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Purpose: Spatially fractionated radiation therapy (SFRT) is a recognized technique for enhancing tumor response in radioresistant and bulky tumors. We analyzed clinical and treatment outcomes in patients with bone and soft tissue sarcomas treated with modern SFRT techniques. Methods and Materials: Patients with metastatic or unresectable sarcoma treated with brass collimator, volumetric modulated arc therapy lattice, or proton SFRT from December 2019 to June 2022 were retrospectively reviewed. Consolidative external beam radiation therapy (EBRT) was delivered at the physician's discretion. Patient and treatment characteristics, treatment response (symptom improvement, local control, and imaging response), and toxicity data were collected. Results: The cohort consisted of 53 patients treated with 61 SFRT treatments. Median age at treatment was 60.0 years. The primary location was soft tissue in 46 courses (75%) and bone in 15 (25%). Fifty-three courses (87%) were treated for symptom relief. The most used SFRT technique was volumetric modulated arc therapy lattice (n = 52, 85%) to a dose of 20 Gy (n = 48, 79%; range, 16-20 Gy). EBRT was delivered post-SFRT in 55 (90%) treatment courses with a median time interval from SFRT to EBRT of 5 days (range, 0-14 days). Median physical EBRT dose and fractionation was 40 Gy (range, 9-73.5 Gy) and 10 fractions (range, 3-33 fractions). Median follow up was 7.4 months (range, 0.2-30 months). One-year overall survival and local control rates were 53% and 82%. Symptom relief was documented with 32 treatment courses (60%). Stable or partial response was observed with 47 treatment courses (90%). Four grade 3 to 4 acute and subacute toxicities were attributable to SFRT (8%). Conclusions: The current series is the largest to date documenting outcomes for SFRT in sarcomas. Our results suggest combined SFRT with EBRT is associated with a favorable toxicity profile and high rates of symptomatic and radiographic responses for metastatic or unresectable sarcomas.

Purpose: This study reports on the risk of radiation-induced myelitis (RM) of the spinal cord from a large single-institutional experience with 1 to 5 fraction stereotactic body radiation therapy (SBRT) to the spine. Methods and Materials: A retrospective review of patients who received spine SBRT to a radiation naïve level at or above the conus medullaris between 2007 and 2019 was performed. Local failure determination was based on SPIne response assessment in Neuro-Oncology criteria. RM was defined as neurologic symptoms consistent with the segment of cord irradiated in the absence of neoplastic disease recurrence and graded by Common Toxicity Criteria for Adverse Events, version 4.0. Rates of adverse events were estimated and dose-volume statistics from delivered treatment plans were extracted for the planning target volumes and spinal cord. Results: A total of 353 lesions in 277 patients were identified that met the specified criteria, for which 270, 70, and 13 lesions received 1-, 3-, and 5-fraction treatments, respectively, with a median follow-up of 46 months (95% confidence interval [CI], 41-52 months) for all surviving patients. The median overall survival was 33.0 months (95% CI, 29-43). The median D0.03cc to the spinal cord was 11.7 Gy (interquartile range [IQR], 10.5-12.4), 16.7 Gy (IQR, 12.8-20.6), and 26.0 Gy (IQR, 24.1-28.1), for 1-, 3-, 5-fractions. Using an a/b = 2Gy for the spinal cord, the median single-fraction equivalent-dose (SFED2) was 11.7 Gy (IQR, 10.2-12.5 Gy) and the normalized biological equivalent dose (nBED2/2) was 19.9 Gy (IQR, 15.4-22.8 Gy). One patient experienced grade 2 RM after a single-fraction treatment. The cumulative probability of RM was 0.3% (95% CI, 0%-2%). Conclusions: Spine SBRT is safe while limiting the spinal cord (as defined on treatment planning magnetic resonance imaging or computed tomography myelogram) D0.03cc to less than 14 Gy, 21.9 Gy, and 30 Gy, for 1, 3, and 5-fractions, consistent with standard guidelines.

