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Background: Lymphopenia is known for its significance on poor survivals in breast cancer patients. Considering full dosimetric data, this study aimed to develop and validate predictive models for lymphopenia after radiotherapy (RT) in breast cancer., Material and Methods: Patients with breast cancer treated with adjuvant RT were eligible in this multicenter study. The study endpoint was lympopenia, defined as the reduction in absolute lymphocytes and graded lymphopenia after RT. The dose-volume histogram (DVH) data of related critical structures and clinical factors were taken into account for the development of dense neural network (DNN) predictive models. The developed DNN models were validated using external patient cohorts., Results: A total of 918 consecutive patients with invasive breast cancer enrolled. The training, testing, and external validating datasets consisted of 589, 203, and 126 patients, respectively. Treatment volumes at nearly all dose levels of the DVH were significant predictors for lymphopenia following RT, including volumes at very low-dose 1 Gy (V1) of organs at risk (OARs) including lung, heart and body, especially ipsilateral-lung V1. A final DNN model, combining full DVH dosimetric parameters of OARs and three key clinical factors, achieved a predictive accuracy of 75 % or higher., Conclusion: This study demonstrated and externally validated the significance of full dosimetric data, particularly the volume of low dose at as low as 1 Gy of critical structures on lymphopenia after radiation in patients with breast cancer. The significance of V1 deserves special attention, as modern VMAT RT technology often has a relatively high value of this parameter. Further study is warranted for RT plan optimization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Radiotherapy has unique immunostimulatory and immunosuppressive effects. Although high-dose radiotherapy has been found to have systemic antitumor effects, clinically significant abscopal effects were uncommon on the basis of irradiating single lesion. Low-dose radiation therapy (LDRT) emerges as a novel approach to enhance the antitumor immune response due to its role as a leverage to reshape the tumor immune microenvironment (TIME). In this article, from bench to bedside, we reviewed the possible immunomodulatory role of LDRT on TIME and systemic tumor immune environment, and outlined preclinical evidence and clinical application. We also discussed the current challenges when LDRT is used as a combination therapy, including the optimal dose, fraction, frequency, and combination of drugs. The advantage of low toxicity makes LDRT potential to be applied in multiple lesions to amplify antitumor immune response in polymetastatic disease, and its intersection with other disciplines might also make it a direction for radiotherapy-combined modalities., (© 2023 UICC.)

Objectives: Examine the significance of contouring the brachial plexus (BP) for toxicity estimation and select metrics for predicting radiation-induced brachial plexopathy (RIBP) after stereotactic body radiotherapy., Materials and Methods: Patients with planning target volume (PTV) ≤ 2 cm from the BP were eligible. The BP was contoured primarily according to the RTOG 1106 atlas, while subclavian-axillary veins (SAV) were contoured according to RTOG 0236. Apical PTVs were classified as anterior (PTV-A) or posterior (PTV-B) PTVs. Variables predicting grade 2 or higher RIBP (RIBP2) were selected through least absolute shrinkage and selection operator regression and logistic regression., Results: Among 137 patients with 140 BPs (median follow-up, 32.1 months), 11 experienced RIBP2. For patients with RIBP2, the maximum physical dose to the BP (BP-D max ) was 46.5 Gy (median; range, 35.7 to 60.7 Gy). Of these patients, 54.5 % (6/11) satisfied the RTOG limits when using SAV delineation; among them, 83.3 % (5/6) had PTV-B. For patients with PTV-B, the maximum physical dose to SAV (SAV-D max ) was 11.2 Gy (median) lower than BP-D max . Maximum and 0.3 cc biologically effective doses to the BP based on the linear-quadratic-linear model (BP-BED max LQL and BP-BED 0.3cc LQL , α/β = 3) were selected as predictive variables with thresholds of 118 and 73 Gy, respectively., Conclusion: Contouring SAV may significantly underestimate the RIBP2 risk in dosimetry, especially for patients with PTV-B. BP contouring indicated BP-BED 0.3cc LQL and BP-BED max LQL as potential predictors of RIBP2., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Radiotherapy (RT) is the mainstay treatment modality for lung cancer. We recently reported that conventionally fractionated radiotherapy (CRT) with daily fractionation of 2Gy significantly increased the activity of indoleamine 2,3-dioxygenase (IDO1), a known immune checkpoint, which predicted poorer long-term survival in patients with non-small cell lung cancer (NSCLC), while stereotactic body radiotherapy (SBRT) using fractionation size of 10Gy did not increase IDO1 activity and had better survival. Here we hypothesized that the hypofractionated SBRT kind of dose fraction stimulates host antitumor immunity via downregulating IDO1 in which CRT could not. We tested this hypothesis in vitro and in vivo using 10Gyx1 and 2Gyx8 fractionations in the laboratory. The results demonstrated that, although there was an initial downregulation after RT, the expression of IDO1 was ultimately