage of volume of an organ receiving at least a dose of 30 Gy), 16% (0%-45%) versus 35% (0%-79%) (P = .047); mean lung dose, 12.4 (3.4-24.3) Gy versus 14.8 (4.1-27.4) Gy (P = .008); and lung V20, 18% (4%-34%) versus 25% (8%-67%) (P = .023).We quantitatively confirm the inferiority of the techniques used in the PORT MA. Our analysis showed a lower therapeutic ratio in the MA plans, which may explain the poor outcomes in the MA. The findings of the MA are not relevant in the era of modern treatment planning.

Patients with extensive-stage small cell lung cancer (ES-SCLC) often develop brain metastases. There is significant controversy regarding the benefit of prophylactic cranial irradiation (PCI) for patients with ES-SCLC. Our objective is to identify ES-SCLC patients who might be most likely to benefit from PCI.We retrospectively reviewed 173 patients with ES-SCLC treated between 2010-2015. Of these, 117 patients were initially diagnosed without brain metastases and received systemic chemotherapy. Following exclusion of patients who received PCI and less than 2 cycles of platinum doublet therapy, 93 patients remained. Patient records were reviewed for clinical and radiographic features previously identified as relevant risk factors. Primary outcome was brain metastasis-free survival (BMFS). Kaplan-Meier analysis, log-rank tests and Cox multivariate models were used to compare outcomes.Median follow-up was 10.7 months (range, 3-58 months). Thirty-eight (40.9%) patients developed brain metastases. Three or more metastatic sites was associated with inferior BMFS on univariable (1-year estimate 43.8% vs. 61.3%; P=0.020) and multivariable (MVA) analysis [hazard ratio (HR) 2.33, 95% CI: 1.08-5.01; P=0.03).Our results suggest that extracranial metastatic burden is associated with an increased risk for brain metastases in patients with ES-SCLC. As there is no clear standard regarding delivery of PCI in this patient population, utilizing the number of metastatic disease sites as a clinical indicator may help to improve selection of patients who benefit from PCI.

To the Editor: We, the undersigned program directors of radiation oncology residency programs, applaud Wu, Vapiwala, and colleagues ( 1 Wu A.J. Vapiwala N. Chmura S.J. et al. Taking “the game” out of the match: A simple proposal. Int J Radiat Oncol Biol Phys. 2015; 93: 945-948 Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar ) for their proposal to restore the fairness that the National Resident Matching Program (NRMP) was intended to create and preserve. The editorial persuasively describes the unintended consequences of behaviors adopted by multiple programs in pursuit of very highly qualified residents. The 5 steps presented in the editorial are voluntary and largely heed the Match Participation Agreement (http://www.nrmp.org/wp-content/uploads/2014/09/2015-MPA-Applicants-and-Programs.pdf), particularly Section 6.0, Restrictions on Persuasion, as well as the Match Communication Code of Conduct (http://www.nrmp.org/code-of-conduct/). Furthermore, beyond a loud declaration of intent to follow the rules in both letter and spirit, this editorial proposes that residency programs refrain from unsolicited contact with applicants after the interview day. Programs will also guide applicants to route all postinterview informational communication through program coordinators, strongly discouraging any direct contact with faculty. Finally, the proposal also calls for the establishment of an anonymous reporting mechanism for violations of NRMP protocol. Taking “the Game” Out of The Match: A Simple ProposalInternational Journal of Radiation Oncology, Biology, PhysicsVol. 93Issue 5PreviewIn the mid-20th century, the process by which US medical school graduates secured plum residency training positions was a “dog-eat-dog” affair. Prestigious hospitals, eager to fill staffing needs, made increasingly premature and time-limited offers (the so-called “exploding offer”), and naïve students, wary of what (if any) offers lay ahead, made hasty commitments (1). Mutual anxiety and fear of missed opportunities drove both parties to create a fiercely competitive and cutthroat culture, eventually inspiring a series of reforms that evolved into the National Resident Matching Program (NRMP). Full-Text PDF

To integrate clinical 3D and 4D PET/CT and radiation treatment planning. In 2009 two 4D PET/CT protocols were standardized for use by Radiation Therapy based on a trial population of 116 4D PET/CT studies. Protocol A acquires the 3D and the 4D PET/CT in the same scan, extending the imaging time of the bed positions over the region of interest. This ROI is post processed separately after the scan is ended. Protocol B uses separate acquisitions for the 3D and the 4D PET/CT. Both scans result in two reconstructions, one for gated data, and one for standard data. Variables such as dose amount (10-15mCi FDG), acquisition times (3–15 minutes per bed), and reconstruction parameters (matrices, filters, bins to phase attenuation, subsets and iterations) have been tested. A committee composed of radiation oncologists, radiologists, physicists and PET technologists meets regularly to review data and technical issues. Over 140 RT patients have been scanned using these 4D PET/CT protocols as of August 1, 2012. Protocol A is best suited for patients who are able to keep their arms overhead for approximately 45 minutes. Many patients have difficulty holding still during this lengthy acquisition. Protocol B results in better patient compliance but requires an extra 25 minutes of scan time for the additional exam. Quantification by imaging physicists may identify reconstruction parameters which can optimize results, and should be carefully considered when structuring the final protocol. Using our standard 3D PET/CT matrices, iterations and subsets for initial reconstruction of the gated 4D PET/CT yielded good visual quality, lowering the FWHM (Gaussian) filter slightly to give a better edge of definition to the ROI by decreasing the smoothing effect on the images prior to binning. Our 3D PET/CT FDG dose is 10mCi, with uptake time of 90 minutes and 2–3 minutes scan time per bed; our 4D PET/CT FDG dose is 13-15mCi for best visualization of 8–10 bins, with uptake time of 60 minutes and 10 minutes per bed. We are currently studying tumor motion as relates to the optimal number of PET and CT bins for XRT use. Our protocols have been successful but challenges remain. Physical characteristics of the patient, varying levels of technologist skill and knowledge of the mechanics of the hardware/software may affect the outcome of the 4D scan. New techniques are in progress that may decrease acquisition and reconstruction times, these will need to be implemented clinically in a manner similar to what has been described. A multidisciplinary team approach is necessary for a thorough understanding and execution of the process, from patient prep through scan acquisition and therapy planning to radiation treatment.

