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• Clinical and dosimetric risk factors for symptomatic RP after SBRT were analyzed in a large series of patients. • Respiratory comorbidity, previous lung radiation, right lung location, BED10 of the prescription dose, MLD and V20 of total lungs, and MLD of ipsilateral lung were significant factors for higher risk of symptomatic RP. • Should the risk of RP2 be limited less than 10%, the mean doses of total lung and ipsilateral lung be constrained to less than 6 Gy and 20 Gy, respectively. Radiation pneumonitis (RP) can be a potential fatal toxicity of stereotactic body radiation therapy (SBRT) for medically inoperable non-small cell lung cancer (NSCLC). This study aimed to examine the risk factors that predict RP and explore dosimetric tolerance for safe practice in a large institutional series of NSCLC patients. Patients with early-stage and locally recurrent NSCLC who received lung SBRT between 2002 and 2015 formed the study population. The primary endpoint was grade 2 or above radiation pneumonitis (RP2). Lungs were re-contoured consistently by one radiation oncologist according to the RTOG atlas for organs at risk. Dosimetric factors were computed consistently with exclusion of gross tumor volume of either ipsilateral, contralateral, or total lungs. A total of 339 patients were eligible. With a median follow-up of 47 months, RP2 was recorded in 10% patients. History of respiratory comorbidity, previous thoracic radiation, right lung location, mean lung doses of total or ipsilateral lung, and total lung volume receiving 20 Gy were all significantly associated with the risk of RP2. The dosimetric parameters of contralateral lung, including mean dose and volume receiving more than 5, 10, and 20 Gy, were not significantly associated with RP2 (ps > 0.05). A model of combining significant clinical and dosimetric factors had a predictive accuracy AUC of 0.76. According to this model, RP2 can be limited to <10% should the patient have no previous lung radiation and the mean dose of total and ipsilateral lungs be kept less than 6 Gy and 20 Gy, respectively. Dosimetric factors of total or ipsilateral lung together with important clinical factors were significant risk factors for symptomatic radiation pneumonitis after SBRT. Constraining mean lung dose can limit clinically significant lung toxicity. [ABSTRACT FROM AUTHOR]

Purpose This study utilizes a survival model and clinical data with various radiation doses from prospective trials to determine radiation dose–response parameters, such as radiosensitivity, and identify single-nucleotide-polymorphism (SNP) biomarkers that can potentially predict the dose response and guide personalized radiotherapy. Methods The study included 92 consecutive stage-III NSCLC patients with doses varying from 60 to 91 Gy. Logistic regression analysis of survival varying with SNP genotype and radiation dose was used to screen candidates for dose–response analysis. The dose–response parameter, represented by D 50 , was derived by fitting survival data into a model that takes into account both tumor control and treatment mortality. A candidate would be considered as a predictor if the 90% confident intervals (90% CIs) of D 50 for the 2 groups stratified by the SNP genotype were separated. Results One SNP-signature (combining ERCC2:rs238406 and ERCC1:rs11615) was found to predict dose–response. D 50 values are 63.7 (90% CI: 53.5–66.3) Gy and 76.1 (90% CI: 71.3, 84.6) Gy for the 2 groups stratified by the genotypes. Using this biomarker-based model, a personalized dose prescription may be generated to improve 2-year survival from ∼50% to 85% and ∼3% to 73% for hypothetical sensitive and resistant patients, respectively. Conclusions We have developed a survival model that may be used to identify genomic markers, such as ERCC1/2 SNPs, to predict radiation dose–response and potentially guide personalized radiotherapy. [ABSTRACT FROM AUTHOR]