upregulated by both fractionation regimens. The 10Gyx1 regimen had minimum upregulation, while the 2Gyx8 regimen significantly increased in IDO1 expression which was positively correlated with the elevated expressions of p-NF-κB and COX2. Pharmacological inhibition of COX2 abolished RT-induced IDO1 expression. Furthermore, the IDO1 inhibitor, D-1-methyl-tryptophan (D-1MT), exerted RT-related tumor-killing effects in the NSCLC cell lines and mouse models. These findings suggest that, in addition to being an immune suppressor, IDO1 may serve as an adaptive resistance factor in RT. Furthermore, an unappreciated mechanism may exist, where a larger fraction size might be superior to conventional sizes in cancer treatment. This study may provide a rationale for future research in using IDO1 as a biomarker to personalize RT dose fractionation and COX2 inhibitor to decrease radiation immune suppression from CRT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Radiation-induced brachial plexopathy (RIBP), resulting in symptomatic motor or sensory deficits of the upper extremity, is a risk after exposure of the brachial plexus to therapeutic doses of radiation. We sought to model dosimetric factors associated with risks of RIBP after stereotactic body radiotherapy (SBRT)., Methods: From a prior systematic review, 4 studies were identified that included individual patient data amenable to normal tissue complication probability (NTCP) modelling after SBRT for apical lung tumors. Two probit NTCP models were derived: one from 4 studies (including 221 patients with 229 targets and 18 events); and another from 3 studies (including 185 patients with 192 targets and 11 events) that similarly contoured the brachial plexus., Results: NTCP models suggest ≈10% risks associated with brachial plexus maximum dose (D max ) of ∼32-34 Gy in 3 fractions and ∼40-43 Gy in 5 fractions. RIBP risks increase with increasing brachial plexus D max . Compared to previously published data from conventionally-fractionated or moderately-hypofractionated radiotherapy for breast, lung and head and neck cancers (which tend to utilize radiation fields that circumferentially irradiate the brachial plexus), SBRT (characterized by steep dose gradients outside of the target volume) exhibits a much less steep dose-response with brachial plexus D max  > 90-100 Gy in 2-Gy equivalents., Conclusions: A dose-response for risk of RIBP after SBRT is observed relative to brachial plexus D max . Comparisons to data from less conformal radiotherapy suggests potential dose-volume dependences of RIBP risks, though published data were not amenable to NTCP modelling of dose-volume measures associated with RIBP after SBRT., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: The adverse events during antiangiogenic therapy inevitably influence a patient's quality of life. Therefore, biomarkers to identify patients who will experience adverse events would be very valuable in treatment planning., Materials and Methods: Between September 2016 and December 2019, patients scheduled for single-agent apatinib were prospectively enrolled and underwent 18 F-RGD positron emission tomography/computed tomography (PET/CT) pre-treatment. Maximum and mean standard uptake values (SUV max and SUV mean ) were obtained from thyroid, liver, gastric cardia, gastric body, gastric pylorus and spleen. Statistical methods included the independent sample t-test, Mann-Whitney U-test, receiver operating characteristic curve analysis and chi-squared test., Results: In total, 60 patients were initially screened and consented for 18 F-RGD PET/CT scans. The three most frequent adverse events were fatigue (50%), hypertension (36%) and nausea (36%), accounting for 72% in the 50 patients included in the analysis. SUV max and SUV mean of thyroid and liver were significantly associated with fatigue, whereas SUV max and SUV mean of thyroid and spleen were significantly associated with hypertension and SUV max and SUV mean of thyroid and gastric cardia were significantly associated with nausea (all P < 0.05). The most significant predictors of adverse events were 18 F-RGD SUV max-liver for fatigue (area under the curve [AUC] = 0.682), SUV max-spleen for hypertension (AUC = 0.688) and SUV max-gastric cardia for nausea (AUC = 0.698). Classified by the cut-off values for SUV max-liver (4.57), SUV max-spleen (6.77) and SUV max-gastric cardia (2.10), patients with low RGD SUV max in liver, spleen and gastric cardia had statistically higher incidence of fatigue (67.9% versus 27.3%, P = 0.002), hypertension (55.6% versus 13.0%, P = 0.004) and nausea (61.1% versus 21.9%, P = 0.006)., Conclusions: Low pre-treatment 18 F-RGD uptake in the liver, spleen and gastric cardia were predictive of the adverse events fatigue, hypertension and nausea during apatinib treatment, respectively., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: This study aimed to examine the effect of radiation esophagitis (RE) and the dynamics of RE on subsequent survival in non-small cell lung cancer (NSCLC) patients who underwent radiotherapy., Experimental Design: Patients with NSCLC treated with fractionated thoracic radiotherapy enrolled in prospective trials were eligible. RE was graded prospectively according to Common Terminology Criteria for Adverse Events (CTCAE) v3.0 per protocol requirement weekly during-RT and 1 month after RT. This study applied conditional survival assessment which has advantage over