Oxaliplatin based systemic therapy regimens have improved the prognosis of patients with colorectal cancer (CRC) and with this, there has been increased interest in the integration of local therapies to oligometastatic and oligoprogressive sites. There is a vast body of literature exploring the benefits of cytoreduction with surgery and stereotactic body radiation therapy (SBRT) approaches. We report our rates of local control (LC) and overall survival (OS) for patients with oligometastatic/progressive CRC with lung metastases treated with SBRT.Single institution retrospective review of patients diagnosed with oligometastatic or oligoprogressive CRC with dominant metastases to the lungs who were treated with SBRT between September 2009 and December 2022. Oligometastatic disease was defined as newly diagnosed, untreated CRC with up to 5 metastases, up to 3 in one organ. Oligoprogressive disease was defined as CRC with 1 - 2 distant sites that continued to progress on active treatment while the primary site was controlled. Survival was estimated using Kaplan-Meier. Association between local control and patient factors was analyzed using log-rank test.A total of 84 patients with oligometastatic or oligoprogressive CRC were treated with SBRT to 124 lung lesions. Colon cancer was the primary site for 54 patients with a median age at time of SBRT of 66 years (IQR 57 - 73) and a median tumor diameter of 1.20 cm (IQR 0.93 - 1.90). Rectal cancer was the primary site for 30 patients, median age was 60 years (IQR 49 - 70) and median tumor diameter was 1.10 cm (IQR 0.80 - 1.48). Median dose for the entire cohort was 6000 cGy (range 5000 - 6000) with median number of fractions 5 (range 3 - 5). Median follow-up after SBRT was 24 months. Overall, there were 9 local failures at last follow-up. Almost half (n = 42) of the patients experienced distant recurrence. Median local control (LC) for the entire cohort was not reached, 2-yr LC and 5-yr LC were 94.6% and 85.7% respectively. There were no differences in LC between colon and rectal cancer (p = 0.29). Actuarial median overall survival was 71 months (95% CI 44.3 - 97.7) and 5-yr OS was 50.2%. Due to the small number of events, we were unable to identify patient factors associated with local failure on univariate or multivariate analysis.Cytoreductive SBRT is an effective treatment option for patients with oligometastatic or oligoprogressive CRC with dominant lung metastases offering excellent rates of LC. Most patients failed distantly highlighting the importance of additional systemic therapies.

To some radiation oncologists, 50 Gy/5 fractions has been considered controversial, as they feel the nominal BED of 100 Gy might be too low for long-term local control of some lesions. We analyzed a large cohort of these patients using a deep learning model to predict local recurrence (LR) and used explainability techniques to extract new dose features important to the model's prediction. Subsequently, we determined optimal cut-points for the most significant metrics to provide actionable criteria for treatment planning in these patients.A total of 535 SBRT lung cancer patients treated between 2009 and 2017 were retrospectively analyzed using a deep learning approach. All patients had NSCLC and all of them were treated with 50 Gy in 5 fractions (100 Gy BED, α/β = 10). Mean clinical maximum tumor diameter was 2.2 cm. There were 31 LR in the dataset with mean follow-up time of 28 months. Mean age was 75 years. CT images, 3D dose distribution and patient demographic details were used to train a deep learning survival model to predict time to failure and probability of local control. Validation, training, and testing were in accordance with TRIPOD criteria. 80 % of the data were used for 5-fold cross-validation (10 iterations) and 20 % was held for independent testing. The Grad-CAM method was applied to identify regions of the dose distribution that are the most significant to the model's decision-making. Based on the results, appropriate dose metrics were proposed, and optimal cut-points were determined to distinguish between lower and higher LR-risk patients.The model has an acceptable performance (c-index: 0.72, 95% CI: 0.68-0.75); the testing c-index was 0.69. Grad-CAM showed that the model's spatial attention was mostly concentrated in the tumor's "PTV-GTV" region. Statistically significant criteria are in Table 1.A novel deep learning model for prediction of LR, incorporating 3D dose data, CT images and patient demographics, was developed and tested. Grad-CAM demonstrated superior significance of peripheral (PTV-GTV) dose features. Subsequently determined optimal cut-points have significant prognostic power (log rank, p<0.001) and could be used as additional criteria in treatment planning. While these data have repercussions in treatment planning, they do not suggest that a significantly higher BED for the prescription dose is necessary for tumor control in NSCLC. Nevertheless, it might be effective to slightly elevate the prescribed dose, i.e., from 100 Gy BED to 104 Gy BED.

<h3>Background</h3> Patients with PNS are frequently excluded from clinical trials involving ICIs due to safety concerns. Herein, we study the safety and clinical outcomes of ICIs in patients with solid tumors and PNS. <h3>Methods</h3> Data was collected on patients with PNS and solid tumors receiving ICI between 2015 and 2022 at 7 institutions. A panel of 22 different PNS was predefined and PNS confirmed by specialists were included. Patients were classified into: Cohort 1 (PNS pre-ICI initiation); Cohort 2 (PNS post-ICI initiation). To evaluate the impact of PNS on clinical outcomes, patients with metastatic non-small cell lung cancer (mNSCLC) from both cohorts were matched to patients with mNSCLC and without PNS at each institution up to a 1:3 ratio by (1)age, (2)sex, (3)ICI class, (4)concurrent chemotherapy, and (5)number of prior systemic therapies. Overall survival (OS) and time to treatment failure (TTF) were estimated using the Kaplan-Meier method. Distributions were compared between patients with and without PNS using a log rank. Treatment-related adverse events (trAEs) were reported per Common Terminology Criteria for Adverse Events v5.0. <h3>Results</h3> Among 99 patients with PNS treated with ICIs, median follow-up time was 34 months. The most represented cancer type was NSCLC (n=37,37%,table 1). 15/30 patients with neurologic PNS had neural autoantibodies. In Cohort 1(n=49), PNS worsened in 14(29%) patients after a median time of 1.6 months (IQR:0.6–4.0) following ICI initiation. For Cohort 2 (n=50), median time between ICI initiation and onset of new PNS was 3.8 months (IQR:1.3–10.3). In the overall cohort, trAEs occurred in 37(37%) and grade ≥3 trAEs occurred in 15 (15%) patients. The exacerbation or new diagnosis of PNS prompted temporary/permanent interruption of ICI in 14(14%) patients of which 6/14(43%) had neurologic PNS. 52(53%) patients required PNS-directed immunosuppressive therapy. We then matched 31 patients with mNSCLC and PNS from Cohorts 1 and 2 to 79 without PNS, treated with ICIs. There was no significant difference in OS or TTF between patients with mNSCLC with and without PNS (figure 1), and the prevalence of trAEs was similar between both groups. Any grade trAEs occurred in 10/31(32%) patients with PNS vs. 31/79(39%) without PNS, while grade≥3 trAEs occurred in 3(9.7%) vs. 14(18%) patients, respectively. <h3>Conclusions</h3> Among patients with PNS, ICIs appeared to be tolerated, albeit with a high rate of worsening of pre-existing PNS. In the matched cohort of patients with NSCLC with and without PNS, the clinical outcomes and safety profiles were similar. <h3>Ethics Approval</h3> This study is approved by the institutional review board (IRB) at DFCI and local IRBs at participating centers per institutional policy and the Declaration of Helsinki.