• Computer simulation showed a strong sparing effect on circulating immune cells. • Threshold FLASH dose rate consistent with reported FLASH dose rate in animal studies. • FLASH effect only with large dose per fraction. • Threshold FLASH dose rate for humans one order of magnitude less than that for mice. • Maybe not that challenging to develop a photon-based clinical FLASH-RT system. "FLASH" radiotherapy (RT) is a potential paradigm-changing RT technology with marked tumor killing and normal tissue sparing. However, the mechanism of the FLASH effect is not well understood. We hypothesize that the ultra-high dose rate FLASH-RT significantly reduces the killing of circulating immune cells which may partially contribute to the reported FLASH effect. This computation study directly models the effect of radiation dose rate on the killing of circulating immune cells. The model considers an irradiated volume that takes up A % of cardiac output and contains B % of total blood. The irradiated blood volume and dose were calculated for various A %, B %, blood circulation time, and irradiation time (which depends on the dose rate). The linear-quadratic model was used to calculate the extent of killing of circulating immune cells at ultra-high vs. conventional dose rates. A strong sparing effect on circulating blood cells by FLASH-RT was noticed; i.e., killing of circulating immune cells reduced from 90% to 100% at conventional dose rates to 5–10% at ultra-high dose rates. The threshold FLASH dose rate was determined to be ~40 Gy/s for mice in an average situation (A % = 50%), consistent with the reported FLASH dose rate in animal studies, and it was approximately one order of magnitude lower for humans than for mice. The magnitude of this sparing effect increased with the dose/fraction, reached a plateau at 30–50 Gy/fraction, and almost completely vanished at 2 Gy/fraction. We have calculated a strong sparing effect on circulating immune cells by FLASH-RT, which may contribute to the reported FLASH effects in animal studies. [ABSTRACT FROM AUTHOR]

Highlights • Changes in PET/CT tumor volume at mid-treatment correlate with lung cancer survival. • There is an inverse relationship between PET-volume reduction and overall survival. • Mid-treatment PET/CT-adapted therapy may improve overall survival for lung cancer. Abstract Background and purpose This study tested the hypotheses that 1) changes in mid-treatment fluorodeoxyglucose (FDG)-positron emission tomography (PET) parameters are predictive of overall survival (OS) and 2) mid-treatment FDG-PET–adapted treatment has the potential to improve survival in patients with non-small cell lung cancer (NSCLC). Material and methods Patients with stage I-III NSCLC requiring daily fractionated radiation were eligible. FDG-PET-CT scans were obtained prior to and mid-treatment with radiotherapy at 40–50 Gy. The normalized maximum standardized uptake value (NSUVmax), normalized mean SUV (NSUVmean), PET-metabolic tumor volume (MTV), total lesion glycolysis (TLG), and computed tomography-based gross tumor volume (CT-GTV) were consistently measured for all patients. The primary study endpoint was OS. Results The study is comprised of 102 patients who received 3-dimensional conformal radiotherapy, among whom 30 patients who received mid-treatment PET-adapted dose escalation radiotherapy. All PET-CT parameters decreased significantly (P < 0.001) mid-treatment, with greater reductions in FDG-volumetric parameters compared to FDG-activity factors. Mid-treatment changes in MTV (P = 0.053) and TLG (P = 0.021) were associated with OS, while changes in NSUVmax, NSUVmean, and CT-GTV were not (all Ps>0.1). Patients receiving conventional radiation (60-70 Gy) with MTV reductions greater than the mean had a median survival of 14 months, compared to those with MTV reductions less than the mean who had a median survival of 22 months. By contrast, patients receiving mid-treatment PET-adapted radiation with MTV reductions greater than the mean had a median survival of 33 months, compared to those with MTV reductions less than the mean who had a median survival of 19 months. Overall, PET-adapted treatment resulted in a 19% better 5-year survival than conventional radiation. Conclusion Changes in mid-treatment PET-volumetric parameters were significantly associated with survival in NSCLC. A greater reduction in the mid-treatment MTV was associated with worse survival in patients treated with standard radiation, but with better survival in patients who received mid-treatment PET-adapted treatment. [ABSTRACT FROM AUTHOR]

• EDIC significantly correlated with lymphocyte nadir during thoracic radiotherapy. • Lymphocyte nadir and EDIC were independent factors for survival outcome in LS-SCLC. EDIC appear to have a better survival prediction accuracy than lymphocyte nadir. • More attention should be paid to EDIC to avoid circulating lymphocyte toxicity. Effective dose to immune cell (EDIC), an estimated radiation dose to the circulating lymphocytes, is of significance for overall survival (OS) in non-small cell lung cancer. This study aimed to validate the EDIC's OS effect on limited-stage small cell lung cancer (LS-SCLC). This study included LS-SCLC patients received definitive chemo-radiation in one single center from 2012 to 2017. All patients had multiple complete-blood-count tests including lymphocyte count at pre-, during- and end- radiotherapy. EDIC, computed according to doses of the lung, heart, and the total body, was assessed for its correlation with lymphocyte nadir, OS and progression free survival (PFS). Of 503 eligible patients, the mean EDIC was 7.34 Gy. The mean lymphocyte nadir was 0.48 × 109 cells/L, significantly lower than 1.65 × 109 cells/L at pre-radiotherapy (p < 0.001). EDIC was significantly correlated with lymphocyte nadir under both univariate (p < 0.001) and multivariable linear regression (p < 0.001). Multivariable analysis showed EDIC (HR = 0.1072, p = 0.005) and lymphocyte nadir (HR = 0.345, p = 0.003) were both significant for OS. EDIC was also significant for PFS (HR = 1.046, p = 0.026). The C-indexes of OS prediction were 0.593, 0.617, 0.676, and 0.684, for lymphocyte nadir alone, EDIC alone, combined lymphocyte nadir model, and combined EDIC model, respectively. This study demonstrated that EDIC is an independent predictor for lymphocyte nadir, PFS and OS. EDIC may serve as a predictor for lymphocyte nadir and a surrogate marker for OS in LS-SCLC. More attention should be paid to EDIC to decease the lymphocyte toxicity and improve survival. [ABSTRACT FROM AUTHOR]