traditional survival analysis as it assesses the survival from the event instead of from the baseline. P -value less than 0.05 was considered to be significant. The primary endpoint is overall survival., Results: A total of 177 patients were eligible, with a median follow-up of 5 years. The presence of RE, the maximum RE grade, the evolution of RE and the onset timing of RE events were all correlated with subsequent survival. At all conditional time points, patients first presented with RE grade1 (initial RE1) had significant inferior subsequent survival (multivariable HRs median: 1.63, all P -values<0.05); meanwhile those with RE progressed had significant inferior subsequent survival than those never develop RE (multivariable HRs median: 2.08, all P -values<0.05). Multivariable Cox proportional-hazards analysis showed significantly higher C-indexes for models with inclusion of RE events than those without (all P -values<0.05)., Conclusion: This study comprehensively evaluated the impact of RE with conditional survival assessment and demonstrated that RE is associated with inferior survival in NSCLC patients treated with RT., Competing Interests: The authors declare that they have no conflict of interests., (© 2021 Chinese National Cancer Center. Published by Elsevier B.V.)

Purpose: "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., Methods: 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., Results: 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., Conclusion: 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., Competing Interests: Declaration of Competing Interest This work was partially supported by the USA National Cancer Institute, National Institutes of Health, R01 CA142840 (Kong). The authors declare that they have no other known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: 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., Methods: 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., Results: 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., Conclusion: We have presented a framework of developing an immune OAR model that has the potential to predict and minimize RIL in radiotherapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Guidelines have recommended prophylactic cranial irradiation (PCI) for patients with limited-stage small-cell lung cancer with at least a partial response after thoracic chemoradiation. However, the survival advantage has been small and was observed in an era before magnetic resonance imaging and surveillance. Neurotoxicity also remains a concern, especially in older adults. Thus, patients have a complex value-laden decision to make. We sought to better understand the role physicians play in patient decision making and introduce a patient decision aid (PDA) to potentially facilitate these discussions., Materials and Methods: An e-mail survey was sent to International Association for the Study of Lung Cancer members querying their personal perspectives and professional recommendations regarding PCI for limited-stage small-cell lung cancer., Results: We received 295 responses. Most were from the United States (35%) and Europe (35%) and were radiation (45%) or medical (43%) oncologists. Of those responding, 88% and 50% reported they would recommend PCI to a 50- and 70-year-old patient, respectively. Also, 79% reported that they would wish to receive PCI if faced with this decision. The physicians who would have chosen PCI if faced with the decision were 27.6 and 12.9 times more likely to recommend PCI to a 50- and 70-year-old patient, respectively, than were physicians who would not undergo PCI themselves. Most of the respondents had positive responses to the proposed PDA., Conclusion: Physician bias appears to play a role in PCI counseling, and most physicians reported that the provided PDA was better than their present method for discussing PCI and would help patients make such value-laden choices., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background and Purpose: Current methods to estimate risk of radiation-induced lung toxicity (RILT) rely on dosimetric parameters. We aimed to improve prognostication by incorporating clinical and cytokine data, and to investigate how these factors may interact with the effect of mean lung dose (MLD) on RILT., Materials and Methods: Data from 125 patients treated from 2004 to 2013 with definitive radiotherapy for stages I-III NSCLC on four prospective clinical trials were analyzed. Plasma levels of 30 cytokines were measured pretreatment, and at 2 and 4weeks midtreatment. Penalized logistic regression models based on combinations of MLD, clinical factors, and cytokine levels were developed. Cross-validated estimates of log-likelihood and area under the receiver operating characteristic curve (AUC) were used to assess accuracy., Results: In prognosticating grade 3 or greater RILT by MLD alone, cross-validated log-likelihood and AUC were -28.2 and 0.637, respectively. Incorporating clinical features and baseline cytokine levels increased log-likelihood to -27.6 and AUC to 0.669. Midtreatment cytokine data did not further increase log-likelihood or AUC. Of the 30 cytokines measured, higher levels of 13 decreased the effect of MLD on RILT, corresponding to a lower odds ratio for RILT per Gy MLD, while higher levels of 4 increased the association., Conclusions: Although the added prognostic benefit from cytokine data in our model was modest, understanding how clinical and