Purpose: Global and regional liver function assessments are important for defining the magnitude and spatial distribution of dose to preserve functional liver parenchyma and reduce incidence of hepatotoxicity from radiation therapy for intrahepatic cancer treatment. This individualized liver function-guided radiation therapy strategy is critical for patients with heterogeneous and poor liver function, often observed in cirrhotic patients treated for hepatocellular carcinoma. This study aimed to validate k1 as a measure of global and regional function through comparison with 2 well-regarded global function measures: indocyanine green retention (ICGR) and albumin-bilirubin (ALBI). Methods and Materials: Seventy-nine dynamic gadoxetic acid enhanced magnetic resonance imaging scans were acquired in 40 patients with hepatocellular carcinoma in institutional review board approved prospective protocols. Portal venous perfusion (kpv) was quantified from gadoxetic acid enhanced magnetic resonance imaging using a dual-input 2-compartment model, and gadoxetic acid uptake rate (k1) was fitted using a linearized single-input 2-compartment model chosen for robust k1 estimation. Four image-derived measures of global liver function were tested: (1) mean k1 multiplied by liver volume (k1VL) (functional volume), (2) mean k1 multiplied by blood distribution volume (k1Vdis), (3) mean kpv, and (4) liver volume (VL). The measure's correlation with corresponding ICGR and ALBI tests was assessed using linear regression. Voxel-wise similarity between k1 and kpv was compared using Spearman ranked correlation. Results: Significant correlations (P < .05) with ICGR and ALBI were found for k1VL, k1Vdis, and VL (in order of strength), but not for mean kpv. The mean ranked correlation coefficient between k1 and kpv maps was 0.09. k1 and kpv maps were predominantly mismatched in patients with poor liver function. Conclusions: The metric combining function and liver volume (k1VL) was a stronger measure of global liver function compared with perfusion or liver volume alone, especially in patients with poor liver function. Gadoxetic acid uptake rate is promising for both global and regional liver function.

Purpose: Stereotactic body radiation therapy (SBRT) use has increased among patients without pathologic confirmation (PC) of lung cancer. Empirical SBRT without PC raises concerns about variation in workup and patient selection, but national trends have not been well described. In this study, we assessed patterns of empirical SBRT use, workup, and causes of death among a large national non-small cell lung cancer (NSCLC) cohort. Methods and Materials: We identified 2221 patients treated with SBRT for cT1-T2aN0M0 NSCLC in the Veterans Affairs health care system from 2008 to 2015. We reviewed their pretreatment workup and assessed associations between absence of PC and clinical and demographic factors. We compared causes of death between PC and non-PC groups and used Cox proportional hazards modeling to compare overall survival and lung cancer specific survival (LCSS) between these groups. Results: Treatment without PC varied from 0% to 61% among Veterans Affairs medical centers, with at least 5 cases of stage I NSCLC. Overall, 14.9% of patients were treated without PC and 8.8% did not have a biopsy attempt. Ten percent of facilities were responsible for almost two-thirds (62%) of cases of treatment without PC. Of non-PC patients, 95.5% had positron emission tomography scans, 40.6% had biopsy procedures attempted, and 12.7% underwent endobronchial ultrasound. Non-PC patients were more likely to have cT1 tumors and live outside the histoplasmosis belt. Age, sex, smoking status, and Charlson comorbidity index were similar between groups. Lung cancer was the most common cause of death in both groups. Overall survival was similar between groups, whereas non-PC patients had better LCSS (hazard ratio = 0.77, P = .031). Conclusions: Empirical SBRT use varied widely among institutions and appropriate radiographic workup was consistently used in this national cohort. Future studies should investigate determinants of variation and reasons for higher LCSS among non-PC patients.