Multiple publications report degradation of dosimetric coverage of mobile tumor volumes treated with MLC-based IMRT. The discrepancy between planned and delivered doses has been attributed to the interplay between the dynamic delivery of the radiation and respiratory motion of the tumor. We hypothesize that using an ITV planning approach coupled with compensator based IMRT will result in better agreement between planned and delivered dose distributions. MLC and compensator-based IMRT plans were generated in Pinnacle treatment planning system for a series of previously treated patients (5 pancreatic, 5 esophageal, and 4 liver cases). The PTV coverage and OAR sparing were matched yielding nearly identical DVHs. The dose distributions were measured with a bi-planar diode array dosimeter (Delta 4, ScandiDos AB, Uppsala, Sweden). It has a 0.5 cm spacing between diodes in the central 6x6 cm2 and 1 cm elsewhere on the 20x20 cm2 detector boards. The dosimeter was placed on an acrylic table manufactured and programmed for two-dimensional motion. The motion platform moved on an engraved ramp with a 10° inclination and a motion pattern that was determined from a 4D-CT of an esophageal case. For the specific data set presented, motion was varied by amplitude (24, 14.5, 10, and 6 mm), while frequency remained at 12 cycles per minute. Gamma analysis, using a 3% /3 mm passing criteria, was performed by using motion measurements as the target dose and static measurements as the reference dose. The average percentage of readings that agreed with the original plan for motions of 24, 14.4 and 10 mm was statistically significantly higher using compensators as compared to MLCs. For 24 mm motion the compensator Avg = 95.62% (STD = 1.58), while the MLC Avg = 86.76 (STD = 3.57) p = 0.0031; for 14.4 mm motion and compensators, Avg = 99.03% (STD = 1.31), MLC Avg = 93.59% (STD = 1.98) p = 0.0311. For 10 mm motion and compensators, Avg = 99.97% (STD = .02), MLC Avg = 97.53 (STD = 2.93) p = 0.0360 For 6 mm motion both compensator and MLC deliveries averaged over 99% agreement with the intended delivery. Compared to compensator-based IMRT delivery, the interplay between the dynamic delivery and respiration induced motion significantly degrades the delivered dose distribution in MLC-based IMRT for motion larger than 10 mm.

Chloroquine has been shown to increase the cellular retention and nuclear incorporation of 125I-labeled monoclonal antibody (MAb) 425, a murine anti-epidermal growth factor receptor monoclonal antibody, in human high-grade glioma cells in vitro. The objective of this study was to examine the effect of chloroquine on the biodistribution of 125I-MAb 425 in an intracerebral xenogeneic transplant of glioma cells. Nude rats were stereotaxically implanted in the right hemisphere with A1207 human high-grade glioma cells. After 14 days, animals were injected i.v. with chloroquine (40 mg/kg) followed 2 h later by an 125I-MAb 425 (9 MBq) infusion. Tissue distributions were performed up to 168 h post 125I-MAb 425 injection. From 24 to 168 h, tumor-to-contralateral left brain ratios increased from 9 to 15 for 125I-MAb 425 alone, and 7 to 13 for the 125I-MAb 425/chloroquine combination, respectively. A single administration of chloroquine did not result in any significant difference in radiolabeled MAb accumulation in either the tumor site or other tissues. We conclude that chloroquine did not increase the amount of 125I-MAb 425 into the tumor; however, it is safe to administer i.v. at the 40 mg/kg dose. Under these experimental conditions, the increased radioactive accumulation observed for in vitro data did not translate into similar in vivo results.

ABSTRACT Cancer sequencing efforts have demonstrated that cancer is the most complex and heterogeneous disease that affects humans. However, radiation therapy, one of the most common cancer treatments, is prescribed based on an empiric one-size-fits all approach. We propose that the field of radiation oncology is operating under an outdated null hypothesis: that all patients are biologically similar and should uniformly respond to the same dose of radiation. We have previously developed the Genomic Adjusted Radiation Dose (GARD), a method which accounts for biological heterogeneity and can be utilized to predict optimal RT dose for an individual patient. In this article, we utilize GARD to characterize the biological imprecision of one-size-fits-all RT dosing schemes which result in both over- and under-dosing for the majority of patients treated with RT. To elucidate this inefficiency, and therefore the opportunity for improvement using a personalized dosing scheme, we develop a patient-specific competing hazards-style mathematical model combining the canonical equations for tumor control (TCP) and normal tissue complication probabilities (NTCP). This model simultaneously optimizes tumor control and toxicity by personalizing RT dose using patient-specific genomics. Using data from two prospectively collected cohorts of patients with non-small-cell lung cancer, we validate the competing hazards model by demonstrating that it predicts the results of RTOG 0617. We show how 0617 failure can be explained by the biological imprecision of empiric uniform dose escalation which results in 80% of patients being over-exposed to normal tissue toxicity without potential tumor control benefit. In conclusion, our data reveals a tapestry of radiosensitivity heterogeneity, provides a biological framework that explains the failure of empiric RT dose escalation, and quantifies the opportunity to improve clinical outcomes in lung cancer by incorporating genomics into RT.