• A 5-compartment immune OAR model with radiation dose to each compartment. • Incorporate lymphocyte radiosensitivity into the model. • First study to develop an immune OAR model that has a potential to guide personalized radiotherapy. • Test the model in 51 patients. • Potential to compare lymphocyte radiosensitivity in vivo and in vitro for each patient. Associations between radiation-induced lymphopenia (RIL) and survival have been extensively reported. However, the immune system is not considered as an organ-at-risk (OAR) in radiotherapy. This study aimed to develop the framework of an immune OAR model that may be utilized to predict and minimize RIL. A dynamic model was first developed for lymphocyte trafficking among 5 compartments of the immune system. Radiation dose to the circulating lymphocytes in each compartment was calculated based on the doses to fixed structures of each immune compartment and blood flow patterns. A RIL model was developed based on lymphocyte dynamics, lymphocyte radiosensitivity and reproductivity, and the dose to the lymphocytes. The model was tested in 51 patients by fitting it to weekly-measured absolute lymphocyte counts (ALC) for each patient, considering lymphocyte radiosensitivity and reproductivity as patient-dependent fitting parameters. The fitting was almost perfect for 20 patients, with sum of square of errors (SSE) between measured and predicted ALCs < 0.5. It was acceptable for another 27 patients, with SSE = 0.5~4.0. Only 4 patients had SSE > 4.0. The fitting also provided a method of in vivo estimation of radiosensitivity (α) for each patient. The median α was 0.40 Gy−1 for the 51 patients, consistent with in vitro measured data of 0.41 Gy−1 in the literature. We have presented a framework of developing an immune OAR model that has the potential to predict and minimize RIL in radiotherapy. [ABSTRACT FROM AUTHOR]

Highlights • Pericardial effusion is significantly associated with heart/pericardial dosimetric factors. • Pericardial effusion does not have a significant effect on survival. • The irradiated volume of pericardium, rather than the heart dose, is associated with inferior survival. • The risk of death may be decreased by minimizing the dose to pericardium. Abstract Background and purpose Higher cardiac dose was associated with worse overall survival in the RTOG0617 study. Pericardial effusion (PCE) is a common cardiac complication of thoracic radiation therapy (RT). We investigated whether doses of radiation to the heart and pericardium are associated with PCE and overall survival in patients treated with thoracic radiation for non-small cell lung cancer (NSCLC). Materials and methods A total of 94 patients with medically inoperable/unresectable NSCLC treated with definitive RT in prospective studies were reviewed for this secondary analysis. Heart and pericardium were contoured consistently according to the RTOG1106 Atlas, with the great vessels and thymus of the upper mediastinal structures included in the upper part of pericardium, only heart chambers included in the heart structure. Clinical factors and dose–volume parameters associated with PCE or survival were identified via Cox proportional hazards modeling. The risk of PCE and death were mapped using DVH atlases. Results Median follow-up for surviving patients was 58 months. The overall rate of PCE was 40.4%. On multivariable analysis, dosimetric factors of heart and pericardium were significantly associated with the risk of PCE. Pericardial V30 and V55 were significantly correlated with overall survival, but presence of PCE and heart dosimetric factors were not. Conclusion PCE was associated with both heart and pericardial doses. The significance of pericardial dosimetric parameters, but not heart chamber parameters, on survival suggests the potential significance of radiation damage to the cranial region of pericardium. [ABSTRACT FROM AUTHOR]