Purpose: To present a systematic approach to the reirradiation special medical physics consult (ReRT-SMPC) process. Materials and Methods: An in-house reirradiation committee of physicians and physicists was formed to develop a streamlined and well-documented approach to ReRT-SMPCs. Dosimetric goals and considerations for tissue repair were generated by the committee with input from the literature, clinical trial guidelines, and physician experience. Procedural workflow was also defined. Results: The total number of ReRT-SMPCs performed in our department in 2018 was 401, corresponding to 369 unique patients and 16% of the total number of patients receiving external beam radiation in our department that year. This constituted a large increase over the 183 ReRT-SMPCs performed in 2017. We have found that a standardized ReRT-SMPC workflow helps to safeguard patients, documents the clinical decision-making process for medical and legal purposes, and facilitates the peer-review process. The data being collected from each consult along with toxicity and outcomes data can be used to help inform future re-treatment guidelines. Conclusions: As the number of patients returning for additional courses of radiation continues to increase, a uniform method for the ReRT-SMPC workflow and analysis is a powerful tool for ensuring patient safety, understanding and predicting treatment toxicity, and refining reirradiation dosimetric limits.

BACKGROUND: Declining liver function is a concerning side effect associated with radiation therapy. Biomarkers of liver toxicity would be useful in personalizing therapy. METHODS: As part of two prospective clinical trials examining adaptive radiation therapy, we collected serum samples from patients receiving liver radiation. We performed a screen of 22 cytokines using a multiplex assay then used ELISA to quantify the cytokines of greatest interest. Subjects were split into screening and validation cohorts. Toxicity was defined as an increase in Child-Pugh score of 2 points or greater within 6 months. Logistic regression models were used to estimate the relationship between our toxicity endpoint and serum cytokine concentrations. RESULTS: Our initial screen (46 subjects, 11 events) identified hepatocyte growth factor (HGF), CD40L (CD154), and eotaxin (CCL11) as potentially predictive of toxicity. We then tested these markers in an expanded patient cohort (104 subjects, 18 events) with a batch correction due to varying age of the samples which confirmed that high HGF and low CD40L were associated with a subsequent decline in liver function following radiation therapy. Multivariate analysis factoring in baseline Child-Pugh score and mean liver radiation dose demonstrated that HGF and CD40L were potentially predictive of toxicity (HGF OR 4.3, P = .009; CD40L OR 0.5 P = .06). Additionally, higher than median baseline HGF levels (1.4 ng/ml) were significantly associated with decreased survival following liver radiation (27.1 vs 14.5 months, P = .03). CONCLUSIONS: Our study identifies high HGF and low CD40L as potential markers of liver toxicity following radiation therapy.

Purpose: Previous studies suggest that stereotactic body radiation therapy (SBRT) is associated with higher toxicity rates for central lung tumors relative to peripheral tumors when using 3 fraction SBRT. The initial results from Radiation Therapy Oncology Group study 0813 suggest a safe toxicity profile of SBRT administered in 5 fractions for central non-small cell lung cancer (NSCLC). We reviewed our institutional data to evaluate the safety and efficacy of SBRT for central NSCLC. Methods and materials: We reviewed our prospectively collected SBRT database for patients with central NSCLC who received SBRT between 2008 and 2014. The most frequent dose and fractionations were 50 Gy in 5 fractions (59%) and 48 Gy in 4 fraction (30%). Local control (LC), regional control, metastasis-free survival, and overall survival were calculated using Kaplan-Meier estimates. The National Cancer Institute Common Terminal Criteria for Adverse Events were used for toxicity grading. Results: A total of 110 central lung tumors in 103 patients were included. The median age was 74 years (range, 40-95 years), and the median follow-up time of living patients was 50 months. The mean tumor size was 20 mm (range, 5-70 mm). The 5 year rate of LC, regional control, and distant control was 89%, 77%, and 82%, respectively. The median and 5-year overall survival were 3.5 years and 35%, respectively. No treatment variables were associated with tumor control or other clinical outcomes. A single patient experienced grade 3 radiation pneumonitis (0.97%). The rate of late toxicity grade ≥3 was 9.7% (grade 3, 7.7%; grade 4, 0.97%; grade 5, 0.97%) and included pneumonitis (3.9%), bronchial necrosis (2.9%), myocardial dysfunction (1.9%), and worsening heart failure (0.97%). Conclusions: SBRT for central NSCLC provides high rates of LC. Despite excellent LC, patients remain at risk for regional and distant failure. The rate of grade 3 pneumonitis was consistent with that of prior reports. We observed low rates of grade 4-5 toxicity potentially attributable to SBRT. Our results contribute to the growing body of data in support of the safety of SBRT for central NSCLC.