We hypothesized that the addition of concurrent ipilimumab (IPI) with chemoradiotherapy followed by consolidative nivolumab (NIVO) would be safe and tolerable for patients with unresectable stage III non-small cell lung cancer (NSCLC). We report early outcomes and toxicity associated with this regimen in a phase I/II clinical trial.The study was designed as a prospective, multicenter phase I/II trial. Eligible patients had ECOG 0-1 and unresectable stage III NSCLC. Therapy included a platinum-based chemotherapy doublet with concurrent radiotherapy to 60 Gy in 30 fractions over six weeks and two doses of concurrent IPI (1 mg/kg) given weeks 1 and 4. Maintenance NIVO was initiated 1-3 weeks after completion of chemoradiotherapy/IPI and given every 4 weeks (480 mg) for up to 12 cycles. The primary endpoints were to evaluate the safety and tolerability of the regimen (Phase I) and the 12-month PFS (Phase II). Treatment-related toxicity was assessed according to CTCAE v5.0. Time to event analysis was performed with Kaplan Meier (KM) and Cox proportional hazard (CPH) models. Results are reported with 95% confidence intervals (CI).Nineteen of a planned 55 patients were enrolled in the trial which was discontinued without proceeding to the Phase II component due to exceeding the futility boundary for toxicity. The median follow-up was 21 months by the reverse KM method. The 12-month PFS estimate was 54% (CI 29-78) and the median PFS was 19 months (CI 6-not reached). The 12-month OS estimate was 60% (CI 36-84) while the median OS was not reached. Ten patients (53%, CI 29-76) experienced grade 2 or higher (G2+) pneumonitis. The median time to development of G2+ pneumonitis was 5.5 months and the risk of G2+ pneumonitis at 6- and 12-months was 57% (CI 30-84) and 74% (CI 49-99), respectively. Sixteen patients (84%, CI 68-100) had any G3+ treatment related toxicity. The most common G3+ toxicities were pulmonary (8 patients, 42%, CI 20-67) and cytopenias (7 patients, 37%, CI 16-62). Five patients (26%, CI 6-46) had possible treatment related G5 toxicity, including three patients with possible treatment related G5 pulmonary toxicity (16%, CI 0-32). There was no difference in the mean percent of lung volume receiving 20 Gy (V20) between those with and without G2+ pneumonitis (26%, CI 20-32 vs 21%, CI 16-27, P = 0.18), nor in the mean lung dose (14 Gy, CI 10-17 vs 15 Gy, CI 12-18, P = 0.35). Neither mean lung dose nor lung V20 were associated with time to G2+ pneumonitis on univariable CPH.The combination of concurrent IPI with standard chemoradiation followed by maintenance NIVO for unresectable stage III NSCLC is associated with significant toxicity which may limit opportunities for improved outcomes, although the sample size in this trial is small. Alternative strategies or sequencing should be explored to integrate immunotherapy with cytotoxic chemotherapy and radiation for patients with unresectable stage III NSCLC.

70 Background: Often in esophageal targets that move with respiration, endoscopically implanted fiducial markers are placed under ultrasound guidance within 1 cm from the superior and inferior tumor border. Our group has previously reported the stability of this method. 3D 18F-FDG PET/CT is obtained for initial staging of esophageal cancer and has altered the tumor volume in many sites. The correlation of these two methods for GTV delineation is currently undefined. Methods: Twenty-one patients with esophageal cancer were selected for this retrospective, IRB-approved analysis. Each patient underwent fiducial placement (by one of six endoscopists) at the inferior and superior borders of the tumor and received PET/CT prior to Radiotherapy (RTx). PET/CT images were imported into an image analysis software system for measurements. The distance between fiducial markers and MTV defined by 2.5 SUV contour (method 1) and MTV using a threshold above mean liver uptake (method 2) was calculated. The fiducials were located on CT. The distance between the centroid and MTV border was measured. The Concordance Correlation Coefficient (CCC) was calculated to determine the correlation between results from the two methods. Results: In method 1 the median distance between MTV (2.5 SUV) and fiducials was 1.0 cm (0.0 cm - 2.8 cm) and 1.0 cm (0.0 cm - 6.9 cm) for inferior and superior borders, respectively. In method 2 median distance between MTV and fiducials was 1.14 cm (0.0 cm - 2.62 cm) and 1.64 cm (0.33 cm – 6.84 cm) for inferior and superior borders, respectively. The CCC indicated poor agreement between methods for both distances (0.57 and 0.87 for inferior fiducial distance and superior fiducial distance, respectively). There was no correlation between MTV-to-fiducial distances greater than 2 cm and the endoscopist that performed the fiducial implantation. Conclusions: Although the methods of defining the MTV had poor strength of agreement, both methods demonstrated a robust correlation between inferior fiducial marker placement and inferior PET/CT uptake. The superior fiducial marker and MTV border illustrated discordance – unrelated to the endoscopist.

The potential role of integrating 4D PET/CT based volumes into the treatment planning of esophageal cancer patients is not well defined. In our study, we evaluated whether there would be a potential dosimetric photon advantage of treating patients with maximum inhale vs. exhale technique.