biologic factors interact with the MLD-RILT relationship represents a novel framework for understanding and investigating the multiple factors contributing to radiation-induced toxicity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: To study the risk factors for radiation-induced lung toxicity (RILT) after stereotactic body radiation therapy (SBRT) of the thorax., Methods and Materials: Published studies on lung toxicity in patients with early-stage non-small cell lung cancer (NSCLC) or metastatic lung tumors treated with SBRT were pooled and analyzed. The primary endpoint was RILT, including pneumonitis and fibrosis. Data of RILT and risk factors were extracted from each study, and rates of grade 2 to 5 (G2+) and grade 3 to 5 (G3+) RILT were computed. Patient, tumor, and dosimetric factors were analyzed for their correlation with RILT., Results: Eighty-eight studies (7752 patients) that reported RILT incidence were eligible. The pooled rates of G2+ and G3+ RILT from all 88 studies were 9.1% (95% confidence interval [CI]: 7.15-11.4) and 1.8% (95% CI: 1.3-2.5), respectively. The median of median tumor sizes was 2.3 (range, 1.4-4.1) cm. Among the factors analyzed, older patient age (P=.044) and larger tumor size (the greatest diameter) were significantly correlated with higher rates of G2+ (P=.049) and G3+ RILT (P=.001). Patients with stage IA versus stage IB NSCLC had significantly lower risks of G2+ RILT (8.3% vs 17.1%, odds ratio = 0.43, 95% CI: 0.29-0.64, P<.0001). Among studies that provided detailed dosimetric data, the pooled analysis demonstrated a significantly higher mean lung dose (MLD) (P=.027) and V20 (P=.019) in patients with G2+ RILT than in those with grade 0 to 1 RILT., Conclusions: The overall rate of RILT is relatively low after thoracic SBRT. Older age and larger tumor size are significant adverse risk factors for RILT. Lung dosimetry, specifically lung V20 and MLD, also significantly affect RILT risk., (Copyright © 2016. Published by Elsevier Inc.)

Purpose: This study compared treatment outcomes of stereotactic body radiation therapy (SBRT) with those of surgery in stage I non-small cell lung cancer (NSCLC)., Methods and Materials: Eligible studies of SBRT and surgery were retrieved through extensive searches of the PubMed, Medline, Embase, and Cochrane library databases from 2000 to 2012. Original English publications of stage I NSCLC with adequate sample sizes and adequate SBRT doses were included. A multivariate random effects model was used to perform a meta-analysis to compare survival between treatments while adjusting for differences in patient characteristics., Results: Forty SBRT studies (4850 patients) and 23 surgery studies (7071 patients) published in the same period were eligible. The median age and follow-up duration were 74 years and 28.0 months for SBRT patients and 66 years and 37 months for surgery patients, respectively. The mean unadjusted overall survival rates at 1, 3, and 5 years with SBRT were 83.4%, 56.6%, and 41.2% compared to 92.5%, 77.9%, and 66.1% with lobectomy and 93.2%, 80.7%, and 71.7% with limited lung resections. In SBRT studies, overall survival improved with increasing proportion of operable patients. After we adjusted for proportion of operable patients and age, SBRT and surgery had similar estimated overall and disease-free survival., Conclusions: Patients treated with SBRT differ substantially from patients treated with surgery in age and operability. After adjustment for these differences, OS and DFS do not differ significantly between SBRT and surgery in patients with operable stage I NSCLC. A randomized prospective trial is warranted to compare the efficacy of SBRT and surgery., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Thoracic radiotherapy (RT) is an integral part of the management of small-cell lung cancer (SCLC) because its administration provides a survival benefit in patients with limited-stage disease. However, there are many areas of controversy with respect to the delivery of curative RT, and these include definition of the target to be irradiated. A current area of concern is defining what the RT portal must encompass with respect to the mediastinal lymph nodes; that is, whether one should electively treat all mediastinal nodes, or selectively include those with some clinical risk for harboring disease, or perhaps omit elective nodal irradiation altogether. The purpose of the present report is therefore to address the concepts underlying elective or selective nodal irradiation as it applies to SCLC, looking at clinical, imaging, and RT reports to help define the parameters appropriate to treating individual patients.

Lymphatic spread is an important pathway of progression in non-small-cell lung cancer (NSCLC), along with local spread and distant metastasis. The probability of lymph node (LN) involvement is dependent on the site of the primary tumor, stage, and histology. Elective nodal irradiation (ENI) is the irradiation of clinical and radiological uninvolved LN to account for microscopic tumor invasion in these LNs because we have not been able to determine the extent of LN spread accurately. The clinical value of ENI is uncertain. The impact of ENI is dependent on many (staging-, treatment-, and patient-related) factors. The purpose of this report is to analyze the current status of ENI and to provide comprehensive in-depth analysis and guidance on how to generally approach this issue in NSCLC.