Introduction: Radiation therapy for the management of intrahepatic malignancies can adversely affect liver function. Liver damage has been associated with increased levels of inflammatory cytokines, including tumor necrosis factor alpha (TNFα). We hypothesized that an inflammatory state, characterized by increased soluble TNFα receptor (sTNFR1), mediates sensitivity of the liver to radiation. Materials/Methods: Plasma samples collected during 3 trials of liver radiation for liver malignancies were assayed for sTNFR1 level via enzyme-linked immunosorbent assay (ELISA). Univariate and multivariate logistic regression and longitudinal models were used to characterize associations between liver toxicity (defined as a ≥2-point increase in Child-Pugh [CP] score within 6 months of radiation treatment) and sTNFR1 levels, ALBI score, biocorrected mean liver dose (MLD), age, and baseline laboratory values. Results: Samples from 78 patients given liver stereotactic body radiation therapy [SBRT] (92%) or hypofractionated radiation were examined. There was a significant association between liver toxicity and sTNFR1 levels, and higher values were associated with increased toxicity over a range of mean liver doses. When ALBI score and biocorrected dose were included in the model with sTNFR1, baseline ALBI score and change in ALBI (ΔALBI) were significantly associated with toxicity, but sTNFR1 was not. Baseline aminotransferase levels also predicted toxicity but not independently of ALBI score. Conclusions: Elevated plasma sTNFR1 levels are associated with liver injury after liver radiation, suggesting that elevated inflammatory cytokine activity is a predictor of radiation-induced liver dysfunction. Future studies should determine whether administration of agents that decrease inflammation prior to treatment is warranted.

Purpose: To develop statistical dose-volume histogram (DVH)–based metrics and a visualization method to quantify the comparison of treatment plans with historical experience and among different institutions. Methods and materials: The descriptive statistical summary (ie, median, first and third quartiles, and 95% confidence intervals) of volume-normalized DVH curve sets of past experiences was visualized through the creation of statistical DVH plots. Detailed distribution parameters were calculated and stored in JavaScript Object Notation files to facilitate management, including transfer and potential multi-institutional comparisons. In the treatment plan evaluation, structure DVH curves were scored against computed statistical DVHs and weighted experience scores (WESs). Individual, clinically used, DVH-based metrics were integrated into a generalized evaluation metric (GEM) as a priority-weighted sum of normalized incomplete gamma functions. Historical treatment plans for 351 patients with head and neck cancer, 104 with prostate cancer who were treated with conventional fractionation, and 94 with liver cancer who were treated with stereotactic body radiation therapy were analyzed to demonstrate the usage of statistical DVH, WES, and GEM in a plan evaluation. A shareable dashboard plugin was created to display statistical DVHs and integrate GEM and WES scores into a clinical plan evaluation within the treatment planning system. Benchmarking with normal tissue complication probability scores was carried out to compare the behavior of GEM and WES scores. Results: DVH curves from historical treatment plans were characterized and presented, with difficult-to-spare structures (ie, frequently compromised organs at risk) identified. Quantitative evaluations by GEM and/or WES compared favorably with the normal tissue complication probability Lyman-Kutcher-Burman model, transforming a set of discrete threshold-priority limits into a continuous model reflecting physician objectives and historical experience. Conclusions: Statistical DVH offers an easy-to-read, detailed, and comprehensive way to visualize the quantitative comparison with historical experiences and among institutions. WES and GEM metrics offer a flexible means of incorporating discrete threshold-prioritizations and historic context into a set of standardized scoring metrics. Together, they provide a practical approach for incorporating big data into clinical practice for treatment plan evaluations.