Purpose: Three methods of calculating ventilation from 4D CT image sets have been explored by several research groups. This study is to investigate the differences of these three local ventilation calculations. Methods: Optical flow (OF) deformable image registration of the normal end expiration and inspiration phases of 4D‐CT images was used to correlate the voxels between the two phases. The OF was validated using a 4D pixel‐ based and point‐validated breathing thorax model, consisting of a 4D‐CT image data set along with associated landmarks. Ventilation derived from 4D‐CTs from 20 esophageal patients were retrospectively analyzed. Differences between the ventilation images generated by three methods, the Jacobian, the DeltaV, and the HU, were examined on a voxel‐to‐voxel basis. The Jacobian method uses the first derivative of the deformation field to approximate the change in volume of voxels. The DeltaV method directly calculates the volume change. The HU method uses the change in Houndsfield Units (HUs) of corresponding voxels to calculate ventilation. Results: The target registration error (TRE) for the deformable image registration was an average of 1.6±0.68 mm and maximum of 3.1 mm. Average difference between the DeltaV and the Jacobian ventilation as a percentage of the maximum ventilation value was 0.51±0.3% (range 0.33% to 1.32%). Average difference between the DeltaV and HU ventilation was 2.4±4.5 % (range 0.4% to 19.2 %). A small number of voxels show significant differences. We speculate that the larger differences were due to some image registration variances. Regions of highest and lowest ventilation matched well for all methods. Conclusions: Highs and lows in ventilation were more pronounced in the DeltaV method compared to the Jacobian. In general the differences between the two ventilation methods were small. However, the differences between the DeltaV and the HU methods were considerably larger.

Purpose/Objective(s)RTOG1106 is designed to individualize adaptive radiotherapy (RT) based on PET response during concurrent chemoRT for Stage III NSCLC. This study aimed to examine the consistency across institutions of: 1) PET-based metabolic tumor volume (MTV) versus CT-based gross tumor volume (GTV); and 2) the feasibility of generating during-RT PET based adaptive plans.Materials/MethodsEleven RTOG lung committee member Institutes participated this study on pre-RT and during-RT PET-CT scans of one T4N2M0 NSCLC of the right lower lobe. The initial plan (A) based on pre-RT PET-CT was to 74 Gy. An adaptive plan (B) used during-RT PET-CT to create an adapted boost, after 50 Gy to the initial planning target volume (PTV). The final adaptive plan limited total mean lung dose (MLD) to 20 Gy, and other organs at risk (OARs) to institutional or RTOG0617 criteria. Target/OAR volumes and doses and doses to 95% of PTV were compared between centers.ResultsThe variations in PET-MTVs were not significantly different from CT-GTVs of primary tumors and nodal diseases either pre- or during-RT (P = NS). However, variations of these volumes were remarkable, ranging 1.4 to 9.2 fold of maximum over minimum for individual targets. Nodal CT-GTV pre-RT and CT-GTVs during-RT had the greatest variation, with a maximum magnitude above 5 fold of the minimum. During-RT GTV and MTV had greater variations than pre-RT GTV and MTV, with during-RT CT-GTV having the greatest difference from one physician to another. There were also remarkable variations in OAR volumes, with maximum up to 4 fold greater than minimum for one structure. Using during-RT PET and with some individual instruction, 11/11 centers were capable of generating adaptive plan to escalate PTV doses. Plan A generated a mean PTV dose of 73.3 Gy (95% CI 73.2-74.2) with MLD of 20.3 (95% CI 19.3-21.3) Gy. Plan Bs PTV dose was escalated to a mean of 83 Gy (95% CI 81-85), with a MLD of 19.0 Gy (95% CI 18.3-19.2). Plan B reduced the mean esophageal, heart V40, esophageal V60, and maximum cord doses, with a small increase (0.8 Gy) increase in the maximum esophageal dose. All adaptive had MLD<20 Gy.ConclusionsAlthough there were significant variations between target and OAR volumes, there were no significant differences in variations between CT-GTVs and PET-MTVs on either pre- or during-RT scans. Adaptive planning among RTOG centers is able to provide relatively consistent PTV dose escalation and OAR dose reduction. Purpose/Objective(s)RTOG1106 is designed to individualize adaptive radiotherapy (RT) based on PET response during concurrent chemoRT for Stage III NSCLC. This study aimed to examine the consistency across institutions of: 1) PET-based metabolic tumor volume (MTV) versus CT-based gross tumor volume (GTV); and 2) the feasibility of generating during-RT PET based adaptive plans. RTOG1106 is designed to individualize adaptive radiotherapy (RT) based on PET response during concurrent chemoRT for Stage III NSCLC. This study aimed to examine the consistency across institutions of: 1) PET-based metabolic tumor volume (MTV) versus CT-based gross tumor volume (GTV); and 2) the feasibility of generating during-RT PET based adaptive plans. Materials/MethodsEleven RTOG lung committee member Institutes participated this study on pre-RT and during-RT PET-CT scans of one T4N2M0 NSCLC of the right lower lobe. The initial plan (A) based on pre-RT PET-CT was to 74 Gy. An adaptive plan (B) used during-RT PET-CT to create an adapted boost, after 50 Gy to the initial planning target volume (PTV). The final adaptive plan limited total mean lung dose (MLD) to 20 Gy, and other organs at risk (OARs) to institutional or RTOG0617 criteria. Target/OAR volumes and doses and doses to 95% of PTV were compared between centers. Eleven RTOG lung committee member Institutes participated this study on pre-RT and during-RT PET-CT scans of one T4N2M0 NSCLC of the right lower lobe. The initial plan (A) based on pre-RT PET-CT was to 74 Gy. An adaptive plan (B) used during-RT PET-CT to create an adapted boost, after 50 Gy to the initial planning target volume (PTV). The final adaptive plan limited total mean lung dose (MLD) to 20 Gy, and other organs at risk (OARs) to institutional or RTOG0617 criteria. Target/OAR volumes and doses and doses to 95% of PTV were compared between centers. ResultsThe variations in PET-MTVs were not significantly different from CT-GTVs of primary tumors and nodal diseases either pre- or during-RT (P = NS). However, variations of these volumes were remarkable, ranging 1.4 to 9.2 fold of maximum over minimum for individual targets. Nodal CT-GTV pre-RT and CT-GTVs during-RT had the greatest variation, with a maximum magnitude above 5 fold of the minimum. During-RT GTV and MTV had greater variations than pre-RT GTV and MTV, with during-RT CT-GTV having the greatest difference from one physician to another. There were also remarkable variations in OAR volumes, with maximum up to 4 fold greater than minimum for one structure. Using during-RT PET and with some individual instruction, 11/11 centers were capable of generating adaptive plan to escalate PTV doses. Plan A generated a mean PTV dose of 73.3 Gy (95% CI 73.2-74.2) with MLD of 20.3 (95% CI 19.3-21.3) Gy. Plan Bs PTV dose was escalated to a mean of 83 Gy (95% CI 81-85), with a MLD of 19.0 Gy (95% CI 18.3-19.2). Plan B reduced the mean esophageal, heart V40, esophageal V60, and maximum cord doses, with a small increase (0.8 Gy) increase in the maximum esophageal dose. All adaptive had MLD<20 Gy. The variations in PET-MTVs were not significantly different from CT-GTVs of primary tumors and nodal diseases either pre- or during-RT (P = NS). However, variations of these volumes were remarkable, ranging 1.4 to 9.2 fold of maximum over minimum for individual targets. Nodal CT-GTV pre-RT and CT-GTVs during-RT had the greatest variation, with a maximum magnitude above 5 fold of the minimum. During-RT GTV and MTV had greater variations than pre-RT GTV and MTV, with during-RT CT-GTV having the greatest difference from one physician to another. There were also remarkable variations in OAR volumes, with maximum up to 4 fold greater than minimum for one structure. Using during-RT PET and with some individual instruction, 11/11 centers were capable of generating adaptive plan to escalate PTV doses. Plan A generated a mean PTV dose of 73.3 Gy (95% CI 73.2-74.2) with MLD of 20.3 (95% CI 19.3-21.3) Gy. Plan Bs PTV dose was escalated to a mean of 83 Gy (95% CI 81-85), with a MLD of 19.0 Gy (95% CI 18.3-19.2). Plan B reduced the mean esophageal, heart V40, esophageal V60, and maximum cord doses, with a small increase (0.8 Gy) increase in the maximum esophageal dose. All adaptive had MLD<20 Gy. ConclusionsAlthough there were significant variations between target and OAR volumes, there were no significant differences in variations between CT-GTVs and PET-MTVs on either pre- or during-RT scans. Adaptive planning among RTOG centers is able to provide relatively consistent PTV dose escalation and OAR dose reduction. Although there were significant variations between target and OAR volumes, there were no significant differences in variations between CT-GTVs and PET-MTVs on either pre- or during-RT scans. Adaptive planning among RTOG centers is able to provide relatively consistent PTV dose escalation and OAR dose reduction.