Purpose: Limits on mean lung dose (MLD) allow for individualization of radiation doses at safe levels for patients with lung tumors. However, MLD does not account for individual differences in the extent or spatial distribution of pulmonary dysfunction among patients, which leads to toxicity variability at the same MLD. We investigated dose rearrangement to minimize the radiation dose to the functional lung as assessed by perfusion single photon emission computed tomography (SPECT) and maximize the target coverage to maintain conventional normal tissue limits. Methods and materials: Retrospective plans were optimized for 15 patients with locally advanced non-small cell lung cancer who were enrolled in a prospective imaging trial. A staged, priority-based optimization system was used. The baseline priorities were to meet physical MLD and other dose constraints for organs at risk, and to maximize the target generalized equivalent uniform dose (gEUD). To determine the benefit of dose rearrangement with perfusion SPECT, plans were reoptimized to minimize the generalized equivalent uniform functional dose (gEUfD) to the lung as the subsequent priority. Results: When only physical MLD is minimized, lung gEUfD was 12.6 ± 4.9 Gy (6.3-21.7 Gy). When the dose is rearranged to minimize gEUfD directly in the optimization objective function, 10 of 15 cases showed a decrease in lung gEUfD of >20% (lung gEUfD mean 9.9 ± 4.3 Gy, range 2.1-16.2 Gy) while maintaining equivalent planning target volume coverage. Although all dose-limiting constraints remained unviolated, the dose rearrangement resulted in slight gEUD increases to the cord (5.4 ± 3.9 Gy), esophagus (3.0 ± 3.7 Gy), and heart (2.3 ± 2.6 Gy). Conclusions: Priority-driven optimization in conjunction with perfusion SPECT permits image guided spatial dose redistribution within the lung and allows for a reduced dose to the functional lung without compromising target coverage or exceeding conventional limits for organs at risk.

Background: Spine stereotactic body radiation therapy (SBRT) is becoming widely accepted as first-line treatment of oligometastatic spine disease as well as in the postoperative setting. The reported incidence of myelopathy is very low and guidelines vary widely on the maximum tolerable dose of the spinal cord and thecal sac. Methods and materials: Between April 2008 and December 2010, radiation parameters were exported for 46 patients treated with spine SBRT at the Mayo Clinic. Using an in-house data mining program, dose-volume histogram constraints were extracted, including dose prescription, dose fractionation, planning target volume, planning target volume coverage, maximum dose to the cord, D2cc thecal sac, and D2cc spinal cord. Diagnostic magnetic resonance imaging scans and/or computed tomography myelograms were fused with the planning set to delineate the cord and thecal sac for receiver operating characteristic analysis of cord and thecal sac subvolume doses. A high-resolution planning at-risk volume was created in 1-mm increments for cord (1-7 mm) and the thecal sac (1-2 mm) to examine dose gradients that might be correlated with toxicity. Results: No patients experienced myelopathy with a median follow-up of 14 months. The most common toxicities were pain and nausea. Median values of D2cc maximum dose (maximum dose received by 2 cc of the organ at risk; biologically equivalent 2-Gy dose maximum [EQD2]) for cord and thecal sac were 38.5 Gy (range, 7.5-67.9 Gy) and 67.7 Gy (range, 15.5-155.8 Gy), respectively. Median values for high-dose subvolumes for cord and thecal sac were 2 times higher than the doses for 5% predicted grade 3 cord toxicity as recommended in the current literature. Cord D0.1cc[EQD2] ≥23.8 Gy was correlated with pain flare (n = 5). Thecal sac D2cc [EQD2] ≥29.3 Gy was a significant indicator of nausea. Conclusion: Current guidelines may overestimate the risk of myelopathy from spine SBRT. The current study's population included both radiation-naïve and retreatment cases, but no myelopathy was observed despite exceeding recommended spine limits.