Ventilation imaging using 4DCT would facilitate integration of lung functional information in radiation therapy (RT) treatment planning to spare normal functional lung volumes. This study uses the diffeomorphic morphons (DM) deformable image registration (DIR) method and the ΔV ventilation calculation algorithm to derive ventilation from 4DCT scans and evaluate the effects of radiation treatment on lung ventilation.

569 Background: We have previously identified a multigene expression model of tumor radiosensitivity with validation in four independent cohorts (breast, rectal, esophageal, and head and neck). This model predicts a radiosensitivity index (RSI) that is directly proportional to tumor radioresistance, (RSI, high index = radioresistance). The purpose of this study was to assess differences in RSI between primary colon cancer and metastases. Methods: Patients were identified from our institutional IRB-approved prospective observational protocol. A total of 704 metastatic and 1,362 primary lesions were obtained from a de-identified meta-data pool. Gene expression was obtained from Affymetrix Hu-RSTA-2a520709 microarrays. RSI was calculated using the previously published ranked based algorithm. An independent cohort of 38 lung and liver colon metastases treated with 60 Gy in 5 fractions stereotactic body radiotherapy (SBRT) was used for validation. Results: The most common sites of metastases included liver (n=374; 53%), lung (n=116; 17%), and lymph nodes (n=40; 6%). Sixty percent of metastatic tumors compared with 54% of primaries were in the RSI-radioresistant (RSI-RR) peak, suggesting that metastatic tumors may be slightly more radioresistant than primaries (p=0.01). In contrast, when we analyzed metastases based on anatomical site, we uncovered large differences in RSI. The median RSIs for metastases in descending order of radioresistance were ovary (0.48), abdomen (0.47), liver (0.43), brain (0.42), lung (0.32), and lymph nodes (0.31), p&lt;0.0001. These findings were confirmed when the analysis was restricted to lesions from the same patient (n=69). In our independent cohort of lung and liver metastases, lung metastases had an improved outcome over patients with liver metastases (2 yr local control, lung vs. liver metastases; 100% vs. 74.0%, p=0.027). Conclusions: Assessment of radiosensitivity between primary and metastatic tissues of colon cancer histology, reveals significant differences based on anatomical location of metastases. These initial results warrant validation in a larger clinical cohort.

Increasing evidence in the management of oligometastases with SBRT reveals differences in outcomes based on primary histology and dose selection. We have previously identified a multigene expression index for tumor radiosensitivity (RSI) with validation in multiple cohorts, including breast, rectal, esophageal, lung, prostate, and head and neck. An analysis from our group revealed differences in RSI between colon cancer metastases based on anatomical location. In this study, we assessed RSI in liver and lung metastases of various primary histologies. Patients were identified from our institutional IRB-approved prospective observational protocol. A total of 459 metastatic liver and 298 metastatic lung lesions were obtained from a de-identified meta-data pool. Gene expression was from a high-density microarray. The previously tested RSI 10 gene assay was run on tissue samples ranked according to gene expression. Radiosensitivity was calculated using the previously published algorithm. Overall, there was no significant difference in RSI values of liver and lung metastases. The median RSI for all liver lesions was 0.42 (Q1, 0.28; Q3, 0.49) versus lung lesions 0.38 (Q1, 0.30; Q3, 0.48), P = .71. The most common primary histology for liver metastases were colorectal (n = 374; 81%), pancreas (n = 18; 4%), and breast (n = 15; 3%). There were significant differences in RSI of liver metastases based on histology. The median RSIs for liver metastases in descending order of radioresistance were skin (0.54), colorectal (0.43), stomach (0.43), pancreas (0.42), lung (0.35), breast (0.34), small intestine (0.22), and anal (0.21); P = .0002. A total of 58 patients had multiple liver tissue samples. When averaging RSI values from the same patient, significant differences continued to be noted based on primary histology: colorectal (0.43), breast (0.34), and small intestine (0.20); P = .046. The most common primary histology for lung metastases were colorectal (n = 116; 39%), skin (n = 43; 14%), and soft tissue (n = 36; 12%). Similarly, significant differences were noted based on primary histology in lung metastases. The median RSIs for metastases in descending order of radioresistance were soft tissue (0.48), endometrium (0.46), oral cavity (0.45), skin (0.40), kidney (0.33), colorectal (0.32), and breast (0.32); P < .0001. Similar trends were noted when averaging RSI values of multiple lung lesions from the same patient (n = 30): soft tissue (0.54), skin (0.38), colorectal (0.37), breast (0.36), and kidney (0.35); P = .20. In this first of its kind analysis assessing the radiosensitivity of liver and lung metastases, we find significant differences based on primary histology. As we move towards an era of personalized radiation delivery, this study suggests primary histology may be an important factor to consider in SBRT radiation dose selection.

7553 Background: Vorinostat (V) is a potent class I & II (HDAC 6) inhibitor of histone deacetylases. In A549 and A375 cell lines (CL’s), V intensified RT induced decrease in clonogenic survival via impaired DNA repair. In CL's V downregulated thymidylate synthase (TS), a target of pemetrexed (P). Methods: This is a phase I trial of V plus C (cisplatin) or CP (carboplatin), P and RT for ECOG PS 0-1 pts with stage IIIA/B non-squamous NSCLC. V was dose-escalated in a 3+3 design (V at dose levels (DL1-3) 100, 200 and 300mg) with CRT: C (75 mg/m2) and P (500mg/m2) Q21 days x 4 with folic acid, B12, steroids), and RT (60 Gy). DL1b included CP AUC 5, P, RT and V 100mg. V was dosed for 3 consecutive days before cycle 1, and was then taken orally once a day 3 times/week during CRT. Surgical resection after CRT was allowed. The primary endpoint was to determine the MTD. Correlative analyses include TS and HDAC expression. This study was approved & funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Merck & Co., Inc. Results: Eighteen pts (51 - 80 years) enrolled from May 2010 to September 2014. Three evaluable (Ev) pts were treated on DL 1 (V 100), with no DLT. 3 Ev pts, and 2 Non-Ev pts (1 not eligible, 1 discontinued due to P-associated rash) were treated on DL 2 (V 200). At DL2, 2 pts had a DLT of grade (G) 4 hyponatremia (HNa). Accrual resumed with 3 pts on DL1, with 2 DLTs at DL1 (HNa and heart failure). Six pts were treated on DL1b with no DLTs. G 1 & 2 toxicities: nausea, anorexia, dysphagia, dehydration, esophagitis, fatigue, pain. G 3 toxicities: nausea, hyperglycemia, anemia, leukopenia. Fourteen pts completed 4 cycles of CRT and V. Two pts stopped V due to myelosuppression. One pt developed CLL 18 months after therapy. Among all pts the best response to date is CR:2, PR:4, SD: 8 pts. Three pts underwent resection, with no viable tumor in 2 specimens. With a median follow up of 15.4 months, the median PFS/OS have not been reached. Conclusions: With the exception of G4 HNa, no unexpected toxicities were noted with V and CRT. Esophagitis was mild. Assessment of PFS/OS and correlatives are ongoing. The recommended Phase 2 dose is CP AUC 5, P 500mg/m2 and V100mg 3x/week with RT. Clinical trial information: NCT01059552.

7538 Background: The standard management for stage I non-small cell lung cancer is surgical resection and SBRT. Adjuvant therapy is typically not given in this group of lung cancer patients. Unfortunately, 14% to 23% who undergo surgery for a stage I NSCLC ultimately fail distantly. Methods: Moffitt Cancer Center (MCC) has launched a major initiative termed Total Cancer Care (TCC) to innovate personalized compiling 40,000 tumor microarray databank linked to longitudinal clinical data. We conducted a retrospective chart review of pathologic T1-T2N0 NSCLC patients in the TCC database, and classified patients according to their recurrence pattern. CEL files from Affymetrix microarray from pathologic specimens from these patients were obtained from TCC, and gene expression profile was analyzed. Results: We identified a cohort of 143 patient treated with surgical resection. 56 patients were without evidence of disease at least 3 years following surgery (Control cohort), 34 patients failed locally and in regional lymph nodes (Loco-regional failure cohort), and 53 patients developed distant metastasis (distant failure cohort). 144 genes were identified that showed significant differences in RNA expression level between control cohort vs. distant failure cohort. However, only 1 gene was associated with loco-regional failure. 144 genes identified were validated against the Director’s Challenge database. Over 90% of the genes identified from this study correctly predicted survival outcome from the Director’s Challenge database. Conclusions: We have identified a group of genes that predict distant metastasis among surgically resected pathologic T1-T2N0 adenocarcinoma of the lung. We are currently developing the scoring system to classify this earliest stage lung adenocarcinoma patients into 3 groups, low risk, intermediate risk, and high risk for distant failure based on our gene signature. The outcome of this study will identify a select group of stage I lung adenocarcinoma patients who will benefit from adjuvant chemotherapy after local therapy with surgery or SBRT. Ultimately, we are planning to translate these findings to a clinical trial.

Purpose: To investigate the effects of radiation therapy (RT) treatment dose on ventilation. Methods: Optical flow deformable image registration of the normal end‐expiration and end‐inspiration phases of 4DCT images was used to correlate the voxels between the two phases. 4DCT sets from before and after RT were used to derive ventilation for 3 SBRT lung patients. Planning dose and normalized ventilation were superimposed on the CT volume resulting in each voxel having a volume, a normalized ventilation and a dose. From these values a 3D dose‐ventilation‐volume surfaces was created. The surface was integrated over dose to reduce the 3D surface to a 2D histogram that is easier to interpret. Results: For lung tissue regions receiving more than 20 Gy, a decrease in ventilation was observed in the three patients. Patient A (time between scans, T=26 months) showed an increase in ventilation for regions receiving a dose smaller than 20 Gy, whereas patients B (T=3 months) and C (T=6 months) did not show any change for these regions. Mean ventilation within the 20 Gy region for patient A was 0.57 before RT and 0.51 after RT; and 0.54 before and 0.48 after RT for the 30 Gy region. Mean ventilation for the 20 Gy region for patient B was 0.49 before RT and 0.47 after RT, for the 30 Gy region mean ventilation was 0.49 Gy before and 0.45 Gy after RT. Patient C's mean ventilation for the 20 Gy region was 0.54 before RT and 0.50 after RT, for the 30 Gy region mean ventilation was 0.54 before RT and 0.49 after RT. Conclusions: Ventilation before and after radiation therapy can be measured using 4DCT and deformable image registration techniques. In a preliminary application of this approach for three patients, changes in ventilation were observed with a weak correlation between ventilation change and dose. Partially supported by a grant from Varian Medical Systems.

The major problem with ventilation distribution calculations using DIR and 4DCT is the motion artifacts in 4DCT. Quite often not all phases would exhibit mushroom motion artifacts. If the ventilation series similarity is sufficiently robust, the ventilation distribution can be calculated using only the artifact-free phases. This study investigated the ventilation similarity among the data derived from different respiration phases. Fifteen lung cancer cases were analyzed. In each case, DIR was performed between the end-expiration phase and all other phases. Ventilation distributions were then calculated using the deformation matrices. The similarity was compared between the series ventilation distributions. The correlation between the majority phases was reasonably good, with average SCC values between 0.28 and 0.70 for the original data and 0.30 and 0.75 after smoothing. The better correlation between the neighboring phases, with average SCC values between 0.55 and 0.70 for the original data, revealed the nonlinear property of the dynamic ventilation. DSC analysis showed the same trend. To reduce the errors if motion artifacts are present, the phases without serious mushroom artifacts may be used. To minimize the effect of the nonlinearity in dynamic ventilation, the calculation phase should be chosen as close to the end-inspiration as possible.

Background: Barrett's esophagus (BE) represents the major risk factor for esophageal adenocarcinoma (EA). Among EA patients treated with chemoradiation, tumor response is well described; however, it is unclear if this therapy affects the underlying BE. We hypothesize that chemoradiation as treatment for EA does not eliminate associated BE. Methods: Retrospective chart review performed at the Moffitt Cancer Center from 1/1/00 to 8/8/08. We identified 43 patients with EA arising from BE who were treated curatively, receiving either definitive or neoadjuvant chemoradiation. Staging endoscopy reports were used to obtain a pre-treatment description of the BE. To determine if BE was present after chemoradiation, surgical pathology and surveillance endoscopy reports were reviewed. Chemotherapeutic regimens and dose and the length of the esophagus included in the radiation treatment field were reviewed. Results: Chemoradiation consisted of an average dose of 50.4 Gy of radiation with cisplatin and 5-FU. BE was present after chemoradiation in 93% (40/43) of cases [95% CI 0.80-0.98]. 26 patients received neoadjuvant chemoradiation prior to esophagectomy. In all 26 cases, residual BE remained in the surgical specimen. In 62% (16/26) of these cases, the BE persisted while no tumor was microscopically detectable. 17 patients received definitive chemoradiation. Residual BE was identified in 82% (14/17) by surveillance endoscopy [95% CI 0.56-0.95]. The median length of BE was 6.0 cm, interquartile range 4.5-8.5 cm. The median length of esophagus included in the radiation field was 13.0 cm, interquartile range 11.0-15.5 cm. Conclusions: Chemoradiation for treatment of EA does not eliminate associated BE. Introducing endoscopic ablation of BE into the multi-disciplinary treatment approach for patients with EA who achieve complete response to definitive chemoradiation may translate into improved survival by preventing metachronous cancers from arising in the residual BE.

To date, radiation oncologists at the H. Lee Moffitt Cancer Center and Research Institute (Tampa, FL) have treated 29 patients with stereotactic radiotherapy (10 Gy × 5 fractions) to peripheral lung tumors (SBRT), as well as 5 patients in standard fractionation (2 Gy × 35 fractions) to small central lesions (IGRT). All were treated on a Novalis stereotactic treatment machine equipped with an ExacTrac Treatment Verification System (BrainLAB) for image-guided treatment delivery. The SBRT patients were immobilized using the BodyFix system (Medical Intelligence), while the standard fractionation patients were immobilized using VacLoc cradles (MedTec). The SBRT patients underwent bronchoscopic placement of gold Visicoil fiducials for target visualization. SBRT patients also underwent abdominal compression to minimize respiratory excursion. All patients were simulated on a 4D CT scanner (Phillips) and ITVs were generated to account for respiratory motion. PTV margins were at the discretion of the treating physician. All patients were initially set up to isocenter using external marks. They then underwent stereoscopic x-ray position verification before treatment. Relevant table shifts (lateral, longitudinal, vertical) were implemented if departmental tolerances were exceeded. Angular rotations (lateral, longitudinal, vertical) were also recorded. The SBRT patients were also re-imaged halfway through treatment. Further sets of images were taken daily at the discretion of the physicist and/or treating physician. To date, 385 sets of images have been taken on the SBRT patients during 145 daily treatments, and 192 sets of images during 168 treatments in the patients undergoing traditionally fractionated IGRT. To determine differences in patient setup variability with the two immobilization systems (BodyFix and MedTec) and implications in treatment planning. Couch shifts (lateral, longitudinal, and vertical) and angular rotations in three axial planes have been recorded and analyzed for each set (n = 577) of stereoscopic images taken. Data regarding lateral, longitudinal, and vertical table shifts have been analyzed (see Table). Analysis of angular rotations (skew) is ongoing. Initial findings demonstrate statistically improved reproducibility of patient position using the BodyFix immobilization system. Updated results, with additional patients/data points, will be presented at the Annual Meeting.TableAnalysis of Patient ShiftsMean (Standard Dev)MedianMinimumMaximumShifts (mm)SBRTIGRTSBRTIGRTSBRTIGRTSBRTIGRTLateral2.4 (1.2)4.1 (1.4)2.23.90.82.75.06.3Longitudinal3.1 (2.1)6.8 (2.0)2.77.31.14.511.89.1Vertical2.0 (1.2)3.4 (1.3)1.62.70.82.46.65.3 Open table in a new tab